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Sample records for cisplatin

  1. Cisplatin nanocapsules.

    Science.gov (United States)

    de Kroon, Anton I P M; Staffhorst, Rutger W H M; Kruijff, Ben de; Burger, Koert N J

    2005-01-01

    Cisplatin nanocapsules represent a novel lipid formulation of the anticancer drug cis-diamminedichloroplatinum(II), in which nanoprecipitates of cisplatin are covered by a phospholipid bilayer coat consisting of an equimolar mixture of phosphatidylcholine and phosphatidylserine. Cisplatin nanocapsules are characterized by an unprecedented cisplatin-to-lipid molar ratio and exhibit strongly improved cytotoxicity against tumor cells in vitro compared with the free drug. Here, methods for preparing and characterizing cisplatin nanocapsules are reported. PMID:15721377

  2. Prevention of cisplatin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Hayati Fatemeh

    2016-01-01

    Full Text Available Cisplatin has a well-established role in the treatment of broad spectrum of malignancies; however its use is limited because of cisplatin-induced nephrotoxicity (CIN which can be progressive in more than 50% of cases. The most important risk factors for CIN include higher doses of cisplatin, previous cisplatin chemotherapy, underlying kidney damage and concurrent treatment with other potential nephrotoxin agents, such as aminoglycosides, nonsteroidal anti-inflammatory agents, or iodinated contrast media. Different strategies have been offered to diminish or prevent nephrotoxicity of cisplatin. The standard approach for prevention of CIN is the administration of lower doses of cisplatin in combination with full intravenous hydration prior and after cisplatin administration. Cisplatin-induced oxidative stress in the kidney may be prevented by natural antioxidant compounds. The results of this review show that many strategies for prevention of CIN exist, however, attention to the administration of these agent for CIN is necessary.

  3. Cisplatin Induced Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Seyed Seifollah Beladi Mousavi

    2014-02-01

    The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of lower doses of cisplatin in combination with the administration of full intravenous isotonic saline before and after cisplatin administration. Although a number of pharmacologic agents including sodium thiosulfate, N-acetylcysteine, theophylline and glycine have been evaluated for prevention of nephrotoxicity, none have proved to have an established role, thus, additional clinical studies will be required to confirm their probable effects.

  4. Cisplatin induced paroxysmal supraventricular tachycardia

    OpenAIRE

    Waseem Raja; M Hussain Mir; Imtiyaz Dar; Muzamil Ahmad Banday; Irfan Ahmad

    2013-01-01

    Cisplatin or cis-diamminedichloroplatinum (CDDP) is the first member of a class of platinum-containing anti-cancer drugs that act by binding to and causing cross-linking of deoxyribonucleic acid, which ultimately triggers apoptosis. Cisplatin has a broad-spectrum antineoplastic activity against various types of human tumors. Unfortunately, the optimal usefulness of Cisplatin is limited secondary to its dose related toxicity especially nephrotoxicity. Cisplatin chemotherapy is also associated ...

  5. Cisplatin induced paroxysmal supraventricular tachycardia

    Directory of Open Access Journals (Sweden)

    Waseem Raja

    2013-01-01

    Full Text Available Cisplatin or cis-diamminedichloroplatinum (CDDP is the first member of a class of platinum-containing anti-cancer drugs that act by binding to and causing cross-linking of deoxyribonucleic acid, which ultimately triggers apoptosis. Cisplatin has a broad-spectrum antineoplastic activity against various types of human tumors. Unfortunately, the optimal usefulness of Cisplatin is limited secondary to its dose related toxicity especially nephrotoxicity. Cisplatin chemotherapy is also associated with cardiotoxic effects that may range from silent arrhythmias to heart failure and even sudden cardiac death. These effects are more pronounced when cisplatin is combined with other cardiotoxic drugs. Here, we report a case of patient of cancer lung who developed paroxysmal supraventricular tachycardia following administration of Cisplatin. A brief review of the literature follows.

  6. Cisplatin-Induced Eosinophilic Pneumonia

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    Hideharu Ideguchi

    2014-01-01

    Full Text Available A 67-year-old man suffering from esophageal cancer was admitted to our hospital complaining of dyspnea and hypoxemia. He had been treated with cisplatin, docetaxel, and fluorouracil combined with radiotherapy. Chest computed tomography revealed bilateral ground-glass opacity, and bronchoalveolar lavage fluid showed increased eosinophils. Two episodes of transient eosinophilia in peripheral blood were observed after serial administration of anticancer drugs before the admission, and drug-induced lymphocyte stimulation test to cisplatin was positive. Thus cisplatin-induced eosinophilic pneumonia was suspected, and corticosteroid was effectively administered. To our knowledge, this is the first reported case of cisplatin-induced eosinophilic pneumonia.

  7. Molecular mechanism of cisplatin resistance

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Cisplatin is widely used in the treatment of many tumors,particularly in ovarian cancer.GST-π,metallothionein(MT), multidrug resistance associated proteins(MRPs), nucleotide excision repair(NER), mismatch repair(MMR) and oncogenes contribute to drug resistance of cisplatin.

  8. Pharmacokinetics and inner ear transport of cisplatin

    OpenAIRE

    Hellberg, Victoria

    2015-01-01

    Background Cisplatin is a commonly used platinum anti-cancer drug. Regrettably cisplatin has dose-limiting ototoxic side effects, e.g. the drug can induce an irreversible hearing loss. The ototoxic mechanisms of cisplatin have not been elucidated in the human ear and no clinically useful oto-protectors are yet available. Cisplatin is a necessary part of many treatment regimes. Its beneficial therapeutic effects might be reduced if cisplatin was excluded from the treatmen...

  9. Neuronal involvement in cisplatin neuropathy

    DEFF Research Database (Denmark)

    Krarup-Hansen, A; Helweg-Larsen, Susanne Elisabeth; Schmalbruch, H;

    2007-01-01

    Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron...... processes of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of...

  10. Membrane Transition Temperature Determines Cisplatin Response.

    Science.gov (United States)

    Raghunathan, Krishnan; Ahsan, Aarif; Ray, Dipankar; Nyati, Mukesh K; Veatch, Sarah L

    2015-01-01

    Cisplatin is a classical chemotherapeutic agent used in treating several forms of cancer including head and neck. However, cells develop resistance to the drug in some patients through a range of mechanisms, some of which are poorly understood. Using isolated plasma membrane vesicles as a model system, we present evidence suggesting that cisplatin induced resistance may be due to certain changes in the bio-physical properties of plasma membranes. Giant plasma membrane vesicles (GPMVs) isolated from cortical cytoskeleton exhibit a miscibility transition between a single liquid phase at high temperature and two distinct coexisting liquid phases at low temperature. The temperature at which this transition occurs is hypothesized to reflect the magnitude of membrane heterogeneity at physiological temperature. We find that addition of cisplatin to vesicles isolated from cisplatin-sensitive cells result in a lowering of this miscibility transition temperature, whereas in cisplatin-resistant cells such treatment does not affect the transition temperature. To explore if this is a cause or consequence of cisplatin resistance, we tested if addition of cisplatin in combination with agents that modulate GPMV transition temperatures can affect cisplatin sensitivity. We found that cells become more sensitive to cisplatin when isopropanol, an agent that lowers GPMV transition temperature, was combined with cisplatin. Conversely, cells became resistant to cisplatin when added in combination with menthol that raises GPMV transition temperatures. These data suggest that changes in plasma membrane heterogeneity augments or suppresses signaling events initiated in the plasma membranes that can determine response to cisplatin. We postulate that desired perturbations of membrane heterogeneity could provide an effective therapeutic strategy to overcome cisplatin resistance for certain patients. PMID:26484687

  11. Understanding cisplatin resistance using cellular models.

    OpenAIRE

    STORDAL, BRITTA KRISTINA

    2007-01-01

    PUBLISHED Many mechanisms of cisplatin resistance have been proposed from studies of cellular models of resistance including changes in cellular drug accumulation, detoxification of the drug, inhibition of apoptosis and repair of the DNA adducts. A series of resistant models were developed from CCRF-CEM leukaemia cells with increasing doses of cisplatin from 100 ng/ml. This produced increasing resistance up to 7-fold with a treatment dose of 1.6 ?g/ml. Cisplatin resistance i...

  12. Understanding cisplatin resistance using cellular models

    OpenAIRE

    Stordal, Britta; Davey, Mary

    2007-01-01

    Many mechanisms of cisplatin resistance have been proposed from studies of cellular models of resistance including changes in cellular drug accumulation, detoxification of the drug, inhibition of apoptosis and repair of the DNA adducts. A series of resistant models were developed from CCRF-CEM leukaemia cells with increasing doses of cisplatin from 100 ng/ml. This produced increasing resistance up to 7-fold with a treatment dose of 1.6 microg/ml. Cisplatin resistance in these cells correlated...

  13. Parthenolide reduces cisplatin-induced renal damage

    International Nuclear Information System (INIS)

    Inflammatory events contribute to cisplatin-induced renal damage. Cisplatin promotes increased production of reactive oxygen species, which can activate nuclear factor-κB (NF-κB) that lead to increased expression of proinflammatory mediators which could intensify the cytotoxic effects of cisplatin. In this study, we evaluated the effect of parthenolide, a selective inhibitor of NF-κB, on renal damage caused by cisplatin use. A total of 94 male Wistar rats were divided into six groups: Group A (18 rats) were treated with saline; Group B (12 rats) received dimethylsulfoxide plus saline (the solvent for parthenolide); Group C (12 rats) received parthenolide (3 mg/kg) plus saline; Group D (20 rats) received cisplatin (5 mg/kg, i.p.); Group E (12 rats) received dimethylsulfoxide plus cisplatin (5 mg/kg, i.p.); and Group F (21 rats) received parthenolide (3 mg/kg) plus cisplatin (5 mg/kg, i.p.). Dimethylsulfoxide or parthenolide were administered at 24 h and 1 h prior to cisplatin injection, and again at 24 h and 48 h after. At 2, 3 and 5 days after saline or cisplatin injection, blood and urine samples were collected for measurement of creatinine, sodium and potassium and the kidneys removed for histological, morphometric, electrophoretic mobility shift assay (EMSA), apoptosis and immunohistochemical studies. Cisplatin-treated rats presented higher plasma creatinine, as well as greater immunostaining for ED1 (macrophages/monocytes) and NF-κB in the renal cortices and outer medullae. The increase of NF-κB activation was confirmed by EMSA. Cisplatin-injected rats also presented higher urinary levels of lipid peroxidation and acute tubular necrosis. All of these alterations were reduced by treatment with parthenolide. This effect seems to be related, at least in part, to the restriction of renal inflammatory process observed in parthenolide + cisplatin treated rats

  14. Compound list: cisplatin [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available cisplatin CSP 00132 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/cisplat...in.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/cisplat...bc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Kidney/Single/cisplatin.Rat.in_vivo.Kidney.Single.zip ftp://ft...p.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Kidney/Repeat/cisplatin.Rat.in_vivo.Kidney.Repeat.zip ... ...in_vivo/Liver/Repeat/cisplatin.Rat.in_vivo.Liver.Repeat.zip ftp://ftp.bioscienced

  15. Cisplatin Scheduling and Dosing Aspects

    OpenAIRE

    Jongh, Felix

    2003-01-01

    textabstractIn 1965, during experiments on the effects of electric fields on cell growth and division, Rosenberg and co-workers found that an electric current delivered between platinum electrodes inhibited the proliferation of Escherichia coli bacteria. This inhibitory effect was found to be related to the formation of inorganic platinum complexes. Additional research showed that the cis isomer of dichlorodiammineplatinum II (cisplatin) is an active inhibitor of cell division, whereas the tr...

  16. Riboflavin ameliorates cisplatin induced toxicities under photoillumination.

    Directory of Open Access Journals (Sweden)

    Iftekhar Hassan

    Full Text Available BACKGROUND: Cisplatin is an effective anticancer drug that elicits many side effects mainly due to induction of oxidative and nitrosative stresses during prolonged chemotherapy. The severity of these side effects consequently restricts its clinical use under long term treatment. Riboflavin is an essential vitamin used in various metabolic redox reactions in the form of flavin adenine dinucleotide and flavin mononucleotide. Besides, it has excellent photosensitizing property that can be used to ameliorate these toxicities in mice under photodynamic therapy. METHODS AND FINDINGS: Riboflavin, cisplatin and their combinations were given to the separate groups of mice under photoilluminated condition under specific treatment regime. Their kidney and liver were excised for comet assay and histopathological studies. Furthermore, Fourier Transform Infrared Spectroscopy of riboflavin-cisplatin combination in vitro was also conducted to investigate any possible interaction between the two compounds. Their comet assay and histopathological examination revealed that riboflavin in combination with cisplatin was able to protect the tissues from cisplatin induced toxicities and damages. Moreover, Fourier Transform Infrared Spectroscopy analysis of the combination indicated a strong molecular interaction among their constituent groups that may be assigned for the protective effect of the combination in the treated animals. CONCLUSION: Inclusion of riboflavin diminishes cisplatin induced toxicities which may possibly make the cisplatin-riboflavin combination, an effective treatment strategy under chemoradiotherapy in pronouncing its antineoplastic activity and sensitivity towards the cancer cells as compared to cisplatin alone.

  17. Nanoparticle formulations of cisplatin for cancer therapy.

    Science.gov (United States)

    Duan, Xiaopin; He, Chunbai; Kron, Stephen J; Lin, Wenbin

    2016-09-01

    The genotoxic agent cisplatin, used alone or in combination with radiation and/or other chemotherapeutic agents, is an important first-line chemotherapy for a broad range of cancers. The clinical utility of cisplatin is limited both by intrinsic and acquired resistance and dose-limiting normal tissue toxicity. That cisplatin shows little selectivity for tumor versus normal tissue may be a critical factor limiting its value. To overcome the low therapeutic ratio of the free drug, macromolecular, liposomal, and nanoparticle drug delivery systems have been explored toward leveraging the enhanced permeability and retention effect and promoting delivery of cisplatin to tumors. Here, we survey recent advances in nanoparticle formulations of cisplatin, focusing on agents that show promise in preclinical or clinical settings. WIREs Nanomed Nanobiotechnol 2016, 8:776-791. doi: 10.1002/wnan.1390 For further resources related to this article, please visit the WIREs website. PMID:26848041

  18. Mechanisms of cisplatin-induced muscle atrophy

    International Nuclear Information System (INIS)

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin

  19. Mechanisms of cisplatin-induced muscle atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sato, Ken [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Chiba, Yoshihiko [Department of Biology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Yamazaki, Mitsuaki [Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 9300194 (Japan); Matoba, Motohiro [Department of Palliative Medicine and Psychooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045 (Japan); Narita, Minoru, E-mail: narita@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan)

    2014-07-15

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.

  20. Cellular Responses to Cisplatin-Induced DNA Damage

    Directory of Open Access Journals (Sweden)

    Alakananda Basu

    2010-01-01

    Full Text Available Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development of more effective therapeutic strategies for the treatment of cancer.

  1. Membrane Transition Temperature Determines Cisplatin Response

    OpenAIRE

    Raghunathan, Krishnan; Ahsan, Aarif; Ray, Dipankar; Nyati, Mukesh K.; Veatch, Sarah L.

    2015-01-01

    Cisplatin is a classical chemotherapeutic agent used in treating several forms of cancer including head and neck. However, cells develop resistance to the drug in some patients through a range of mechanisms, some of which are poorly understood. Using isolated plasma membrane vesicles as a model system, we present evidence suggesting that cisplatin induced resistance may be due to certain changes in the bio-physical properties of plasma membranes. Giant plasma membrane vesicles (GPMVs) isolate...

  2. Increased nephrotoxicity of combination taxol and cisplatin chemotherapy in gynecologic cancers as compared to cisplatin alone.

    Science.gov (United States)

    Merouani, A; Davidson, S A; Schrier, R W

    1997-01-01

    To investigate the increased nephrotoxicity of taxol and cisplatin combination chemotherapy in gynecologic cancers as compared to cisplatin alone, the medical records of 25 patients with gynecological cancers were reviewed for evaluation of nephrotoxicity after chemotherapy treatment. The data included age, serum creatinine, calculated creatinine clearance, initial and cumulative dose of cisplatin and taxol, primary site of the cancer, renal ultrasound and hydration protocols. Renal function was evaluated before, during and 6 months after chemotherapy. Renal dysfunction was defined as a greater than 25% decrease in creatinine clearance. Comparing 11 patients treated with taxol and cisplatin versus 14 treated with cisplatin alone, there was a significant difference in effect on renal function. Nine of 11 patients (81%) treated with the combination chemotherapy had a greater than 25% decrease in creatinine clearance while only 4 of the 14 patients (29%) treated with cisplatin alone had such a decrease in creatinine clearance (p < 0.004). The patients treated with the combination chemotherapy, however, received a higher dose of cisplatin (80.4 vs. 66.4 mg/m2, p < 0.02) and were treated longer (6.7 vs. 4.3 months, p < 0.002). Nevertheless, when the patients were matched for age, initial dose and cumulative dose of cisplatin, a higher frequency of nephrotoxicity persisted in patients treated with taxol and cisplatin as compared to cisplatin alone (72 as compared to 20%, p < 0.02). The patients in both groups were comparably hydrated; prerenal failure and urinary tract obstruction were excluded in all patients. Six months after completion of chemotherapy, a significantly lower creatinine clearance was still observed in patients treated with taxol and cisplatin combination therapy (46 vs. 76 ml/min, p < 0.01). In summary, a retrospective analysis of renal function in patients with gynecological cancers showed an increased nephrotoxicity in patients treated with taxol and

  3. Tumour resistance to cisplatin: a modelling approach

    Science.gov (United States)

    Marcu, L.; Bezak, E.; Olver, I.; van Doorn, T.

    2005-01-01

    Although chemotherapy has revolutionized the treatment of haematological tumours, in many common solid tumours the success has been limited. Some of the reasons for the limitations are: the timing of drug delivery, resistance to the drug, repopulation between cycles of chemotherapy and the lack of complete understanding of the pharmacokinetics and pharmacodynamics of a specific agent. Cisplatin is among the most effective cytotoxic agents used in head and neck cancer treatments. When modelling cisplatin as a single agent, the properties of cisplatin only have to be taken into account, reducing the number of assumptions that are considered in the generalized chemotherapy models. The aim of the present paper is to model the biological effect of cisplatin and to simulate the consequence of cisplatin resistance on tumour control. The 'treated' tumour is a squamous cell carcinoma of the head and neck, previously grown by computer-based Monte Carlo techniques. The model maintained the biological constitution of a tumour through the generation of stem cells, proliferating cells and non-proliferating cells. Cell kinetic parameters (mean cell cycle time, cell loss factor, thymidine labelling index) were also consistent with the literature. A sensitivity study on the contribution of various mechanisms leading to drug resistance is undertaken. To quantify the extent of drug resistance, the cisplatin resistance factor (CRF) is defined as the ratio between the number of surviving cells of the resistant population and the number of surviving cells of the sensitive population, determined after the same treatment time. It is shown that there is a supra-linear dependence of CRF on the percentage of cisplatin-DNA adducts formed, and a sigmoid-like dependence between CRF and the percentage of cells killed in resistant tumours. Drug resistance is shown to be a cumulative process which eventually can overcome tumour regression leading to treatment failure.

  4. Tumour resistance to cisplatin: a modelling approach

    International Nuclear Information System (INIS)

    Although chemotherapy has revolutionized the treatment of haematological tumours, in many common solid tumours the success has been limited. Some of the reasons for the limitations are: the timing of drug delivery, resistance to the drug, repopulation between cycles of chemotherapy and the lack of complete understanding of the pharmacokinetics and pharmacodynamics of a specific agent. Cisplatin is among the most effective cytotoxic agents used in head and neck cancer treatments. When modelling cisplatin as a single agent, the properties of cisplatin only have to be taken into account, reducing the number of assumptions that are considered in the generalized chemotherapy models. The aim of the present paper is to model the biological effect of cisplatin and to simulate the consequence of cisplatin resistance on tumour control. The 'treated' tumour is a squamous cell carcinoma of the head and neck, previously grown by computer-based Monte Carlo techniques. The model maintained the biological constitution of a tumour through the generation of stem cells, proliferating cells and non-proliferating cells. Cell kinetic parameters (mean cell cycle time, cell loss factor, thymidine labelling index) were also consistent with the literature. A sensitivity study on the contribution of various mechanisms leading to drug resistance is undertaken. To quantify the extent of drug resistance, the cisplatin resistance factor (CRF) is defined as the ratio between the number of surviving cells of the resistant population and the number of surviving cells of the sensitive population, determined after the same treatment time. It is shown that there is a supra-linear dependence of CRF on the percentage of cisplatin-DNA adducts formed, and a sigmoid-like dependence between CRF and the percentage of cells killed in resistant tumours. Drug resistance is shown to be a cumulative process which eventually can overcome tumour regression leading to treatment failure

  5. Weekly scheduling of cisplatin: feasibility, efficacy and perspective

    OpenAIRE

    Planting, André

    1996-01-01

    textabstractIn this thesis studies of weekly administration of cisplatin are presented. Weekly administration of cisplatin is not new: already in the seventies weekly cisplatin regimens were explored but they were abandoned because of hematologic, renal and gastrointestinal toxicity. The administration of cisplatin in the outpatient setting and without adequate hydration certainly has contributed to the failure of these studies. A better understanding of the pathophysiology of renal toxicity ...

  6. Cetuximab intensifies cisplatin-induced testicular toxicity.

    Science.gov (United States)

    Levi, Mattan; Popovtzer, Aron; Tzabari, Moran; Mizrachi, Aviram; Savion, Naphtali; Stemmer, Salomon M; Shalgi, Ruth; Ben-Aharon, Irit

    2016-07-01

    Epidermal growth factor receptor (EGFR) has proliferative properties in the testis. Cetuximab, an anti-EGFR, is administered together with chemotherapy to patients with various types of cancer. This studies aim was to investigate the effect of cetuximab on testicular function. Adult male mice were injected with cetuximab (10 mg/kg), cisplatin (8 mg/kg) or a combination of both, and killed one week or one month later. The doses were chosen by human equivalent dose calculation. Testicular function was evaluated by epididymal-spermatozoa total motile count and sperm motility, weights of testes and epididymides, and the level of anti-Müllerian hormone (AMH) in the serum. Immunohistochemistry was performed to examine germ cell proliferation (Ki-67), apoptosis (Terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labelling), reserve (DAZL-Deleted in azoospermia-like, Promyelocytic leukaemia zinc-finger), blood vessels (CD34) and Sertoli cells (GATA-4). Administration of cetuximab alone increased testicular apoptosis and decreased epididymal-spermatozoa total motile count over time. When added to cisplatin, cetuximab exacerbated most of the recorded testicular parameters, compared with the effect of cisplatin alone, including testis and epididymis weights, epididymal-spermatozoa total motile count, AMH concentration, meiosis and apoptosis. In conclusion, cetuximab has only a mild effect on testicular reserve, but when added to cisplatin, it exacerbates cisplatin-induced testicular toxicity. PMID:27184186

  7. Cisplatin Targeting of Bacterial Ribosomal RNA Hairpins

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    Gayani N. P. Dedduwa-Mudalige

    2015-09-01

    Full Text Available Cisplatin is a clinically important chemotherapeutic agent known to target purine bases in nucleic acids. In addition to major deoxyribonucleic acid (DNA intrastrand cross-links, cisplatin also forms stable adducts with many types of ribonucleic acid (RNA including siRNA, spliceosomal RNAs, tRNA, and rRNA. All of these RNAs play vital roles in the cell, such as catalysis of protein synthesis by rRNA, and therefore serve as potential drug targets. This work focused on platination of two highly conserved RNA hairpins from E. coli ribosomes, namely pseudouridine-modified helix 69 from 23S rRNA and the 790 loop of helix 24 from 16S rRNA. RNase T1 probing, MALDI mass spectrometry, and dimethyl sulfate mapping revealed platination at GpG sites. Chemical probing results also showed platination-induced RNA structural changes. These findings reveal solvent and structural accessibility of sites within bacterial RNA secondary structures that are functionally significant and therefore viable targets for cisplatin as well as other classes of small molecules. Identifying target preferences at the nucleotide level, as well as determining cisplatin-induced RNA conformational changes, is important for the design of more potent drug molecules. Furthermore, the knowledge gained through studies of RNA-targeting by cisplatin is applicable to a broad range of organisms from bacteria to human.

  8. Technological development of injectable cisplatin solution

    International Nuclear Information System (INIS)

    To develop a cisplatin formulation at 1mg/mL concentration by setting the solution preparation procedure for parenteral administration, with good physical, chemical, biological and microbiological stability. two formulation variants of cisplatin: one solution with and the other without acetate buffer. Both were followed in terms of physical and chemical stability for 3 months. The formulations used raw material from IMPEX SA company, which has 99.74 % power as certified by the manufacturer analysis. Three batches of 10mg cistoplatin at pilot scale in amber 10 R vials, 3 batches of 50 mg cisplatin in amber 50 H vials and the dose was 1mg/ml. Excipients were used to give isotony and stability to the formulation with 0.1 N chlorhydric acid and injection water for vehicle. The high performance liquid chromatography allowed evaluating the stability to determine the expiry date of the drug. The biological and microbiological methods determined lack of pyrogens and sterility respectively

  9. Duration of cisplatin excretion in breast milk

    OpenAIRE

    Hays, Karen; Ryu, Rachel J.; Swisher, Elizabeth M.; Reed, Eddie; McManus, Terry; Rybeck, Blanche; Petros, William P.; Hebert, Mary F.

    2013-01-01

    Cisplatin, a platinum-based chemotherapy agent, is commonly used in treating cancers that may affect women of childbearing age, including cervical cancer, triple-negative breast cancer, and pediatric tumors in adolescents. The authors found that platinum was undetectable in breast milk at 66 hours and beyond following a 70 mg dose of intravenous cisplatin. Relative infant dose of platinum was calculated to be between 0.29% and 0.40% of the maternal dose corrected for body weight. This case de...

  10. Strong adsorption of Al-doped carbon nanotubes toward cisplatin

    Science.gov (United States)

    Li, Wei; Li, Guo-Qing; Lu, Xiao-Min; Ma, Juan-Juan; Zeng, Peng-Yu; He, Qin-Yu; Wang, Yin-Zhen

    2016-08-01

    The adsorption of cisplatin molecule on Al-doped CNTs is investigated using density functional theory. The obtained results indicate that Al-doped carbon nanotubes can strongly absorb cisplatin. After absorbing cisplatin, the symmetry of CNTs has some changes. We innovatively defined a parameter of symmetry variation which relates to the adsorption. By analyzing the electronic structure, it can be concluded that under the circumstance that cisplatin was absorbed by Al-doped CNTs through aluminum atom of Al-doped CNTs. In conclusion, Al-doped CNTs is a kind of potential delivery carrier with high quality for anticancer drug cisplatin.

  11. A Mathematical Model for Cisplatin Cellular Pharmacodynamics

    Directory of Open Access Journals (Sweden)

    Ardith W. El-Kareh

    2003-03-01

    Full Text Available A simple theoretical model for the cellular pharmacodynamics of cisplatin is presented. The model, which takes into account the kinetics of cisplatin uptake by cells and the intracellular binding of the drug, can be used to predict the dependence of survival (relative to controls on the time course of extracellular exposure. Cellular pharmacokinetic parameters are derived from uptake data for human ovarian and head and neck cancer cell lines. Survival relative to controls is assumed to depend on the peak concentration of DNA-bound intracellular platinum. Model predictions agree well with published data on cisplatin cytotoxicity for three different cancer cell lines, over a wide range of exposure times. In comparison with previously published mathematical models for anticancer drug pharmacodynamics, the present model provides a better fit to experimental data sets including long exposure times (∼100 hours. The model provides a possible explanation for the fact that cell kill correlates well with area under the extracellular concentration-time curve in some data sets, but not in others. The model may be useful for optimizing delivery schedules and for the dosing of cisplatin for cancer therapy.

  12. Effect of Cisplatin on the Flexibility of Linear DNA

    Institute of Scientific and Technical Information of China (English)

    JI Chao; ZHANG Ling-Yun; HOU Xi-Miao; DOU Shuo-Xing; WANG Peng-Ye

    2011-01-01

    With the aid of an atomic force microscope (AFM), we study the interaction between linear DNA fragment and cisplatin. For different cisplatin concentrations, the AFM used to observe the conformation of DNA has a gradual change. The contour length, the end-to-end distance and the local bend angles of the linear DNA fragment can be accurately measured. The persistence length of DNA interacting with cisplatin is decreased with the increasing cisplatin concentration. Furthermore, it is demonstrated that the local bend angles of DNA chains are increased by the binding interaction of cisplatin.%@@ With the aid of an atomic force microscope (AFM), we study the interaction between linear DNA fragment and cisplatin.For different cisplatin concentrations, the AFM used to observe the conformation of DNA has a gradual change.The contour length, the end-to-end distance and the local bend angles of the linear DNA fragment can be accurately measured.The persistence length of DNA interacting with cisplatin is decreased with the increasing cisplatin concentration.Furthermore, it is demonstrated that the local bend angles of DNA chains are increased by the binding interaction of cisplatin.

  13. Dendritic Cell Protection from Cisplatin Nephrotoxicity Is Independent of Neutrophils

    Directory of Open Access Journals (Sweden)

    Raghu K. Tadagavadi

    2015-08-01

    Full Text Available Cisplatin is a very effective chemotherapeutic agent used against a wide range of solid tumors. A major adverse effect of cisplatin therapy is acute kidney injury (AKI. Neutrophils are reported to infiltrate and exacerbate injury in a wide range of sterile inflammatory models of tissue injury. Here, we studied the kinetics of neutrophil infiltration into kidneys and their role in cisplatin-mediated AKI. Mice treated with cisplatin showed an increase in circulating neutrophils 24 and 48 h after cisplatin administration. Cisplatin treatment caused an increase in kidney leukocytes with neutrophils accounting for the majority of the infiltrating leukocytes. The extent of neutrophil infiltration coincided with the severity of kidney injury and renal dysfunction. To examine the functional relevance of infiltrating neutrophils in cisplatin nephrotoxicity, we depleted neutrophils using a neutrophil-specific antibody (anti-Ly-6G. This antibody resulted in greater than 90% depletion of neutrophils in both the blood and kidney. Of note, depletion of neutrophils had no impact on the extent of cisplatin-induced AKI as compared to non-depleted mice. Earlier, we reported that dendritic cell depletion in CD11c-DTRtg mice causes exacerbation of AKI and a dramatic increase in renal neutrophils. Thus, we also examined the role of neutrophils in dendritic cell-depleted mice treated with cisplatin. Dendritic cell depletion exacerbated AKI in spite of neutrophil depletion. These data demonstrate that cisplatin nephrotoxicity is not mediated by neutrophils and that dendritic cells protect kidneys via neutrophil-independent mechanisms.

  14. Flavonoids, the emerging dietary supplement against cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Athira, K V; Madhana, Rajaram Mohanrao; Lahkar, Mangala

    2016-03-25

    The letter illustrates the emerging potential of flavonoids as dietary supplement to ameliorate cisplatin-induced nephrotoxicity and refers to the recent article on ''Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat'' by Chtourou et al. They demonstrated that supplementation of naringin, a flavanone glycoside, found in grape and citrus fruit species, can attenuate cisplatin-induced renal dysfunction via restoration of redox balance and suppression of inflammation, NF-κB activation and apoptosis. The chemotherapeutic efficacy of cisplatin has always compelled the researchers to find solution to ameliorate its side effects. In recent years, numerous candidates have been evaluated for their protective potential against cisplatin-induced nephrotoxicity and flavonoids have come up with promising results. The future prospects might be promising with a proper refinement and collective integration of the preclinical and clinical research in the field of flavonoid supplementation to cisplatin therapy. PMID:26876905

  15. ELISA-like Analysis of Cisplatinated DNA Using Magnetic Separation

    OpenAIRE

    Kristyna Smerkova; Marcela Vlcnovska; Simona Dostalova; Vedran Milosavljevic; Pavel Kopel; Tomas Vaculovic; Sona Krizkova; Marketa Vaculovicova; Vojtech Adam; Rene Kizek

    2015-01-01

    Cisplatin belongs to the most widely used cytostatic drugs. The determination of the presence of the DNA-cisplatin adducts may not only signal the guanine-rich regions but also monitor the interaction reaction between DNA and the drug in terms of speed of interaction. In this work, the combined advantages of magnetic particles-based isolation/purification with fluorescent properties of quantum dots (QDs) and antibodies targeted on specific recognition of DNA-cisplatin adducts are demonstra...

  16. Cisplatin-induced downregulation of OCTN2 affects carnitine wasting

    OpenAIRE

    Lancaster, Cynthia; Hu, Chaoxin; Franke, Ryan; Filipski, Kelly; Orwick, S.J.; Chen, Zhaoyuan; Zuo, Zhili; Loos, Walter; Sparreboom, Alex

    2010-01-01

    textabstractPurpose: Carnitine is an essential cofactor for mitochondrial fatty acid oxidation that is actively reabsorbed by the luminal transporter Octn2 (Slc22a5). Because the nephrotoxic agent cisplatin causes urinary loss of carnitine in humans, we hypothesized that cisplatin may affect Octn2 function. Experimental Design: Excretion of carnitine and acetylcarnitine was measured in urine collected from mice with or without cisplatin administration. The transport of carnitine was assessed ...

  17. Crystal Structures of Cisplatin Bound to a Human Copper Chaperone

    Energy Technology Data Exchange (ETDEWEB)

    Boal, Amie K.; Rosenzweig, Amy C.; (NWU)

    2010-08-16

    Copper trafficking proteins, including the chaperone Atox1 and the P{sub 1B}-type ATPase ATP7B, have been implicated in cellular resistance to the anticancer drug cisplatin. We have determined two crystal structures of cisplatin-Atox1 adducts that reveal platinum coordination by the conserved CXXC copper-binding motif. Direct interaction of cisplatin with this functionally relevant site has significant implications for understanding the molecular basis for resistance mediated by copper transport pathways.

  18. Radiosensitizers in cervical cancer. Cisplatin and beyond

    International Nuclear Information System (INIS)

    Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutical modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be assayed. A strategy currently being investigated is the use of newer radiosensitizers alone or in combination with platinum compounds. In the present work, we present preclinical information on known and newer cytotoxic agents as radiosensitizers on cervical cancer models, as well as the clinical information emanating from early phase trials that incorporate them to the cervical cancer management. In addition, we present the perspectives on the combined approach of radiation therapy and molecular target-based drugs with proven radiosensitizing capacity

  19. C-phycocyanin attenuates cisplatin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Lim, Beom Jin; Jeong, Jin Young; Chang, Yoon-Kyung; Na, Ki-Ryang; Lee, Kang Wook; Shin, Young-Tai; Choi, Dae Eun

    2012-01-01

    Although cisplatin is a highly effective antineoplastic agent, nephrotoxicity is its major clinical problem. Recently, it was reported that Spirulina, a blue-green algae, has potent antioxidant properties. The aim of this study was to establish the possible protective role of C-phycocyanin (PC), one of the active ingredients of Spirulina, against cisplatin-induced nephrotoxicity. This study was carried out using human kidney-2 (HK-2) cells and male C57BL6 mice. Cells and mice were divided into four groups; untreated control group, PC-treated control group, cisplatin-treated group, and PC plus cisplatin-treated group. The molecular, functional, and structural parameters were measured. PC significantly attenuated blood urea nitrogen, serum creatinine, renal histological damages, and apoptotic cell death in cisplatin-treated mice. The cisplatin-induced cell death was significantly attenuated in cells pretreated with PC. PC also significantly attenuated the elevation of p-ERK, p-JNK, and p-p38 induced by cisplatin treatment. The expression of Bax, caspase-9, and caspase-3 in cisplatin-treated cells were also decreased by PC treatment. In conclusion, PC ameliorates cisplatin-induced nephrotoxicity and, at least in part, suppression of p-ERK, p-JNK, p-p38, Bax, caspase-9, and caspase-3 may be involved in this mechanism. PMID:22681485

  20. Walnut consumption protects rats against cisplatin-induced neurotoxicity.

    Science.gov (United States)

    Shabani, Mohammad; Nazeri, Masoud; Parsania, Shahrnaz; Razavinasab, Moazamehosadat; Zangiabadi, Nasser; Esmaeilpour, Khadije; Abareghi, Fatemeh

    2012-10-01

    Walnut is extensively used in traditional medicine for treatment of various ailments. It is described as an anticancer, anti-inflammatory, blood purifier and antioxidant agent. In this study, we investigated whether or not Walnut could protect neurons against cisplatin-induced neurotoxicity in rats. Dietary walnut (6%) was assessed for its neuroprotective effects through the alteration in performance of hippocampus- and cerebellum-related behaviors following chronic cisplatin treatment (5 mg/kg/week for 5 consecutive weeks) in male rats. We also evaluated the effect of cisplatin and walnut administration on nociception. We showed that exposure of adolescent rats to cisplatin resulted in significant decrease in explorative behaviors and memory retention. Walnut consumption improved memory and motor abilities in cisplatin treated rats, while walnut alone did not show any significant changes in these abilities compared to saline. Cisplatin increased latency of response to nociception, and walnut reversed this effect of cisplatin. We conclude that walnuts in the diet following anticancer drugs such as cisplatin might have a protective effect against cisplatin-induced disruptions in motor and cognitive function. However, further studies are needed to elucidate the exact mechanisms of this protective effect of walnut and to explore underlying mechanisms. PMID:22935099

  1. Effects of cisplatin on potassium currents in CT26 cells

    Directory of Open Access Journals (Sweden)

    Naveen Sharma

    2016-01-01

    Conclusion: Potassium currents were detected in CT26 cells and the currents were reduced by the application of tetraethylammonium (TEA chloride, iberiotoxin, a big conductance calcium-activated potassium channel blocker and barium. The potassium currents were enhanced to 192< by the application of cisplatin (0.5 mM. Moreover, the increase of potassium currents by cisplatin was further inhibited by the application of TEA confirming the action of cisplatin on potassium channels. In addition, relative current induced by cisplatin in CT26 cells was bit larger than in normal IEC-6 cells.

  2. Real-time monitoring of cisplatin-induced cell death.

    Directory of Open Access Journals (Sweden)

    Hamed Alborzinia

    Full Text Available Since the discovery of cisplatin more than 40 years ago and its clinical introduction in the 1970s an enormous amount of research has gone into elucidating the mechanism of action of cisplatin on tumor cells. With a novel cell biosensor chip system allowing continuous monitoring of respiration, glycolysis, and impedance we followed cisplatin treatment of different cancer cell lines in real-time. Our measurements reveal a first effect on respiration, in all cisplatin treated cell lines, followed with a significant delay by interference with glycolysis in HT-29, HCT-116, HepG2, and MCF-7 cells but not in the cisplatin-resistant cell line MDA-MB-231. Most strikingly, cell death started in all cisplatin-sensitive cell lines within 8 to 11 h of treatment, indicating a clear time frame from exposure, first response to cisplatin lesions, to cell fate decision. The time points of most significant changes were selected for more detailed analysis of cisplatin response in the breast cancer cell line MCF-7. Phosphorylation of selected signal transduction mediators connected with cellular proliferation, as well as changes in gene expression, were analyzed in samples obtained directly from sensor chips at the time points when changes in glycolysis and impedance occurred. Our online cell biosensor measurements reveal for the first time the time scale of metabolic response until onset of cell death under cisplatin treatment, which is in good agreement with models of p53-mediated cell fate decision.

  3. Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Satoshi Tanida

    2012-01-01

    Full Text Available Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis. Cisplatin resistance arises through a multifactorial mechanism involving reduced drug uptake, increased drug inactivation, increased DNA damage repair, and inhibition of transmission of DNA damage recognition signals to the apoptotic pathway. In addition, a new mechanism has recently been revealed, in which the oncoprotein c-Myc suppresses bridging integrator 1 (BIN1, thereby releasing poly(ADP-ribosepolymerase 1, which results in increased DNA repair activity and allows cancer cells to acquire cisplatin resistance. The present paper focuses on the molecular mechanisms of cisplatin-induced apoptosis and of cisplatin resistance, in particular on the involvement of BIN1 in the maintenance of cisplatin sensitivity.

  4. Rationally engineered polymeric cisplatin nanoparticles for improved antitumor efficacy

    Energy Technology Data Exchange (ETDEWEB)

    Paraskar, Abhimanyu; Soni, Shivani; Basu, Sudipta; Srivats, Shyam; Roy, Rituparna Sinha; Sengupta, Shiladitya [BWH-HST Center for Biomedical Engineering, Harvard Medical School, 65 Landsdowne street, Cambridge, MA 02139 (United States); Amarasiriwardena, Chitra J; Lupoli, Nicola, E-mail: ssengupta2@partners.org [Channing Laboratory, Department of Medicine, Brigham and Women' s Hospital, Harvard Medical School, 65 Landsdowne street, Cambridge, MA 02139 (United States)

    2011-07-01

    The use of cisplatin, a first line chemotherapy for most cancers, is dose-limited due to nephrotoxicity. While this toxicity can be addressed through nanotechnology, previous attempts at engineering cisplatin nanoparticles have been limited by the impact on the potency of cisplatin. Here we report the rational engineering of a novel cisplatin nanoparticle by harnessing a novel polyethylene glycol-functionalized poly-isobutylene-maleic acid (PEG-PIMA) copolymer, which can complex with cis-platinum (II) through a monocarboxylato and a coordinate bond. We show that this complex self-assembles into a nanoparticle, and exhibits an IC{sub 50} = 0.77 {+-} 0.11 {mu}M comparable to that of free cisplatin (IC{sub 50} = 0.44 {+-} 0.09 {mu}M). The nanoparticles are internalized into the endolysosomal compartment of cancer cells, and release cisplatin in a pH-dependent manner. Furthermore, the nanoparticles exhibit significantly improved antitumor efficacy in a 4T1 breast cancer model in vivo, with limited nephrotoxicity, which can be explained by preferential biodistribution in the tumor with reduced kidney concentrations. Our results suggest that the PEG-PIMA-cisplatin nanoparticle can emerge as an attractive solution to the challenges in cisplatin chemotherapy.

  5. Reduction of cisplatin-induced nephrotoxicity in vivo by selenomethionine: the effect on cisplatin-DNA adducts.

    Science.gov (United States)

    García Sar, Daniel; Montes-Bayón, Maria; Blanco González, Elisa; Sierra Zapico, Luisa M; Sanz-Medel, Alfredo

    2011-06-20

    Cisplatin is one of the most effective chemotherapeutic agents, although its clinical use is limited by severe renal toxicity. This toxicity seems to be related to the accumulation of the drug in kidney tissues, leading to renal failure. For this reason, several compounds have been evaluated to ameliorate the nephrotoxicity induced by cisplatin. In the present investigation, we report the effect of the oral administration of selenomethionine before intraperitoneal cisplatin treatment. The preadministration of this Se species has been shown to have an important effect in reducing renal damage induced by cisplatin by increasing the excreted urea and improving creatinine clearance. Quantification of the level of DNA--cisplatin adducts in kidney and liver tissues was carried out by postcolumn isotope dilution analysis using liquid chromatography-inductively coupled plasma (LC-ICP-MS) as speciation set up. The level of DNA--cisplatin adducts in rats given Se-methionine in the drinking water before cisplatin administration was considerably lower in kidney tissues with respect to the animals drinking only water. Such effects were not observed in liver tissue. Initial speciation studies of Pt and Se conducted in kidney tissues of exposed animals by HPLC-ICP-MS have revealed the presence of cisplatin as part of a complex with Se-methionine, which can be eventually excreted into urine. This Pt--Se complex could explain the observed reduction of the kidney damage in Se-methionine-treated animals. PMID:21491944

  6. Dendrimers bind antioxidant polyphenols and cisplatin drug.

    Directory of Open Access Journals (Sweden)

    Amine Abderrezak

    Full Text Available Synthetic polymers of a specific shape and size play major role in drug delivery systems. Dendrimers are unique synthetic macromolecules of nanometer dimensions with a highly branched structure and globular shape with potential applications in gene and drug delivery. We examine the interaction of several dendrimers of different compositions mPEG-PAMAM (G3, mPEG-PAMAM (G4 and PAMAM (G4 with hydrophilic and hydrophobic drugs cisplatin, resveratrol, genistein and curcumin at physiological conditions. FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyse drug binding mode, the binding constant and the effects of drug complexation on dendrimer stability and conformation. Structural analysis showed that cisplatin binds dendrimers in hydrophilic mode via Pt cation and polymer terminal NH(2 groups, while curcumin, genistein and resveratrol are located mainly in the cavities binding through both hydrophobic and hydrophilic contacts. The overall binding constants of durg-dendrimers are ranging from 10(2 M(-1 to 10(3 M(-1. The affinity of dendrimer binding was PAMAM-G4>mPEG-PAMAM-G4>mPEG-PAMAM-G3, while the order of drug-polymer stability was curcumin>cisplatin>genistein>resveratrol. Molecular modeling showed larger stability for genisten-PAMAM-G4 (ΔG = -4.75 kcal/mol than curcumin-PAMAM-G4 ((ΔG = -4.53 kcal/mol and resveratrol-PAMAM-G4 ((ΔG = -4.39 kcal/mol. Dendrimers might act as carriers to transport hydrophobic and hydrophilic drugs.

  7. Influence of amifostine on the pharmacokinetics of cisplatin in cancer patients

    NARCIS (Netherlands)

    Korst, A.E.C.; Sterre, M.L.T. van der; Gall, H.E.; Fichtinger-Schepman, A.M.J.; Vermorken, J.B.; Vijgh, W.J.F. van der

    1998-01-01

    The pharmacokinetics of cisplatin was investigated in 13 patients receiving 18 courses of cisplatin alone or in combination with amifostine to investigate the influence of amifostine (WR 2721; Ethyol) on the pharmacokinetics of cisplatin. Cisplatin was administered as a 1-h i.v. infusion, whereas am

  8. EPS8 inhibition increases cisplatin sensitivity in lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Lidija K Gorsic

    Full Text Available Cisplatin, a commonly used chemotherapeutic, is associated with ototoxicity, renal toxicity and neurotoxicity, thus identifying means to increase the therapeutic index of cisplatin may allow for improved outcomes. A SNP (rs4343077 within EPS8, discovered through a genome wide association study of cisplatin-induced cytotoxicity and apoptosis in lymphoblastoid cell lines (LCLs, provided impetus to further study this gene. The purpose of this work was to evaluate the role of EPS8 in cellular susceptibility to cisplatin in cancerous and non-cancerous cells. We used EPS8 RNA interference to determine the effect of decreased EPS8 expression on LCL and A549 lung cancer cell sensitivity to cisplatin. EPS8 knockdown in LCLs resulted in a 7.9% increase in cisplatin-induced survival (P = 1.98 × 10(-7 and an 8.7% decrease in apoptosis (P = 0.004 compared to control. In contrast, reduced EPS8 expression in lung cancer cells resulted in a 20.6% decrease in cisplatin-induced survival (P = 5.08 × 10(-5. We then investigated an EPS8 inhibitor, mithramycin A, as a potential agent to increase the therapeutic index of cisplatin. Mithramycin A decreased EPS8 expression in LCLs resulting in decreased cellular sensitivity to cisplatin as evidenced by lower caspase 3/7 activation following cisplatin treatment (42.7% ± 6.8% relative to control P = 0.0002. In 5 non-small-cell lung carcinoma (NSCLC cell lines, mithramycin A also resulted in decreased EPS8 expression. Adding mithramycin to 4 NSCLC cell lines and a bladder cancer cell line, resulted in increased sensitivity to cisplatin that was significantly more pronounced in tumor cell lines than in LCL lines (p<0.0001. An EGFR mutant NSCLC cell line (H1975 showed no significant change in sensitivity to cisplatin with the addition of mithramycin treatment. Therefore, an inhibitor of EPS8, such as mithramycin A, could improve cisplatin treatment by increasing sensitivity of tumor relative to normal cells.

  9. γ-Glutamyl Transpeptidase-Deficient Mice Are Resistant to the Nephrotoxic Effects of Cisplatin

    OpenAIRE

    Hanigan, Marie H.; Lykissa, Ernest D.; Townsend, Danyelle M.; Ou, Ching-Nan; Barrios, Roberto; Lieberman, Michael W.

    2001-01-01

    We have proposed that the nephrotoxicity of cisplatin, a widely used chemotherapy drug, is the result of the binding of cisplatin to glutathione and the subsequent metabolism of the cisplatin-glutathione complex via a γ-glutamyl transpeptidase (GGT)-dependent pathway in the proximal tubules. To test the hypothesis that GGT activity is essential for the nephrotoxicity of cisplatin, the effects of cisplatin were examined in wild-type and GGT-deficient mice. Mice were treated with 15 mg cisplati...

  10. Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice

    OpenAIRE

    Kim Sung-Ho; Jung Uhee; Jo Sung-Kee; Ju Eun-Jin; Park Hae-Ran; Yee Sung-Tae

    2009-01-01

    Abstract Background Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice. Methods HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of ...

  11. Identification of Cisplatin-Binding Proteins Using Agarose Conjugates of Platinum Compounds

    OpenAIRE

    Takatoshi Karasawa; Martha Sibrian-Vazquez; Strongin, Robert M.; Peter S Steyger

    2013-01-01

    Cisplatin is widely used as an antineoplastic drug, but its ototoxic and nephrotoxic side-effects, as well as the inherent or acquired resistance of some cancers to cisplatin, remain significant clinical problems. Cisplatin's selectivity in killing rapidly proliferating cancer cells is largely dependent on covalent binding to DNA via cisplatin's chloride sites that had been aquated. We hypothesized that cisplatin's toxicity in slowly proliferating or terminally differentiated cells is primari...

  12. Evaluation of nanoparticle delivered cisplatin in beagles

    Science.gov (United States)

    Feldhaeusser, Brittany; Platt, Simon R.; Marrache, Sean; Kolishetti, Nagesh; Pathak, Rakesh K.; Montgomery, David J.; Reno, Lisa R.; Howerth, Elizabeth; Dhar, Shanta

    2015-08-01

    Intracranial neoplasia is a significant cause of morbidity and mortality in both human and veterinary patients, and is difficult to treat with traditional therapeutic methods. Cisplatin is a platinum (Pt)-containing chemotherapeutic agent approved by the Food and Drug Administration; however, substantial limitations exist for its application in canine brain tumor treatment due to the difficulty in crossing the blood-brain barrier (BBB), development of resistance, and toxicity. A modified Pt(iv)-prodrug of cisplatin, Platin-M, was recently shown to be deliverable to the brain via a biocompatible mitochondria-targeted lipophilic polymeric nanoparticle (NP) that carries the drug across the BBB and to the mitochondria. NP mediated controlled release of Platin-M and subsequent reduction of this prodrug to cisplatin allowed cross-links to be formed with the mitochondrial DNA, which have no nucleotide excision repair system, forcing the overactive cancer cells to undergo apoptosis. Here, we report in vitro effects of targeted Platin-M NPs (T-Platin-M-NPs) in canine glioma and glioblastoma cell lines with results indicating that this targeted NP formulation is more effective than cisplatin. In both the cell lines, T-Platin-M-NP was significantly more efficacious compared to carboplatin, another Pt-based chemotherapy, which is used in the settings of recurrent high-grade glioblastoma. Mitochondrial stress analysis indicated that T-Platin-M-NP is more effective in disrupting the mitochondrial bioenergetics in both the cell types. A 14-day distribution study in healthy adult beagles using a single intravenous injection at 0.5 mg kg-1 (with respect to Platin-M) of T-Platin-M-NPs showed high levels of Pt accumulation in the brain, with negligible amounts in the other analyzed organs. Safety studies in the beagles monitoring physical, hematological, and serum chemistry evaluations were within the normal limits on days 1, 7, and 14 after injection of either 0.5 mg kg-1 or 2 mg kg

  13. Systems biology of cisplatin resistance: past, present and future.

    Science.gov (United States)

    Galluzzi, L; Vitale, I; Michels, J; Brenner, C; Szabadkai, G; Harel-Bellan, A; Castedo, M; Kroemer, G

    2014-01-01

    The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant

  14. Temozolomide and cisplatin in relapsed/refractory acute leukemia

    Directory of Open Access Journals (Sweden)

    Rasul Muhammad

    2009-05-01

    Full Text Available Abstract Cisplatin depletes MGMT and increases the sensitivity of leukemia cells to temozolomide. We performed a phase I study of cisplatin and temozolomide in patients with relapsed and refractory acute leukemia. Fifteen patients had AML, 3 had ALL, and 2 had biphenotypic leukemia. The median number of prior chemotherapy regimens was 3 (1–5. Treatment was well tolerated up to the maximal doses of temozolomide 200 mg/m2/d times 7 days and cisplatin 100 mg/m2 on day 1. There was one complete remission in this heavily pretreated patient population. Five of 20 (25% patients demonstrated a significant reduction in bone marrow blasts.

  15. Poly(amido)amine (PAMAM) dendrimer-cisplatin complexes for chemotherapy of cisplatin-resistant ovarian cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Yellepeddi, Venkata Kashyap; Vangara, Kiran Kumar; Palakurthi, Srinath, E-mail: palakurthi@tamhsc.edu [Texas A and M Health Science Center, Irma Lerma Rangel College of Pharmacy (United States)

    2013-09-15

    Dendrimer-cisplatin complexes were prepared using PAMAM dendrimers with terminal -NH{sub 2} and -COOH groups as well as biotin-conjugated dendrimers. Preformulation parameters of dendrimer-cisplatin complexes were studied using differential scanning calorimetry (DSC) and inductively coupled plasma-mass spectrometry (ICP-MS). Cytotoxicity and mechanism of cytotoxicity of dendrimer-cisplatin complexes was investigated in OVCAR-3, SKOV, A2780 and cisplatin-resistant CP70 human ovarian cancer cell lines. The loading of cisplatin in dendrimers was {approx}11 % (w/w). PAMAM G4 dendrimers with amine surface groups (biotinylated and native) have shown 2.5- to 3.0-fold reduction in IC{sub 50} values in ovarian cancer cells when compared with carboxylate surface dendrimers (p < 0.05). A correlation was observed among cytotoxicity of the complexes, cellular uptake, and platinum-DNA adduct formation. Treatment with dendrimer-cisplatin complexes resulted in a 7.0-fold increase (p < 0.05) in expression of apoptotic genes (Bcl2, Bax, p53) and 13.2- to 27.1-fold increase (p < 0.05) in the activity of caspases 3, 8, and 9 in vitro. Results suggest that PAMAM dendrimers can be used as potential carrier for cisplatin chemotherapy of ovarian cancer.

  16. Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer

    DEFF Research Database (Denmark)

    Szallasi, Zoltan Imre; Eklund, Aron Charles; Li, Qiyuan;

    2010-01-01

    1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are......PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer...... share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu...

  17. [Cisplatin influence on: the radiosensitivity and recovery of yeast cells].

    Science.gov (United States)

    2013-01-01

    The effect of the simultaneous combined action of ionizing radiation and cisplatin on the radiosensitivity and liquid holding recovery (LHR) of diploid yeast cells was studied. It was shown that regardless of the cisplatin concentration (0; 0.002; 0.01; 0.02 g/ml) the radiosensitivity of cells was increased by 1.3 times. The ability of a cell to the LHR was progressively decreased with the increasing cisplatin concentration up to the complete inhibition. It was shown that the LHR of yeast cells after a combined action of ionizing radiation and chemical agents is mainly inhibited due to formation of a greater proportion of irreversible damage. The con- stant of recovery, characterizing the probability of recovery per a unit of time, was independent on cisplatine concentration. PMID:25508873

  18. Vincristine, bleomycin, mitomycin C, cisplatin combination

    International Nuclear Information System (INIS)

    During the past five years the EORTC Gynecological Cancer Cooperative Group (G.C.C.G.) performed several studies in patients with disseminated squamous cell carcinoma of the uterine cervix (SCCUC). The first trial protocol (55802) studies the efficacy and toxicity of a bleomycin-mitomycin C based regimen to which vincristine and cisplatin were added (VBMP). The overall response rate in 50 evaluable patients was 40% and median time to progression was 48 weeks and 32 weeks for patients with complete response (16%) and partial response respectively. Of interest was that the complete remission rate in patients with only distant metastases was 30% (for patients with only lung and/or lymph nodes metastases 40%) and some of these patients had long term disease-free survival. The toxicity of the VBMP regimen was acceptable to the patients

  19. Computational metallomics of the anticancer drug cisplatin.

    Science.gov (United States)

    Calandrini, Vania; Rossetti, Giulia; Arnesano, Fabio; Natile, Giovanni; Carloni, Paolo

    2015-12-01

    Cisplatin, cis-diamminedichlorido-platinum(II), is an important therapeutic tool in the struggle against different tumors, yet it is plagued with the emergence of resistance mechanisms after repeated administrations. This hampers greatly its efficacy. Overcoming resistance problems requires first and foremost an integrated and systematic understanding of the structural determinants and molecular recognition processes involving the drug and its cellular targets. Here we review a strategy that we have followed for the last few years, based on the combination of modern tools from computational chemistry with experimental biophysical methods. Using hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) simulations, validated by spectroscopic experiments (including NMR, and CD), we have worked out for the first time at atomic level the structural determinants in solution of platinated cellular substrates. These include the copper homeostasis proteins Ctr1, Atox1, and ATP7A. All of these proteins have been suggested to influence the pre-target resistance mechanisms. Furthermore, coupling hybrid QM/MM simulations with classical Molecular Dynamics (MD) and free energy calculations, based on force field parameters refined by the so-called "Force Matching" procedure, we have characterized the structural modifications and the free energy landscape associated with the recognition between platinated DNA and the protein HMGB1, belonging to the chromosomal high-mobility group proteins HMGB that inhibit the repair of platinated DNA. This may alleviate issues relative to on-target resistance process. The elucidation of the mechanisms by which tumors are sensitive or refractory to cisplatin may lead to the discovery of prognostic biomarkers. The approach reviewed here could be straightforwardly extended to other metal-based drugs. PMID:26490711

  20. Protective Effect of Minocycline Against Cisplatin-induced Ototoxicity

    OpenAIRE

    Lee, Chi-Kyou; Shin, Jang-In; Cho, Yang-Sun

    2011-01-01

    Objectives Cisplatin, a widely used chemotherapeutic agent, has serious side effects, including nephrotoxicity and ototoxicity. Minocycline is a semisynthetic second-generation tetracycline that exerts anti-inflammatory and neuroprotective effects. The purpose of this study was to elucidate the protective effect of minocycline against cisplatin-induced ototoxicity in the auditory hair cell. Methods The House Ear Institute-Organ of Corti 1 (HEI-OC1) cell line and guinea pigs were used for in v...

  1. Irinotecan/cisplatin versus Etoposide/cisplatin for Patients with Extensive Stage Small Cell Lung Cancer: A Systematic Review

    OpenAIRE

    Yao, Nan; Jiang, Lei; Yang, Kehu; Yancheng YE; Denghai MI; Guangtao MIN

    2009-01-01

    Background and objective It is unclear whether etoposide/cisplatin (EP) regimen is the optimal chemotherapy regimen in the treatment patients with extensive small cell lung cancer (SCLC), this study was aimed to evaluate the efficacy and safety of patients with extensive SCLC treated with irinotecan/cisplatin (IP) versus EP. Methods We searched EMBASE, PubMed, the Cochrane Library, China journal full-text database (CJFD), Chinese scientific journal full-text database (CSJD), Chinese biomedici...

  2. Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism.

    Science.gov (United States)

    Ai, Zhihong; Lu, Yang; Qiu, Songbo; Fan, Zhen

    2016-04-01

    Cisplatin is currently one of the most effective chemotherapeutic drugs used for treating ovarian cancer; however, resistance to cisplatin is common. In this study, we explored an experimental strategy for overcoming cisplatin resistance of human ovarian cancer from the new perspective of cancer cell metabolism. By using two pairs of genetically matched cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable α subunit of HIF-1, HIF-1α, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1α degradation but did not downregulate HIF-1α in their cisplatin-resistant counterparts. Overexpression of a degradation-resistant HIF-1α (HIF-1α ΔODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1α or pharmacological promotion of HIF-1α degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. We further demonstrated that knockdown of HIF-1α improved the response of cisplatin-resistant ovarian cancer cells to cisplatin by redirecting the aerobic glycolysis in the resistant cancer cells toward mitochondrial oxidative phosphorylation, leading to cell death through overproduction of reactive oxygen species. Our findings suggest that the HIF-1α-regulated cancer metabolism pathway could be a novel target for overcoming cisplatin resistance in ovarian cancer. PMID:26801746

  3. Biodegradable polymeric system for cisplatin delivery: Development, in vitro characterization and investigation of toxicity profile

    Energy Technology Data Exchange (ETDEWEB)

    Alam, Noor; Khare, Vaibhav; Dubey, Ravindra; Saneja, Ankit [Formulation and Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu (India); Kushwaha, Manoj; Singh, Gurdarshan; Sharma, Neelam; Chandan, Balkrishan [PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu (India); Gupta, Prem N., E-mail: pngupta10@gmail.com [Formulation and Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu (India)

    2014-05-01

    Cisplatin is one of the most potent anticancer agent used in the treatment of various solid tumors, however, its clinical use is limited due to severe adverse effects including nephrotoxicity. In this investigation cisplatin loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles were developed and characterized for various in vitro characteristics including size distribution, zeta potential, drug loading and release profile. PLGA nanoparticles were successfully developed as investigated using scanning electron microscopy and exhibited average particles size and zeta potential as 284.8 nm and − 15.8 mV, respectively. Fourier transform infrared spectroscopy and differential scanning calorimetry indicated an absence of any polymer–drug interactions. Cisplatin nanoparticles exhibited in vitro anticancer activity against A549 cells comparable to that of cisplatin solution. The biodistribution study in mice indicated that the kidney cisplatin level was significantly (p < 0.01) lower with cisplatin nanoparticles than cisplatin solution. Following two cycles of cisplatin treatment, a week apart, blood urea nitrogen level was found to be higher in case of cisplatin solution as compared to cisplatin nanoparticles. Further, there was a significant (p < 0.01) increase in plasma creatinine level in case of cisplatin solution as compared to cisplatin nanoparticles. Histopathological examination of kidney from cisplatin nanoparticles treated group revealed no kidney damage, however, a sign of nephrotoxicity was observed in the case of cisplatin solution. The results suggest that PLGA nanoparticle based formulation could be a potential option for cisplatin delivery. - Highlights: • Cisplatin is detected by LCMS following complexation with DDTC. • Nanoparticles showed lower cisplatin accumulation in the kidney. • Nephrotoxicity was evaluated by BUN and creatinine level and by histopathology. • Nanoparticles exhibited lower nephrotoxicity.

  4. Knockdown of retinoblastoma protein may sensitize glioma cells to cisplatin through inhibition of autophagy.

    Science.gov (United States)

    Liu, Xiangyu; Sun, Kangjian; Wang, Handong; Dai, Yuyuan

    2016-05-01

    Glioblastoma multiforme (GBM) is one of the deadliest forms of cancer due to its limited sensitivity to chemotherapy and radiotherapy. Cisplatin (CCDP) is a widely used chemotherapeutic agent for tumors, but the agent often results in the development of chemo-resistance. In several cancers, cisplatin resistance is associated with autophagy induction. Here, we found that in glioma cells cisplatin treatment induced autophagy. Our data indicates that the autophagy induction plays a critical role in cisplatin resistance of glioma cells, knockdown of RB inhibited autophagy induced by cisplatin, and inhibition of autophagy improved cisplatin-induced apoptosis. It suggests that a combination of autophagy inhibitors with cisplatin may improve the therapeutic efficiency of cisplatin towards GBM with acquired resistance. PMID:27048711

  5. Antitumorigenic Evaluation of Thalidomide Alone and in Combination with Cisplatin in DBA2/J Mice

    Directory of Open Access Journals (Sweden)

    Jean Marie B. Ruddy

    2002-01-01

    thalidomide failed to inhibit cell proliferation. However, cisplatin treatment with or without thalidomide, significantly inhibited the multiplication of both cell lines in a dose dependent manner. Thalidomide does not appear to be a beneficial adjuvant to cisplatin treatment.

  6. Prognostic value of serum leptin in advanced lung adenocarcinoma patients with cisplatin/pemetrexed chemotherapy

    OpenAIRE

    MOU, WENJUN; Xue, Hui; TONG, HONGLI; Sun, Shengjie; Zhang, Zhuhong; Zhang, Chunyan; Sun, Qiyu; Dong, Jing; Wen, Xinyu; YAN, GUANGTAO; Tian, Yaping

    2014-01-01

    Cisplatin/pemetrexed chemotherapy has been established as a standard treatment in lung adenocarcinoma. However, the response to the cisplatin/pemetrexed combination varies considerably among patients due to individual variations. Thus, novel biomarkers are required to aid the prediction of the response to the cisplatin/pemetrexed combination. We hypothesized that leptin expression may be a determinant for prognosis in lung adenocarcinoma patients with cisplatin/pemetrexed chemotherapy. Serum ...

  7. Pretreatment with Darbepoetin Attenuates Renal Injury in a Rat Model of Cisplatin-Induced Nephrotoxicity

    OpenAIRE

    Choi, Dae Eun; Jeong, Jin Young; Lim, Beom Jin; Lee, Kang Wook; Shin, Young-Tai; Na, Ki-Ryang

    2009-01-01

    Background/Aims Darbepoetin alfa (DPO) exhibits comparable renoprotective effects to erythropoietin (EPO) in several animal models of acute renal injury. We examined whether DPO also attenuated renal injury in a rat model of cisplatin nephrotoxicity. Methods Male Spague-Dawley rats were divided into four groups: untreated, DPO-treated, cisplatin-injected, and DPO-treated cisplatin-injected. DPO pretreatment was conducted 24 hours after and just before cisplatin administration. Ninety-six hour...

  8. Targeting Gb3 and apoptosis-related proteins to overcome cisplatin resistance

    OpenAIRE

    Tyler, Andreas

    2016-01-01

    Background Cisplatin is used for treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC) but treatment with cisplatin often leads to acquired resistance to cisplatin, resulting in poor patient survival. Globotriaosylceramide (Gb3) and multidrug resistance protein 1 (MDR1) have been associated with cisplatin resistance. Gb3 serves as a receptor for verotoxin-1 (VT-1), which induces apoptosis, and has been shown to have a functional dependency to MDR1 and heat s...

  9. Theoretical study of cisplatin adsorption on silica

    Energy Technology Data Exchange (ETDEWEB)

    Simonetti, S., E-mail: ssimonet@uns.edu.ar [Departamento de Fisica and IFISUR, Universidad Nacional del Sur-CONICET, Av. Alem 1253, 8000 Bahia Blanca (Argentina); Departamentos de Ciencias Basicas e Ingenieria Mecanica, Universidad Tecnologica Nacional, 11 de Abril 461, 8000 Bahia Blanca (Argentina); Company, A. Diaz; Brizuela, G.; Juan, A. [Departamento de Fisica and IFISUR, Universidad Nacional del Sur-CONICET, Av. Alem 1253, 8000 Bahia Blanca (Argentina)

    2011-11-15

    The adsorption of cisplatin and its complexes, cis-[PtCl(NH{sub 3}){sub 2}]{sup +} and cis-[Pt(NH{sub 3}){sub 2}]{sup 2+}, on a SiO{sub 2}(1 1 1) hydrated surface has been studied by the Atom Superposition and Electron Delocalization method. The adiabatic energy curves for the adsorption of the drug and its products on the delivery system were considered. The electronic structure and bonding analysis were also performed. The molecule-surface interactions are formed at expenses of the OH surface bonds. The more important interactions are the Cl-H bond for cis-[PtCl{sub 2}(NH{sub 3}){sub 2}] and cis-[PtCl(NH{sub 3}){sub 2}]{sup +} adsorptions, and the Pt-O interaction for cis-[Pt(NH{sub 3}){sub 2}]{sup 2+} adsorption. The Cl p orbitals and Pt s, p y d orbitals of the molecule and its complexes, and the s H orbital and, the s and p orbitals of the O atoms of the hydrated surface are the main contribution to the surface bonds.

  10. Cisplatin inhibits bone healing during distraction osteogenesis.

    Science.gov (United States)

    Stine, Kimo C; Wahl, Elizabeth C; Liu, Lichu; Skinner, Robert A; Vanderschilden, Jacquelyn; Bunn, Robert C; Montgomery, Corey O; Suva, Larry J; Aronson, James; Becton, David L; Nicholas, Richard W; Swearingen, Christopher J; Lumpkin, Charles K

    2014-03-01

    Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five-dose CDP regimen (2 mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (p CDP regimen were observed in TNFR1KO mice. The two-dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP. PMID:24259375

  11. Structural changes of linear DNA molecules induced by cisplatin

    International Nuclear Information System (INIS)

    Interaction between long DNA molecules and activated cisplatin is believed to be crucial to anticancer activity. However, the exact structural changes of long DNA molecules induced by cisplatin are still not very clear. In this study, structural changes of long linear double-stranded DNA (dsDNA) and short single-stranded DNA (ssDNA) induced by activated cisplatin have been investigated by atomic force microscopy (AFM). The results indicated that long DNA molecules gradually formed network structures, beads-on-string structures and their large aggregates. Electrostatic and coordination interactions were considered as the main driving forces producing these novel structures. An interesting finding in this study is the beads-on-string structures. Moreover, it is worth noting that the beads-on-string structures were linked into the networks, which can be ascribed to the strong DNA–DNA interactions. This study expands our knowledge of the interactions between DNA molecules and cisplatin. - Highlights: • We investigate structural changes of dsDNA and ssDNA induced by cisplatin. • AFM results indicated long dsDNA formed network, beads-on-string and aggregates. • ssDNA can form very similar structures as those of long linear dsDNA. • A possible formation process of theses novel structure is proposed

  12. DNA-crosslinker cisplatin eradicates bacterial persister cells.

    Science.gov (United States)

    Chowdhury, Nityananda; Wood, Thammajun L; Martínez-Vázquez, Mariano; García-Contreras, Rodolfo; Wood, Thomas K

    2016-09-01

    For all bacteria, nearly every antimicrobial fails since a subpopulation of the bacteria enter a dormant state known as persistence, in which the antimicrobials are rendered ineffective due to the lack of metabolism. This tolerance to antibiotics makes microbial infections the leading cause of death worldwide and makes treating chronic infections, including those of wounds problematic. Here, we show that the FDA-approved anti-cancer drug cisplatin [cis-diamminodichloroplatinum(II)], which mainly forms intra-strand DNA crosslinks, eradicates Escherichia coli K-12 persister cells through a growth-independent mechanism. Additionally, cisplatin is more effective at killing Pseudomonas aeruginosa persister cells than mitomycin C, which forms inter-strand DNA crosslinks, and cisplatin eradicates the persister cells of several pathogens including enterohemorrhagic E. coli, Staphylococcus aureus, and P. aeruginosa. Cisplatin was also highly effective against clinical isolates of S. aureus and P. aeruginosa. Therefore, cisplatin has broad spectrum activity against persister cells. Biotechnol. Bioeng. 2016;113: 1984-1992. © 2016 Wiley Periodicals, Inc. PMID:26914280

  13. Mass spectrometric studies on the interaction of cisplatin and insulin.

    Science.gov (United States)

    Li, Jing; Yue, Lei; Liu, Yaqin; Yin, Xinchi; Yin, Qi; Pan, Yuanjiang; Yang, Lirong

    2016-04-01

    The interaction of antitumor drug, cisplatin (cis-[PtCl2(NH3)2], CDDP) with insulin from porcine pancreas has been investigated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and high resolution hybrid ion trap/time-of-flight mass spectrometry (MALIDI-TOF/TOF-MS and ESI-IT/TOF MS). The MALDI-TOF/TOF-MS results demonstrated that the presence of cisplatin complex resulted in the reduction of the disulfide bond in porcine pancreas after the incubations of the two substances were performed in vitro. It indicated that the presence of cisplatin would destroy the native configuration of insulin, which may lead to the inactivation of insulin. High resolution mass values and the characteristic isotopic pattern of the platinated insulin ions allowed the analysis of platinated mono-, di- and triadducts of cisplatin and insulin in the incubations under different conditions. The laser-induced dissociation of the monoadduct obtained in MALDI source was carried out and one platinum was found to bind to insulin B chain was determined. The platinum binding sites were further identified to be the N terminus (B chain), cysteine 7 (B chain) and cysteine 19 (B chain) residues by electrospray ionization tandem mass spectrometry. The identification of the interaction between insulin and cisplatin broadens the horizon of the knowledge in the interaction of the proteins and metallodrugs. PMID:26724920

  14. Cisplatin and radiation: Interaction probabilities and therapeutic possibilities

    International Nuclear Information System (INIS)

    This paper examines the probability of interactions occurring between drug lesions and radiation lesions in DNA for the cytotoxic and radiosensitizing agent cisplatin. The number of cisplatin-induced DNA adducts and radiation-induced strand breaks after a given dose of each agent are known for given cell systems, from which the probability that these lesions will interact can be estimated. Results of these calculations indicate that the probability of interaction could be high, depending on the distance over which two lesions can interact and the probability of repair of the interaction lesion. Calculated lesion numbers have been compared with known data on radiation modification, including illustrations of inconsistencies. In the second part of the paper, ways in which combined therapy with cisplatin and radiation can be improved are described. Development of methods to predict which types of tumor and which individual tumors within a given type are sensitive to the cytotoxic and radiosensitizing effects of the drug would aid rational selection of patients for combination treatments. Immunocytochemical methods sensitive enough to monitor cisplatin-DNA interactions in patients are available and may be useful in this context. The delivery and maintenance of higher tumor concentrations of radiosensitizer offers a further possibility for improvement. Studies of intratumoral injection of cisplatin have shown promise for achieving this goal while limiting normal tissue toxicity.46 references

  15. Structural damage of chicken red blood cells exposed to platinum nanoparticles and cisplatin

    DEFF Research Database (Denmark)

    Kutwin, Marta; Sawosz, Ewa; Jaworski, Sławomir; Kurantowicz, Natalia; Strojny, Barbara; Chwalibog, André

    2014-01-01

    platinum nanoparticles (NP-Pt) and cisplatin with blood compartments are important for future applications. This study investigated structural damage, cell membrane deformation and haemolysis of chicken embryo red blood cells (RBC) after treatment with cisplatin and NP-Pt. Cisplatin (4 μg/ml) and NP-Pt (2...

  16. Infrasound sensitizes human glioblastoma cells to cisplatin-induced apoptosis.

    Science.gov (United States)

    Rachlin, Kenneth; Moore, Dan H; Yount, Garret

    2013-11-01

    The development of nontoxic agents that can selectively enhance the cytotoxicity of chemotherapy is an important aim in oncology. This study evaluates the ability of infrasound exposure to sensitize glioblastoma cells to cisplatin-induced apoptosis. The infrasound was delivered using a device designed to replicate the unique infrasound emissions measured during external Qigong treatments. Human glioblastoma cell lines harboring wild-type p53 (U87) or mutant p53 (U251, SF210, and SF188) were treated in culture with cisplatin, infrasound emissions, or the combination of the 2 agents. Induction of apoptosis was quantified after 24 hours by flow cytometry following annexin V/propidium iodide staining. Infrasound emissions alone, delivered at moderate levels (~10 mPa) with dynamic frequency content (7-13 Hz), did not induce apoptosis, yet combining infrasound with cisplatin augmented the induction of apoptosis by cisplatin in all the 4 cell lines (P infrasound exposure was quantified by fluorescence microscopy as well as flow cytometry, demonstrating increased cell membrane permeability. The 4 cell lines differed in the degree to which infrasound exposure increased calcein uptake, and these differences were predictive of the extent to which infrasound enhanced cisplatin-induced apoptosis. When exposed to specific frequencies, membrane permeabilization also appeared to be differentially responsive for each cell line, suggesting the potential for selective targeting of tissue types using isolated infrasonic frequencies. Additionally, the pressure amplitudes used in this study were several orders of magnitude less than those used in similar studies involving ultrasound and shock waves. The results of this study provide support for using infrasound to enhance the chemotherapeutic effects of cisplatin in a clinical setting. PMID:23165942

  17. EFFECT OF ANTHOCYANIN FRACTION ON CISPLATIN-INDUCED NEPHROTOXICITY

    OpenAIRE

    Adikay Sreedevi; Belide Pavani

    2012-01-01

    Present study was designed to evaluate the effect of anthocyanin fraction of Syzygium cumini on cisplatin-induced nephrotoxicity in male Albino rats. Anthocyanin fraction was administered by gastric intubation at two dose levels. Animals were divided into 5 groups. Group I animals received vehicle. On day 1, Group II animals received cisplatin (6 mg/kg, i,p., single dose). Group III (7.5mg/kg) and IV (15mg/kg) received anthocyanin fraction respectively at 1 hr before, 24 hr and 48 hr after ci...

  18. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats

    OpenAIRE

    Ko, Je-Won; Lee, In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-01-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological al...

  19. Quantitative strategies to determine cisplatin adducts with DNA nucleotides in drosofila larvae and tumoral cell cultures

    International Nuclear Information System (INIS)

    Full text: The antitumoral effect of cisplatin [cis-diamminodichloroplatinum(II)] in mammals is related to its binding to DNA components. A novel sensitive and selective method is proposed to quantify cisplatin-DNA adducts induced in vivo in somatic cells of Drosophila melanogaster at biologically relevant concentrations. The method uses HPLC-ICPMS in combination with species-specific isotope dilution analysis (cisplatin enriched in 194Pt). For the first time, a cisplatin-DNA adduct is quantified by this approach. The obtained results show the great potential of this system to advance our molecular understanding of the biological effects of cisplatin. (author)

  20. Induction chemotherapy with docetaxel, cisplatin and S-1 followed by proton beam therapy concurrent with cisplatin in patients with T4b nasal and sinonasal malignancies

    International Nuclear Information System (INIS)

    For the treatment of patients with T4b nasal and sinonasal malignancies, definitive chemoradiotherapy was contraindicated due to the risk of brain damage and blindness. However, combination chemotherapy with docetaxel, cisplatin and S-1 is well tolerated and effective. We conducted a retrospective analysis to evaluate the efficacy and feasibility of induction chemotherapy using docetaxel, cisplatin and S-1 followed by proton beam therapy concurrent with cisplatin. Thirteen patients treated with docetaxel, cisplatin and S-1 were analyzed. Docetaxel, cisplatin and S-1 consisted of 60-70 mg/m2/day docetaxel on day 1, 70 mg/m2/day cisplatin on day 1 and 60-80 mg/m2/day S-1 on days 1-14. Treatment was repeated every 3-4 weeks with a maximum number of three treatment cycles. According to the response to docetaxel, cisplatin and S-1, patients received either proton beam therapy concurrent with 20 mg/m2/day cisplatin on days 1-4 every 3 weeks or proton beam therapy alone. Neutropenia represented the most common Grade 3/4 hematological toxicity (76.9%), while the most frequently observed non-hematological toxicity was nausea (23.0%). After the completion of docetaxel, cisplatin and S-1, the overall response rate was 38.4% (5 of 13), with 1 patient achieving complete response and 4 patients achieving partial response. Subsequently, 10 patients received proton beam therapy concurrent with cisplatin, 2 received proton beam therapy alone and 1 received palliative radiation. No severe toxicity was observed during proton beam therapy. After the completion of proton beam therapy, 11 patients (84.6%) achieved complete response and no brain damage or blindness occurred. Induction chemotherapy with docetaxel, cisplatin and S-1 followed by proton beam therapy concurrent with cisplatin is well tolerated and displays promising antitumor activity that warrants further investigation. (author)

  1. Preparation and stability of lipid-coated nanocapsules of cisplatin: anionic phospholipid specificity.

    Science.gov (United States)

    Velinova, Maria J; Staffhorst, Rutger W H M; Mulder, Willem J M; Dries, Arno S; Jansen, Bart A J; de Kruijff, Ben; de Kroon, Anton I P M

    2004-05-27

    Cisplatin nanocapsules represent a novel lipid formulation of the anti-cancer drug cis-diamminedichloroplatinum(II) (cisplatin), in which nanoprecipitates of cisplatin are coated by a phospholipid bilayer consisting of a 1:1 mixture of zwitterionic phosphatidylcholine (PC) and negatively charged phosphatidylserine (PS). Cisplatin nanocapsules are characterized by an unprecedented cisplatin-to-lipid ratio and exhibit increased in vitro cytotoxicity compared to the free drug [Nat. Med. 8, (2002) 81]. In the present study, the stability of the cisplatin nanocapsules was optimized by varying the lipid composition of the bilayer coat and monitoring in vitro cytotoxicity and the release of contents during incubations in water and in mouse serum. The release of cisplatin from the PC/PS (1:1) nanocapsules in water increased with increasing temperature with a t(1/2) of 6.5 h at 37 degrees C. At 4 degrees C, cisplatin was retained in the nanocapsules for well over 8 days. Replacement of PS by either phosphatidylglycerol or phosphatidic acid revealed that nanocapsules prepared of PS were more stable, which was found to be due to the ability of PS to form a stable cisplatin-PS coordination complex. Mouse serum had a strong destabilizing effect on the cisplatin nanocapsules. The PC/PS formulation lost over 80% of cisplatin within minutes after resuspension in serum. Incorporation of poly(ethylene glycol 2000) (PEG)-derivatized phosphatidylethanolamine and cholesterol in the bilayer coat extended the lifetime of the cisplatin nanocapsules in mouse serum to almost an hour. The results demonstrate that specificity in the interaction of cisplatin with anionic phospholipids is an important criterium for the formation and stability of cisplatin nanocapsules. PMID:15157616

  2. Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line

    Directory of Open Access Journals (Sweden)

    Zhang Ping

    2006-09-01

    Full Text Available Abstract Background Cisplatin is widely used for chemotherapy of head and neck squamous cell carcinoma. However, details of the molecular mechanism responsible for cisplatin resistance are still unclear. The aim of this study was to identify the expression of genes related to cisplatin resistance in oral squamous cell carcinoma cells. Methods A cisplatin-resistant cell line, Tca/cisplatin, was established from a cisplatin-sensitive cell line, Tca8113, which was derived from moderately-differentiated tongue squamous cell carcinoma. Global gene expression in this resistant cell line and its sensitive parent cell line was analyzed using Affymetrix HG-U95Av2 microarrays. Candidate genes involved in DNA repair, the MAP pathway and cell cycle regulation were chosen to validate the microarray analysis results. Cell cycle distribution and apoptosis following cisplatin exposure were also investigated. Results Cisplatin resistance in Tca/cisplatin cells was stable for two years in cisplatin-free culture medium. The IC50 for cisplatin in Tca/cisplatin was 6.5-fold higher than that in Tca8113. Microarray analysis identified 38 genes that were up-regulated and 25 that were down-regulated in this cell line. Some were novel candidates, while others are involved in well-characterized mechanisms that could be relevant to cisplatin resistance, such as RECQL for DNA repair and MAP2K6 in the MAP pathway; all the genes were further validated by Real-time PCR. The cell cycle-regulated genes CCND1 and CCND3 were involved in cisplatin resistance; 24-hour exposure to 10 μM cisplatin induced a marked S phase block in Tca/cisplatin cells but not in Tca8113 cells. Conclusion The Tca8113 cell line and its stable drug-resistant variant Tca/cisplatin provided a useful model for identifying candidate genes responsible for the mechanism of cisplatin resistance in oral squamous cell carcinoma. Our data provide a useful basis for screening candidate targets for early diagnosis

  3. Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line

    International Nuclear Information System (INIS)

    Cisplatin is widely used for chemotherapy of head and neck squamous cell carcinoma. However, details of the molecular mechanism responsible for cisplatin resistance are still unclear. The aim of this study was to identify the expression of genes related to cisplatin resistance in oral squamous cell carcinoma cells. A cisplatin-resistant cell line, Tca/cisplatin, was established from a cisplatin-sensitive cell line, Tca8113, which was derived from moderately-differentiated tongue squamous cell carcinoma. Global gene expression in this resistant cell line and its sensitive parent cell line was analyzed using Affymetrix HG-U95Av2 microarrays. Candidate genes involved in DNA repair, the MAP pathway and cell cycle regulation were chosen to validate the microarray analysis results. Cell cycle distribution and apoptosis following cisplatin exposure were also investigated. Cisplatin resistance in Tca/cisplatin cells was stable for two years in cisplatin-free culture medium. The IC50 for cisplatin in Tca/cisplatin was 6.5-fold higher than that in Tca8113. Microarray analysis identified 38 genes that were up-regulated and 25 that were down-regulated in this cell line. Some were novel candidates, while others are involved in well-characterized mechanisms that could be relevant to cisplatin resistance, such as RECQL for DNA repair and MAP2K6 in the MAP pathway; all the genes were further validated by Real-time PCR. The cell cycle-regulated genes CCND1 and CCND3 were involved in cisplatin resistance; 24-hour exposure to 10 μM cisplatin induced a marked S phase block in Tca/cisplatin cells but not in Tca8113 cells. The Tca8113 cell line and its stable drug-resistant variant Tca/cisplatin provided a useful model for identifying candidate genes responsible for the mechanism of cisplatin resistance in oral squamous cell carcinoma. Our data provide a useful basis for screening candidate targets for early diagnosis and further intervention in cisplatin resistance

  4. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Sun Yunguang [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zheng Siyuan [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J. [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Carbone, David P. [Department of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zhao Zhongming, E-mail: zhongming.zhao@vanderbilt.edu [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Lu Bo, E-mail: bo.lu@vanderbilt.edu [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States)

    2012-03-01

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  5. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    International Nuclear Information System (INIS)

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non–small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  6. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.

    NARCIS (Netherlands)

    Vermorken, J.B.; Remenar, E.; Herpen, C.M.L. van; Gorlia, T.; Mesia, R.; Degardin, M.; Stewart, J.S.; Jelic, S.; Betka, J.; Preiss, J.H.; Weyngaert, D. van den; Awada, A.; Cupissol, D.; Kienzer, H.R.; Rey, A.; Desaunois, I.; Bernier, J.; Lefebvre, J.L.

    2007-01-01

    BACKGROUND: Phase 2 studies suggest that the standard regimen of cisplatin and fluorouracil (PF) plus docetaxel (TPF) improves outcomes in squamous-cell carcinoma of the head and neck. We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced, unresectable disease. M

  7. Nebivolol Ameliorates Cisplatin-Induced Nephrotoxicity in Rats.

    Science.gov (United States)

    Morsy, Mohamed A; Heeba, Gehan H

    2016-06-01

    Treatment with cisplatin is associated with dose-limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a β1 -adrenoceptor antagonist, exhibits vasodilatory and antioxidative properties. This study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as demonstrated by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor-alpha, caspase-3, angiotensin II and endothelin-1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre-treatment with Nω -nitro-L-arginine methyl ester, the non-specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin-induced nephrotoxicity that is most likely through its antioxidant, anti-inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin-1 levels. PMID:26617394

  8. DSC Study on Brain Tubulin and the Effect of Cisplatin

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The thermal property of the polymerization of brain tubulin was studied by a high-sensitivity differential scanning calorimeter. The phenomenon that heat flows increased and decreased consistently and obviously was observed. This phenomenon was called heat flow oscillation. It was probably correlated to the dynamic instability of microtubules. The effect of cisplatin on it was reported, too.

  9. Stability, accumulation and cytotoxicity of an albumin-cisplatin adduct

    DEFF Research Database (Denmark)

    Møller, Charlotte; Tastesen, Hanne Sørup; Gammelgaard, Bente;

    2010-01-01

    The accumulation and cytotoxicity of a 10 µmol L¿¹ equimolar human serum albumin-cisplatin adduct (HSA-Pt) was investigated in suspension Ehrlich Ascites Tumor Cells (EATC) and adherent Ehrlich Lettré Ascites Cells (Lettré). HSA-Pt did not induce apoptosis nor was it taken up by the cells to any...

  10. Electroacupuncture alleviates cisplatin-induced nausea in rats

    Science.gov (United States)

    Cui, Yingxue; Wang, Linpeng; Shi, Guangxia; Liu, Lu; Pei, Pei; Guo, Jianyou

    2016-01-01

    Objective Acupuncture has been shown to be effective for the treatment of chemotherapy-related nausea and vomiting. The aim of this study was to explore the mechanisms of action underlying the anti-emetic effect of electroacupuncture (EA). Design Forty-eight rats received saline (n=12) or 6 mg/kg cisplatin (n=36) to establish a chemotherapy-induced nausea and vomiting model. EA was performed at CV12 (n=12), bilateral PC6 (n=12), or sham points (n=12) 3 days before and 1–2 days after cisplatin administration (4–5 times in total), at 0.5–1 mA intensity and 2/15 Hz frequency for 10 min. Kaolin intake, food intake and bodyweight change were evaluated as markers of nausea and vomiting severity. Concentrations of serotonin (5-hydroxytryptamine, 5-HT) in the duodenum and c-Fos expression in the nucleus of the solitary tract (NTS) were measured using high performance liquid chromatography and immunohistochemistry, respectively. Results Cisplatin administration led to increased kaolin intake and reduced food intake and bodyweight over the following 2 days. EA at CV12 significantly reversed the cisplatin-induced change in kaolin intake (on days 1 and 2) and food intake and bodyweight (on day 1). EA at CV12 also attenuated the cisplatin-induced increase in 5-HT in the duodenum and suppressed c-Fos expression in the NTS. EA at PC6 influenced kaolin intake (on day 1 only) and c-Fos expression, but had no statistically significant effect on food intake, bodyweight or 5-HT expression. Conclusions This study demonstrated beneficial effects of EA on chemotherapy-induced nausea and vomiting in a rat model. The anti-emetic effect of EA may be mediated through inhibition of 5-HT secretion in the duodenum and activity of the NTS. PMID:26386034

  11. Determination of free cisplatin in medium by differential pulse polarography after ultrasound and cisplatin treatment of a cancer cell culture

    Czech Academy of Sciences Publication Activity Database

    Bernard, V.; Fojt, Lukáš; Škorpíková, J.; Mornstein, V.

    2011-01-01

    Roč. 48, č. 1 (2011), s. 59-62. ISSN 0301-1208 R&D Projects: GA ČR(CZ) GAP205/10/2378 Keywords : Cisplatin * Differential pulse polarography * Ovarian carcinoma cells A2780 Subject RIV: BO - Biophysics Impact factor: 1.142, year: 2011

  12. Protective effect of metalloporphyrins against cisplatin-induced kidney injury in mice.

    Directory of Open Access Journals (Sweden)

    Hao Pan

    Full Text Available Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins (FeTMPyP and MnTBAP, water soluble complexes, in cisplatin-induced renal damage and their ability to scavenge peroxynitrite. In cisplatin-induced nephropathy study in mice, renal nitrative stress was evident by the increase in protein nitration. Cisplatin-induced nephrotoxicity was also evident by the histological damage from the loss of the proximal tubular brush border, blebbing of apical membranes, tubular epithelial cell detachment from the basement membrane, or intra-luminal aggregation of cells and proteins and by the increase in blood urea nitrogen and serum creatinine. Cisplatin-induced apoptosis and cell death as shown by Caspase 3 assessments, TUNEL staining and DNA fragmentation Cisplatin-induced nitrative stress, apoptosis and nephrotoxicity were attenuated by both metalloporphyrins. Heme oxygenase (HO-1 also plays a critical role in metalloporphyrin-mediated protection of cisplatin-induced nephrotoxicity. It is evident that nitrative stress plays a critical role in cisplatin-induced nephrotoxicity in mice. Our data suggest that peroxynitrite is involved, at least in part, in cisplatin-induced nephrotoxicity and protein nitration and cisplatin-induced nephrotoxicity can be prevented with the use of metalloporphyrins.

  13. Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice

    International Nuclear Information System (INIS)

    Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice. HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of 3 edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Anticancer effects of HemoHIM with cisplatin were evaluated in melanoma-bearing mice. We used a Cr51-release assay to measure the activity of NK/Tc cell and ELISA to evaluate the production of cytokines. In melanoma-bearing mice, cisplatin (4 mg/kg B.W.) reduced the size and weight of the solid tumors, and HemoHIM supplementation with cisplatin enhanced the decrease of both the tumor size (p < 0.1) and weight (p < 0.1). HemoHIM itself did not inhibit melanoma cell growth in vitro, and did not disturb the effects of cisplatin in vitro. However HemoHIM administration enhanced both NK cell and Tc cell activity in mice. Interestingly, HemoHIM increased the proportion of NK cells in the spleen. In melanoma-bearing mice treated with cisplatin, HemoHIM administration also increased the activity of NK cells and Tc cells and the IL-2 and IFN-γ secretion from splenocytes, which seemed to contribute to the enhanced efficacy of cisplatin by HemoHIM. Also, HemoHIM reduced nephrotoxicity as seen by tubular cell of kidney destruction. HemoHIM may be a beneficial supplement during cisplatin chemotherapy for enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin

  14. Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    Kim Sung-Ho

    2009-03-01

    Full Text Available Abstract Background Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice. Methods HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of 3 edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Anticancer effects of HemoHIM with cisplatin were evaluated in melanoma-bearing mice. We used a Cr51-release assay to measure the activity of NK/Tc cell and ELISA to evaluate the production of cytokines. Results In melanoma-bearing mice, cisplatin (4 mg/kg B.W. reduced the size and weight of the solid tumors, and HemoHIM supplementation with cisplatin enhanced the decrease of both the tumor size (p in vitro, and did not disturb the effects of cisplatin in vitro. However HemoHIM administration enhanced both NK cell and Tc cell activity in mice. Interestingly, HemoHIM increased the proportion of NK cells in the spleen. In melanoma-bearing mice treated with cisplatin, HemoHIM administration also increased the activity of NK cells and Tc cells and the IL-2 and IFN-γ secretion from splenocytes, which seemed to contribute to the enhanced efficacy of cisplatin by HemoHIM. Also, HemoHIM reduced nephrotoxicity as seen by tubular cell of kidney destruction. Conclusion HemoHIM may be a beneficial supplement during cisplatin chemotherapy for enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin.

  15. Overexpression of long non-coding RNA PVT1 in ovarian cancer cells promotes cisplatin resistance by regulating apoptotic pathways

    OpenAIRE

    Liu, Enling; Liu, Zheng; Zhou, Yuxiu; MI, RUORAN; Wang, Dehua

    2015-01-01

    Ovarian cancer is the most lethal gynecologic malignancy. Cisplatin is a very effective cancer chemotherapy drug, but cisplatin resistance is a crucial problem of therapy failure. Overexpression of PVT1 has been demonstrated in ovarian cancer. The mRNA level of PVT1 in ovarian cancer tissues of cisplatin-resistant patients and cisplatin-sensitive patients, cisplatin-resistant cells SKOV-3/DDP and A2780/DDP, cisplatin-sensitive cells SKOV-3 and A2780 were determined by qRT-PCR. The influence o...

  16. Cisplatin induces Bmi-1 and enhances the stem cell fraction in head and neck cancer.

    Science.gov (United States)

    Nör, Carolina; Zhang, Zhaocheng; Warner, Kristy A; Bernardi, Lisiane; Visioli, Fernanda; Helman, Joseph I; Roesler, Rafael; Nör, Jacques E

    2014-02-01

    Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs). These unique cells, named here cancer stem cells (CSCs), proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6)] for their survival and self-renewal in HNSCC. Here, we hypothesized that cisplatin enhances the stem cell fraction in HNSCC. To address this hypothesis, we generated xenograft HNSCC tumors with University of Michigan-squamous cell carcinoma 22B (UM-SCC-22B) cells and observed that cisplatin treatment increased (P = .0013) the fraction of CSCs [i.e., aldehyde dehydrogenase activity high and cluster of differentiation 44 high (ALDH(high)CD44(high))]. Cisplatin promoted self-renewal and survival of CSCs in vitro, as seen by an increase in the number of orospheres in ultralow attachment plates and induction in B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) and octamer-binding transcription factor 4 expression. Cisplatin-resistant cells expressed more Bmi-1 than cisplatin-sensitive cells. IL-6 potentiated cisplatin-induced orosphere formation generated when primary human HNSCC cells were sorted for ALDH(high)CD44(high) immediately after surgery and plated onto ultralow attachment plates. IL-6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation (indicative of stemness) was unaffected by treatment with cisplatin in UM-SCC-22B cells, whereas IL-6-induced extracellular signal-regulated kinase (ERK) phosphorylation (indicative of differentiation processes) was partially inhibited by cisplatin. Notably, cisplatin-induced Bmi-1 was inhibited by interleukin-6 receptor blockade in parental and cisplatin-resistant cells. Taken together, these results demonstrate that cisplatin enhances the fraction of CSCs

  17. Protective effects of ghrelin on cisplatin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Nojiri, Takashi; Hosoda, Hiroshi; Kimura, Toru; Tokudome, Takeshi; Miura, Koichi; Takabatake, Hiroyuki; Miyazato, Mikiya; Okumura, Meinoshin; Kangawa, Kenji

    2016-08-01

    Cisplatin is a potent chemotherapeutic agent that has activity against malignant tumors. However, cisplatin causes various adverse effects, such as nephrotoxicity, which are associated with high morbidity and mortality. Recent studies have revealed that the mechanism of cisplatin nephrotoxicity includes a robust inflammatory response. Since ghrelin has been shown to have anti-inflammatory properties, we hypothesized that ghrelin might have protective effects against cisplatin nephrotoxicity. Mice were randomly divided into three groups: control, cisplatin with vehicle, and cisplatin with ghrelin. Ghrelin (0.8μg/kg/min via osmotic-pump, subcutaneously) or vehicle administration was started one day before cisplatin injection. At 72h after cisplatin administration (20mg/kg, intraperitoneally), we measured serum blood urea nitrogen and creatinine, urine albumin/creatinine, renal mRNA levels of monocyte chemoattractant protein-1, interleukin-6, tumor necrosis factor-α, interleukin-1β, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin by real-time polymerase chain reaction, and histological changes. Ghrelin significantly attenuated the increase in serum blood urea nitrogen and creatinine induced by cisplatin. Ghrelin tended to attenuate the increase in urine albumin/creatinine, although not significantly. Cisplatin-induced renal tubular injury and apoptosis were significantly attenuated by ghrelin pretreatment. Consequently, ghrelin significantly attenuated renal mRNA levels of monocyte chemoattractant protein-1, interleukin-6, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin. In conclusion, ghrelin produces protective effects in cisplatin-induced nephrotoxicity through inhibition of inflammatory reactions. Pretreatment with ghrelin may become a new prophylactic candidate for cisplatin-induced nephrotoxicity. PMID:27298204

  18. Evaluating the various phases of cisplatin-induced emesis in rats

    OpenAIRE

    Shi, Jun

    2014-01-01

    Use of cisplatin as a chemotherapeutic agent causes acute and delayed emesis. Kaolin, saccharin solution and normal feed consumption have been evaluated as an index of cisplatin-induced emesis in rats; however, the most preferable of these methods for evaluating the various phases of emesis remains unclear. In the current study, kaolin, saccharin solution and normal feed consumption following cisplatin administration (6 mg/kg intraperitoneally) were simultaneously investigated in rats. Kaolin...

  19. Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury.

    Science.gov (United States)

    Chen, Cheng-Lung; Liao, Jiunn-Wang; Hu, Oliver Yoa-Pu; Pao, Li-Heng

    2016-09-01

    Tubular cell apoptosis significantly contributes to cisplatin-induced acute kidney injury (AKI) pathogenesis. Although KCa3.1, a calcium-activated potassium channel, participates in apoptosis, its involvement in cisplatin-induced AKI is unknown. Here, we found that cisplatin treatment triggered an early induction of KCa3.1 expression associated with HK-2 cell apoptosis, the development of renal tubular damage, and apoptosis in mice. Treatment with the highly selective KCa3.1 blocker TRAM-34 suppressed cisplatin-induced HK-2 cell apoptosis. We further assessed whether KCa3.1 mediated cisplatin-induced AKI in genetic knockout and pharmacological blockade mouse models. KCa3.1 deficiency reduced renal function loss, renal tubular damage, and the induction of the apoptotic marker caspase-3 in the kidneys of cisplatin-treated KCa3.1 (-/-) mice. Pharmacological blockade of KCa3.1 by TRAM-34 similarly attenuated cisplatin-induced AKI in mice. Furthermore, we dissected the mechanisms underlying cisplatin-induced apoptosis reduction via KCa3.1 blockade. We found that KCa3.1 blockade attenuated cytochrome c release and the increase in the intrinsic apoptotic mediators Bax, Bak, and caspase-9 after cisplatin treatment. KCa3.1 blocking inhibited the cisplatin-induced activation of the endoplasmic reticulum (ER) stress mediator caspase-12, which is independent of calcium-dependent protease m-calpain activation. Taken together, KCa3.1 blockade protects against cisplatin-induced AKI through the attenuation of apoptosis by interference with intrinsic apoptotic and ER stress-related mediators, providing a potential target for the prevention of cisplatin-induced AKI. PMID:26438401

  20. Voluntary Exercise Prevents Cisplatin-Induced Muscle Wasting during Chemotherapy in Mice

    OpenAIRE

    Pernille Hojman; Jonas Fjelbye; Bo Zerahn; Jesper F Christensen; Christine Dethlefsen; Lonkvist, Camilla K.; Claus Brandt; Hanne Gissel; Bente Klarlund Pedersen; Julie Gehl

    2014-01-01

    Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight, food intake as well as muscle mass, strength and signalling. Mice were treated weekly with 4 mg/kg cisplatin or saline for 6 weeks, and randomized to voluntary wheel running or not. Cisplatin treatm...

  1. Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin and Other Platinum Complexes

    OpenAIRE

    Hall, Matthew D.; Telma, Katherine A.; Chang, Ki-Eun; Lee, Tobie D.; Madigan, James P.; Lloyd, John R.; Goldlust, Ian S.; Hoeschele, James D.; Gottesman, Michael M.

    2014-01-01

    The platinum drugs cisplatin, carboplatin and oxaliplatin are highly utilized in the clinic and as a consequence are extensively studied in the laboratory setting. In this study, we examined the literature and found a significant number of studies (11 - 34%) in prominent cancer journals utilizing cisplatin dissolved in dimethylsulfoxide (DMSO). However, dissolving cisplatin in DMSO for laboratory-based studies results in ligand displacement and changes the structure of the complex. We examine...

  2. Antioxidant effect of carnosine pretreatment on cisplatin-induced renal oxidative stress in rats

    OpenAIRE

    S. Noori; Mahboob, Tabassum

    2010-01-01

    Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species. Carnosine is a naturally occurring dipeptide and has a scavenging property. The aim of present study was to assess the lipid peroxidation and antioxidant enzymes in association with oxidative stress in cisplatin -treated and 10 subsequent doses of carnosine-pretreated rats. 24 male Albino Wistar rats, were randomly divided into four groups (n=6). Group I remains untreated; Group II received Cisplatin (3 mg ...

  3. The antioxidant and antigenotoxic effects of pycnogenol(®) on rats treated with cisplatin.

    Science.gov (United States)

    Aydin, Birsen; Unsal, Meftun; Sekeroglu, Zulal A; Gülbahar, Yavuz

    2011-09-01

    Oxidative stress and inflammation are implicated in the pathogenesis of cisplatin-induced toxicity. Pycnogenol® is known for its strong antioxidant and anti-inflammatory effects. In this study, the possible protective effects of pycnogenol on kidney, bone marrow, and red blood cells in rats treated with cisplatin were investigated. The rats were divided into four groups. Group 1 was the control and groups 2, 3, and 4 were orally treated with pycnogenol (200 mg/kg bw, o.p) for 5 days, treated with cisplatin (7 mg/kg bw, i.p.) on the fifth day and treated with cisplatin plus pycnogenol, respectively. Antioxidative parameters in kidney and red blood cells were measured. Chromosome anomalies in bone marrow and renal histopathology were also investigated. Activities of pro-oxidant enzymes (myeloperoxidase and xanthine oxidase), malondialdehyde, and nitric oxide levels significantly increased but antioxidant enzymes activities decreased in the kidneys and red blood cells after cisplatin treatment. Pycnogenol treatment prior to the administration of cisplatin significantly decreased cisplatin-induced injury, as evidenced by its normalizing these parameters. Chromosomal aberrations decreased and mitotic index frequencies increased in bone marrow treated with cisplatin plus pycnogenol. These findings suggest that pycnogenol may be a useful protective agent against the toxicity associated with cisplatin therapy. PMID:20676799

  4. Hydrogen sulfide: A novel nephroprotectant against cisplatin-induced renal toxicity.

    Science.gov (United States)

    Dugbartey, George J; Bouma, Hjalmar R; Lobb, Ian; Sener, Alp

    2016-07-01

    Cisplatin is a potent chemotherapeutic agent for the treatment of various solid-organ cancers. However, a plethora of evidence indicates that nephrotoxicity is a major side effect of cisplatin therapy. While the antineoplastic action of cisplatin is due to formation of cisplatin-DNA cross-links, which damage rapidly dividing cancer cells upon binding to DNA, its nephrotoxic effect results from metabolic conversion of cisplatin into a nephrotoxin and production of reactive oxygen species, causing oxidative stress leading to renal tissue injury and potentially, kidney failure. Despite therapeutic targets in several pre-clinical and clinical studies, there is still incomplete protection against cisplatin-induced nephrotoxicity. Hydrogen sulfide (H2S), the third discovered gasotransmitter next to nitric oxide and carbon monoxide, has recently been identified in several in vitro and in vivo studies to possess specific antioxidant, anti-inflammatory and anti-apoptotic properties that modulate several pathogenic pathways involved in cisplatin-induced nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and displays recent findings in the H2S field that could disrupt such mechanisms to ameliorate cisplatin-induced renal injury. PMID:27095538

  5. Nephroprotective effect of bee honey and royal jelly against subchronic cisplatin toxicity in rats.

    Science.gov (United States)

    Ibrahim, Abdelazim; Eldaim, Mabrouk A Abd; Abdel-Daim, Mohamed M

    2016-08-01

    Cisplatin is one of the most potent and effective chemotherapeutic agents. However, its antineoplastic use is limited due to its cumulative nephrotoxic side effects. Therefore, the present study was undertaken to examine the nephroprotective potential of dietary bee honey and royal jelly against subchronic cisplatin toxicity in rats. Male Wistar rats were randomly divided into controls, cisplatin-treated, bee honey-pretreated cisplatin-treated and royal jelly-pretreated cisplatin-treated groups. Bee honey and royal jelly were given orally at doses of 20 and 100 mg/kg, respectively. Subchronic toxicity was induced by cisplatin (1 mg/kg bw, ip), twice weekly for 10 weeks. Cisplatin treated animals revealed a significant increase in serum level of renal injury products (urea, creatinine and uric acid). Histopathologically, cisplatin produced pronounced tubulointerstitial injuries, upregulated the fibrogenic factors, α-smooth muscle actin (α-SMA) and transforming growth factor β1(TGF-β1), and downregulated the cell proliferation marker, bromodeoxyuridine (Brdu). Dietary bee honey and royal jelly normalized the elevated serum renal injury product biomarkers, improved the histopathologic changes, reduced the expression of α-SMA and TGF-β1 and increased the expression of Brdu. Therefore, it could be concluded that bee honey, and royal jelly could be used as dietary preventive natural products against subchronic cisplatin-induced renal injury. PMID:25720368

  6. Molecular mechanisms of cisplatin resistance in cervical cancer

    OpenAIRE

    Zhu, Xueqiong

    2016-01-01

    Haiyan Zhu, Hui Luo, Wenwen Zhang, Zhaojun Shen, Xiaoli Hu, Xueqiong Zhu Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China Abstract: Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to tr...

  7. Molecular mechanisms of cisplatin resistance in cervical cancer

    OpenAIRE

    Zhu H; Luo H; Zhang W; Shen Z; Hu X; Zhu X

    2016-01-01

    Haiyan Zhu, Hui Luo, Wenwen Zhang, Zhaojun Shen, Xiaoli Hu, Xueqiong Zhu Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China Abstract: Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the ...

  8. Cisplatin and derivatives with radiation therapy: for what clinical use?

    International Nuclear Information System (INIS)

    Since its discovery by Rosenberg in 1965, cisplatin and its derivatives have appeared as the most important chemotherapeutic agents, particularly for their radiosensitizing properties and their clinical use with radiation. In spite of numerous preclinical and clinical studies, optimal schedules of platin and radiotherapy combination have to be defined. The first part of this overview will describe biological mechanisms of interaction between radiation therapy and platinum derivatives. The second part will report the major clinical impact of their association. (author)

  9. Propofol depresses cisplatin cytotoxicity via the inhibition of gap junctions.

    Science.gov (United States)

    Zhang, Yuan; Wang, Xiyan; Wang, Qin; Ge, Hui; Tao, Liang

    2016-06-01

    The general anesthetic, propofol, affects chemotherapeutic activity, however, the mechanism underlying its effects remains to be fully elucidated. Our previous study showed that tramadol and flurbiprofen depressed the cytotoxicity of cisplatin via the inhibition of gap junction (GJ) intercellular communication (GJIC) in connexin (Cx)32 HeLa cells. The present study investigated whether the effects of propofol on the cytotoxicity of cisplatin were mediated by GJ in U87 glioma cells and Cx26‑transfected HeLa cells. Standard colony formation assay was used to determine the cytotoxicity of cisplatin. Parachute dye coupling assay was used to measure GJ function, and western blot analysis was used to determine the expression levels of Cx32. The results revealed that exposure of the U87 glioma cells and the Cx26-transfected HeLa cells to cisplatin for 1 h reduced clonogenic survival in low density cultures (without GJs) and high density cultures (with GJs). However, the toxic effect was higher in the high density culture. In addition, pretreatment of the cells with propofol significantly reduced cisplatin‑induced cytotoxicity, but only in the presence of functional GJs. Furthermore, propofol significantly inhibited dye coupling through junctional channels, and a long duration of exposure of the cells to propofol downregulated the expression levels of Cx43 and Cx26. These results demonstrated that the inhibition of GJIC by propofol affected the therapeutic efficacy of chemotherapeutic drugs. The present study provides evidence of a novel mechanism underlying the effects of analgesics in counteracting chemotherapeutic efficiency. PMID:27082707

  10. The in vivo genotoxicity of cisplatin, isoflurane and halothane evaluated by alkaline comet assay in Swiss albino mice.

    Science.gov (United States)

    Brozovic, Gordana; Orsolic, Nada; Knezevic, Fabijan; Horvat Knezevic, Anica; Benkovic, Vesna; Sakic, Katarina; Borojevic, Nikola; Dikic, Domagoj

    2011-08-01

    The aim of this study was to evaluate the genotoxicity of repeated exposure to isoflurane or halothane and compare it with the genotoxicity of repeated exposure to cisplatin. We also determined the genotoxicity of combined treatment with inhalation anaesthetics and cisplatin on peripheral blood leucocytes (PBL), brain, liver and kidney cells of mice. The mice were divided into six groups as follows: control, cisplatin, isoflurane, cisplatin-isoflurane, halothane and cisplatin-halothane, and were exposed respectively for three consecutive days. The mice were treated with cisplatin or exposed to inhalation anaesthetic; the combined groups were exposed to inhalation anaesthetic after treatment with cisplatin. The alkaline comet assay was performed. All drugs had a strong genotoxicity (Pdamage on the PBL and kidney cells, in contrast to halothane, which had stronger genotoxicity on brain and liver cells. The combination of cisplatin and isoflurane induced lower genotoxicity on PBL than isoflurane alone (Pbrain cells, but in the combined treatment with cisplatin, the effect decreased to the level of cisplatin alone. Halothane also induced the strongest DNA damage of the liver cells, while the combination with cisplatin increased its genotoxicity even more. The genotoxicity of cisplatin and isoflurane on kidney cells were nearly at the same level, but halothane caused a significantly lower effect. The combinations of inhalation anaesthetics with cisplatin had stronger effects on kidney cells than inhalation anaesthetics alone. The observed drugs and their combinations induced strong genotoxicity on all of the mentioned cells. PMID:21509577

  11. Pharmacological Protection From Radiation {+-} Cisplatin-Induced Oral Mucositis

    Energy Technology Data Exchange (ETDEWEB)

    Cotrim, Ana P. [Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Yoshikawa, Masanobu [Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Department of Clinical Pharmacology, Tokai University School of Medicine, Kanagawa (Japan); Sunshine, Abraham N.; Zheng Changyu [Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Sowers, Anastasia L.; Thetford, Angela D.; Cook, John A.; Mitchell, James B. [Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Baum, Bruce J., E-mail: bbaum@dir.nidcr.nih.gov [Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States)

    2012-07-15

    Purpose: To evaluate if two pharmacological agents, Tempol and D-methionine (D-met), are able to prevent oral mucositis in mice after exposure to ionizing radiation {+-} cisplatin. Methods and Materials: Female C3H mice, {approx}8 weeks old, were irradiated with five fractionated doses {+-} cisplatin to induce oral mucositis (lingual ulcers). Just before irradiation and chemotherapy, mice were treated, either alone or in combination, with different doses of Tempol (by intraperitoneal [ip] injection or topically, as an oral gel) and D-met (by gavage). Thereafter, mice were sacrificed and tongues were harvested and stained with a solution of Toluidine Blue. Ulcer size and tongue epithelial thickness were measured. Results: Significant lingual ulcers resulted from 5 Multiplication-Sign 8 Gy radiation fractions, which were enhanced with cisplatin treatment. D-met provided stereospecific partial protection from lingual ulceration after radiation. Tempol, via both routes of administration, provided nearly complete protection from lingual ulceration. D-met plus a suboptimal ip dose of Tempol also provided complete protection. Conclusions: Two fairly simple pharmacological treatments were able to markedly reduce chemoradiation-induced oral mucositis in mice. This proof of concept study suggests that Tempol, alone or in combination with D-met, may be a useful and convenient way to prevent the severe oral mucositis that results from head-and-neck cancer therapy.

  12. Cisplatin-induced Casepase-3 activation in different tumor cells

    Science.gov (United States)

    Shi, Hua; Li, Xiao; Su, Ting; Zhang, Yu-Hai

    2008-12-01

    Apoptosis plays an essential role in normal organism development which is one of the main types of programmed cell death to help tissues maintain homeostasis. Defective apoptosis can result in cell accumulation and therefore effects on tumor pathogenesis, progression and therapy resistance. A family of proteins, known as caspases, is typically activated in the early stages of apoptosis. Therefore, studying the kinetics of activation of caspases induced by antitumor drugs can contribute to antitumor drug discovery and explanation of the molecular mechanisms. This paper detected the Caspase-3 activity induced by cisplatin in human adenoid cystic carcinoma cell line (ACC-M), human hepatocellular liver carcinoma cell line (HepG2) and human epithelial carcinoma cell line (Hela) with stably expressing ECFP-DEVDDsRed (CD3) probe, a fluorescent probe consisting of Enhanced Cyan Fluorescent Protein (ECFP), red fluorescent protein (DsRed) and a linker with a recognition site of Caspase-3, by using the capillary electrophoresis (CE) and fluorescence resonance energy transfer (FRET) imaging system. Under the same concentration of cisplatin, ACC-M cells responded the most rapidly, and then HepG2 cells and Hela cells, respectively, in the early 30 hours. Later, HepG2 cells represented acceleration in the Caspase-3 activation speed and reached full activation the earliest comparing to other two cell types. The results demonstrated that ACC-M cell is more sensitive than the other two cell types under the treatment of cisplatin.

  13. Pharmacological Protection From Radiation ± Cisplatin-Induced Oral Mucositis

    International Nuclear Information System (INIS)

    Purpose: To evaluate if two pharmacological agents, Tempol and D-methionine (D-met), are able to prevent oral mucositis in mice after exposure to ionizing radiation ± cisplatin. Methods and Materials: Female C3H mice, ∼8 weeks old, were irradiated with five fractionated doses ± cisplatin to induce oral mucositis (lingual ulcers). Just before irradiation and chemotherapy, mice were treated, either alone or in combination, with different doses of Tempol (by intraperitoneal [ip] injection or topically, as an oral gel) and D-met (by gavage). Thereafter, mice were sacrificed and tongues were harvested and stained with a solution of Toluidine Blue. Ulcer size and tongue epithelial thickness were measured. Results: Significant lingual ulcers resulted from 5 × 8 Gy radiation fractions, which were enhanced with cisplatin treatment. D-met provided stereospecific partial protection from lingual ulceration after radiation. Tempol, via both routes of administration, provided nearly complete protection from lingual ulceration. D-met plus a suboptimal ip dose of Tempol also provided complete protection. Conclusions: Two fairly simple pharmacological treatments were able to markedly reduce chemoradiation-induced oral mucositis in mice. This proof of concept study suggests that Tempol, alone or in combination with D-met, may be a useful and convenient way to prevent the severe oral mucositis that results from head-and-neck cancer therapy.

  14. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Xue [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China); Li, Ling [Department of Brain Cognition Computing Lab, University of Kent, Kent CT2 7NZ (United Kingdom); Jiang, Hong; Jiang, Keping; Jin, Ye [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China); Zheng, Jianhua, E-mail: zhengjianhua1115@126.com [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China)

    2014-02-14

    Highlights: • Phosphorylation of mTOR is abnormal activation in SKOV3/DDP ovarian cancer cells. • Downregulation of mTOR by DHA helps to sensitize the SKOV3/DDP cells to chemotherapy. • DHA has the potential of induce autophagy in cancer cells. - Abstract: Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells.

  15. Morphine, a potential antagonist of cisplatin cytotoxicity, inhibits cisplatin-induced apoptosis and suppression of tumor growth in nasopharyngeal carcinoma xenografts

    Science.gov (United States)

    Cao, Long-Hui; Li, Hui-Ting; Lin, Wen-Qian; Tan, Hong-Ying; Xie, Lan; Zhong, Zhong-Jian; Zhou, Jian-Hua

    2016-01-01

    Morphine is an opioid analgesic drug often used for pain relief in cancer patients. However, there is growing evidence that morphine may modulate tumor growth, progression and metastasis. In this study, we evaluated whether morphine modulates cisplatin-induced apoptosis in human nasopharyngeal carcinoma CNE-2 cells and whether morphine affects the antitumor activity of cisplatin on tumor growth in human nasopharyngeal carcinoma CNE-2 xenografts in nude mice. We showed that a pretreatment with morphine (1 μg/ml) inhibited the sensitivity of CNE-2 cells to cisplatin by inhibiting cisplatin-induced CNE-2 cell apoptosis, decreasing caspase-3 activity and increasing the Bcl-2/Bax ratio. However, a high dose of morphine (1000 μg/ml) had the opposite effect. We also showed that at a low dose, morphine enhances chemoresistance in an in vivo nasopharyngeal carcinoma (NPC) model by inhibiting cisplatin-induced apoptosis and decreasing neovascularization. Taken together, our results indicate that a low dose of morphine may lead to chemoresistance of cisplatin in NPC models in vitro and in vivo by inhibiting cisplatin-induced apoptosis and decreasing neovascularization. PMID:26729257

  16. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

    International Nuclear Information System (INIS)

    Highlights: • Phosphorylation of mTOR is abnormal activation in SKOV3/DDP ovarian cancer cells. • Downregulation of mTOR by DHA helps to sensitize the SKOV3/DDP cells to chemotherapy. • DHA has the potential of induce autophagy in cancer cells. - Abstract: Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells

  17. A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract.

    Science.gov (United States)

    Hillcoat, B L; Raghavan, D; Matthews, J; Kefford, R; Yuen, K; Woods, R; Olver, I; Bishop, J; Pearson, B; Coorey, G

    1989-06-01

    One hundred eight patients with recurrent or metastatic transitional cell carcinoma of the urothelial tract were randomized to receive cisplatin (C) 80 mg/m2 on day 1 every 4 weeks, or methotrexate (M) 50 mg/m2 on days 1 and 15 plus C 80 mg/m2 on day 2 every 4 weeks (C + M). Fifty-three eligible patients were randomized to C + M and 55 to C. In the C + M arm, 45% of patients responded (complete response [CR], 9%) and 31% (CR, 9%) in the C arm (P = .18). In the C arm, 20 patients failing or relapsing after C received M. Two patients responded, and four with progressive disease (PD) and one with a previous partial response (PR) showed no change. The median survival was 8.7 months (C + M arm) and 7.2 months (C arm), P = .7. Relapse-free survival was not significantly different, but C + M was associated with a significantly increased time to disease progression (median, 5.0 months, v 2.8 months for C arm). The response of untreated patients (37%) was not different from those with prior treatment (39%). On the C + M arm, 92% of patients and 96% of patients on the C arm received 85% or more of the scheduled C dose. Significantly more grade 3 or 4 hematological toxicity (27% v 2%; P = .01) and mucositis (20% v 0%; P = .0005) occurred in patients on the C + M arm. Although the initial response rates seen on the combination arm look superior, and the time to disease progression is increased, these effects have not translated into a clinically important increase in the duration of survival and were associated with increased toxicity. PMID:2654329

  18. Studies of radioactive cisplatin ({sup 191}Pt) for tumour imaging and therapy

    Energy Technology Data Exchange (ETDEWEB)

    Areberg, J

    2000-01-01

    A radioactive variant of the cytostatic agent cis-dichlorodiammineplatinum(II), cisplatin, was synthesised from {sup 191}PtCl{sub 4}. The {sup 191}Pt-cisplatin was found to be a sterile product of high radionuclide, radiochemical and chemical purity. The pharmacokinetics of platinum in tumour tissue and organs at risk of fourteen patients undergoing treatment with cisplatin were studied by exchanging a small fraction of the prescribed amount of cisplatin with {sup 191}Pt-cisplatin. The uptake and retention of platinum were investigated by gamma camera measurements up to ten days after infusion of {sup 191}Pt-cisplatin. Highest concentration of platinum was found in the liver, on average 5.7 {+-} 0.5 {mu}g/g normalised to a given amount of 180 mg cisplatin. Corresponding value for the kidneys was 1.9 {+-} 0.3 {mu}g/g. Uptake of platinum in tumours was visualised in five patients with an average maximum concentration of 4.9 {+-} 1.0 {mu}g/g normalised to a given amount of 180 mg cisplatin. The data from the pharmacokinetic study was used together with data from the literature to estimate the absorbed dose and effective dose to patients receiving radioactive cisplatin. The effective doses were calculated to be 0.10 {+-} 0.02 mSv/MBq, 0.17 {+-} 0.04 mSv/MBq and 0.23 {+-} 0.05 mSv/MBq for {sup 191}Pt-, {sup 193m}Pt-, and {sup 195m}Pt-cisplatin respectively. The combined effect of the radio- and chemotoxicity from {sup 191}Pt-cisplatin was investigated both in vitro and in vivo. A cervical cancer cell line was incubated with cisplatin or {sup 191}Pt-cisplatin with various concentrations and specific activities. It was shown that the surviving fraction was smaller for cells treated with {sup 191}Pt-cisplatin than for cells treated with the same concentration of non-radioactive cisplatin. The surviving fraction decreased with increasing specific activity. Isobologram technique showed that the radio- and chemotoxicity interacted in a supra-additive (synergistic) manner. In

  19. Studies of radioactive cisplatin (191Pt) for tumour imaging and therapy

    International Nuclear Information System (INIS)

    A radioactive variant of the cytostatic agent cis-dichlorodiammineplatinum(II), cisplatin, was synthesised from 191PtCl4. The 191Pt-cisplatin was found to be a sterile product of high radionuclide, radiochemical and chemical purity. The pharmacokinetics of platinum in tumour tissue and organs at risk of fourteen patients undergoing treatment with cisplatin were studied by exchanging a small fraction of the prescribed amount of cisplatin with 191Pt-cisplatin. The uptake and retention of platinum were investigated by gamma camera measurements up to ten days after infusion of 191Pt-cisplatin. Highest concentration of platinum was found in the liver, on average 5.7 ± 0.5 μg/g normalised to a given amount of 180 mg cisplatin. Corresponding value for the kidneys was 1.9 ± 0.3 μg/g. Uptake of platinum in tumours was visualised in five patients with an average maximum concentration of 4.9 ± 1.0 μg/g normalised to a given amount of 180 mg cisplatin. The data from the pharmacokinetic study was used together with data from the literature to estimate the absorbed dose and effective dose to patients receiving radioactive cisplatin. The effective doses were calculated to be 0.10 ± 0.02 mSv/MBq, 0.17 ± 0.04 mSv/MBq and 0.23 ± 0.05 mSv/MBq for 191Pt-, 193mPt-, and 195mPt-cisplatin respectively. The combined effect of the radio- and chemotoxicity from 191Pt-cisplatin was investigated both in vitro and in vivo. A cervical cancer cell line was incubated with cisplatin or 191Pt-cisplatin with various concentrations and specific activities. It was shown that the surviving fraction was smaller for cells treated with 191Pt-cisplatin than for cells treated with the same concentration of non-radioactive cisplatin. The surviving fraction decreased with increasing specific activity. Isobologram technique showed that the radio- and chemotoxicity interacted in a supra-additive (synergistic) manner. In an in vivo model, nude mice with xenografted tumours were given physiological saline

  20. Radiochemotherapy including cisplatin alone versus cisplatin + 5-fluorouracil for locally advanced unresectable stage IV squamous cell carcinoma of the head and neck

    Energy Technology Data Exchange (ETDEWEB)

    Tribius, Silke; Kilic, Yasemin [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf, Hamburg (Germany); Kronemann, Stefanie [Dept. of Radiation Oncology, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany); Schroeder, Ursula [Dept. of Head and Neck Surgery, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany); Hakim, Samer [Dept. of Oro-Maxillo-Facial Surgery, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany); Schild, Steven E. [Dept. of Radiation Oncology, Mayo Clinic, Scottsdale, AZ (United States); Rades, Dirk [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf, Hamburg (Germany); Dept. of Radiation Oncology, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany)

    2009-10-15

    Background and purpose: the optimal radiochemotherapy regimen for advanced head-and-neck cancer is still debated. This nonrandomized study compares two cisplatin-based radiochemotherapy regimens in 128 patients with locally advanced unresectable stage IV squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: concurrent chemotherapy consisted of either two courses cisplatin (20 mg/m{sup 2}/d1-5 + 29-33; n = 54) or two courses cisplatin (20 mg/m{sup 2}/d1-5 + 29-33) + 5-fluorouracil (5-FU; 600 mg/m{sup 2}/d1-5 + 29-33; n = 74). Results: at least one grade 3 toxicity occurred in 25 of 54 patients (46%) receiving cisplatin alone and in 52 of 74 patients (70%) receiving cisplatin + 5-FU. The latter regimen was particularly associated with increased rates of mucositis (p = 0.027) and acute skin toxicity (p = 0.001). Seven of 54 (13%) and 20 of 74 patients (27%) received only one chemotherapy course due to treatment-related acute toxicity. Late toxicity in terms of xerostomia, neck fibrosis, skin toxicity, and lymphedema was not significantly different. The 2-year locoregional control rates were 67% after cisplatin alone and 52% after cisplatin + 5-FU (p = 0.35). The metastases-free survival rates were 79% and 69%, respectively (p = 0.65), and the overall survival rates 70% and 51%, respectively (p = 0.10). On multivariate analysis, outcome was significantly associated with performance status, T-category, N-category, hemoglobin level prior to radiotherapy, and radiotherapy break > 1 week. Conclusion: two courses of fractionated cisplatin (20 mg/m{sup 2}/day) alone appear preferable, as this regimen resulted in similar outcome and late toxicity as two courses of cisplatin + 5-FU, but in significantly less acute toxicity. (orig.)

  1. Radiochemotherapy including cisplatin alone versus cisplatin + 5-fluorouracil for locally advanced unresectable stage IV squamous cell carcinoma of the head and neck

    International Nuclear Information System (INIS)

    Background and purpose: the optimal radiochemotherapy regimen for advanced head-and-neck cancer is still debated. This nonrandomized study compares two cisplatin-based radiochemotherapy regimens in 128 patients with locally advanced unresectable stage IV squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: concurrent chemotherapy consisted of either two courses cisplatin (20 mg/m2/d1-5 + 29-33; n = 54) or two courses cisplatin (20 mg/m2/d1-5 + 29-33) + 5-fluorouracil (5-FU; 600 mg/m2/d1-5 + 29-33; n = 74). Results: at least one grade 3 toxicity occurred in 25 of 54 patients (46%) receiving cisplatin alone and in 52 of 74 patients (70%) receiving cisplatin + 5-FU. The latter regimen was particularly associated with increased rates of mucositis (p = 0.027) and acute skin toxicity (p = 0.001). Seven of 54 (13%) and 20 of 74 patients (27%) received only one chemotherapy course due to treatment-related acute toxicity. Late toxicity in terms of xerostomia, neck fibrosis, skin toxicity, and lymphedema was not significantly different. The 2-year locoregional control rates were 67% after cisplatin alone and 52% after cisplatin + 5-FU (p = 0.35). The metastases-free survival rates were 79% and 69%, respectively (p = 0.65), and the overall survival rates 70% and 51%, respectively (p = 0.10). On multivariate analysis, outcome was significantly associated with performance status, T-category, N-category, hemoglobin level prior to radiotherapy, and radiotherapy break > 1 week. Conclusion: two courses of fractionated cisplatin (20 mg/m2/day) alone appear preferable, as this regimen resulted in similar outcome and late toxicity as two courses of cisplatin + 5-FU, but in significantly less acute toxicity. (orig.)

  2. Vascular damage in testicular cancer patients : A study on endothelial activation by bleomycin and cisplatin in vitro

    NARCIS (Netherlands)

    Nuver, Janine; De Haas, Esther C.; Van Zweeden, Martine; Gietema, Jourik A.; Meijer, Coby

    2010-01-01

    Following treatment with bleomycin- and cisplatin-containing chemotherapy, testicular cancer patients frequently develop vascular complications, which may result from damage to endothelial cells. Understanding bleomycin- and cisplatin-induced endothelial alterations may help to develop strategies to

  3. Cisplatin-incorporated nanoparticles of poly(acrylic acid-co-methyl methacrylate copolymer

    Directory of Open Access Journals (Sweden)

    Lee KD

    2013-08-01

    Full Text Available Kyung Dong Lee,1,* Young-Il Jeong,2,* Da Hye Kim,3,4 Gyun-Taek Lim,2 Ki-Choon Choi5 1Department of Oriental Medicine Materials, Dongshin University, Naju, South Korea; 2Department of Polymer Engineering, Chonnam National University, Gwangju, South Korea; 3Faculty of Life and Environmental Science, Shimane University, Matsue, Japan; 4United Graduate School of Agricultural Sciences, Tottori University, Tottori, Japan; 5Grassland and Forages Division, National Institute of Animal Science, Rural Development Administration, Cheonan, South Korea *These authors contributed equally to this work Background: Although cisplatin is extensively used in the clinical field, its intrinsic toxicity limits its clinical use. We investigated nanoparticle formations of poly(acrylic acid-co-methyl methacrylate (PAA-MMA incorporating cisplatin and their antitumor activity in vitro and in vivo. Methods: Cisplatin-incorporated nanoparticles were prepared through the ion-complex formation between acrylic acid and cisplatin. The anticancer activity of cisplatin-incorporated nanoparticles was assessed with CT26 colorectal carcinoma cells. Results: Cisplatin-incorporated nanoparticles have small particle sizes of less than 200 nm with spherical shapes. Drug content was increased according to the increase of the feeding amount of cisplatin and acrylic acid content in the copolymer. The higher acrylic acid content in the copolymer induced increase of particle size and decrease of zeta potential. Cisplatin-incorporated nanoparticles showed a similar growth-inhibitory effect against CT26 tumor cells in vitro. However, cisplatin-incorporated nanoparticles showed improved antitumor activity against an animal tumor xenograft model. Conclusion: We suggest that PAA-MMA nanoparticles incorporating cisplatin are promising carriers for an antitumor drug-delivery system. Keywords: cisplatin, nanoparticle, poly(acrylic acid-co-methyl methacrylate, ion complexes

  4. Cisplatin Induces Bmi-1 and Enhances the Stem Cell Fraction in Head and Neck Cancer

    Directory of Open Access Journals (Sweden)

    Carolina Nör

    2014-02-01

    Full Text Available Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs. These unique cells, named here cancer stem cells (CSCs, proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6] for their survival and self-renewal in HNSCC. Here, we hypothesized that cisplatin enhances the stem cell fraction in HNSCC. To address this hypothesis, we generated xenograft HNSCC tumors with University of Michigan-squamous cell carcinoma 22B (UM-SCC-22B cells and observed that cisplatin treatment increased (P = .0013 the fraction of CSCs [i.e., aldehyde dehydrogenase activity high and cluster of differentiation 44 high (ALDHhighCD44high]. Cisplatin promoted self-renewal and survival of CSCs in vitro, as seen by an increase in the number of orospheres in ultralow attachment plates and induction in B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1 and octamer-binding transcription factor 4 expression. Cisplatin-resistant cells expressed more Bmi-1 than cisplatinsensitive cells. IL-6 potentiated cisplatin-induced orosphere formation generated when primary human HNSCC cells were sorted for ALDHhighCD44high immediately after surgery and plated onto ultralow attachment plates. IL-6-induced signal transducer and activator of transcription 3 (STAT3 phosphorylation (indicative of stemness was unaffected by treatment with cisplatin in UM-SCC-22B cells, whereas IL-6-induced extracellular signal-regulated kinase (ERK phosphorylation (indicative of differentiation processes was partially inhibited by cisplatin. Notably, cisplatin-induced Bmi-1 was inhibited by interleukin-6 receptor blockade in parental and cisplatin-resistant cells. Taken together, these results demonstrate that cisplatin enhances the fraction of CSCs

  5. Molecular architecture of nanocapsules, bilayer-enclosed solid particles of Cisplatin.

    Science.gov (United States)

    Chupin, Vladimir; de Kroon, Anton I P M; de Kruijff, Ben

    2004-10-27

    Cisplatin nanocapsules represent a lipid formulation of the anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) characterized by an unprecedented cisplatin-to-lipid ratio and exhibiting strongly improved cytotoxicity against tumor cells in vitro as compared to the free drug (Burger, K. N. J., et al. Nat. Med. 2002, 8, 81-84). Cisplatin nanocapsules are prepared by the repeated freezing and thawing of an equimolar dispersion of phosphatidylserine (PS) and phosphatidylcholine (PC) in a concentrated aqueous solution of cisplatin. Here, the molecular architecture of these novel nanostructures was elucidated by solid-state NMR techniques. 15N NMR and 2H NMR spectra of nanocapsules containing 15N- and 2H-labeled cisplatin, respectively, demonstrated that the core of the nanocapsules consists of solid cisplatin devoid of free water. Magic-angle spinning 15N NMR showed that approximately 90% of the cisplatin in the core is present as the dichloro species. The remaining 10% was accounted for by a newly discovered dinuclear Pt compound that was identified as the positively charged chloride-bridged dimer of cisplatin. NMR techniques sensitive to lipid organization, 31P NMR and 2H NMR, revealed that the cisplatin core is coated by phospholipids in a bilayer configuration and that the interaction between solid core and bilayer coat exerts a strong ordering effect on the phospholipid molecules. Compared to phospholipids in liposomal membranes, the motion of the phospholipid headgroups is restricted and the ordering of the acyl chains is increased, particularly in PS. The implications of these findings for the structural organization, the mechanism of formation, and the mode of action of cisplatin nanocapsules are discussed. PMID:15493941

  6. Cisplatin Induces Bmi-1 and Enhances the Stem Cell Fraction in Head and Neck Cancer12

    Science.gov (United States)

    Nör, Carolina; Zhang, Zhaocheng; Warner, Kristy A; Bernardi, Lisiane; Visioli, Fernanda; Helman, Joseph I; Roesler, Rafael; Nör, Jacques E

    2014-01-01

    Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs). These unique cells, named here cancer stem cells (CSCs), proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6)] for their survival and self-renewal in HNSCC. Here, we hypothesized that cisplatin enhances the stem cell fraction in HNSCC. To address this hypothesis, we generated xenograft HNSCC tumors with University of Michigan-squamous cell carcinoma 22B (UM-SCC-22B) cells and observed that cisplatin treatment increased (P = .0013) the fraction of CSCs [i.e., aldehyde dehydrogenase activity high and cluster of differentiation 44 high (ALDHhighCD44high)]. Cisplatin promoted self-renewal and survival of CSCs in vitro, as seen by an increase in the number of orospheres in ultralow attachment plates and induction in B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) and octamer-binding transcription factor 4 expression. Cisplatin-resistant cells expressed more Bmi-1 than cisplatinsensitive cells. IL-6 potentiated cisplatin-induced orosphere formation generated when primary human HNSCC cells were sorted for ALDHhighCD44high immediately after surgery and plated onto ultralow attachment plates. IL-6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation (indicative of stemness) was unaffected by treatment with cisplatin in UM-SCC-22B cells, whereas IL-6-induced extracellular signal-regulated kinase (ERK) phosphorylation (indicative of differentiation processes) was partially inhibited by cisplatin. Notably, cisplatin-induced Bmi-1 was inhibited by interleukin-6 receptor blockade in parental and cisplatin-resistant cells. Taken together, these results demonstrate that cisplatin enhances the fraction of CSCs and suggest

  7. Chronic low vitamin intake potentiates cisplatin-induced intestinal epithelial cell apoptosis in WNIN rats

    Institute of Scientific and Technical Information of China (English)

    Bodiga Vijayalakshmi; Boindala Sesikeran; Putcha Udaykumar; Subramaniam Kalyanasundaram; Manchala Raghunath

    2006-01-01

    AIM: To investigate if cisplatin alters vitamin status and if VR modulates cisplatin induced intestinal apoptosis and oxidative stress in Wistar/NIN (WNIN) male rats.METHODS: Weanling, WNIN male rats (n = 12 per group) received adlibitum for 17 wk: control diet (20%protein) or the same with 50% vitamin restriction. They were then sub-divided into two groups of six rats each and administered cisplatin (2.61 mg/kg bodyweight)once a week for three wk or PBS (vehicle control).Intestinal epithelial cell (IEC) apoptosis was monitored by morphometry, Annexin-V binding, M30 cytodeath assay and DNA fragmentation. Structural and functional integrity of the villus were assessed by villus height /crypt depth ratio and activities of alkaline phosphatase,lys, ala-dipeptidyl amino-peptidase, respectively. To assess the probable mechanism(s) of altered apoptosis,oxidative stress parameters, caspase-3 activity, and expression of Bcl-2 and Bax were determined.RESULTS: Cisplatin per se decreased plasma vitamin levels and they were the lowest in VR animals treated with cisplatin. As expected VR increased only villus apoptosis, whereas cisplatin increased stem cell apoptosis in the crypt. However, cisplatin treatment of VR rats increased apoptosis both in villus and crypt regions and was associated with higher levels of TBARS,protein carbonyls and caspase-3 activity, but lower GSH concentrations. VR induced decrease in Bcl-2 expression was further lowered by cisplatin. Bax expression,unaffected by VR was increased on cisplatin treatment.Mucosal functional integrity was severely compromised in cisplatin treated VR-rats.CONCLUSION: Low intake of vitamins increases the sensitivity of rats to cisplatin and promotes intestinal epithelial cell apoptosis.

  8. Cisplatin induces resistance by triggering differentiation of testicular embryonal carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Paolo B Abada

    Full Text Available Although testicular germ cell tumors are generally quite responsive to treatment with cisplatin, a small fraction of them acquire resistance during therapy. Even when cisplatin treatment is successful the patient is often left with a residual teratoma at the site of the primary tumor suggesting that cisplatin may trigger differentiation in some tumors. Using the human embryonal carcinoma cell line NTera2/D1, we confirmed that exposure to the differentiating agent retinoic acid produced a reduction in pluripotency markers NANOG and POU5F1 (Oct3/4 and an acute concentration-dependent increase in resistance to both cisplatin and paclitaxel that reached as high as 18-fold for cisplatin and 61-fold for paclitaxel within four days. A two day exposure to cisplatin also produced a concentration-dependent decrease in the expression of the NANOG and POU5F1 and increased expression of three markers whose levels increase with differentiation including Nestin, SCG10 and Fibronectin. In parallel, exposure to cisplatin induced up to 6.2-fold resistance to itself and 104-fold resistance to paclitaxel. Paclitaxel did not induce differentiation or resistance to either itself or cisplatin. Neither retinoic acid nor cisplatin induced resistance in cervical or prostate cancer cell lines or other germ cell tumor lines in which they failed to alter the expression of NANOG and POU5F1. Forced expression of NANOG prevented the induction of resistance to cisplatin by retinoic acid. We conclude that cisplatin can acutely induce resistance to itself and paclitaxel by triggering a differentiation response in pluripotent germ cell tumor cells.

  9. Cisplatin induces resistance by triggering differentiation of testicular embryonal carcinoma cells.

    Science.gov (United States)

    Abada, Paolo B; Howell, Stephen B

    2014-01-01

    Although testicular germ cell tumors are generally quite responsive to treatment with cisplatin, a small fraction of them acquire resistance during therapy. Even when cisplatin treatment is successful the patient is often left with a residual teratoma at the site of the primary tumor suggesting that cisplatin may trigger differentiation in some tumors. Using the human embryonal carcinoma cell line NTera2/D1, we confirmed that exposure to the differentiating agent retinoic acid produced a reduction in pluripotency markers NANOG and POU5F1 (Oct3/4) and an acute concentration-dependent increase in resistance to both cisplatin and paclitaxel that reached as high as 18-fold for cisplatin and 61-fold for paclitaxel within four days. A two day exposure to cisplatin also produced a concentration-dependent decrease in the expression of the NANOG and POU5F1 and increased expression of three markers whose levels increase with differentiation including Nestin, SCG10 and Fibronectin. In parallel, exposure to cisplatin induced up to 6.2-fold resistance to itself and 104-fold resistance to paclitaxel. Paclitaxel did not induce differentiation or resistance to either itself or cisplatin. Neither retinoic acid nor cisplatin induced resistance in cervical or prostate cancer cell lines or other germ cell tumor lines in which they failed to alter the expression of NANOG and POU5F1. Forced expression of NANOG prevented the induction of resistance to cisplatin by retinoic acid. We conclude that cisplatin can acutely induce resistance to itself and paclitaxel by triggering a differentiation response in pluripotent germ cell tumor cells. PMID:24475288

  10. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Scagliotti, G.V.; Parikh, P.; Pawel, J. von;

    2008-01-01

    Purpose Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. Patients and Methods This noninferiority, phase III, randomized study...... neutropenia (P = .002); and alopecia (P common. Conclusion In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin....../gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type Udgivelsesdato: 2008/7/20...

  11. Dimethyl sulfoxide inactivates the anticancer effect of cisplatin against human myelogenous leukemia cell lines in in vitro assays

    OpenAIRE

    Rahul Raghavan; Sanith Cheriyamundath; Joseph Madassery

    2015-01-01

    Objectives: To investigate the effect of DMSO on cisplatin induced cytotoxicity (invitro) against K562 (Human mylogenous leukemia) cell line and to study the cisplatin-DMSO adduct formation using UV-spectrophotometer. Materials and methods: Effect of DMSO on the cytotoxicity of cisplatin was studied in K562 (Chronic mylogenous leukemia) cell line by MTT assay. Cisplatin-DMSO adduct formation was studied by continuously monitoring the increase in absorption peaks for 30 minutes using UV-s...

  12. Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers

    OpenAIRE

    Li, Feng; Shanmugam, Muthu K.; Siveen, Kodappully Sivaraman; Wang, Fan; Ong, Tina H.; Loo, Ser Yue; Swamy, Mahadeva M.M.; Mandal, Somnath; Kumar, Alan Prem; Goh, Boon Cher; Kundu, Tapas; Ahn, Kwang Seok; Wang, Ling Zhi; Hui, Kam Man; Sethi, Gautam

    2015-01-01

    Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated whether garcinol, a polyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin. We found that garcinol inhibited the viability of a panel of diverse HNSCC cell lines, enhanced the apoptotic effect of cisplatin, suppressed constitutive as well as cisplatin-induced NF-κB act...

  13. Cisplatin induces primary necrosis through poly(ADP-ribose) polymerase 1 activation in kidney proximal tubular cells

    OpenAIRE

    Park, Seulgee; Yoon, Sang Pil; Kim, Jinu

    2015-01-01

    Treatment with cisplatin for cancer therapy has a major side effect such as nephrotoxicity; however, the role of poly (ADP-ribose) polymerase 1 (PARP1) in necrosis in response to cisplatin nephrotoxicity remains to be defined. Here we report that cisplatin induces primary necrosis through PARP1 activation in kidney proximal tubular cells derived from human, pig and mouse. Treatment with high dose of cisplatin for 4 and 8 hours induced primary necrosis, as represented by the percentage of prop...

  14. Suppression of Poly(rC)-Binding Protein 4 (PCBP4) reduced cisplatin resistance in human maxillary cancer cells

    Science.gov (United States)

    Ito, Yumi; Narita, Norihiko; Nomi, Nozomi; Sugimoto, Chizuru; Takabayashi, Tetsuji; Yamada, Takechiyo; Karaya, Kazuhiro; Matsumoto, Hideki; Fujieda, Shigeharu

    2015-01-01

    Cisplatin plays an important role in the therapy for human head and neck cancers. However, cancer cells develop cisplatin resistance, leading to difficulty in treatment and poor prognosis. To analyze cisplatin-resistant mechanisms, a cisplatin-resistant cell line, IMC-3CR, was established from the IMC-3 human maxillary cancer cell line. Flow cytometry revealed that, compared with IMC-3 cells, cisplatin more dominantly induced cell cycle G2/M arrest rather than apoptosis in IMC-3CR cells. That fact suggests that IMC-3CR cells avoid cisplatin-induced apoptosis through induction of G2/M arrest, which allows cancer cells to repair damaged DNA and survive. In the present study, we specifically examined Poly(rC)-Binding Protein 4 (PCBP4), which reportedly induces G2/M arrest. Results showed that suppression of PCBP4 by RNAi reduced cisplatin-induced G2/M arrest and enhanced apoptosis in IMC-3CR cells, resulting in the reduction of cisplatin resistance. In contrast, overexpression of PCBP4 in IMC-3 cells induced G2/M arrest after cisplatin treatment and enhanced cisplatin resistance. We revealed that PCBP4 combined with Cdc25A and suppressed the expression of Cdc25A, resulting in G2/M arrest. PCBP4 plays important roles in the induction of cisplatin resistance in human maxillary cancers. PCBP4 is a novel molecular target for the therapy of head and neck cancers, especially cisplatin-resistant cancers. PMID:26196957

  15. Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study

    DEFF Research Database (Denmark)

    Urup, Thomas; Pawlak, W Z; Petersen, P M;

    2013-01-01

    Adrenocortical carcinoma (ACC) is a rare disease with a poor response to chemotherapy. Cisplatin is the most widely investigated drug in the treatment of ACC and in vitro studies have indicated activity of taxanes. The objectives of this study were to evaluate the efficacy and toxicity of cisplatin...

  16. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ko, Je-Won; Lee, In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-12-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological alterations, including degeneration/necrosis of hepatocytes, vacuolation, and sinusoidal dilation. In addition, an increase in the malondialdehyde (MDA) concentration and a decrease in the reduced glutathione (GSH) content and catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) activities were observed in the cisplatin-treated rat hepatic tissues. In contrast, PYC treatment effectively prevented cisplatin-induced hepatotoxicity, including the elevation of aminotransferase and histopathological lesions, in a dosedependent manner. Moreover, PYC treatment also induced antioxidant activity by decreasing MDA level and increasing GSH content and SOD and GST activities in liver tissues. These results indicate that PYC has a protective effect against acute hepatotoxicity induced by cisplatin in rats, and that the protective effects of PYC may be due to inhibiting lipid peroxidation and increasing antioxidant activity. PMID:25628728

  17. Chromosomal aberrations induced in mice bone marrow by treating with cisplatin and irradiation

    International Nuclear Information System (INIS)

    Background: The aim of this study was to quantify the combined effect of cisplatin and radiation on chromosomal damage with emphasis on the time interval between cisplatin and radiation. Methods and materials: Bone marrow of female NMRI-nu(+)mice was taken as a model system for a highly proliferative tissue irradiated with cobalt-60 (1 to 4 Gy). Cisplatin was injected intraperitoneally (ip) at 1.1 to 36 mg/kg. Cisplatin was given at various time intervals before and after radiation. Bone marrow and metaphases were prepared according to standard procedures. Results: The percentage of aberrant metaphases after radiation or cisplatin alone increased in a dose-dependent manner (sigmoidal dose-response curve). Combining both modalities led to additive values at all time points for the percentage of aberrant metaphases. Borderline significant (p<0.05) supraadditive effects were found 2 hours before or 1 hour after irradiation. However, a supraadditive percentage of aberrant chromosomes was found only at 2 or 1.5 hours with cisplatin before irradiation indicating the dependence of supraadditivity on the chosen parameter. Conclusion: It is doubtful to expect a true supraadditive or 'radiosensitizing' effect, e.g. in the clinical setting from combined treatment with cisplatin and radiation. Rather, cisplatin might act as an independent cytotoxic agent. (orig.)

  18. ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics

    International Nuclear Information System (INIS)

    Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60 kD to 80 kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics. - Highlights: • Cholangiocarcinoma may adapt to cisplatin through mitochondrial fusion. • ABT737 sensitizes cholangiocarcinoma to cisplatin by promoting fission and mitophagy. • p62 might participate in the regulation of mitochondrial fission and mitophagy

  19. Collateral sensitivity to cisplatin in KB-8-5-11 drug-resistant cancer cells.

    LENUS (Irish Health Repository)

    Doherty, Ben

    2014-01-01

    KB-8-5-11 cells are a drug-resistant cervical cell model that overexpresses ABCB1 (P-glycoprotein). KB-8-5-11 has become sensitive to non-ABCB1 substrate cisplatin. Understanding the mechanism of collateral sensitivity to cisplatin may lead to biomarker discovery for platinum sensitivity in patients with cancer.

  20. Sub-nephrotoxic cisplatin sensitizes rats to acute renal failure and increases urinary excretion of fumarylacetoacetase.

    Science.gov (United States)

    Vicente-Vicente, Laura; Sánchez-Juanes, Fernando; García-Sánchez, Omar; Blanco-Gozalo, Víctor; Pescador, Moisés; Sevilla, María A; González-Buitrago, José Manuel; López-Hernández, Francisco J; López-Novoa, José Miguel; Morales, Ana Isabel

    2015-04-16

    Nephrotoxicity limits the therapeutic efficacy of the antineoplastic drug cisplatin. Due to dosage adjustment and appropriate monitoring, most therapeutic courses with cisplatin produce no or minimal kidney damage. However, we studied whether even sub-nephrotoxic dosage of cisplatin poses a potential risk for the kidneys by predisposing to acute kidney injury (AKI), specifically by lowering the toxicity threshold for a second nephrotoxin. With this purpose rats were treated with a single sub-nephrotoxic dosage of cisplatin (3mg/kg, i.p.) and after two days, with a sub-nephrotoxic regime of gentamicin (50mg/kg/day, during 6 days, i.p.). Control groups received only one of the drugs or the vehicle. Renal function and renal histology were monitored throughout the experiment. Cisplatin treatment did not cause any relevant functional or histological alterations in the kidneys. Rats treated with cisplatin and gentamicin, but not those under single treatments, developed an overt renal failure characterized by both renal dysfunction and massive tubular necrosis. In addition, the urinary excretion of fumarylacetoacetase was increased in cisplatin-treated animals at subtoxic doses, which might be exploited as a cisplatin-induced predisposition marker. In fact, the urinary level of fumarylacetoacetase prior to the second nephrotoxin correlated with the level of AKI triggered by gentamicin in predisposed animals. PMID:25677510

  1. Cisplatin-DNA adduct formation in rat spermatozoa and its effect on fetal development

    NARCIS (Netherlands)

    Hooser, S.T.; Dijk-Knijnenburg, C.M. van; Waalkens-Berendsen, I.D.H.; Smits-van Prooije, A.E.; Snoeij, N.J.; Baan, R.A.; Fichtinger-Schepman, M.J.

    2000-01-01

    Exposure of males to some genotoxic chemicals causes DNA damage in spermatozoa resulting in embryotoxicity and developmental defects in their offspring. This study demonstrates that cisplatin-DNA adducts could be measured in spermatozoa following treatment with the antineoplastic drug, cisplatin. Th

  2. Cisplatin-induced ototoxicity : Morphological evidence of spontaneous outer hair cell recovery in albino guinea pigs?

    NARCIS (Netherlands)

    Cardinaal, RM; de Groot, JCMJ; Huizing, EH; Veldman, JE; Smoorenburg, GF

    2000-01-01

    Cisplatin is frequently used in the treatment of various forms of malignancies. Its therapeutic efficacy, however, is limited by the occurrence of sensorineural hearing loss. Little is known about the course of hearing loss over longer time intervals after cessation of cisplatin administration. Infr

  3. ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Zhongqi [Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021 (China); Yu, Huimei [Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021 (China); Cui, Ni [Bethune Medical College, Jilin University, Changchun, Jilin 130021 (China); Kong, Xianggui; Liu, Xiaomin; Chang, Yulei [State Key Laboratory of Luminescence and Applications, Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences, Changchun, Jilin 130033 (China); Wu, Yao [Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021 (China); Sun, Liankun, E-mail: sunlk@jlu.edu.cn [Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021 (China); Wang, Guangyi, E-mail: wgymd@sina.com [Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021 (China)

    2015-07-01

    Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60 kD to 80 kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics. - Highlights: • Cholangiocarcinoma may adapt to cisplatin through mitochondrial fusion. • ABT737 sensitizes cholangiocarcinoma to cisplatin by promoting fission and mitophagy. • p62 might participate in the regulation of mitochondrial fission and mitophagy.

  4. Concurrent chemoradiotherapy with gemcitabine and cisplatin for pancreatic cancer: from the laboratory to the clinic

    International Nuclear Information System (INIS)

    Purpose: We have reported that gemcitabine and concurrent radiation is a promising therapy for patients with pancreatic cancer. We investigated whether the addition of cisplatin, which may increase the systemic efficacy of gemcitabine, would be synergistic with gemcitabine and/or radiation in human pancreatic cancer cell lines. Methods and Materials: BxPc3 and Panc-1 human pancreatic cancer cells were treated with three different schedules before radiation: (A) a sequential incubation of gemcitabine for 2 h followed by cisplatin for 2 h, (B) gemcitabine for 2 h, followed by washout of drug, replenishment of media for a 24-h incubation, followed by cisplatin for 2 h, and (C) gemcitabine for 24 h with a concurrent incubation of cisplatin for the last 2 h. Cells were assessed for clonogenic survival using a standard assay. Synergism was evaluated by the median effect analysis. Results: The schedule shown to be maximally synergistic for both cell lines was the consecutive 2-h gemcitabine, 2-h cisplatin exposure, particularly at surviving fractions of <0.5. Cisplatin did not produce radiosensitization nor did it affect gemcitabine-mediated radiosensitization. Conclusion: Cisplatin produces synergistic cytotoxicity with gemcitabine without compromising gemcitabine-mediated radiosensitization. On the basis of these laboratory and previous clinical observations, we have initiated a Phase I trial of cisplatin plus gemcitabine and radiotherapy in patients with unresectable pancreatic cancer

  5. Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleural mesothelioma

    DEFF Research Database (Denmark)

    Frank, H.; Palshof, T.; Sørensen, Jens Benn

    2008-01-01

    The aim was to evaluate the activity of cisplatin and vinorelbine in previously untreated, inoperable patients having histologically verified malignant pleural mesothelioma (MPM), normal organ function, and performance status 0-2. Treatment was vinorelbine 25 mg m(-2) i.v. weekly and cisplatin 10...

  6. Two cases of cisplatin-induced permanent renal failure following neoadjuvant chemotherapy for esophageal cancer

    Directory of Open Access Journals (Sweden)

    Tomohiko Sasaki

    2016-01-01

    Conclusion: Although cisplatin-related nephrotoxicity is a well-recognized complication, there have been few reports of renal failure requiring hemodialysis in cancer patients. In this report, we present their clinical courses and the pathological findings of cisplatin-related renal failure.

  7. Effect of Eisenia foetida Extract against Cisplatin-Induced Kidney Injury in Rats.

    Science.gov (United States)

    Jamshidzadeh, Akram; Heidari, Reza; Golzar, Tahereh; Derakhshanfar, Amin

    2016-09-01

    Kidney injury is a deleterious side effect accompanied by therapeutic uses of cisplatin as an antineoplastic agent. However, no therapeutic option is available against this complication. This study was designed to evaluate the protective role of a glycoprotein extract obtained from Eisenia foetida against cisplatin-induced nephrotoxicity. Rats were treated with cisplatin (7.5 mg/kg, intraperitoneally, i.p.) and Eisenia foetida extract (300 and 500 mg/kg, i.p. and/or oral). Serum creatinine (Cr) and blood urea nitrogen (BUN) were significantly elevated in cisplatin-treated rats. A significant amount of lipid peroxidation was detected in drug-treated animals. Furthermore, kidney histopathological findings revealed acute tubular necrosis and hyaline cast formation caused by cisplatin. Eisenia foetida extract administration (300 and 500 mg/kg, i.p.) significantly reduced serum BUN and creatinine and lipid peroxidation in kidney tissue. Moreover, cisplatin-induced histopathological lesions were alleviated by Eisenia foetida extract. This investigation concluded that Eisenia foetida extract ameliorated cisplatin-induced nephrotoxicity. This protection might be mediated by preventing cisplatin-induced oxidative stress. PMID:26864051

  8. Management of cisplatin toxicity and chromosomal aberration by vitamin E in male rats

    International Nuclear Information System (INIS)

    Cisplatin is one of the most active antineoplastic drugs showing a broad therapeutic activity spectrum against different types of human neoplasms. To elvaute the subacute toxicity of the drug and to test the probable preventive effect of vitamin E in rats, forty-eight male albino rats were used in this study. Animals were classified into four groups, control, vitamin E, cisplatin and vitamin E with cisplatin. Vitamin E was administered orally at a dose of 2 mg/rat for two weeks prior to cisplatin intraperitoneal injection (5 mg/kg as a single dose) and then administration of vitamin E which was continued for two another weeks (end of experiment). The changes in body weight, counts of RBC and WBC, lipid peroxide, Na+, K+, chromosomal aberration and aldosterone hormone were recorded. Cisplatin administration caused 57.4% and 60% mortality at 3 and 5 weeks intervals. Regular intake of vitamin E induced significant role against the physiological disorders and chromosomal alterations occurred after cisplatin drug administration. The present study is directed to demonstrate the toxic effect of cisplatin on mortality, body weight, blood cells, aldosterone hormone, lipid peroxidation, Na+, K+, urea, creatinia as well as on chromosomal pattern and the efficacy of vitamin E in modulating cisplatin toxicity

  9. Protective effect of speman on cisplatin-induced testicular and epididymal toxicity in mice

    Directory of Open Access Journals (Sweden)

    S B Sainath

    2011-01-01

    Full Text Available Testicular cancer is the most common cancer affecting men of reproductive age. Advances in treatment of the disease, which includes the administration of cisplatin, have brought the 5-year survival rate to over 90%. This high cure rate, coupled with young age of patients, makes elucidation of the impact of the treatment on reproduction become increasingly important. The objective of the present study was to investigate the protective effect of speman, a non-hormonal herbal formulation, on cisplatin-induced suppressed male reproductive health in mice. Male mice were treated with cisplatin or speman alone or in combination and assessed for spermatogenesis and steroidogenesis. Significant decrease in the weights of testes and epididymis was observed in cisplatin treated animals. Injection of cisplatin significantly decreased epididymal sperm count, viable sperms, motile sperms and hypo-osmotic swelling (HOS-tail coiled sperms with a significant reduction in the testicular steroidogenic enzyme activities and serum testosterone levels, whereas co-administration of speman with cisplatin showed a significant improvement in the selected reproductive parameters over cisplatin alone treated mice indicating the beneficial effect of speman to combat cisplatin-induced suppressed reproduction in male mice.

  10. Pharmacogenomics of Cisplatin Sensitivity in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Maimon C. Rose

    2014-10-01

    Full Text Available Cisplatin, a platinum-based chemotherapeutic drug, has been used for over 30 years in a wide variety of cancers with varying degrees of success. In particular, cisplatin has been used to treat late stage non-small cell lung cancer (NSCLC as the standard of care. However, therapeutic outcomes vary from patient to patient. Considerable efforts have been invested to identify biomarkers that can be used to predict cisplatin sensitivity in NSCLC. Here we reviewed current evidence for cisplatin sensitivity biomarkers in NSCLC. We focused on several key pathways, including nucleotide excision repair, drug transport and metabolism. Both expression and germline DNA variation were evaluated in these key pathways. Current evidence suggests that cisplatin-based treatment could be improved by the use of these biomarkers.

  11. Pharmacogenomics of Cisplatin Sensitivity in Non-small Cell Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    Maimon C Rose; Elina Kostyanovskaya; R Stephanie Huang

    2014-01-01

    Cisplatin, a platinum-based chemotherapeutic drug, has been used for over 30 years in a wide variety of cancers with varying degrees of success. In particular, cisplatin has been used to treat late stage non-small cell lung cancer (NSCLC) as the standard of care. However, therapeutic outcomes vary from patient to patient. Considerable efforts have been invested to identify biomark-ers that can be used to predict cisplatin sensitivity in NSCLC. Here we reviewed current evidence for cisplatin sensitivity biomarkers in NSCLC. We focused on several key pathways, including nucleotide excision repair, drug transport and metabolism. Both expression and germline DNA variation were evaluated in these key pathways. Current evidence suggests that cisplatin-based treatment could be improved by the use of these biomarkers.

  12. EFFECTS OF C60 FULLERENE — CISPLATIN COMPLEX ON HONEYBEE Apis mellifera L.

    Directory of Open Access Journals (Sweden)

    Kuznietsova H. M.

    2015-08-01

    Full Text Available The toxicity of С60 fullerene, traditional cytostatic cisplatin and С60 fullerene-cisplatin complex on honeybee Apis mellifera L. toxicity estimation test system was assessed. Water-soluble pristine C60 fullerenes were nontoxic for honeybee when consumed with the food in doses equivalent nontoxic and effective ones for mammalian. Cisplatin toxicity for honeybee in the doses exceed the same for mammalian in 2 times was observed as fallows: honeybee 56% death occurred after consumption of 60 mg/kg of bee weight. С60 fullerene-cisplatin complex proved to be more toxic for honeybee in comparison with free cisplatin and caused honeybee 50% lethality after consumption of 40 mg/kg bee weight.

  13. Decursin Mediated Protection on Cisplatin-induced Nephrotoxicity in SD Rats and BDF1 Mice

    Institute of Scientific and Technical Information of China (English)

    Jiang Cheng-zhe; Han Ilhyun; Choung Seyoung

    2012-01-01

    Tisplatin is one of the valuable icancer agents against several types of neoplasm. However, nephrotoxicity is the major adverse effect representing in cisplatin therapy. In this study, the animal tests detecting protective effects of a natural compound, Decursin, on cisplatin-induced nephrotoxicity were examined by using in vivo model. Pretreatment Decursin 10, 20 and 40 mg · kg^-1 at 48, 24 and 6 h, and administration of a single dose of Cisplatin 5.2 mg · kg^-1. Nephrotoxicity was evaluated by serum BUN and creatinine examination. There was significant difference in body weights, serum BUN and creatinine levels of the normal group. Based on the new understanding of the protective mechanisms of cisplatin-induced nephrotocivity, new strategies can be developed to prevent renal injury or to enhance recovery after cisplatin treatment.

  14. Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer

    DEFF Research Database (Denmark)

    Roberts, J T; von der Maase, H; Sengeløv, L;

    2006-01-01

    PURPOSE: To compare long-term survival in patients with locally advanced and metastatic transitional cell carcinoma (TCC) of the urothelium treated with gemcitabine plus cisplatin (GC) or methotrexate/vinblastine/doxorubicin/cisplatin (MVAC). PATIENTS AND METHODS: Efficacy data from a large....... These results strengthen the role of GC as a standard of care in patients with locally advanced and metastatic transitional-cell carcinoma (TCC)....

  15. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer

    DEFF Research Database (Denmark)

    Maase, Hans von der; Sengeløv, Lisa; Roberts, James T.;

    2005-01-01

    PURPOSE: To compare long-term survival in patients with locally advanced       or metastatic transitional cell carcinoma (TCC) of the urothelium treated       with gemcitabine/cisplatin (GC) or       methotrexate/vinblastine/doxorubicin/cisplatin (MVAC). PATIENTS AND       METHODS: Efficacy data...... patients with locally advanced or       metastatic TCC...

  16. Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice

    Directory of Open Access Journals (Sweden)

    Carlton Susan M

    2010-03-01

    Full Text Available Abstract Background Cisplatin is primarily used for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Both are known to cause dose related, cumulative toxic effects on the peripheral nervous system and thirty to forty percent of cancer patients receiving these agents experience painful peripheral neuropathy. The mechanisms underlying painful platinum-induced neuropathy remain poorly understood. Previous studies have demonstrated important roles for TRPV1, TRPM8, and TRPA1 in inflammation and nerve injury induced pain. Results In this study, using real-time, reverse transcriptase, polymerase chain reaction (RT-PCR, we analyzed the expression of TRPV1, TRPM8, and TRPA1 induced by cisplatin or oxaliplatin in vitro and in vivo. For in vitro studies, cultured E15 rat dorsal root ganglion (DRG neurons were treated for up to 48 hours with cisplatin or oxaliplatin. For in vivo studies, trigeminal ganglia (TG were isolated from mice treated with platinum drugs for three weeks. We show that cisplatin and oxaliplatin-treated DRG neurons had significantly increased in TRPV1, TRPA1, and TRPM8 mRNA expression. TG neurons from cisplatin treated mice had significant increases in TRPV1 and TRPA1 mRNA expression while oxaliplatin strongly induced only TRPA1. Furthermore, compared to the cisplatin-treated wild-type mice, cisplatin-treated TRPV1-null mice developed mechanical allodynia but did not exhibit enhancement of noxious heat- evoked pain responses. Immunohistochemistry studies showed that cisplatin-treated mice had no change in the proportion of the TRPV1 immunopositive TG neurons. Conclusion These results indicate that TRPV1 and TRPA1 could contribute to the development of thermal hyperalgesia and mechanical allodynia following cisplatin-induced painful neuropathy but that TRPV1 has a crucial role in cisplatin-induced thermal hyperalgesia in vivo.

  17. Effect of boldo (Peumus boldus Molina) infusion on lipoperoxidation induced by cisplatin in mice liver.

    Science.gov (United States)

    Fernández, J; Lagos, P; Rivera, P; Zamorano-Ponce, E

    2009-07-01

    Peumus boldus Molina (Monimiaceae), commonly referred to as 'boldo', is used in traditional Chilean medicine to treat hepatic and gastrointestinal diseases. Its leaves are rich in antioxidant compounds, principally alkaloids and flavonoids. This study evaluates the protective effect of a complete boldo leaf infusion on lipoperoxidation (MDA determination at 532 nm) induced by cisplatin in mice liver. To determine if the observed effect can be explained by the action of boldine or catechin, each compound was studied separately. The mice were divided into 8 groups (n = 6): (I) not treated; (II) treated with cisplatin 6 mg/Kg b.w.; (III) treated with boldo leaf infusion 5%; (IV) pretreated with boldo leaf infusion 5% and treated with cisplatin 6 mg/Kg b.w.; (V) treated with boldine 50 mg/Kg b.w.; (VI) pretreated with boldine 50 mg/Kg b.w. and treated with cisplatin 6 mg/kg.b.w.; (VII) treated with catechin; and (VIII) pretreated with catechin 50 mg/Kg b.w. and treated with cisplatin 6 mg/Kg b.w. As expected, the treatment with cisplatin significantly increased (p < 0.01) lipoperoxidation in comparison with the non-treated group. Pretreatment with boldo leaf infusion significantly diminished (p < 0.05) the lipoperoxidation induced by cisplatin with respect to the animals not pretreated with the infusion. The pretreatments with boldine and catechin significantly diminished (p < 0.05) the lipoperoxidation induced by cisplatin with respect to the group treated only with cisplatin. The results suggest that the boldo infusion is acting as a protector with respect to the oxidative hepatic damage caused by cisplatin, and that this protective ability would be due to the presence in the infusion of the natural antioxidants boldine and principally catechin. These findings suggest the potential use of the infusion as a chemoprotector. PMID:19145575

  18. An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.

    Science.gov (United States)

    Xylinas, Evanguelos; Hassler, Melanie R; Zhuang, Dazhong; Krzywinski, Martin; Erdem, Zeynep; Robinson, Brian D; Elemento, Olivier; Clozel, Thomas; Shariat, Shahrokh F

    2016-01-01

    Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is effective in MIBC; however, it has not been widely adopted by the community. One reason is that many patients do not respond to neoadjuvant chemotherapy, and no biomarker currently exists to identify these patients. It is also not clear whether a strategy to sensitize chemoresistant patients may exist. We sought to identify cisplatin-resistance patterns in preclinical models of bladder cancer, and test whether treatment with the epigenetic modifier decitabine is able to sensitize cisplatin-resistant bladder cancer cell lines. Using a screening approach in cisplatin-resistant bladder cancer cell lines, we identified dysregulated genes by RNA sequencing (RNAseq) and DNA methylation assays. DNA methylation analysis of tumors from 18 patients receiving cisplatin-based chemotherapy was used to confirm in vitro results. Cisplatin-resistant bladder cancer cells were treated with decitabine to investigate epigenetic sensitization of resistant cell lines. Our results show that HOXA9 promoter methylation status is associated with response to cisplatin-based chemotherapy in bladder cancer cell lines and in metastatic bladder cancer. Bladder cancer cells resistant to cisplatin chemotherapy can be sensitized to cisplatin by the DNA methylation inhibitor decitabine. Our data suggest that HOXA9 promoter methylation could serve as potential predictive biomarker and decitabine might sensitize resistant tumors in patients receiving cisplatin-based chemotherapy. PMID:27598218

  19. Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Kothandapani, Anbarasi [Department of Biochemistry and Cancer Biology, University of Toledo-Health Science Campus, Toledo, OH 43614 (United States); Gopalakrishnan, Kathirvel [Physiological Genomics Laboratory, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614 (United States); Kahali, Bhaskar; Reisman, David [Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, FL 32610 (United States); Patrick, Steve M., E-mail: Stephan.Patrick@utoledo.edu [Department of Biochemistry and Cancer Biology, University of Toledo-Health Science Campus, Toledo, OH 43614 (United States)

    2012-10-01

    Chromatin remodeling complex SWI/SNF plays important roles in many cellular processes including transcription, proliferation, differentiation and DNA repair. In this report, we investigated the role of SWI/SNF catalytic subunits Brg1 and Brm in the cellular response to cisplatin in lung cancer and head/neck cancer cells. Stable knockdown of Brg1 and Brm enhanced cellular sensitivity to cisplatin. Repair kinetics of cisplatin DNA adducts revealed that downregulation of Brg1 and Brm impeded the repair of both intrastrand adducts and interstrand crosslinks (ICLs). Cisplatin ICL-induced DNA double strand break repair was also decreased in Brg1 and Brm depleted cells. Altered checkpoint activation with enhanced apoptosis as well as impaired chromatin relaxation was observed in Brg1 and Brm deficient cells. Downregulation of Brg1 and Brm did not affect the recruitment of DNA damage recognition factor XPC to cisplatin DNA lesions, but affected ERCC1 recruitment, which is involved in the later stages of DNA repair. Based on these results, we propose that SWI/SNF chromatin remodeling complex modulates cisplatin cytotoxicity by facilitating efficient repair of the cisplatin DNA lesions. -- Highlights: Black-Right-Pointing-Pointer Stable knockdown of Brg1 and Brm enhances cellular sensitivity to cisplatin. Black-Right-Pointing-Pointer Downregulation of Brg1 and Brm impedes the repair of cisplatin intrastrand adducts and interstrand crosslinks. Black-Right-Pointing-Pointer Brg1 and Brm deficiency results in impaired chromatin relaxation, altered checkpoint activation as well as enhanced apoptosis. Black-Right-Pointing-Pointer Downregulation of Brg1 and Brm affects recruitment of ERCC1, but not XPC to cisplatin DNA lesions.

  20. PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Huijuan; Wang, Ke; Liu, Wenxin; Hao, Quan, E-mail: quan_haotj@126.com

    2014-02-07

    Highlights: • Overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin. • KRT10 is a downstream molecule of PTEN involved in the resistance-reversing effect. • Overexpression of KRT10 enhanced the chemosensitivity of C13K cells to cisplatin. - Abstract: Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer.

  1. PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression

    International Nuclear Information System (INIS)

    Highlights: • Overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin. • KRT10 is a downstream molecule of PTEN involved in the resistance-reversing effect. • Overexpression of KRT10 enhanced the chemosensitivity of C13K cells to cisplatin. - Abstract: Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer

  2. Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway

    Science.gov (United States)

    Wu, Tao; Wang, Min-Cong; Jing, Li; Liu, Zhi-Yan; Guo, Hui; Liu, Ying; Bai, Yi-Yang; Cheng, Yang-Zi; Nan, Ke-Jun; Liang, Xuan

    2015-01-01

    Resistance to cisplatin-based therapy is a major challenge in the control of lung cancer progression. However, the underlying mechanisms remain largely unclear. Autophagy is closely associated with resistance to lung cancer therapy, but the function of autophagy in cisplatin treatment is still controversial. Here, we investigated whether autophagy was involved in lung adenocarcinoma resistance to cisplatin and further elucidated the underlying molecular mechanisms. Cisplatin-refractory lung adenocarcinoma cells increased autophagic vacuole formation detected by monodansylcadaverine staining. When exposed to cisplatin, lung adeno-carcinoma cells demonstrated increased levels of autophagy detected by MAP1A/1B LC3B and mammalian homologue of yeast Atg6 (Beclin-1) expression using Western blot analysis. Activation of cisplatin-induced autophagic flux was increased by using chloroquine (CQ), which can accumulate LC3B-II protein and increase punctate distribution of LC3B localization. The combination of cisplatin with CQ was more potent than cisplatin alone in inhibiting lung adenocarcinoma cell growth, which also increased cisplatin-induced apoptosis. Compared to cisplatin treatment alone, the combination of cisplatin and CQ decreased p-AMPK and increased p-mTOR protein expressions, in addition, the AMPK inhibitor Compound C plus cisplatin downregulated p-AMPK and upregulated p-mTOR as well as depressed LC3B cleavage. These findings demonstrate that activation of autophagy is a hallmark of cisplatin exposure in human lung adenocarcinoma cells, and that there is a cisplatin-induced autophagic response via activation of the AMPK/mTOR signaling pathway. We speculate that autophagy can be used as a novel therapeutic target to overcome cisplatin-resistant lung adenocarcinoma. PMID:26715839

  3. Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin

    Directory of Open Access Journals (Sweden)

    Jacquemont Céline

    2012-04-01

    Full Text Available Abstract Background Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment. Since the Fanconi anemia (FA pathway is a DNA damage response pathway required for cellular resistance to DNA interstrand crosslinking agents, identification of small molecules that inhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin. Results Through a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel proteasome inhibitor (Chembridge compound 5929407. Isobologram analyses demonstrated that half of the identified molecules sensitized ovarian cancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, including bortezomib (proteasome inhibitor, CA-074-Me (cathepsin B inhibitor and 17-AAG (HSP90 inhibitor, synergized with cisplatin specifically in FA-proficient ovarian cancer cells (2008 + FANCF, but not in FA-deficient isogenic cells (2008. In addition, geldanamycin (HSP90 inhibitor and two CHK1 inhibitors (UCN-01 and SB218078 exhibited a significantly stronger synergism with cisplatin in FA

  4. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qing [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Guo, Dong [Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Dong, Zhongqi [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Zhang, Wei [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Zhang, Lei; Huang, Shiew-Mei [Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD (United States); Polli, James E. [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Shu, Yan, E-mail: yshu@rx.umaryland.edu [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States)

    2013-11-15

    The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT{sub 3}) receptor antagonists, such as ondansetron, should be investigated in patients. - Highlights: • Nephrotoxicity significantly limits clinical use of the chemotherapeutic

  5. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

    International Nuclear Information System (INIS)

    The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, such as ondansetron, should be investigated in patients. - Highlights: • Nephrotoxicity significantly limits clinical use of the chemotherapeutic cisplatin

  6. A high-performance liquid chromatographic assay for determination of cisplatin in plasma, cancer cell, and tumor samples.

    Science.gov (United States)

    Lopez-Flores, A; Jurado, R; Garcia-Lopez, P

    2005-01-01

    A method for determination of cis-diaminedichloroplatinum (II) (cisplatin) in ultrafiltered plasma, cell, and tumour samples is described. Cisplatin separation was carried out on a reversed-phase column using methanol-acetonitrile-water as the mobile phase. The flow rate was maintained constant at 1.6 mL/min and analysis was performed at 23 degrees C. Detection was carried out by absorbance at 254 nm. The method was linear in the range of 0.2-10 microg/mL, and the coefficients of variation were accumulation of cisplatin in cancer cells and in tumours of mice receiving treatment with cisplatin and evaluated the pharmacokinetics of cisplatin in nu/nu mice after intraperitoneal (i.p.) administration. The method proved to be adequate for measuring cisplatin both in vitro and in vivo and could be suitable for studies of cisplatin pharmacokinetics in animal models. PMID:16112590

  7. Toxic effects of cisplatin cytostatic drug in mussel Mytilus galloprovincialis.

    Science.gov (United States)

    Trombini, Chiara; Garcia da Fonseca, Taina; Morais, Matilde; Rocha, Thiago Lopes; Blasco, Julián; Bebianno, Maria João

    2016-08-01

    Antineoplastic drugs used in chemotherapy were detected in aquatic environment: despite the very low concentrations (ng L(-1) to ug L(-1)), due to their potent mechanism of action they could have adverse effects on non-target aquatic organisms particularly under chronic exposure. Cisplatin (CDDP) is one of the most effective anticancer drug currently in use but information on its ecotoxicological effects is very limited. In this study, Mytilus galloprovincialis was used to investigate the toxic effects related to CDDP exposure. Mussels were exposed to cisplatin (100 ng L(-1)) for 14 days: antioxidant (superoxide dismutase, catalase, total and selenium-dependent glutathione peroxidase) and phase II (glutathione-S-transferase) enzymes activities, oxidative damage (lipid peroxidation), genotoxicity (DNA damage) and neurotoxicity (acetylcholinesterase) was evaluated. Results indicate that CDDP at tested concentration induce changes in the antioxidant capacity, oxidative stress in target organs (digestive gland and gills) as well as DNA damage in mussel hemocytes and neurotoxicity representing a risk for non-target organisms. PMID:27183200

  8. Specific cationic emission of cisplatin following ionization by swift protons

    Science.gov (United States)

    Moretto-Capelle, Patrick; Champeaux, Jean-Philippe; Deville, Charlotte; Sence, Martine; Cafarelli, Pierre

    2016-05-01

    We have investigated collision-induced ionization and fragmentation by 100 keV protons of the radio sensitizing molecule cisplatin, which is used in cancer treatments. A large emission of HCl+ and NH2+ is observed, but surprisingly, no cationic fragments containing platinum are detected, in contrast to ionization-dissociation induced by electronic collision. Theoretical investigations show that the ionization processes take place on platinum and on chlorine atoms. We propose new ionization potentials for cisplatin. Dissociation limits corresponding to the measured fragmentation mass spectrum have been evaluated and the theoretical results show that the non-observed cationic fragments containing platinum are mostly associated with low dissociation energies. We have also investigated the reaction path for the hydrogen transfer from the NH3 group to the Cl atom, as well as the corresponding dissociation limits from this tautomeric form. Here again the cations containing platinum correspond to lower dissociation limits. Thus, the experimental results suggest that excited states, probably formed via inner-shell ionization of the platinum atom of the molecule, correlated to higher dissociation limits are favored.

  9. Overexpression of long non-coding RNA PVT1 in ovarian cancer cells promotes cisplatin resistance by regulating apoptotic pathways.

    Science.gov (United States)

    Liu, Enling; Liu, Zheng; Zhou, Yuxiu; Mi, Ruoran; Wang, Dehua

    2015-01-01

    Ovarian cancer is the most lethal gynecologic malignancy. Cisplatin is a very effective cancer chemotherapy drug, but cisplatin resistance is a crucial problem of therapy failure. Overexpression of PVT1 has been demonstrated in ovarian cancer. The mRNA level of PVT1 in ovarian cancer tissues of cisplatin-resistant patients and cisplatin-sensitive patients, cisplatin-resistant cells SKOV-3/DDP and A2780/DDP, cisplatin-sensitive cells SKOV-3 and A2780 were determined by qRT-PCR. The influence of the knockdown or overexpression of PVT1 on cisplatin resistance was measured by measuring the cytotoxicity of cisplatin and the apoptotic rate of ovarian cancer cells was detected by CCK-8 assay and flow cytometry, respectively. The mRNA levels and protein expression of TGF-β1, Smad4, p-Smad4 and Caspase-3 in apoptotic pathways were determined. The mRNA level of PVT1 was significantly higher in ovarian cancer tissues of cisplatin-resistant patients and cisplatin-resistant cells. SKOV-3/DDP and A2780/DDP cell viability and the percentage of apoptotic cells after transfection with PVT-1 siRNA and treated with cisplatin was markedly lower and higher than the control, respectively. Moreover, the overexpression of PVT1 exhibited the anti-apoptotic property in SKOV-3 and A2780 cells after transfection with LV-PVT1-GFP and treated with cisplatin. The mRNA levels and protein expression of TGF-β1, p-Smad4 and Caspase-3 were much higher in cisplatin-resistant cells transfected with siPVT1. Overexpression of LncRNA PVT1 in ovarian cancer promotes cisplatin resistance by regulating apoptotic pathways. PMID:26884974

  10. Effects of Roselle and Ginger on cisplatin-induced reproductive toxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Amr Amin; AlaaEldin A. Hamza

    2006-01-01

    Aim: To evaluate the protective effects of Hibiscus sabdariffa (Roselle) and Zingiber officinale (Ginger) against cisplatin-induced reproductive toxicity in rats and to study the mechanisms underlying these effects. Methods:which began 21 days before a single cisplatin I.p. Injection (10 mg/kg body weight). Results: Extracts of H. Sabdariffa and Z. Officinale reduced the extent of cisplatin-induced sperm abnormality and enhanced sperm motility. Both extracts restored the control level of malondialdehyde (MDA) (lipid peroxidation marker) in the cisplatin-treated testis.The cisplatin injection induced decline in the levels of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were significantly reversed to control levels in groups where cisplatin was preceded by the administration of either H. Sabdariffa or Z. Officinale. Conclusion: Both H. Sabdariffa and Z. Officinale treatment increased the activities of testicular antioxidant enzymes and restored sperm motility of cisplatin-treated rats. The protective effects of tested plants are, therefore, suggested to be mediated by their potent antioxidant activities.

  11. The effects of oral grape seed extract on Cisplatin-induced cytogenotoxicity in mice

    International Nuclear Information System (INIS)

    The present investigation was directed to study the possible chemoprotective activity of orally administered grape seed extract (GSE) against cisplatin-induced cytotoxicity and genotoxicity towards mouse somatic and germinal cells in vivo. Pretreatment of mice with GSE (100mg/kg/day) for 7 days and simultaneously with a single dose of cisplatin (2.2 or 5.5 mg/kg, i.p.) for another day, significantly reduced the frequency of bone marrow micronucleated polychromatic erythrocytes by factors of 1.9 and 1.28, respectively. Furthermore, GSF caused a reduction in bone marrow suppression induced by cisplatin treatment, particularly before the lower dose. In mail germline, orally administration of GSE (100mg/kg/day) for 7 consecutive days before and 7 consecutives days after treatment with a single dose of cisplatin (2.2 or 5.5 mg/kg, i.p.), significantly elevated the levels of sperm motility reduced by cisplatin treatment. Furthermore, GSE significantly decreased the elevated levels sperm head abnormality induced with cisplatin by factors of 1.6 and 1.2, respectively. Our results indicate that GSE plays a role in attenuating the genotoxicity induced by cisplatin and many provide the development of secondary malignancy and abnormal reproductive outcomes risk. (author)

  12. Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase.

    Science.gov (United States)

    LaPensee, Elizabeth W; Schwemberger, Sandy J; LaPensee, Christopher R; Bahassi, El Mustapha; Afton, Scott E; Ben-Jonathan, Nira

    2009-08-01

    Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients. Given that prolactin (PRL) acts as an anti-apoptotic/survival factor in the breast, we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs. Treatment of breast cancer cells with PRL caused variable resistance to taxol, vinblastine, doxorubicin and cisplatin. PRL prevented cisplatin-induced G(2)/M cell cycle arrest and apoptosis. In the presence of PRL, significantly less cisplatin was bound to DNA, as determined by mass spectroscopy, and little DNA damage was seen by gamma-H2AX staining. PRL dramatically increased the activity of glutathione-S-transferase (GST), which sequesters cisplatin in the cytoplasm; this increase was abrogated by Jak and mitogen-activated protein kinase inhibitors. PRL upregulated the expression of the GSTmu, but not the pi, isozyme. A GST inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL. In conclusion, PRL confers resistance against cisplatin by activating a detoxification enzyme, thereby reducing drug entry into the nucleus. These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer, which is characterized by high expression of both PRL and its receptor. Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options. PMID:19443905

  13. Effect of the BRCA1-SIRT1-EGFR axis on cisplatin sensitivity in ovarian cancer

    Science.gov (United States)

    Li, Da; Wu, Qi-Jun; Bi, Fang-Fang; Chen, Si-Lei; Zhou, Yi-Ming; Zhao, Yue; Yang, Qing

    2016-01-01

    There is accumulating evidence that breast cancer 1 (BRCA1), sirtuin 1 (SIRT1), and epidermal growth factor receptor (EGFR) help to modulate cisplatin cytotoxicity. The role of dynamic crosstalk among BRCA1, SIRT1, and EGFR in cisplatin sensitivity remains largely unknown. We found that BRCA1, SIRT1, and EGFR levels were increased in cisplatin-resistant ovarian cancers compared with those in cisplatin-sensitive ovarian cancers. Hypomethylation in the BRCA1 promoter was associated with BRCA1 activation, significantly elevated SIRT1 levels, decreased nicotinamide adenine dinucleotide (NAD)-mediated SIRT1 activity, and decreased EGFR levels. Treatment with 5 and 10 μg/ml cisplatin induced a gradual increase in BRCA1 and SIRT1 levels and a gradual decrease in NAD levels and NAD-mediated SIRT1 activity, whereas EGFR levels were increased or decreased by treatment with 5 or 10 μg/ml cisplatin, respectively. The overexpression of SIRT1 or the enhancement of SIRT1 activity synergistically enhanced the BRCA1-mediated effects on EGFR transcription. In contrast, the knockdown of SIRT1 or the inhibition of SIRT1 activity inhibited the BRCA1-mediated effects on EGFR transcription. BRCA1 regulates EGFR through a BRCA1-mediated balance between SIRT1 expression and activity. Those results improve our understanding of the basic molecular mechanism underlying BRCA1-related cisplatin resistance in ovarian cancer.

  14. Improvement of combined modality therapy with cisplatin and radiation using electroporation of tumors

    International Nuclear Information System (INIS)

    Purpose: To evaluate whether a local drug delivery method, i.e., electroporation of tumors, increases the radiosensitizing effect of cisplatin. Methods and Materials: Subcutaneous Ehrlich-Lettre ascites (EAT) tumors in CBA mice were treated either by cisplatin, electric pulses, or ionizing radiation. In electrochemotherapy protocol, electric pulses were given to the tumor 3 min after intravenous injection of cisplatin. The interval between electrochemotherapy and irradiation was 20 min. Treatment effectiveness was evaluated by tumor growth delay and local tumor curability. Results: Electrochemotherapy of EAT tumors proved to be effective treatment, resulting in 12% tumor cures, whereas treatment with cisplatin or electric pulses alone did not yield any tumor cures. As expected, injection of cisplatin 20 min prior to irradiation, increased radioresponse of tumors from 27% to 73% tumor cures. Electroporation of tumors also increased radiation response of tumors to 54% tumor cures. Electrochemotherapy given prior to irradiation increased radioresponsiveness of tumors, resulting in 92% tumor cures. Conclusions: This study shows that delivery of cisplatin into the cells by electroporation of tumors increases the radiosensitizing effect of cisplatin. However, some effect may also be ascribed to application of electric pulses to the tumors that in our study also predisposed tumor cells to radiation damage

  15. Structure Determination of Cisplatin-Amino Acid Analogues by Infrared Multiple Photon Dissociation Action Spectroscopy

    Science.gov (United States)

    He, Chenchen; Bao, Xun; Zhu, Yanlong; Strobehn, Stephen; Kimutai, Bett; Nei, Y.-W.; Chow, C. S.; Rodgers, M. T.; Gao, Juehan; Oomens, J.

    2015-06-01

    To gain a better understanding of the binding mechanism and assist in the optimization of relevant drug and chemical probe design, both experimental and theoretical studies were performed on a series of amino acid-linked cisplatin derivatives, including glycine-, lysine-, and ornithine-linked cisplatin, Gplatin, Kplatin, and Oplatin, respectively. Cisplatin, the first FDA-approved platinum-based anticancer drug, has been widely used in cancer chemotherapy. Its pharmacological mechanism has been identified as its ability to coordinate to genomic DNA, and guanine is its major target. In previous reports, cisplatin was successfully utilized as a chemical probe to detect solvent accessible sites in ribosomal RNA (rRNA). Among the amino-acid-linked cisplatin derivatives, Oplatin exhibits preference for adenine over guanine. The mechanism behind its different selectivity compared to cisplatin may relate to its potential of forming a hydrogen bond between the carboxylate group in Pt (II) complex and the 6-amino moiety of adenosine stabilizes A-Oplatin products. Tandem mass spectrometry analysis also indicates that different coordination sites of Oplatin on adenosine affect glycosidic bond stability. Infrared multiple photon dissociation (IRMPD) action spectroscopy experiments were performed on all three amino acid-linked cisplatin to characterize their structures. An extensive theoretical study has been performed on Gplatin to guide the selection of the most effective theory and basis set based on its geometric information. The results for Gplatin provide the foundation for characterization of the more complex amino acid-linked cisplatin derivatives, Oplatin and Kplatin. Structural and energetic information elucidated for these compounds, particularly Oplatin reveal the reason for its alternative selectivity compared to cisplatin.

  16. Ondansetron Can Enhance Cisplatin-Induced Nephrotoxicity via Inhibition of Multiple Toxin and Extrusion Proteins (MATEs)

    Science.gov (United States)

    Li, Qing; Guo, Dong; Dong, Zhongqi; Zhang, Wei; Zhang, Lei K.; Huang, Shiew-Mei; Polli, James E.; Shu, Yan

    2013-01-01

    The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, such as ondansetron, should be investigated in patients. PMID:24001450

  17. Origin of using cisplatin over transplatin for cancer treatment: An ab initio study

    Science.gov (United States)

    Li, Sa; Jena, Puru; Department of Physics, Virginia Commonwealth University Team

    2011-03-01

    Eventhough cisplatin has been used as a chemotherapy anti-cancer drug for over 40 years the thermodynamics and kinetics of the reactions are still largely unknown. Cisplatin molecules are known to be attacked by water molecules before they react with DNA. As a result, two Cl atoms are eliminated. The active piece in the cell, therefore, is not cisplatin but (NH3)2 Pt 2+ . To explain why only cisplatin but not transplatin functions as anticancer drug, we used first principles method to study the dechlorination process in cis- and transplatin. Although transplatin molecule is more stable than cisplatin by 0.52 eV, we found cisplatin to be more favorable for reaction due to the following reasons: 1) the energy cost to remove a Cl atom is less from cisplatin than transplatin. 2) cis-form (NH3)2 Pt 2+ derived from cisplatin with N-Pt-N angle of 97r is lower in energy than trans-form derived from transplatin with N-Pt-N angle of 180r. The rotation barrier for N-Pt-N changing from 180r to 97r is about 1.0 eV. 3) When cis-form of (NH3)2 Pt 2+ reacts with two Guanines in DNA, the two N atoms in Guanines can readily bind to the Pt atom in cisplatin. The transplatin due to steric reasons does not provide that opportunity. This work is supported by grants from the Department of Energy.

  18. Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer

    International Nuclear Information System (INIS)

    P21(WAF1/Cip1) binds to cyclin-dependent kinase complexes and inhibits their activities. It was originally described as an inhibitor of cancer cell proliferation. However, many recent studies have shown that p21 promotes tumor progression when accumulated in the cell cytoplasm. So far, little is known about the correlation between cytoplasmic p21 and drug resistance. This study was aimed to investigate the role of p21 in the cisplatin resistance of ovarian cancer. RT-PCR, western blot and immunofluorescence were used to detect p21 expression and location in cisplatin-resistant ovarian cancer cell line C13* and its parental line OV2008. Regulation of cytoplasmic p21 was performed through transfection of p21 siRNA, Akt2 shRNA and Akt2 constitutively active vector in the two cell lines; their effects on cisplatin-induced apoptosis were evaluated by flow cytometry. Tumor tissue sections of clinical samples were analyzed by immunohistochemistry. p21 predominantly localizes to the cytoplasm in C13* compared to OV2008. Persistent exposure to low dose cisplatin in OV2008 leads to p21 translocation from nuclear to cytoplasm, while it had not impact on p21 localization in C13*. Knockdown of cytoplasmic p21 by p21 siRNA transfection in C13* notably increased cisplatin-induced apoptosis through activation of caspase 3. Inhibition of p21 translocation into the cytoplasm by transfection of Akt2 shRNA into C13* cells significantly increased cisplatin-induced apoptosis, while induction of p21 translocation into the cytoplasm by transfection of constitutively active Akt2 in OV2008 enhanced the resistance to cisplatin. Immunohistochemical analysis of clinical ovarian tumor tissues demonstrated that cytoplasmic p21 was negatively correlated with the response to cisplatin based treatment. Cytoplasmic p21 is a novel biomarker of cisplatin resistance and it may represent a potential therapeutic target for ovarian tumors that are refractory to conventional treatment

  19. The Effect of Mirtazapine on Cisplatin-Induced Oxidative Damage and Infertility in Rat Ovaries

    OpenAIRE

    Durdu Altuner; Mine Gulaboglu; Omer Erkan Yapca; Nihal Cetin

    2013-01-01

    Cisplatin causes infertility due to ovarian toxicity. The toxicity mechanism is unknown, but evidence suggests oxidative stress. In this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p.) and mirtazapine (15 mg/kg p.o.) or mirtazapine (30 mg/kg p.o.) for 10 days. After t...

  20. Comment on: A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats

    Directory of Open Access Journals (Sweden)

    Hamid Nasri

    2013-01-01

    Full Text Available Cisplatin (cis-diamminedichloroplatinum II, as one of the most applicable and potent anticancer medication, is used in the treatment of a various pediatric and adult malignancies. However, it gives side-effects such as renal toxicity which is dose-dependent, and thus limited its usage. Treatment with cisplatin induces the inflammatory mechanisms, which leads to a reduction in the antioxidant levels, leading to a failure of the antioxidant protection against free-radical damage generated by antitumor drugs. The oxidative stress, induced by cisplatin in the kidney was partially inhibited by antioxidant therapy using selenium, glutathione, flavonoids, and superoxide dismutase.

  1. Concomitant radiochemotherapy of cervical cancer. Is it justified to reduce the dosage of cisplatin?

    International Nuclear Information System (INIS)

    Purpose: to review the experiences regarding the therapeutic response and side effects of concomitant radiochemotherapy of cervical cancer carried out with different cisplatin doses. Patients and methods: at the Municipal Center for Oncoradiology, Budapest, Hungary, 92 patients with cervical cancer were treated with concomitant radiochemotherapy in the period between July 2002 and March 2007. The total dose of high-energy external radiation (megavoltage) treatment was 50.4 Gy with a fraction dose of 1.8 Gy on the small pelvis. Before irradiation, cisplatin 40 mg/m2, 30 mg/m2, or 20 mg/m2 was administered once a week. Results: In 17 cases, the cisplatin dose was 30 mg/m2; during radiochemotherapy the number of cisplatin treatments was equal to or more than four in 14 patients (82%). After administering 40 mg/m2 cisplatin to 64 patients, chemotherapy in four or more treatments could only be applied in 37 cases (58%). Eleven patients received cisplatin at the dose of 20 mg/m2; in ten (91%) of them, the number of treatments was four or more. By comparing the side effects, it can be stated that hematologic side effects (mostly leukopenia) grade 3 occurred in 12% of the patients receiving cisplatin 30 mg/m2, and grade G3-4 in 16% of the 40-mg/m2 cisplatin group. For cisplatin 30 mg/m2, 82% of hematologic side effects were in the G1 range. There was no significant difference between the 20- and 30-mg/m2 regimens. As for the gastrointestinal toxicity, similar side effects grade 1 were detected, which occurred in 58% and 38% of the patients receiving 30 mg/m2 and 40 mg/m2, respectively. Conclusion: on the basis of a detailed analysis, the correlation between the number of treatments, the therapeutic and the side effects could be verified. In the course of dose reduction, there was no significant difference when comparing the results of therapy, however, the quality of life was better if cisplatin 30 mg/m2 was administered instead of 40 mg/m2. If cisplatin 20 mg/m2 was given

  2. Fenofibrate reduces cisplatin-induced apoptosis of renal proximal tubular cells via inhibition of JNK and p38 pathways.

    Science.gov (United States)

    Thongnuanjan, Penjai; Soodvilai, Sirima; Chatsudthipong, Varanuj; Soodvilai, Sunhapas

    2016-01-01

    Cisplatin is widely used as a standard chemotherapy for solid tumors. The major adverse effect of cisplatin is nephrotoxicity in proximal tubular cells, via oxidative stress, DNA damage, cell apoptosis, and inflammation. The aim of this study was to investigate the pharmacological effect and mechanism of fibrate drugs on cisplatin-induced renal proximal tubular cell death. Cisplatin decreased cell viability of LLC-PK1 and HK-2 cells in a dose-dependent manner. Cisplatin-induced apoptosis was attenuated by co-treatment with fenofibrate while less so with clofibrate and bezafibrate. Fenofibrate's protective effect was not complimented by co-treatment with GW6471, a PPARα antagonist, indicating the protective effect occurred via a PPARα-independent mechanism. Treating cells with cisplatin induced reactive oxygen species (ROS), c-JUN N-terminal kinase (JNK), and p38 kinase (p38), but not extracellular signal-regulated kinase (ERK). Fenofibrate reversed cisplatin-induced JNK and p38 activation, but had no effect on ROS production. The findings suggest fenofibrate's protective effect on cisplatin-induced cytotoxicity is mediated by inhibition of JNK and p38. Moreover, fenofibrate did not alter cisplatin's antitumor effect on cancer cell lines including T84, SW-480, HepG2, and SK-LU-1 cells. Therefore, fenofibrate may be a candidate agent for further development as an adjuvant to cisplatin treatment. PMID:27193727

  3. Knockdown of Akt Sensitizes Osteosarcoma Cells to Apoptosis Induced by Cisplatin Treatment

    Directory of Open Access Journals (Sweden)

    Changwei Yang

    2011-05-01

    Full Text Available Akt plays an important role in the inhibition of apoptosis induced by chemotherapy and other stimuli. We therefore investigated if knockdown of Akt2 promoted drug-induced apoptosis in cultured osteosarcoma cells in vitro. SAOS-2 cells were transfected with Akt2 siRNA. The sensitivity of the transformed cell line to the chemotherapeutic drug cisplatin was assessed. Reduced expression of Akt2 did not directly inhibit the growth rate of the transfected cells; however, it significantly increased their sensitivity to cisplatin. Knockdown of Akt2, together with cisplatin treatment, promoted the expression of p53 up-regulated modulator of apoptosis (PUMA. It is possible that the augmentation of cisplatin cytotoxicity may be mediated by PUMA activation. The results of this study suggest that knockdown of Akt2 expression may have therapeutic applications in enhancing the efficacy of chemotherapy in patients with osteosarcoma.

  4. Knockdown of Akt Sensitizes Osteosarcoma Cells to Apoptosis Induced by Cisplatin Treatment

    Science.gov (United States)

    Zhang, Guoyou; Li, Ming; Zhu, Xiaodong; Bai, Yushu; Yang, Changwei

    2011-01-01

    Akt plays an important role in the inhibition of apoptosis induced by chemotherapy and other stimuli. We therefore investigated if knockdown of Akt2 promoted drug-induced apoptosis in cultured osteosarcoma cells in vitro. SAOS-2 cells were transfected with Akt2 siRNA. The sensitivity of the transformed cell line to the chemotherapeutic drug cisplatin was assessed. Reduced expression of Akt2 did not directly inhibit the growth rate of the transfected cells; however, it significantly increased their sensitivity to cisplatin. Knockdown of Akt2, together with cisplatin treatment, promoted the expression of p53 up-regulated modulator of apoptosis (PUMA). It is possible that the augmentation of cisplatin cytotoxicity may be mediated by PUMA activation. The results of this study suggest that knockdown of Akt2 expression may have therapeutic applications in enhancing the efficacy of chemotherapy in patients with osteosarcoma. PMID:21686164

  5. Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

    Science.gov (United States)

    Pandey, Ambarish; Sarangi, Sasmit; Chien, Kelly; Sengupta, Poulomi; Papa, Anne-Laure; Basu, Sudipta; Sengupta, Shiladitya

    2014-11-01

    Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

  6. Reversal of cisplatin-induced delay in gastric emptying in rats by ginger (Zingiber officinale).

    Science.gov (United States)

    Sharma, S S; Gupta, Y K

    1998-08-01

    Cisplatin causes nausea, vomiting and inhibition of gastric emptying. We have demonstrated the antiemetic effect of the acetone and ethanolic extract of ginger (Zingiber officinale, Roscoe, Zingiberacae) against cisplatin-induced emesis in dogs. In the present study, the acetone and 50% ethanolic extract of ginger in the doses of 100, 200 and 500 mg/kg (p.o.) and ginger juice, in the doses of 2 and 4 ml/kg, were investigated against cisplatin effect on gastric emptying in rats. All three ginger preparations significantly reversed cisplatin-induced delay in gastric emptying. The ginger juice and acetone extract were more effective than the 50% ethanolic extract. The reversal produced by the ginger acetone extract was similar to that caused by the 5-HT3 receptor antagonist ondansetron; however, ginger juice produced better reversal than ondansetron. Therefore, ginger, an antiemetic for cancer chemotherapy, may also be useful in improving the gastrointestinal side effects of cancer chemotherapy. PMID:9720611

  7. Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

    International Nuclear Information System (INIS)

    Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics. (paper)

  8. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice

    DEFF Research Database (Denmark)

    Hojman, Pernille; Fjelbye, Jonas; Zerahn, Bo;

    2014-01-01

    % (P<0.001), maintained lean body mass (P<0.001) and muscle strength (P<0.001), reversed anorexia and impairments in Akt and protein degradation signalling. Cisplatin-induced muscular inflammation was not prevented by voluntary wheel running, nor was glucose tolerance improved. Exercise training may......Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight......, food intake as well as muscle mass, strength and signalling. Mice were treated weekly with 4 mg/kg cisplatin or saline for 6 weeks, and randomized to voluntary wheel running or not. Cisplatin treatment induced loss of body weight (29.8%, P<0.001), lean body mass (20.6%, P = 0.001), as well as anorexia...

  9. Effect of electroporation on radiosensitization with cisplatin in two cell lines with different chemo- and radiosensitivity

    International Nuclear Information System (INIS)

    Aim. Radiosensitization with cisplatin can be enhanced by electroporation of cells and tumours. The aim of this study was to extend our previous studies on two carcinoma tumour models with different chemo- and radiosensitivity in order to evaluate whether this treatment is effective also on less chemo- and radiosensitive tumour cells. Materials and methods. This in vitro study was performed on carcinoma SCK and EAT-E cells. The cytotoxicity of three-modality treatment consisting of cisplatin, electroporation and irradiation was determined by the clonogenic assay. Results. The radiosensitizing effect of cisplatin on the two cell lines was greatly enhanced by electroporation. By this combined treatment, less chemo and radiosensitive EAT-E cells were rendered as sensitive as more chemo and radiosensitive SCK cells. Conclusion. The enhancement of cisplatin-induced radiosensitization of cells by electroporation could be beneficially used in the treatment of intrinsically less chemo- and radiosensitive tumours. (author)

  10. Carcinoma Matrix Controls Resistance to Cisplatin through Talin Regulation of NF-kB

    Science.gov (United States)

    Eberle, Karen E.; Sansing, Hope A.; Szaniszlo, Peter; Resto, Vicente A.; Berrier, Allison L.

    2011-01-01

    Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012 oral carcinomas to carcinoma matrix supported tumor cell proliferation in response to treatment with cisplatin. Proliferation in response to 30 µM cisplatin was not observed in HN12 cells adherent to other purified extracellular matrices such as Matrigel, collagen I, fibronectin or laminin I. Integrin β1 was important for adhesion to carcinoma matrix to trigger proliferation after treatment with cisplatin. Disruption of talin expression in HN12 cells adherent to carcinoma matrix increased cisplatin induced proliferation. Pharmacological inhibitors were used to determine signaling events required for talin deficiency to regulate cisplatin induced proliferation. Pharmacological inhibition of NF-kB reduced proliferation of talin-deficient HN12 cells treated with 30 µM cisplatin. Nuclear NF-kB activity was assayed in HN12 cells using a luciferase reporter of NF-kB transcriptional activity. Nuclear NF-kB activity was similar in HN12 cells adherent to carcinoma matrix and collagen I when treated with vehicle DMSO. Following treatment with 30 µM cisplatin, NF-kB activity is maintained in cells adherent to carcinoma matrix whereas NF-kB activity is reduced in collagen I adherent cells. Expression of talin was sufficient to trigger proliferation of HN12 cells adherent to collagen I following treatment with 1 and 30 µM cisplatin. Talin overexpression was sufficient to trigger NF-kB activity following treatment with cisplatin in carcinoma matrix adherent HN12 cells in a process disrupted by FAK siRNA. Thus, adhesions within the carcinoma matrix create a matrix environment in which exposure to cisplatin induces proliferation through the function of integrin β1, talin and FAK

  11. Gap junction enhancer increases efficacy of cisplatin to attenuate mammary tumor growth.

    Directory of Open Access Journals (Sweden)

    Stephanie N Shishido

    Full Text Available Cisplatin treatment has an overall 19% response rate in animal models with malignant tumors. Increasing gap junction activity in tumor cells provides the targets to enhance antineoplastic therapies. Previously, a new class of substituted quinolines (PQs acts as gap junction enhancer, ability to increase the gap junctional intercellular communication, in breast cancer cells. We examined the effect of combinational treatment of PQs and antineoplastic drugs in an animal model, showing an increase in efficacy of antineoplastic drugs via the enhancement of gap junctions. Mice were implanted with estradiol-17ß (1.7 mg/pellet before the injection of 1×10⁷ T47D breast cancer cells subcutaneously into the inguinal region of mammary fat pad. Animals were treated intraperitoneally with DMSO (control, cisplatin (3.5 mg/kg, PQ (25 mg/kg, or a combining treatment of cisplatin and PQ. Cisplatin alone decreased mammary tumor growth by 85% while combinational treatment of cisplatin and PQ1 or PQ7 showed an additional reduction of 77% and 22% of tumor growth after 7 treatments at every 2 days, respectively. Histological results showed a significant increase of gap junction proteins, Cx43 and Cx26, in PQ-treated tissues compared to control or cisplatin. Furthermore, evidence of highly stained caspase 3 in tumors of combinational treatment (PQ and cisplatin was seen compared to cisplatin alone. We have showed for the first time an increase in the efficacy of antineoplastic drugs through a combinational treatment with PQs, a specific class of gap junction enhancers.

  12. Selective Cyclooxygenase-2 Inhibitor Prevents Cisplatin-induced Tumorigenesis in A/J Mice

    Directory of Open Access Journals (Sweden)

    Okada,Toshiaki

    2012-06-01

    Full Text Available Cisplatin is used to treat lung cancer;however, it is also a known carcinogen. Cyclooxygenase-2 (COX-2 inhibitors have been shown to prevent carcinogen-induced experimental tumors. We investigated the effect of a COX-2 inhibitor, celecoxib, on cisplatin-induced lung tumors. One hundred twenty 4-week-old A/J mice were divided into 6 groups:group 1, no treatment;group 2, low-dose celecoxib (150mg/kg;group 3, high-dose celecoxib (1,500mg/kg;group 4, cisplatin alone;group 5, cisplatin plus low-dose celecoxib;and group 6, cisplatin plus high-dose celecoxib. Mice in groups 4-6 were administered cisplatin (1.62mg/kg, i.p. once a week for 10 weeks between 7 and 16 weeks of age. All mice were sacrificed at week 30. Tumor incidence was 15.8% in group 1, 25% in group 2, 26.3% in group 3, 60% in group 4, 50% in group 5, and 50% in group 6. Tumor multiplicity was 0.2, 0.3, 0.3, 1.3, 1.0, and 0.6 in groups 1-6, respectively. Tumor multiplicity in the cisplatin-treated mice was reduced by celecoxib treatment in a dose-dependent manner (p<0.05, group 4 vs. group 6. Celecoxib significantly reduced COX-2 expression in cisplatin-induced tumors (p<0.01, group 4 vs. group 6.

  13. Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer

    OpenAIRE

    Roh, Jong-Lyel; Kim, Eun Hye; Park, Jin Young; Kim, Ji Won; Kwon, Minsu; Lee, Byung-Heon

    2014-01-01

    Adaptation to cellular stress is not a vital function of normal cells but is required of cancer cells, and as such might be a sensible target in cancer therapy. Piperlongumine is a naturally occurring small molecule selectively toxic to cancer cells. This study assesses the cytotoxicity of piperlongumine and its combination with cisplatin in head-and-neck cancer (HNC) cells in vitro and in vivo. The effect of piperlongumine, alone and in combination with cisplatin, was assessed in human HNC c...

  14. Amifostine (WR2721) Confers DNA Protection to In Vivo Cisplatin-Treated Murine Peripheral Blood Leukocytes

    OpenAIRE

    Prieto González, E. A.; Fuchs, A. G.; Sánchez, González S.

    2009-01-01

    Amifostine [S-2-3-aminopropil amino ethyl phosphorotioic acid], a modulator agent for antineoplastic drugs involved in free radicals generation has given controversial results in cisplatin treated leukocytes in vitro. We have evaluated the amifostine protection over leukocytes in vivo, using comet assay. Groups of five OF1 male mice were given one of three doses of amifostine (56, 105 and 200 mg/Kg) after a cisplatin single injection (10 mg/Kg). Serum malonyldialdehide levels, catalase and su...

  15. Does dexamethasone enhance control of acute cisplatin induced emesis by ondansetron?

    OpenAIRE

    Smyth, J. F.; Coleman, R E; Nicolson, M.; Gallmeier, W M; Leonard, R C; Cornbleet, M. A.; Allan, S G; Upadhyaya, B K; Bruntsch, U

    1991-01-01

    OBJECTIVE--To determine the contribution of dexamethasone to the efficacy of the 5-hydroxytryptamine antagonist ondansetron in control of cisplatin induced nausea and vomiting. DESIGN--Randomised double blind crossover study. SETTING--Two cancer centres in teaching hospitals, one in the United Kingdom and the other in Germany. SUBJECTS--100 patients (53 men and 47 women) new to cisplatin chemotherapy, 84 of whom completed two consecutive courses of chemotherapy. INTERVENTIONS--Patients were g...

  16. Ondansetron compared with ondansetron plus metoclopramide in the prevention of cisplatin-induced emesis.

    OpenAIRE

    Lee, C. W.; Suh, C. W.; Lee, J. S.; Lee, K. H.; Cho, G. Y.; Kim, S.W.; Kim, S H

    1994-01-01

    To determine the contribution of metoclopramide to the efficacy of ondansetron in control of cisplatin-induced emesis, ondansetron was compared with ondansetron plus metoclopramide for antiemetic efficacy in a randomized double-blind trial. Enrolled 66 patients were treated with cisplatin(60mg/m2) in combination with etoposide, flourouracil, or vinblastine, and randomized to receive either ondansetron alone or ondansetron plus metoclopramide. Sixty patients were evaluable. Complete or major c...

  17. Randomized study on late course accelerated hyperfractionation radiotherapy plus cisplatin in the treatment of esophageal carcinomas

    International Nuclear Information System (INIS)

    Objective: To investigate the therapeutic results of late course accelerated hyperfractionation (LCAH) radiotherapy plus cisplatin as a radiosensitizer in the treatment of esophageal carcinoma. Methods: One hundred and four patients with squamou s cell carcinoma of the esophagus were randomized into two groups: LCAH alone group (53 patients) and LCAH + cisplatin group (51 patients). The same irradiation technique was given for both groups with conventional fractionation (2 Gy daily, 5 times a week) in the first 3 weeks and late course accelerated hyperfractionation (1.5 Cry twice daily, a minimum interfraction interval of 6 hours, 5 days per week) in the last 2 weeks. The total dose was 60 Gy/5 wks. In LCAH + cisplatin group, cisplatin was given simultaneous with 20 mg once daily for 5 days in the 1st and 5th weeks. The acute and late side effects were evaluated during :and after the treatment. Results: The median survival time was 12.2 months and 17.0 months in the LCAH alone group and LCAH + cisplatin group. The 1- and 3-year survival rates in LCAH group were 52.8 % and 20.8%; while those of LCAH + cisplatin group were 58.0 % and 24.0% (P>0.05). The acute gastrointestinal toxicities and hematological toxicities were obvious in LCAH + cisplatin group, but no increased acute esophagitis or late complications was observed. Conclusions: Late course accelerated hyperfractionation radio-therapy used simultaneously with cisplatin tends to increase the overall survival rate compared with the late course accelerated hyperfractionation radiotherapy alone in the treatment of esophageal carcinoma. (authors)

  18. Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo

    OpenAIRE

    Rocha, C R R; Garcia, C C M; Vieira, D B; Quinet, A.; de Andrade-Lima, L C; V. Munford; Belizário, J E; Menck, C F M

    2014-01-01

    Malignant glioma is a severe type of brain tumor with a poor prognosis and few options for therapy. The main chemotherapy protocol for this type of tumor is based on temozolomide (TMZ), albeit with limited success. Cisplatin is widely used to treat several types of tumor and, in association with TMZ, is also used to treat recurrent glioma. However, several mechanisms of cellular resistance to cisplatin restrict therapy efficiency. In that sense, enhanced DNA repair, high glutathione levels an...

  19. Mice with cisplatin and oxaliplatin-induced painful neuropathy develop distinct early responses to thermal stimuli

    OpenAIRE

    Ta Lauren E; Low Philip A; Windebank Anthony J

    2009-01-01

    Abstract Background Cisplatin has been in use for 40 years for treatment of germ line and other forms of cancer. Oxaliplatin is approved for treatment of metastatic colorectal cancer. Thirty to forty percent of cancer patients receiving these agents develop pain and sensory loss. Oxaliplatin induces distinctive cold-associated dysesthesias in up to 80% of patients. Results We have established mouse models of cisplatin and oxaliplatin-induced neuropathy using doses similar to those used in pat...

  20. SOX17 increases the cisplatin sensitivity of an endometrial cancer cell line

    OpenAIRE

    Zhang, Yongli; Jiang, FeiZhou; Bao, Wei; Zhang, Huilin; He, Xiaoying; Wang, Huihui; Wan, Xiaoping

    2016-01-01

    Background Endometrial cancer (EC) is the most common form of malignant gynecological tumor. Treatment with cisplatin (CDDP) is the mainstay of EC chemotherapy. The apoptotic machinery is regarded as an important etiological factor in chemoresistance. Recent evidence has suggested that overexpression of the transcription factor SOX17 prevented apoptosis in tumor cell lines. The effect of SOX17 on apoptosis in EC cisplatin chemoresistance remains unclear. Methods Immunohistochemistry and the r...

  1. REV3L modulates cisplatin sensitivity of non-small cell lung cancer H1299 cells.

    Science.gov (United States)

    Wang, Wenjie; Sheng, Wenjiong; Yu, Chenxiao; Cao, Jianping; Zhou, Jundong; Wu, Jinchang; Zhang, Huojun; Zhang, Shuyu

    2015-09-01

    Lung cancer remains the leading cause of cancer-related mortality worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung cancer. Cisplatin plays a significant role in the management of human lung cancer. Translesion DNA synthesis (TLS) is involved in DNA damage repair. DNA polymerase ζ (Pol ζ) is able to mediate the DNA replication bypass of DNA damage, which is suggested to be involved in chemoresistance. REV3L is the catalytic subunit of Pol ζ. Due to its critical role in translesion DNA synthesis, whether REV3L modulates cisplatin response in NSCLC cells remains unknown. In this study, REV3L overexpression and silencing H1299 cell lines were established. The reports showed that cisplatin induced the expression of REV3L by recruiting Sp1 to its promoter. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. Co-transfection of the reporter with the REV3L overexpression vector or REV3L plus REV7L significantly enhanced the reporter activity. Nuclear condensation and fragmentation of shRNA-REV3L H1299 cells were more pronounced than shRNA-NC H1299 cells after cisplatin exposure, indicating that REV3L overexpression abolished cisplatin-induced DNA damage. Moreover, a forced expression of REV3L conferred the resistance of H1299 cells to cisplatin, whereas the knockdown of REV3L sensitized cisplatin efficacy in H1299 cells. Taken together, we demonstrated that inhibition of REV3L sensitized lung cancer H1299 cells to cisplatin treatment. Thus, REV3L may be a novel target for the chemotherapy of NSCLC. PMID:26165320

  2. Antigenotoxic and anticytotoxic effect of camel milk in mice treated with cisplatin

    OpenAIRE

    Salwa, M. Quita; Lina, A.F. Kurdi

    2010-01-01

    Camel milk (CM) has good nutritive value, in addition to its antigenotoxic and anticytotoxic effects. Therefore the aim of this investigation was to evaluate the capacity of CM to inhibit the micronucleated polychromatic erythrocytes (MnPCEs) in the bone marrow and improve the mitotic activity produced by cisplatin. Cisplatin is one of the most widely used antineoplastic drugs in the treatment of cancer. The 70 adult male Swiss albino mice were divided into seven groups:Gr. I: treated with di...

  3. Economic Analysis of Carboplatin Versus Cisplatin in Lung and Ovarian Cancer

    OpenAIRE

    Zeba M. Khan; Karen L. Rascati; Koeller, Jim M.

    1999-01-01

    Objective: To conduct an economic analysis on the use of carboplatin versus cisplatin over multiple courses in patients with lung [nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC)] or ovarian cancer. Design: This 1-year study was a prospective, multicentre, cost-minimisation evaluation. Direct medical resource utilisation and costs associated with carboplatin and cisplatin administration over 3 to 6 courses of treatment were measured and compared. The perspective of this ev...

  4. Interactions between carbo-platin, cisplatin and ionising radiation in an human ovarian cancer cell line

    International Nuclear Information System (INIS)

    Cisplatin (CDDP) and radiotherapy are frequently used concomitantly in the treatment of various malignant conditions. Because of its toxicity, cisplatin tends to be replaced by carbo-platin (CBDCA) in several indications. Available data regarding the combined effects of cisplatin and carbo-platin with ionising radiation are contradictory. Various concentrations of cisplatin and carbo-platin and various timing of association with radiation have been tested in vitro in a human ovarian cancer cell line. The parental cell line (AOvC-0) and a cisplatin-resistant stable sub-line (AOvC-CDDP/O) (De Pooter et al., Cn Res, 1991) were exposed to carbo-platin (2.5, 5 and 10 M) and to CDDP (1, 2.5 and 5 M), 16 h and 4 h before and 4 h and 16 h after irradiation, respectively. Cell survival was evaluated by a classical clonogenic assay. Exposure of AOvC-0 to 5M CBDCA and of AOvC-CDDDP/O to 10 M CBDCA, before or shortly after radiation exposure, increased cell lethality in a clear supra-additive way, with the highest DEF in the shoulder region of the survival curve and at radiation doses relevant to clinical radiotherapy. In the sensitive cell line, 5 M carbo-platin resulted in an additional lethality equivalent to 4.5 Gy; in the resistant cells, 10M carbo-platin was equivalent to 3.6 Gy. Replacing carbo-platin by cisplatin in an identical set-up demonstrated exclusively simple additivity (DEF = 1). These data suggest that carbo-platin and cisplatin delivered at equi-toxic doses interact with radiation a different way and that, in the present set-up, only carbo-platin enhanced the effects of radiation. Carbo-platin might consequently be a better candidate than cisplatin in some concomitant combinations with radiotherapy. (authors)

  5. Inhibitory activity of Bifidobacterium adolescent combined with cisplatin on melanoma in mice and its mechanism

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The aim of this study is to explore inhibitory activity of Bifidobacterium adolescent combined with cisplatin on the growth of melanoma(B16)in mice and the underlying mechanism.C57 mice were inoculated with B16 cancer cells to construct mouse model of melanoma and treated with bifidobacterium adolescent combined with cisplatin.Ratios of inhibitory activity on the growth of melanoma(B 16)were calculated.Pathology changes of the tumor were observed by HE staining.B 16 cell cycles were examined on a flow cytometer.Lymphocyte proliferation was measured with MTT assay and the T-cell subset was measured by double marked fluorescence.When bifidobacterium of 1010 cfu/L was injected,the ratio of inhibitory activity on the growth of melanoma(B16)reached 54%,which was similar to that of cisplatin group.The ratio of inhibitory activity reached 74.45% when the mice were treated by bifidobacterium combined with cisplatin,HE staining shows that bifidobacterium inhibited B16 cell proliferation and enhanced the cisplati(n)s killing activity on B16 cells.The results of flow cytometry demonstrated that B16 cell proliferation was arrested at G1 stage after treatment with bifidobacterium.The B16 cell proliferation was arrested at S stage after treatment with cisplatin.The CD4+ percentage increased and the difference was significant compared with the normal group after treatment with bifidobacterium,indicating that T-cell immune activity was enhanced.Treatment with bifidobacterium combined with cisplatin can enhance the inhibitory activity on the growth of melanoma(B16)of cisplatin.The mechanism of the inhibitory activity on B 16 cell proliferation is correlated with the enhanced immune activity in mice.

  6. Effect of cisplatin on renal haemodynamics and tubular function in the dog kidney

    DEFF Research Database (Denmark)

    Daugaard, G; Abildgaard, U; Holstein-Rathlou, N H;

    1987-01-01

    Administration of cisplatin (5 mg/kg) to dogs results in polyuric renal failure due initially to a proximal tubular functional impairment. 48-72 h after the cisplatin administration the depressed renal function can be attributed to impairment of proximal as well as distal tubular reabsorptive...... capacities associated with increased renal vascular resistance. The polyuria seems to be due to the impaired reabsorption rate in the distal nephron segments....

  7. Dimethyl Sulfoxide (DMSO) Exacerbates Cisplatin-induced Sensory Hair Cell Death in Zebrafish (Danio rerio)

    OpenAIRE

    Uribe, Phillip M.; Mueller, Melissa A.; Gleichman, Julia S.; Kramer, Matthew D.; Qi Wang; Martha Sibrian-Vazquez; Strongin, Robert M.; Peter S Steyger; Douglas A Cotanche; Matsui, Jonathan I.

    2013-01-01

    Inner ear sensory hair cells die following exposure to aminoglycoside antibiotics or chemotherapeutics like cisplatin, leading to permanent auditory and/or balance deficits in humans. Zebrafish (Danio rerio) are used to study drug-induced sensory hair cell death since their hair cells are similar in structure and function to those found in humans. We developed a cisplatin dose-response curve using a transgenic line of zebrafish that expresses membrane-targeted green fluorescent protein under ...

  8. Effect of electroporation on radiosensitization with cisplatin in two cell lines with different chemo- and radiosensitivity:

    OpenAIRE

    Čemažar, Maja; Grošel, Alenka; Kranjc, Simona; Pipan, Živa; Serša, Gregor

    2003-01-01

    Aim. Radiosensitization with cisplatin can be enhanced by electroporation of cells and tumours. The aim of this study was to extend our previous studies ontwo carcinoma tumour models with different chemo-and radiosensitivity in order to evaluate whether this treatment is effective also on less chemo-and radiosensitive tumour cells. Materials and methods. This in vitro study was performed on carcinoma SCK and EAT-E cells. The cytotoxicity of three-modalitytreatment consisting of cisplatin, ele...

  9. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective

    OpenAIRE

    Barlesi, Fabrice; Chouaid, Christos; Crequit, Jacky; Le Caer, Hervé; Pujol, Jean Louis; Legodec, Julien; Vergnenegre, Alain; Le Treut, Jacques; Fabre-Guillevin, Elizabeth; Loundou, Anderson; Auquier, Pascal; Simeoni, Marie-Claude; Thomas, Pascal A

    2015-01-01

    International audience OBJECTIVES: Adjuvant chemotherapy with vinorelbine plus cisplatin (VC) improves survival in resected non-small-cell lung cancer (NSCLC), but has negative impact on quality of life (QoL). In advanced NSCLC, gemcitabine plus cisplatin (GC) and docetaxel plus cisplatin (DC) exhibit comparable efficacy, with possibly superior QoL compared to VC. This trial investigated these regimens in the adjuvant setting. METHODS: Patients with Stage IB to III NSCLC were eligible foll...

  10. Vetiver oil (Java) attenuates cisplatin-induced oxidative stress, nephrotoxicity and myelosuppression in Swiss albino mice.

    Science.gov (United States)

    Sinha, Sonali; Jothiramajayam, Manivannan; Ghosh, Manosij; Jana, Aditi; Chatterji, Urmi; Mukherjee, Anita

    2015-07-01

    Clinical efficacy of the widely used anticancer drug cisplatin is limited due to its adverse side effects in normal tissues mediated by oxidative stress. This study was aimed to investigate the protective effects of vetiver acetate oil, Java (VO) against cisplatin-induced toxicity in Swiss albino mice. The ameliorating potential was evaluated by orally priming the animals with VO at doses 5, 10 or 20 mg/kg bw for 7 days prior to cisplatin treatment. Acute toxicity in mice was induced by injecting cisplatin (3 mg/kg bw) intraperitoneally for 5 consecutive days. Significant attenuation of renal toxicity was confirmed by histopathological examination, lowered levels of serum blood urea nitrogen, creatinine and reduced DNA damage. VO also compensated deficits in the renal antioxidant system. VO intervention significantly inhibited DNA damage, clastogenic effects, and cell cycle arrest in the bone marrow cells of mice. Hematological parameters indicated attenuation of cisplatin-induced myelosuppression. Overall, this study provides for the first time that VO has a protective role in the abatement of cisplatin-induced toxicity in mice which may be attributed to its antioxidant activity. PMID:25910835

  11. Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines: less involvement of metallothionein

    Directory of Open Access Journals (Sweden)

    Moon Sung-Pyo

    2004-10-01

    Full Text Available Abstract Background Heptaplatin is a new platinum derivative with anticancer activity against various cancer cell lines, including cisplatin-resistant cancer cell lines (Cancer Chemother Pharmacol 1995; 35: 441. Methods Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines has been investigated in connection with metallothionein (MT. Cytotoxicity was determined by an MTT assay. MT mRNA, was determined by RT-PCR assay. Transfection study was carried out to examine the function of MT. Results Of various gastric cancer cell lines, SNU-638 and SNU-601 showed the highest and lowest levels of MT mRNA, respectively, showing 80-fold difference. The IC50 values of SNU-638 to cisplatin, carboplatin and heptaplatin were 11.2-fold, 5.1-fold and 2.0-fold greater than those of SNU-601, respectively. Heptaplatin was more effective against cisplatin-resistant and MT-transfected gastric cancer sublines than cisplatin or carboplatin was. In addition, heptaplatin attenuated cadmium, but not zinc, induction of MT. Conclusion These results indicate that molecular mechanisms of heptaplatin effective against cisplatin-resistant gastric cancer sublines is at least in part due to the less involvement of MT in heptaplatin resistance as well as its attenuation of MT induction.

  12. Amelioration of cisplatin induced nephrotoxicity in Swiss albino mice by Rubia cordifolia extract

    Directory of Open Access Journals (Sweden)

    Joy Jisha

    2008-01-01

    Full Text Available Background: Cisplatin is one of the most effective chemotherapeutics against a wide range of cancers including head, neck, ovarian and lung cancers. But its usefulness is limited by its toxicity to normal tissues, including cells of the kidney proximal tubule. The purpose of the present study is to investigate whether the hydro-alcoholic extract of Rubia cordifolia could decrease the intensity of toxicity in Swiss albino mice. Materials and Methods: Cisplatin at a dose of 12 mg/kg body wt was administered intraperitoneally to Swiss albino mice. Another set of animals was given hydro-alcoholic extract of Rubia cordifolia at different doses along with cisplatin treatment. The antioxidant levels, serum creatinine, serum urea etc. were analyzed. Results: The extract could significantly decrease the cisplatin induced nephrotoxicity as inferred from the tissue antioxidant status in the drug administered animals. Remarkable change was observed in serum creatinine and urea levels. Lipid peroxidation in the kidney and liver tissues was also considerably reduced in Rubia cordifolia extract treated animals. Conclusion: Hydro-alcoholic extracts of Rubia cordifolia are effective in reducing the renal damage caused by the cancer chemotherapeutic drug cisplatin. Since Rubia cordifolia has been in use as an important ingredient in the traditional Ayurvedic system of medicine, it could be safe and beneficial to use this herbal extract as an adjuvant to ameliorate renal damage in patients undergoing cancer chemotherapy with cisplatin.

  13. Mice with cisplatin and oxaliplatin-induced painful neuropathy develop distinct early responses to thermal stimuli

    Directory of Open Access Journals (Sweden)

    Ta Lauren E

    2009-02-01

    Full Text Available Abstract Background Cisplatin has been in use for 40 years for treatment of germ line and other forms of cancer. Oxaliplatin is approved for treatment of metastatic colorectal cancer. Thirty to forty percent of cancer patients receiving these agents develop pain and sensory loss. Oxaliplatin induces distinctive cold-associated dysesthesias in up to 80% of patients. Results We have established mouse models of cisplatin and oxaliplatin-induced neuropathy using doses similar to those used in patients. Adult male C57BL6J mice were treated with daily intraperitoneal injection for 5 days, followed by 5 days of rest, for two cycles. Total cumulative doses of 23 mg/kg cisplatin and 30 mg/kg oxaliplatin were used. Behavioral evaluations included cold plate, von Frey, radiant heat, tail immersion, grip strength and exploratory behavior at baseline and at weekly intervals for 8 weeks. Following two treatment cycles, mice in the cisplatin and oxaliplatin treatment groups demonstrated significant mechanical allodynia compared to control mice. In addition, the cisplatin group exhibited significant thermal hyperalgesia in hind paws and tail, and the oxaliplatin group developed significant cold hyperalgesia in hind paws. Conclusion We have therefore established a model of platinum drug-induced painful peripheral neuropathy that reflects the differences in early thermal pain responses that are observed in patients treated with either cisplatin or oxaliplatin. This model should be useful in studying the molecular basis for these different pain responses and in designing protective therapeutic strategies.

  14. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice.

    Directory of Open Access Journals (Sweden)

    Pernille Hojman

    Full Text Available Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight, food intake as well as muscle mass, strength and signalling. Mice were treated weekly with 4 mg/kg cisplatin or saline for 6 weeks, and randomized to voluntary wheel running or not. Cisplatin treatment induced loss of body weight (29.8%, P < 0.001, lean body mass (20.6%, P = 0.001, as well as anorexia, impaired muscle strength (22.5% decrease, P < 0.001 and decreased glucose tolerance. In addition, cisplatin impaired Akt-signalling, induced genes related to protein degradation and inflammation, and reduced muscle glycogen content. Voluntary wheel running during treatment attenuated body weight loss by 50% (P < 0.001, maintained lean body mass (P < 0.001 and muscle strength (P < 0.001, reversed anorexia and impairments in Akt and protein degradation signalling. Cisplatin-induced muscular inflammation was not prevented by voluntary wheel running, nor was glucose tolerance improved. Exercise training may preserve muscle mass in cancer patients receiving cisplatin treatment, potentially improving physical capacity, quality of life and overall survival.

  15. Evaluating the various phases of cisplatin-induced emesis in rats.

    Science.gov (United States)

    Shi, Jun

    2014-11-01

    Use of cisplatin as a chemotherapeutic agent causes acute and delayed emesis. Kaolin, saccharin solution and normal feed consumption have been evaluated as an index of cisplatin-induced emesis in rats; however, the most preferable of these methods for evaluating the various phases of emesis remains unclear. In the current study, kaolin, saccharin solution and normal feed consumption following cisplatin administration (6 mg/kg intraperitoneally) were simultaneously investigated in rats. Kaolin consumption increased significantly following cisplatin administration and was attenuated by granisetron administration 0-24 h following the injection. Saccharin solution consumption, however, decreased significantly 0-48 h following cisplatin administration, however, was attenuated by administration of granisetron within 0-24 h only. A reduced intake of normal feed was observed in the control group and was reversed by granisetron within the 0-72 h period. The present study indicates that kaolin consumption may be evaluated as an index of cisplatin-induced acute emesis and saccharin solution consumption may be evaluated as an index of delayed emesis, while normal feed consumption as an indicator of anorexia nervosa may be suitable to evaluate all phases of emesis and serve as an indicator of quality of life. PMID:25289087

  16. Possible Protective Effect of Sertraline against Cisplatin-Induced Ototoxicity: An Experimental Study

    Directory of Open Access Journals (Sweden)

    Murat Ozturk

    2013-01-01

    Full Text Available Background/Objective. Cisplatin is a widely used chemotherapeutic agent, but its ototoxicity side effect can occur in the majority of patients. Lots of agents were tried to prevent this, but there is not a routine treatment modality yet. The aim of this study was to evaluate the otoprotective effect of sertraline, which is an antidepressant with neuroprotective effects, against cisplatin, in rats. Design. Experimental animal study. Material and Methods. Forty-eight rats were randomly separated in two groups as groups I and II. Group I was identified as the control group and only a single dose of intraperitoneal cisplatin was administered. In group II, in addition to cisplatin, sertraline was administered to the rats through an oral cannula for ten-day period. Distortion product otoacoustic emission measurements were performed at the first day and the 10th day. Results. When the ototoxicity rates after cisplatin in group I and group II in distortion product otoacoustic emission measurements were compared, it was statistically significantly lower in group II in frequencies of 5652, 6165, 6726, 7336, and 7996 Hz (. Conclusion. Sertraline seems to have a protective effect on cisplatin ototoxicity and could be used to prevent the ototoxicity and also to treat the depression that occurred in cancer patients together.

  17. Cross section calculation for electron impact ionization and elastic scattering from cisplatin

    International Nuclear Information System (INIS)

    One of the drugs which is typically used in chemotherapy is cisplatin (H6N2Cl2Pt). Chemotherapy is often successfully connected with the ionizing radiation treatment. Our work deals with the elastic electron scattering and electron impact ionization of cisplatin molecule. Total cross section for single electron-impact ionization of cisplatin molecule has been calculated with the binary-encounter-Bethe (BEB) model from the ionization threshold up to 5 keV. To obtain input data for the BEB calculations, geometric and electronic structures of the cisplatin have been studied with quantum chemical methods. Elastic cross section for electron collisions with cisplatin have also been evaluated using independent atom method with static-polarization model potential for incident energies ranging from 50 to 3000 eV. The obtained geometric structure of cisplatin is compared with available experimental and theoretical data. Calculated cross sections have been compared with related cross sections for selected purine and pyrimidine bases, they appear to be similar in values

  18. Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer

    DEFF Research Database (Denmark)

    Galsky, Matthew D; Pal, Sumanta K; Chowdhury, Simon;

    2015-01-01

    clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients......BACKGROUND: Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting. METHODS: Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had...

  19. Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate

    OpenAIRE

    Wintzell, My; Löfstedt, Lina; Johansson, Joel; Pedersen, Anne B.; Fuxe, Jonas; Shoshan, Maria

    2012-01-01

    Cisplatin is used in treatment of several types of cancer, including epithelial ovarian carcinoma (EOC). In order to mimic clinical treatment and to investigate longterm effects of cisplatin in surviving cancer cells, two EOC cell lines were repeatedly treated with low doses. In the SKOV-3 cell line originating from malignant ascites, but not in A2780 cells from a primary tumor, this led to emergence of a stable population (SKOV-3-R) which in the absence of cisplatin showed increased motility...

  20. Cisplatin-Induced Non-Oliguric Acute Kidney Injury in a Pediatric Experimental Animal Model in Piglets

    OpenAIRE

    Santiago, Maria José; Fernández, Sarah Nicole; Lázaro, Alberto; González, Rafael; Urbano, Javier; López, Jorge; Solana, Maria José; Toledo, Blanca; del Castillo, Jimena; Tejedor, Alberto; López-Herce, Jesús

    2016-01-01

    Objective To design an experimental pediatric animal model of acute kidney injury induced by cisplatin. Methods Prospective comparative observational animal study in two different phases. Acute kidney injury was induced using three different doses of cisplatin (2, 3 and 5 mg/kg). The development of nephrotoxicity was assessed 2 to 4 days after cisplatin administration by estimating biochemical parameters, diuresis and renal morphology. Analytical values and renal morphology were compared betw...

  1. ER stress and autophagy are involved in the apoptosis induced by cisplatin in human lung cancer cells

    OpenAIRE

    Shi, Shaomin; Tan, Ping; Yan, Bingdi; Gao, Rong; Zhao, Jianjun; Jing WANG; Guo, Jia; Li, Ning; Ma, Zhongsen

    2016-01-01

    Cisplatin [cis-diamminedichloroplatinum II (CDDP)] is one of the most classical and effective chemotherapeutic drugs for the treatment of cancers including lung cancer. However, the presence of cisplatin resistance in cancer lowers its curative effect and limits its usage in the clinic. The aim of the present study was to investigate the underlying mechanisms of cisplatin resistance in lung cancer involving endoplasmic reticulum (ER) stress and autophagy. In the present study, we detected the...

  2. Hyaluronan–cisplatin conjugate nanoparticles embedded in Eudragit S100-coated pectin/alginate microbeads for colon drug delivery

    OpenAIRE

    Tsai, Shiao-Wen; Yu, Ding-Syuan; Tsao, Shu-Wei; Hsu, Fu-Yin

    2013-01-01

    Hyaluronan–cisplatin conjugate nanoparticles (HCNPs) were chosen as colon-targeting drug-delivery carriers due to the observation that a variety of malignant tumors overexpress hyaluronan receptors. HCNPs were prepared by mixing cisplatin with a hyaluronan solution, followed by dialysis to remove trace elements. The cells treated with HCNPs showed significantly lower viability than those treated with cisplatin alone. HCNPs were entrapped in Eudragit S100-coated pectinate/alginate microbeads (...

  3. Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin

    OpenAIRE

    Bratasz, Anna; Weir, Nathan M.; Parinandi, Narasimham L.; Zweier, Jay L.; Sridhar, Rajagopalan; Ignarro, Louis J.; Kuppusamy, Periannan

    2006-01-01

    Ovarian cancer is a gynecological malignancy that is commonly treated by cytoreductive surgery followed by cisplatin treatment. However, the cisplatin treatment, although successful initially, is not effective in the treatment of the recurrent disease that invariably surfaces within a few months of the initial treatment. The refractory behavior is attributed to the increased levels of cellular thiols apparently caused by the cisplatin treatment. This observation prompted us to choose a cytoto...

  4. Xeroderma Pigmentosum Group A Promotes Autophagy to Facilitate Cisplatin Resistance in Melanoma Cells through the Activation of PARP1.

    Science.gov (United States)

    Ge, Rui; Liu, Lin; Dai, Wei; Zhang, Weigang; Yang, Yuqi; Wang, Huina; Shi, Qiong; Guo, Sen; Yi, Xiuli; Wang, Gang; Gao, Tianwen; Luan, Qi; Li, Chunying

    2016-06-01

    Xeroderma pigmentosum group A (XPA), a key protein in the nucleotide excision repair pathway, has been shown to promote the resistance of tumor cells to chemotherapeutic drugs by facilitating the DNA repair process. However, the role of XPA in the resistance of melanoma to platinum-based drugs like cisplatin is largely unknown. In this study, we initially found that XPA was expressed at higher levels in cisplatin-resistant melanoma cells than in cisplatin-sensitive ones. Furthermore, the knockdown of XPA not only increased cellular apoptosis but also inhibited cisplatin-induced autophagy, which rendered the melanoma cells more sensitive to cisplatin. Moreover, we discovered that the increased XPA in resistant melanoma cells promoted poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) activation and that the inhibition of PARP1 could attenuate the cisplatin-induced autophagy. Finally, we proved that the inhibition of PARP1 and the autophagy process made resistant melanoma cells more susceptible to cisplatin treatment. Our study shows that XPA can promote cell-protective autophagy in a DNA repair-independent manner by enhancing the activation of PARP1 in melanoma cells resistant to cisplatin and that the XPA-PARP1-mediated autophagy process can be targeted to overcome cisplatin resistance in melanoma chemotherapy. PMID:26880244

  5. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Directory of Open Access Journals (Sweden)

    Ana-Maria Florea

    2011-03-01

    Full Text Available Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs and might provide new therapeutic strategies and reduce side effects.

  6. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Energy Technology Data Exchange (ETDEWEB)

    Florea, Ana-Maria [Department of Neuropathology, Heinrich-Heine University, Düsseldorf (Germany); Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144, Doha (Qatar)

    2011-03-15

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

  7. The Anti-tumour Agent, Cisplatin, and its Clinically Ineffective Isomer, Transplatin, Produce Unique Gene Expression Profiles in Human Cells

    Directory of Open Access Journals (Sweden)

    Anne M. Galea

    2008-01-01

    Full Text Available Cisplatin is a DNA-damaging anti-cancer agent that is widely used to treat a range of tumour types. Despite its clinical success, cisplatin treatment is still associated with a number of dose-limiting toxic side effects. The purpose of this study was to clarify the molecular events that are important in the anti-tumour activity of cisplatin, using gene expression profi ling techniques. Currently, our incomplete understanding of this drug’s mechanism of action hinders the development of more efficient and less harmful cisplatin-based chemotherapeutics. In this study the effect of cisplatin on gene expression in human foreskin fibroblasts has been investigated using human 19K oligonucleotide microarrays. In addition its clinically inactive isomer, transplatin, was also tested. Dual-fluor microarray experiments comparing treated and untreated cells were performed in quadruplicate. Cisplatin treatment was shown to significantly up- or down-regulate a consistent subset of genes. Many of these genes responded similarly to treatment with transplatin, the therapeutically inactive isomer of cisplatin. However, a smaller proportion of these transcripts underwent differential expression changes in response to the two isomers. Some of these genes may constitute part of the DNA damage response induced by cisplatin that is critical for its anti-tumour activity. Ultimately, the identification of gene expression responses unique to clinically active compounds, like cisplatin, could thus greatly benefit the design and development of improved chemotherapeutics.

  8. MCL-1 is the key target of adjuvant chemotherapy to reverse the cisplatin-resistance in NSCLC.

    Science.gov (United States)

    Ma, Jun; Zhao, Zhenxian; Wu, Kaiming; Xu, Zhe; Liu, Kuanzhi

    2016-08-10

    Cisplatin is one of the most effective chemotherapeutic agents for the treatment of lung cancer. However, the acquired resistance occurred in cancer cells limits the clinical application of cisplatin. MCL-1, which is an important member in the pro-survival Bcl-2 family, plays a critical role in multidrug resistance (MDR). The aim of the present study is to investigate the value of Pan-Bcl-2 inhibitor as sensitizer for the chemotherapy of cisplatin-resistant non-small cell lung cancer (NSCLC) cells. We found the obatoclax but not the ABT-737 significantly decreased the IC50 (half maximal inhibitory concentration) of cisplatin in cisplatin-resistant NSCLC cells. Furthermore, we demonstrated that the mechanism of obatoclax-promoted cell death induced by cisplatin was dependent on the inhibition of MCL-1, which couldn't be inhibited by ABT-737 but is the target of obatoclax. Moreover, inhibition of MCL-1 recovered the function of NOXA and BAK in cisplatin-resistant NSCLC cells, leading to the promotion of mitochondrial apoptosis induced by cisplatin. Interestingly, our date indicated the obatoclax also reversed the cross-resistance in cisplatin-resistant NSCLC cells. Therefore, we demonstrated that the targeted therapy with MCL-1 inhibitors, such as obatoclax, may represent a novel strategy for cancer therapy. PMID:27138804

  9. Changes of the cell cycle regulators and cell cycle arrest in cervical cancer cells after cisplatin therapy

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective To investigate the changes of the cell cycle regulators ATM,Chk2 and p53 and cell cycle arrest in HeLa cells after cisplatin therapy. Methods The proliferation-inhibiting rates of HeLa cells induced by cisplatin of different concentrations were measured by MTT assays. The mRNA and protein expressions of ATM,Chk2 and p53 of HeLa cells with and without cisplatin were detected by RT-PCR and Western blot,respectively. The cell cycle analysis was conducted by flow cytometric analysis. Results Cisplatin...

  10. Hepatoprotective effect of Ficus religiosa latex on cisplatin induced liver injury in Wistar rats

    Directory of Open Access Journals (Sweden)

    Yogesh C. Yadav

    2015-06-01

    Full Text Available AbstractFicus religiosa L., Moraceae, is widely planted in the tropics. The chemical constituents of F. religiosa include tannin, saponin gluanol acetate, β-sitosterol, leucoanthocyanidin, and leucoanthocyanin. These are used for the treatment of pain, inflammation, impotence, menstrual disturbances, and urine related problems, and as uterine tonic. The present study aimed to evaluate hepatoprotective effects of F. religiosa latex on cisplatin induced liver injury in Wistar rats. In experimental protocol contained five groups of rats (n = 6. In which, group I (control was administered acacia (2%, w/v of 5 ml/kg throughout the experiment for 16 days. The group II (cisplatin treated was administered single dose of cisplatin (7.5 mg/kg i.p. on 1st day. Group III (extract control was administered 300 mg/kg p.o. of extract for 1stto 10th day. Group IV (Protective was administered extract (300 mg/kg p.o. of F. religiosa latex for 1st to 10th day and administered single dose of cisplatin (7.5 mg/kg i.p. on 11th day and group V (Curative received single dose of cisplatin (7.5 mg/kg i.p. on day 1st, and administered extract (300 mg/kg p.o. from 7th to 16thdays. On the 6th day in cisplatin treated, 10th day in extract control and 16th day in control, protective and curative, blood withdrawn from retro-orbital sinus of rats for biochemical estimation for serum and dissected out the livers for estimation of antioxidant enzymes and histopathological works. The cisplatin-treated group 2 showed a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and hepatocytes cells degeneration inflammatory infiltrate and necrosis it's were significantly (**p < 0.01 alleviates by protective groups.

  11. Tinospora cordifolia as a protective and immunomodulatory agent in combination with cisplatin against murine visceral leishmaniasis.

    Science.gov (United States)

    Sachdeva, Heena; Sehgal, Rakesh; Kaur, Sukhbir

    2014-02-01

    Effect of pure herb, Tinospora cordifolia was studied for its hepatoprotective, nephroprotective and immunomodulatory activity against high dose cisplatin treatment in Leishmania donovani infected BALB/c mice. Administration of cisplatin (5mg/kg b.wt. daily for 5 days, i.p.) reduced the parasite load in L. donovani infected BALB/c mice but produced damage in liver and kidney as manifested biochemically by an increase in serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), serum urea, serum creatinine and various electrolytes etc. These biochemical analyses were further supported by cisplatin induced morphological changes in kidney, liver and spleen. To combat this pure herb, T. cordifolia (100mg/kg b.wt. for 15 days daily) was used in combination with cisplatin in L. donovani infected BALB/c mice and it was found that all the aforementioned changes were effectively attenuated by T. cordifolia when administered in combination with cisplatin. Moreover, flow cytometric analysis of lymphocyte surface markers of T cells (CD3+, CD4+ and CD8+), NK1.1 and B cells (CD19) indicated prominent enhancement in proliferation and differentiation of lymphocytes. T. cordifolia in combination with cisplatin selectively induced Th1 type of immune response as depicted by enhanced levels of IFN-γ and IL-2 whereas Th2 specific cytokines IL-4 and IL-10 observed a moderate decline. Confirmation of Th1 polarization was further obtained from augmented levels of IgG2a over IgG1 and heightened DTH (delayed type hypersensitivity) response. Thus, our results suggest that treatment by T. cordifolia may be a critical remedy for the amelioration of adverse effects of cisplatin. Thus, this might serve as a novel combination against visceral leishmaniasis in future. PMID:24370645

  12. Migfilin sensitizes cisplatin-induced apoptosis in human glioma cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Jing FAN; Yun-wei OU; Chuan-yue WU; Chun-jiang YU; Yong-mei SONG; Qi-min ZHAN

    2012-01-01

    Aim:Filamin binding LIM protein 1,also known as migfilin,is a skeleton organization protein that binds to mitogen-inducible gene 2 at cell-extracellular matrix adhesions.The aim of this study was to investigate the role of migfilin in cisplatin-induced apoptosis in human glioma cells,to determine the functional domains of migfilin,and to elucidate the molecular mechanisms underlying the regulation of cisplatin-related chemosensitivity.Methods:The human glioma cell lines Hs683,H4,and U-87 MG were transfected with pEGFP-C2-migfilin to elevate the expression level of migfilin.RNA interference was used to reduce the expression of migfilin.To determine the functional domains of migfilin,U-87 MG cells were transfected with plasmids of migfilin deletion mutants.After treatment with cisplatin (40 μmol/L) for 24 h,the cell viability was assessed using the MTS assay,and the cell apoptotic was examined using the DAPI staining assay and TUNEL analysis.Expression levels of apoptosis-related proteins were detected by Western blot analysis.Results:Overexpression of migfilin significantly enhanced cisplatin-induced apoptosis in Hs683,H4,and U-87 MG cells,whereas downregulation of migfilin expression inhibited the chemosensitivity of these cell lines.The N-terminal region of migfilin alone was able to enhance the cisplatin-induced apoptosis.However,despite the existence of the N-terminal region,mutants of migfilin with any one of three LIM domains deleted led to a function loss.Furthermore,apoptotic proteins (PARP and caspase-3) and the anti-apoptotic protein Bcl-xL were modulated by the expression level of migfilin in combination with cisplatin.Conclusion:The LIM1-3 domains of migfilin play a key role in sensitizing glioma cells to cisplatin-induced apoptosis through regulation of apoptosis-related proteins.

  13. Therapeutic Efficacy of Ginger, Cisplatin and Radiation on Chemically-Induced Cancer in Male Albino Rats

    International Nuclear Information System (INIS)

    This study aimed to investigate the in vivo effect of dietary supplementation with ginger to evaluate its therapeutic effect against lung and kidney cancer and in combination with cisplatin as chemotherapy and radiotherapy in male albino rats. 54 male albino rats were divided into nine groups of 6 animals each, all animals were allowed to food and water ad libitum . Group I was treated with 0.5 ml saline, orlly for 12 consecutive weeks serve as con - trol group Group II injected with N-nitrosodimethylamine (NDMA) and carbon tetrachloride (CCl4 ); all groups were injected with NDMA + CCl4 for 6 weeks. Group III were given ginger for 6 consecutive weeks (200 mg/kg, b.wt./day). Group IV animals received cisplatin, group V irradiated with 2 Gy, group VI treated with ginger then irradiated, group VII treated with ginger then injected with cisplatin, group VIII injected with cisplatin then irradiated and group IX treated with ginger and cisplatin then irradiated. Antioxidant status in both kidney and lung tissues were estimated by determining the activity of antioxidant enzyme superoxide dismutase (SOD); as well as the level of reduced glutathione (GSH), Malondialdehyde (MDA) and Nitric oxide (NO). In parallel to histopathological investigations of lung and kidney tissues. In addition, Tumor Necrosis Factor Alpha (TNF-α) level, advanced oxidative protein product (AOPP), urea, creatinine and uric acid. Remarkable disturbances were observed in the levels of all tested parameters in NDMA + CCl4 group. On the other hand, rats injected with the cancer agents then treated with cisplatin+radiation showed moderate improvements in the studied parameters while, treatment with ginger + cisplatin + radiation ameliorated the levels of the disturbed bio

  14. Curcumin prevents cisplatin-induced decrease in the tight and adherens junctions: relation to oxidative stress.

    Science.gov (United States)

    Trujillo, Joyce; Molina-Jijón, Eduardo; Medina-Campos, Omar Noel; Rodríguez-Muñoz, Rafael; Reyes, José Luis; Loredo, María L; Barrera-Oviedo, Diana; Pinzón, Enrique; Rodríguez-Rangel, Daniela Saraí; Pedraza-Chaverri, José

    2016-01-20

    Curcumin is a polyphenol and cisplatin is an antineoplastic agent that induces nephrotoxicity associated with oxidative stress, apoptosis, fibrosis and decrease in renal tight junction (TJ) proteins. The potential effect of curcumin against alterations in TJ structure and function has not been evaluated in cisplatin-induced nephrotoxicity. The present study explored whether curcumin is able to prevent the cisplatin-induced fibrosis and decreased expression of the TJ and adherens junction (AJ) proteins occludin, claudin-2 and E-cadherin in cisplatin-induced nephrotoxicity. Curcumin (200 mg kg(-1)) was administered in three doses, and rats were sacrificed 72 h after cisplatin administration. Curcumin was able to scavenge, in a concentration-dependent way, superoxide anion, hydroxyl radical, peroxyl radical, singlet oxygen, peroxynitrite anion, hypochlorous acid and hydrogen peroxide. Cisplatin-induced renal damage was associated with alterations in plasma creatinine, expression of neutrophil gelatinase-associated lipocalin and of kidney injury molecule-1, histological damage, increase in apoptosis, fibrosis (evaluated by transforming growth factor β1, collagen I and IV and α-smooth muscle actin expressions), increase in oxidative/nitrosative stress (evaluated by Hsp70/72 expression, protein tyrosine nitration, superoxide anion production in isolated glomeruli and proximal tubules, and protein levels of NADPH oxidase subunits p47(phox) and gp91(phox), protein kinase C β2, and Nrf2) as well as by decreased expression of occludin, claudin-2, β-catenin and E-cadherin. Curcumin treatment prevented all the above-described alterations. The protective effect of curcumin against cisplatin-induced fibrosis and decreased proteins of the TJ and AJ was associated with the prevention of glomerular and proximal tubular superoxide anion production induced by NADPH oxidase activity. PMID:26467482

  15. Transportan 10 improves the anticancer activity of cisplatin.

    Science.gov (United States)

    Izabela, Rusiecka; Jarosław, Ruczyński; Magdalena, Alenowicz; Piotr, Rekowski; Ivan, Kocić

    2016-05-01

    The aim of this paper was to examine whether cell-penetrating peptides (CPPs) such as transportan 10 (TP10) or protein transduction domain (PTD4) may improve the anticancer activity of cisplatin (cPt). The complexes of TP10 or PTD4 with cPt were used in the experiments. They were carried out on two non-cancer (HEK293 (human embryonic kidney) and HEL299 (human embryo lung)) and two cancer (HeLa (human cervical cancer) and OS143B (human osteosarcoma 143B)) cell lines. Both complexes were tested (MTT assay) with respect to their anticancer or cytotoxic actions. TAMRA (fluorescent dye)-stained preparations were visualized in a fluorescence microscope. The long-term effect of TP10 + cPt and its components on non-cancer and cancer cell lines was observed in inverted phase contrast microscopy. In the MTT test (cell viability assay), the complex of TP10 + cPt produced a more potent effect on the cancer cell lines (HeLa, OS143B) in comparison to that observed after separate treatment with TP10 or cPt. At the same time, the action of the complex and its components was rather small on non-cancer cell lines. On the other hand, a complex of another CPP with cPt, i.e., PTD4 + cPt, was without a significant effect on the cancer cell line (OS143B). The images of the fluorescent microscopy showed TAMRA-TP10 or TAMRA-TP10 + cPt in the interior of the HeLa cells. In the case of TAMRA-PTD4 or TAMRA-PTD4 + cPt, only the first compound was found inside the cancer cell line. In contrast, none of the tested compounds gained access to the interior of the non-cancer cells (HEK293, HEL299). Long-term incubation with the TP10 + cPt (estimated by inverted phase contrast microscopy) lead to an enhanced action of the complex on cell viability (decrease in the number of cells and change in their morphology) as compared with that produced by each single agent. With regard to the tested CPPs, only TP10 improved the anticancer activity of cisplatin if both compounds were used in the form of a

  16. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy

    DEFF Research Database (Denmark)

    Bellmunt, Joaquim; von der Maase, Hans; Mead, Graham M;

    2012-01-01

    The combination of gemcitabine plus cisplatin (GC) is a standard regimen in patients with locally advanced or metastatic urothelial cancer. A phase I/II study suggested that a three-drug regimen that included paclitaxel had greater antitumor activity and might improve survival....

  17. Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: Impact on NOX-1, inflammation and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    El-Naga, Reem N., E-mail: reemelnaga@hotmail.com

    2014-01-01

    Cisplatin is an effective anti-cancer drug; however, its clinical use is usually associated with nephrotoxicity as a dose-limiting side effect. Several molecular mechanisms have been found to be involved in this nephrotoxicity such as oxidative stress, inflammation and apoptosis. The aim of this study was to explore the potential nephroprotective effect of cardamonin, a flavone found in Alpinia plant, in a rat model of cisplatin-induced nephrotoxicity. The possible mechanisms underlying this nephroprotective effect were investigated. Cardamonin was given at two different doses; 10 and 30 mg/kg orally for two weeks, starting one week before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Acute nephrtoxicity was evident by significantly increased blood urea nitrogen and serum creatinine levels. Also, cisplatin increased lipid peroxidation and depleted reduced glutathione level and superoxide dismutase. Additionally, cisplatin showed a marked pro-inflammatory response as evidenced by significant increase in tissue levels of IL-1β, TNF-α, NF-kB, iNOS, ICAM-1 and MCP-1. Pre-treatment with cardamonin significantly attenuated the nephrotoxic effects, oxidative stress and inflammation induced by cisplatin, in a dose-dependent manner. Also, cardamonin decreased caspase-3 expression and Bax/Bcl-2 ratio as compared to cisplatin group. Besides, cradamonin reversed cisplatin-induced decrease in EGF. Furthermore, up-regulation of NOX-1 was found to be involved in cisplatin-induced nephrotoxicity and its expression was significantly reduced by cardamonin. Histopathological examination further confirmed the nephroprotective effect of cardamonin. Moreover, pre-treatment with subtoxic concentration of cardamonin has significantly enhanced cisplatin cytotoxic activity in four different human cancer cell lines; hela, hepG2, PC3 and HCT116 cancer cell lines. In conclusion, these findings suggest that cardamonin improves therapeutic index of cisplatin and that NOX-1 is

  18. Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: Impact on NOX-1, inflammation and apoptosis

    International Nuclear Information System (INIS)

    Cisplatin is an effective anti-cancer drug; however, its clinical use is usually associated with nephrotoxicity as a dose-limiting side effect. Several molecular mechanisms have been found to be involved in this nephrotoxicity such as oxidative stress, inflammation and apoptosis. The aim of this study was to explore the potential nephroprotective effect of cardamonin, a flavone found in Alpinia plant, in a rat model of cisplatin-induced nephrotoxicity. The possible mechanisms underlying this nephroprotective effect were investigated. Cardamonin was given at two different doses; 10 and 30 mg/kg orally for two weeks, starting one week before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Acute nephrtoxicity was evident by significantly increased blood urea nitrogen and serum creatinine levels. Also, cisplatin increased lipid peroxidation and depleted reduced glutathione level and superoxide dismutase. Additionally, cisplatin showed a marked pro-inflammatory response as evidenced by significant increase in tissue levels of IL-1β, TNF-α, NF-kB, iNOS, ICAM-1 and MCP-1. Pre-treatment with cardamonin significantly attenuated the nephrotoxic effects, oxidative stress and inflammation induced by cisplatin, in a dose-dependent manner. Also, cardamonin decreased caspase-3 expression and Bax/Bcl-2 ratio as compared to cisplatin group. Besides, cradamonin reversed cisplatin-induced decrease in EGF. Furthermore, up-regulation of NOX-1 was found to be involved in cisplatin-induced nephrotoxicity and its expression was significantly reduced by cardamonin. Histopathological examination further confirmed the nephroprotective effect of cardamonin. Moreover, pre-treatment with subtoxic concentration of cardamonin has significantly enhanced cisplatin cytotoxic activity in four different human cancer cell lines; hela, hepG2, PC3 and HCT116 cancer cell lines. In conclusion, these findings suggest that cardamonin improves therapeutic index of cisplatin and that NOX-1 is

  19. Trial on Refinement of Early stage non-small cell lung cancer. Adjuvant chemotherapy with pemetrexed and cisplatin versus vinorelbine and cisplatin: The TREAT protocol

    International Nuclear Information System (INIS)

    Adjuvant chemotherapy has been proven to be beneficial for patients with early stage non-small cell lung cancer. However, toxicity and insufficient dose delivery have been critical issues with the chemotherapy used. Doublet regimens with pemetrexed, a multi-target folate inhibitor, and platin show clear activity in non-small cell lung cancer and are well tolerated with low toxicity rates and excellent delivery. In this prospective, multi-center, open label randomized phase II study, patients with pathologically confirmed non-small cell lung cancer, stage IB, IIA, IIB, T3N1 will be randomized after complete tumor resection either to 4 cycles of the standard adjuvant vinorelbine and cisplatin regimen from the published phase III data, or to 4 cycles of pemetrexed 500 mg/m2 d1 and cisplatin 75 mg/m2 d1, q 3 weeks. Primary objective is to compare the clinical feasibility of these cisplatin doublets defined as non-occurrence of grade 4 neutropenia and/or thrombocytopenia > 7 days or bleeding, grade 3/4 febrile neutropenia and/or infection, grade 3/4 non-hematological toxicity, non-acceptance leading to premature withdrawal and no cancer or therapy related death. Secondary parameters are efficacy (time to relapse, overall survival) and drug delivery. Parameters of safety are hematologic and non-hematologic toxicity of both arms. The TREAT trial was designed to evaluate the clinical feasibility, i.e. rate of patients without dose limiting toxicities or premature treatment withdrawal or death of the combination of cisplatin and pemetrexed as well as the published phase III regimen of cisplatin and vinorelbine. Hypothesis of the study is that reduced toxicities might improve the feasibility of drug delivery, compliance and the convenience of treatment for the patient and perhaps survival. Clinicaltrials.gov NCT00349089

  20. Randomized phase III study comparing paclitaxel-bleomycin, etoposide, and cisplatin (BEP) to standard BEP in intermediate-prognosis germ-cell cancer

    DEFF Research Database (Denmark)

    de Wit, Ronald; Skoneczna, Iwona; Daugaard, Gedske;

    2012-01-01

    To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC).......To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC)....

  1. A randomized, double-blind, multicentre study comparing daily 2 and 5 mg of tropisetron for the control of nausea and vomiting induced by low-dose cisplatin- or non-cisplatin-containing chemotherapy

    NARCIS (Netherlands)

    Wymenga, ANM; vanderGraaf, WTA; Wils, JA; vanHeukelom, LS; vanderLinden, GHM; DullemondWestland, AC; Nooy, M; vanderHeul, C; deBruijn, KM; deVries, EGE

    1996-01-01

    Background: This study compares efficacy safety and tolerability of 2 and 5 mg tropisetron in prevention of nausea and vomiting induced by low-dose cisplatin- or non-cisplatin-containing chemotherapy. Patients and methods: 152 chemotherapy-naive cancer patients were randomized in a double-blind mann

  2. Sappanone A protects mice against cisplatin-induced kidney injury.

    Science.gov (United States)

    Kang, Lin; Zhao, Huanfen; Chen, Chen; Zhang, Xiuzhi; Xu, Mingtang; Duan, Huijun

    2016-09-01

    Cisplatin (CP) is an anti-cancer drug that often causes nephrotoxicity due to enhanced inflammatory response and oxidative stress. Sappanone A (SA), a homoisoflavanone isolated from the heartwood of Caesalpinia sappan, has been known to have antioxidant and anti-inflammatory effects. In this study, we aimed to investigate the protective effects and mechanism of SA on CP-induced kidney injury in mice. The results showed that treatment of SA improved CP-induced histopathalogical injury and renal dysfunction. SA also inhibited CP-induced MPO, MDA, TNF-α and IL-1β production and up-regulated the activities of SOD and GSH-PX decreased by CP. SA significantly inhibited the apoptosis rate of kidney tissues induced by CP. Furthermore, SA was found to inhibit CP-induced NF-κB activation. Treatment of SA up-regulated the expression of Nrf2 and HO-1 in a dose-dependent manner. In vitro, SA dose-dependently inhibited CP-induced TNF-α and IL-1β production and NF-κB activation in HK-2 cells. In conclusion, these results suggested that SA inhibited CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation. SA was a potential therapeutic drug for treating CP-induced kidney injury. PMID:27318179

  3. Collateral methotrexate resistance in cisplatin-selected murine leukemia cells

    Directory of Open Access Journals (Sweden)

    Bhushan A.

    1999-01-01

    Full Text Available Resistance to anticancer drugs is a major cause of failure of many therapeutic protocols. A variety of mechanisms have been proposed to explain this phenomenon. The exact mechanism depends upon the drug of interest as well as the tumor type treated. While studying a cell line selected for its resistance to cisplatin we noted that the cells expressed a >25,000-fold collateral resistance to methotrexate. Given the magnitude of this resistance we elected to investigate this intriguing collateral resistance. From a series of investigations we have identified an alteration in a membrane protein of the resistant cell as compared to the sensitive cells that could be the primary mechanism of resistance. Our studies reviewed here indicate decreased tyrosine phosphorylation of a protein (molecular mass = 66 in the resistant cells, which results in little or no transfer of methotrexate from the medium into the cell. Since this is a relatively novel function for tyrosine phosphorylation, this information may provide insight into possible pharmacological approaches to modify therapeutic regimens by analyzing the status of this protein in tumor samples for a better survival of the cancer patients.

  4. Protective effect of CV247 against cisplatin nephrotoxicity in rats.

    Science.gov (United States)

    Máthé, C; Szénási, G; Sebestény, A; Blázovics, A; Szentmihályi, K; Hamar, P; Albert, M

    2014-08-01

    CV247 (CV), an aqueous mixture of copper (Cu) and manganese (Mn) gluconates, vitamin C and sodium salicylate increased the antitumour effects of cisplatin (CDPP; cis-diamminedichloroplatinum) in vitro. We hypothesized that the antioxidant and cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase 2) inhibitory components of CV can protect the kidneys from CDPP nephrotoxicity in rats. CDPP (6.5 mg/kg, intraperitoneally) slightly elevated serum creatinine (Crea) and blood urea nitrogen (BUN) 12 days after treatment. Kidney histology demonstrated extensive tubular epithelial damage and COX-2 immunoreactivity increased 14 days after treatment. A large amount of platinum (Pt) accumulated in the kidney of CDPP-treated rats. Furthermore, CDPP decreased renal iron (Fe), molybdenum (Mo), zinc (Zn), Cu and Mn concentrations and increased plasma Fe and Cu concentrations. CDPP elevated plasma free radical concentration. Treatment with CV alone for 14 days (twice 3 ml/kg/day orally) did not influence these parameters. Chronic CV administration after CDPP reduced renal histological damage and slightly decreased COX-2 immunoreactivity, while failed to prevent the increase in Crea and BUN levels. Blood free radical concentration was reduced, that is, CV improved redox homeostasis. CV restored plasma Fe and renal Fe, Mo and Zn, while decreased Pt and elevated Cu and Mn concentrations in the kidney. Besides the known synergistic antitumour effects with CDPP, CV partially protected the kidneys from CDPP nephrotoxicity probably through its antioxidant effect. PMID:23653282

  5. The Effects of Nimesulide Combined with Cisplatin on Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    邢丽华; 张珍祥; 徐永健; 张惠兰; 刘剑波

    2004-01-01

    To study the effects of cyclooxygenase 2 selective inhibitor Nimesulide (NIM) combined with Cisplatin (DDP) on human lung cancer and the possible mechanisms, the proliferation and apoptosis of human lung cancer cell line A549 were evaluated by MTT reduction assay and flow cytometry respectively. The inhibitory effect on neoplasia in vivo was tested on nude mice subcutaneously implanted tumor. Our results showed that NIM and DDP could inhibit A549 cell proliferation in a concentration dependent pattern; this action was enhanced when NIM (25 μmol/L) was given in combination with DDP and they worked in a synergistic or additive pattern as DDP concentration ≥ 1 μg/ml. NIM and DDP could induce A549 cells apoptosis and the action was augmented when used in combination (P<0.01). NIM and DDP could inhibit the growth of subcutaneously implan ted tumors on nude mice (P<0.05,P<0.01) and the inhibitory rate of NIM combined with DDP was significantly higher than that of NIM orDDPgroup (P<0.01, P<0.01). It is concluded that combined usc of NIM and DDP has significant synergistic antitumor effects on lung cancer cell line A549 and in animals in vivo. The synergy may be achieved by growth inhibition and apoptosis induction.

  6. Genetic risk factors of cisplatin induced ototoxicity in adult patients.

    Science.gov (United States)

    Talach, T; Rottenberg, J; Gal, B; Kostrica, R; Jurajda, M; Kocak, I; Lakomy, R; Vogazianos, E

    2016-01-01

    Ototoxicity is an important adverse effect of using Cisplatin (cis-diamminedichloroplatinum) (CDDP) as a form of chemotherapy. The clinical picture of CDDP induced ototoxicity includes perceptive hearing impairment (reversible or permanent) and tinnitus. Ototoxicity manifests with considerable variability between patients. The objective of this prospective study was to investigate a possible genetic background to this variability. We assessed ototoxicity induced by therapeutic doses of CDDP in adult patients with germinative testicular tumors, or other tumors treated with an identical CDDP dosage scheme. Audiological examination before, during and after the treatment has shown deterioration in hearing; first in the high-frequencies and with increased CDDP cumulative doses, impairment in other frequencies as well. Occurrence of tinnitus was not dependent on the administered dose of CDDP, or the other risk factors examined in this study. The association of CDDP induced ototoxicity with genetic polymorphisms in candidate genes was examined. Our study has demonstrated an association of early onset of CDDP induced ototoxicity with the presence of two copies of GSTT1 gene (p=0,009) and with T allele of rs9332377 polymorphism in COMT gene (p=0,001). PMID:26774148

  7. Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

    Directory of Open Access Journals (Sweden)

    Laila Ziko

    2015-01-01

    Full Text Available Cisplatin (CisPt is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2 cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death. Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death.

  8. Irinotecan/cisplatin versus Etoposide/cisplatin for Patients with Extensive Stage Small Cell Lung Cancer: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Nan YAO

    2009-08-01

    Full Text Available Background and objective It is unclear whether etoposide/cisplatin (EP regimen is the optimal chemotherapy regimen in the treatment patients with extensive small cell lung cancer (SCLC, this study was aimed to evaluate the efficacy and safety of patients with extensive SCLC treated with irinotecan/cisplatin (IP versus EP. Methods We searched EMBASE, PubMed, the Cochrane Library, China journal full-text database (CJFD, Chinese scientific journal full-text database (CSJD, Chinese biomedicine literature database (CBM for randomized controlled trials comparing IP with EP regimens. Two reviewers independently assessed the quality of included studies and extracted data. We analyzed the data using Review Manager (version 5.0. Results Four randomized controlled trials totaling 1 180 patients were included. The results of meta analysis were as follows: there was no significant difference between IP regimen and EP regimens in one year survive rate (RR=1.22, 95%CI: 0.97-1.54, two year survive rate (RR=2.26, 95%CI: 0.46-11.21. There was significant difference between IP regimen and EP regimens in overall response rate (RR=1.13, 95%CI: 1.03-1.25, grade 3/4 neutropenia (RR=0.48, 95%CI: 0.34-0.69, thrombopenia (RR=0.23, 95%CI: 0.15-0.36, grade 3 anemia (RR=0.55, 95%CI: 0.40-0.77, grade 3/4 diarrhea (RR=9.56, 95%CI: 4.91-18.59, grade 3 nausea/vomiting (RR=1.70, 95%CI: 1.19-2.43. Conclusion There is no significant difference between IP group and EP group with regard to one year survive rate, two year survive rate, but IP regimen improves reponse rate. IP regimen has less hematologic & greater gastrointestinal toxicity compared with EP, EP regimen remain the main standard chemotherapy in the treatment extensive small cell lung cancer due to cheapness, they still need to be confirmed by randomized controlled trials.

  9. Protective Effect of Aqueous and Ethanolic Extracts of Portulaca Oleracea Against Cisplatin Induced Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Gholamreza Karimi

    2010-04-01

    Full Text Available Objective(sPortulaca oleracea L. is a herbaceous weed from portulacaceae family. It can be found in many parts of the world. Modern pharmacological studies have demonstrated that P. oleracea have antioxidant effects. The protective effect of aqueous and ethanolic extract of P. oleracea against cisplatin-induced renal toxicity was studied in rats.Materials and MethodsSingle intraperitoneal injection of 4 mg/kg cisplatin was administrated to rats. After 5 days, blood urea nitrogen (BUN and serum creatinine (Scr concentration were determined. Effect of aqueous and ethanolic extracts, before and after cisplatin injection on BUN and Scr, as well as morphological renal damage, was evaluated. ResultsIt was indicated that treatment with aqueous and ethanolic extracts of P. oleracea in the highest dose (0.8 and 2 g/ kg, 6 and 12 hr before cisplatin injection reduced BUN and Scr. Tubular necrotic damage was not observed either. ConclusionResults suggest that P. oleracea extract may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplan to limit renal injury.

  10. Pemetrexed/cisplatin as first-line chemotherapy for advanced lung cancer with brain metastases

    Science.gov (United States)

    He, Guangzhao; Xiao, Xiaoguang; Zou, Man; Zhang, Chengliang; Xia, Shu

    2016-01-01

    Abstract Background: Brain metastases (BMs) are a common and serious complication of non-small cell lung cancer (NSCLC). Whole-brain radiotherapy (WBRT), surgery, and molecular targeted therapy are usually used to treat NSCLC with BM. Chemotherapeutic options for BM are limited by tumor resistance, ineffective agents, and the blood–brain barrier. Pemetrexed/cisplatin is the preferred chemotherapy in nonsquamous NSCLC, but the efficacy of this treatment for nonsquamous NSCLC with BM is uncertain. Methods: We present a case of nonsquamous NSCLC with asymptomatic BM presenting with irritating cough and right shoulder back pain (unknown sensitizing epidermal growth factor receptor mutations or anaplastic lymphoma kinase). Results: He benefited from administration of first-line chemotherapy of pemetrexed/cisplatin. Partial remission was achieved in the primary lesion of the lungs and BM lesion. He was further given 3 cycles of pemetrexed monotherapy and WBRT. Complete remission was further achieved in BM lesion. Conclusion: The findings of clinical trials and theoretical studies about the current pemetrexed/cisplatin in the treatment of nonsquamous NSCLC with BM are also summarized to provide a reference for the application of pemetrexed/cisplatin in nonsquamous NSCLC with BM. Whether or not pemetrexed/cisplatin is definitely effective in nonsquamous NSCLC with BM must be proven by subsequent phase III clinical trials. PMID:27512852

  11. Determination of platinum by radiochemical neutron activation analysis in neural tissues from rats, monkeys and patients treated with cisplatin

    DEFF Research Database (Denmark)

    Rietz, B.; Krarup-Hansen, A.; Rorth, M.

    2001-01-01

    Cisplatin is one of the most used antineoplastic drugs, essential for the treatment of germ cell tumours. Its use in medical treatment of cancer patients often causes chronic peripheral neuropathy in these patients. The distribution of cisplatin in neural tissues is, therefore, of great interest...

  12. Early responses of the STAT3 pathway to platinum drugs are associated with cisplatin resistance in epithelial ovarian cancer

    Directory of Open Access Journals (Sweden)

    W.J. Sheng

    2013-08-01

    Full Text Available Cisplatin resistance remains one of the major obstacles when treating epithelial ovarian cancer. Because oxaliplatin and nedaplatin are effective against cisplatin-resistant ovarian cancer in clinical trials and signal transducer and activator of transcription 3 (STAT3 is associated with cisplatin resistance, we investigated whether overcoming cisplatin resistance by oxaliplatin and nedaplatin was associated with the STAT3 pathway in ovarian cancer. Alamar blue, clonogenic, and wound healing assays, and Western blot analysis were used to compare the effects of platinum drugs in SKOV-3 cells. At an equitoxic dose, oxaliplatin and nedaplatin exhibited similar inhibitory effects on colony-forming ability and greater inhibition on cell motility than cisplatin in ovarian cancer. Early in the time course of drug administration, cisplatin increased the expression of pSTAT3 (Tyr705, STAT3α, VEGF, survivin, and Bcl-XL, while oxaliplatin and nedaplatin exhibited the opposite effects, and upregulated pSTAT3 (Ser727 and STAT3β. The STAT3 pathway responded early to platinum drugs associated with cisplatin resistance in epithelial ovarian cancer and provided a rationale for new therapeutic strategies to reverse cisplatin resistance.

  13. Dose-dependent effect of 8-day cisplatin administration upon the morphology of the albino guinea pig cochlea

    NARCIS (Netherlands)

    Cardinaal, RM; de Groot, JCMJ; Huizing, EH; Veldman, JE; Smoorenburg, GF

    2000-01-01

    Numerous studies investigating cisplatin ototoxicity in animals have been performed, but it is difficult to derive a clear dose-effect relation from these studies. The degree of cisplatin-induced ototoxicity depends on a multitude of,factors. Many parameters, such as dose, mode of administration, do

  14. Prolonged local persistence of cisplatin-loaded gelatin microspheres and their chemoembolic anti-cancer effect in rabbits

    International Nuclear Information System (INIS)

    Purpose: To confirm prolonged cisplatin release from drug-loaded gelatin microspheres (GMSs) and their improved chemoembolic anti-cancer effect against VX2 liver tumors in rabbits. Materials and methods: Two groups of twelve rabbits each were treated intraarterially either with 2 mg/kg cisplatin-loaded GMSs (=0.04 mg/kg cisplatin) or 0.04 mg/kg cisplatin solution by administering them into the right renal artery. Platinum concentrations within the renal parenchyma were analyzed immediately following infusion (day 0) and on days 1, 3, and 7 using the atomic absorption method. In a second experiment four groups of five rabbits each with implanted VX2 liver tumors were treated intraarterially through the hepatic artery with the following drugs: 2 mg/kg cisplatin-loaded GMSs (=0.04 mg/kg cisplatin) (group I), 2 mg/kg GMSs without any drug (group II), 1.5 mg/kg cisplatin solution (group III) and saline (group IV). Tumor volumes were analyzed pre-injection and 7 days after with MRI allowing calculating the relative tumor growth rate (%). Degree of liver cell necrosis was assessed on the histopathological specimens. Results: The renal parenchymal platinum concentrations (μg/ml) with 4.51 ± 2.25 (day 0), 1.59 ± 0.70 (day 1), 0.72 ± 0.10 (day 3) and 0.20 ± 0.06 (day 7) were significantly more pronounced after cisplatin-loaded GMS on days one and three compared to cisplatin with 1.99 ± 0.55, 0.08 ± 0.03, 0.18 ± 0.01 and 0.10 ± 0.07, respectively. Relative tumor growth rates resulted in 84.5% ± 26.4 (group I); 241.4% ± 145.1 (II); 331.9% ± 72.2 (III), and 413.6% ± 103.6 (IV) with statistical significant differences between groups I and III, and groups I and IV. Similar degrees of necrosis were observed in both GMSs treated groups, while ballooning of hepatocytes was highest in cisplatin-loaded GMSs. Conclusions: With cisplatin-loaded GMSs more pronounced and prolonged local parenchymal cisplatin concentrations may be achieved offering the advantage of an

  15. Low Doses of Cisplatin Induce Gene Alterations, Cell Cycle Arrest, and Apoptosis in Human Promyelocytic Leukemia Cells.

    Science.gov (United States)

    Velma, Venkatramreddy; Dasari, Shaloam R; Tchounwou, Paul B

    2016-01-01

    Cisplatin is a known antitumor drug, but its mechanisms of action are not fully elucidated. In this research, we studied the anticancer potential of cisplatin at doses of 1, 2, or 3 µM using HL-60 cells as a test model. We investigated cisplatin effects at the molecular level using RNA sequencing, cell cycle analysis, and apoptotic assay after 24, 48, 72, and 96 hours of treatment. The results show that many genes responsible for molecular and cellular functions were significantly altered. Cisplatin treatment also caused the cells to be arrested at the DNA synthesis phase, and as the time increases, the cells gradually accumulated at the sub-G1 phase. Also, as the dose increases, a significant number of cells entered into the apoptotic and necrotic stages. Altogether, the data show that low doses of cisplatin significantly impact the viability of HL-60 cells, through modulation of gene expression, cell cycle, and apoptosis. PMID:27594783

  16. Fractionation and delivery schedules in combined radiotherapy-cisplatin for head and neck cancer

    International Nuclear Information System (INIS)

    Full text: Since Rosenberg's initial discovery, cisplatin has become one of the most effective anticancer drugs, with particular significance in head and neck cancer. For advanced disease, where the tumour is unresectable, radiotherapy and chemotherapy, either singularly or combined, remain the possible therapeutic modalities. The majority of the trials using a combination of cisplatin and radiation obtained much better results than the single-agent trials. But the best schedule, dosage and timing between radiation and drug administration are still unknown. Many positive steps were however made to eliminate the cisplatin-produced side effects, as much as possible. The tendency in current trials is to fractionate the drug dose by daily administration and also to hyperfractionate the radiation. In this way the long-term benefits are improved and the toxicity is better tolerated

  17. Salvage chemotherapy for ovarian cancer recurrence: weekly cisplatin in combination with epirubicin or etoposide.

    Science.gov (United States)

    Zanaboni, F; Scarfone, G; Presti, M; Maggi, R; Borello, C; Bolis, G

    1991-10-01

    From December 1986 to April 1990, 40 consecutive ovarian cancer patients who relapsed after response to cisplatin-based chemotherapy regimens were treated with seven courses of weekly cisplatin, in combination with epirubicin or etoposide. The overall response rate obtained with the intensive schedule was 60% and the complete response rate was 25%; median duration of response was 7 months and median survival time, 13.5 months. Responsive cases seem to have longer survival; a prognostic factor for response to salvage treatment and longer survival is the disease-free interval after the first-line chemotherapy. Weekly cisplatin as intensive treatment was very well tolerated and showed acceptable toxicity in both the combination protocols with epirubicin or etoposide. PMID:1959783

  18. Toward overcoming cisplatin resistance via sterically hindered platinum(II) complexes.

    Science.gov (United States)

    Yu, Haiyan; Gou, Shaohua; Wang, Zhimei; Chen, Feihong; Fang, Lei

    2016-05-23

    A number of platinum(II) complexes with steric hindrance derived from (1R,2R)-N(1)-benzylcyclohexane-1,2-diamine derivatives were designed and prepared. Biological assay indicated that most complexes showed antitumor activity against the tested cancer cell lines, especially those with chloride anions as leaving groups had compatible or superior activity to cisplatin and oxaliplatin. Complex 2a, as the most potent agent, is also sensitive to cisplatin resistant SGC7901/CDDP cancer cell line, which has been subsequently studied by cellular uptake, flow cytometry, gel electrophoresis and western blot assays. The steric hindrance resulting from a pending 2-fluorobenzyl moiety of the ligand might be the key factor for its ability to overcome cisplatin resistant cancer cells. PMID:26974381

  19. Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours

    DEFF Research Database (Denmark)

    Sengeløv, Lisa; von der Maase, Hans; Lundbeck, Finn;

    2002-01-01

    This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma of t...... (actuarial rate). Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 randomized patients with invasive bladder cancer.......This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma of the...

  20. Gitelman-like syndrome after cisplatin therapy: a case report and literature review

    Directory of Open Access Journals (Sweden)

    Selhi Sharmila

    2006-05-01

    Full Text Available Abstract Background Cisplatin is a well-known nephrotoxic antineoplastic drug. Chronic hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria is one of the rare complications associated with its use. Case presentation A 42- year-old woman presented with a 20 year-history of hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria after cisplatin-based chemotherapy for ovarian cancer. This patient has had chronic muscle aches and fatigue and has had episodic seizure-like activity and periodic paralysis. Only thirteen other patients with similar electrolyte abnormalities have been described in the literature. This case has the longest follow-up. Conclusion Cisplatin can cause permanent nephrotoxicity, including Gitelman-like syndrome. This drug should be considered among the possible causes of chronic unexplained electrolyte disorders.

  1. Cisplatin as a radiosensitizer in the treatment of solid tumours - a clinical pilot study

    International Nuclear Information System (INIS)

    A variety of experimental tumor models have shown that cisplatin in combination with ionizing radiation enhances tumour regresion. To evaluate the feasibility, efficacy and toxicity of a combined regimen, 25 patients with different solid tumours were treated with cisplatin and photon irradiation. A local tumour control was achieved in 22 cases. Thirteen patients with squamous cell carcinoma of the lung (Tsub(1-3), N1-2, M0) received cisplatin (20 mg/m2 per day) on 5 consecutive days with NaCl hyperhydratation (0,9% NaCl, 24000 ml/24 hours as continuous infusion) in the first and last week of radiatherapy (5 x 2 Gyweek, 56 Gy target volume dose). 12 of 13 patients have shown local tumour control. Increased clinically evident side effects were not observed. From the underlying data the conclusion is drawn that the experimental results are reproducable under clinical conditions and that improved local tumour response rates can be achieved. (orig.)

  2. Synergistic killing of lung cancer cells by cisplatin and radiation via autophagy and apoptosis.

    Science.gov (United States)

    Liu, Min; Ma, Shumei; Liu, Mingbo; Hou, Yufei; Liang, Bing; Su, Xu; Liu, Xiaodong

    2014-06-01

    Cisplatin is a commonly used drug for chemotherapy, however, whether it may be used synergistically with radiotherapy remains unclear. The present study investigated the underlying mechanisms of synergistic killing by radiosensitization and cisplatin, with a focus on the growth inhibition, apoptosis and autophagy of non-small cell human lung cancer cells in vitro and in a tumor xenograft in vivo. A549 cells were used for the in vitro experiments and divided into the following four treatment groups: Sham-irradiated; conventional radiotherapy (CRT) of five doses of 2 Gy every day; hyperfractionated radiotherapy of five doses of 2 Gy (1 Gy twice a day at 4 h intervals) every day; and CRT plus cisplatin. A xenograft tumor-bearing C57BL/6 model was established for the in vivo experiments and the above-mentioned treatments were administered. MTT and colony formation assays were used to detect cell viability and western blotting was performed to detect the levels of protein expression. Monodansylcadaverine staining and the immunofluorescence technique were used to analyze the autophagy rate, while flow cytometry and immunohistochemistry were performed to detect the expression levels of the genes associated with apoptosis and autophagy, including microtubule-associated protein 1 light chain 3 (MAPLC3)-II, phosphoinositide 3-kinase (PI3K) III, Beclin1, phosphorylated protein kinase B (p-AKT), damage-regulated autophagy modulator (DRAM), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, caspase-3 and p21. The MTT assay demonstrated that cisplatin exhibits a dose-dependent cytotoxicity in A549 cells and synergizes with radiation to promote the cell-killing effect of radiation. In the xenograft mouse model of Lewis cells, cisplatin plus ionizing radiation (IR) (five doses of 2 Gy) yielded the most significant tumor suppression. The autophagic vacuoles, the ratio of MAPLC3-II to MAPLC3-I (LC3-II/LC3-I) and the levels of Beclin1 were found to increase in all treatment

  3. Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Gyrd-Hansen, Mads; Lykkesfeldt, Anne E; Issinger, Olaf-Georg; Stenvang, Jan

    2007-01-01

    future breast cancer treatment. In this study, we have investigated the effect of the chemotherapeutic compound cisplatin using a panel of antiestrogen-resistant breast cancer cell lines established from the human breast cancer cell line MCF-7. We show that the antiestrogen-resistant cells are...... parental MCF-7 cells. Our data show that Bcl-2 can protect antiestrogen-resistant breast cancer cells from cisplatin-induced cell death, indicating that the reduced expression of Bcl-2 in the antiestrogen-resistant cells plays a role in sensitizing the cells to cisplatin treatment.......Antiestrogens are currently used for treating breast cancer patients who have estrogen receptor-positive tumors. However, patients with advanced disease will eventually develop resistance to the drugs. Therefore, compounds effective on antiestrogen-resistant tumors will be of great importance for...

  4. Synthesis and studies of anticancer properties of lupane-type triterpenoid derivatives containing a cisplatin fragment.

    Science.gov (United States)

    Emmerich, Daniel; Vanchanagiri, Kranthi; Baratto, Leopoldo C; Schmidt, Harry; Paschke, Reinhard

    2014-03-21

    Both betulinic acid 1 and cisplatin are promising antitumor agents, which induce apoptotic cell death of cancer cells. In the present investigation a new series of betulinic acid-cisplatin conjugates were synthesized and cytotoxicity and selectivity were assessed against five different tumor cell lines. The aim was to combine two structural units, both related with apoptosis induction. The derivatives exerted a dose-dependent antiproliferative action at micromolar concentrations and the effect of these structural variations on anticancer activity was studied and discussed. Several compounds revealed significant antitumor activity, as the most active substance 3-O-acetylbetulinic (2-(2-aminoethyl)aminoethyl)amide (IC50=1.30-2.24 μM). Interestingly, Betulinic acid-cisplatin conjugates were less cytotoxic than the precursors. PMID:24561674

  5. Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice.

    Science.gov (United States)

    Harris, Hannah M; Sufka, Kenneth J; Gul, Waseem; ElSohly, Mahmoud A

    2016-08-01

    Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy. PMID:27214593

  6. Enhancing the efficacy of cisplatin in ovarian cancer treatment – could arsenic have a role

    Directory of Open Access Journals (Sweden)

    Helm C William

    2009-01-01

    Full Text Available Abstract Ovarian cancer affects more than 200,000 women each year around the world. Most women are not diagnosed until the disease has already metastasized from the ovaries with a resultant poor prognosis. Ovarian cancer is associated with an overall 5 year survival of little more than 50%. The mainstay of front-line therapy is cytoreductive surgery followed by chemotherapy. Traditionally, this has been by the intravenous route only but there is more interest in the delivery of intraperitoneal chemotherapy utilizing the pharmaco-therapeutic advantage of the peritoneal barrier. Despite three large, randomized clinical trials comparing intravenous with intraperitoneal chemotherapy showing improved outcomes for those receiving at least part of their chemotherapy by the intraperitoneal route. Cisplatin has been the most active drug for the treatment of ovarian cancer for the last 4 decades and the prognosis for women with ovarian cancer can be defined by the tumor response to cisplatin. Those whose tumors are innately platinum-resistant at the time of initial treatment have a very poor prognosis. Although the majority of patients with ovarian cancer respond to front-line platinum combination chemotherapy the majority will develop disease that becomes resistant to cisplatin and will ultimately succumb to the disease. Improving the efficacy of cisplatin could have a major impact in the fight against this disease. Arsenite is an exciting agent that not only has inherent single-agent tumoricidal activity against ovarian cancer cell lines but also multiple biochemical interactions that may enhance the cytotoxicity of cisplatin including inhibition of deoxyribose nucleic acid (DNA repair. In vitro studies suggest that arsenite may enhance the activity of cisplatin in other cell types. Arsenic trioxide is already used clinically to treat acute promyelocytic leukemia demonstrating its safety profile. Further research in ovarian cancer is warranted to define

  7. Osteopontin Involves Cisplatin Resistance and Poor Prognosis in Oral Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Sheng-Dean Luo

    2015-01-01

    Full Text Available Background. Osteopontin (OPN is a multifunctional cytokine involved in cell survival, migration, and adhesion. However, its role in chemosensitivity in locally advanced oral squamous cell carcinoma (OSCC in humans has not yet been investigated. Methods. We enrolled 121 patients with locally advanced stage IVA/B OSCC receiving cisplatin-based IC followed by CCRT from January 1, 2006, through January 1, 2012. Immunohistochemistry was used to assess OPN expression in OSCC patients’ biopsy specimens from paraffin blocks before treatment. In addition, MTT/colony formation assay was used to estimate the influence of OPN in an oral cancer cell line treated with cisplatin. Results. Of the 121 patients, 94 had positive OPN findings and 52 responded to IC followed by CCRT. Positive osteopontin immunostaining also correlated significantly with positive N status/TNM stage/male gender and smoking. Univariate analyses showed that patients whose tumors had a low expression of OPN were more likely to respond to chemotherapy and have a significantly better OS than those whose tumors had a high expression of OPN. Multivariate analysis revealed that prolonged survival was independently predicted for patients with stage IVA disease, negative lymph nodes, and negative expressions of OPN and for those who received chemotherapy with Docetaxel/cisplatin/fluorouracil (TPF. An oral cancer line stimulated with OPN exhibited a dose-dependent resistance to cisplatin treatment. Conversely, endogenous OPN depletion by OPN-mediated shRNA increased sensitivity to cisplatin. Conclusions. A positive expression of OPN predicts a poor response and survival in patients with locally advanced stage IVA/B OSCC treated with cisplatin-based IC followed by CCRT.

  8. Dose escalation of cisplatin with 5-fluorouracil in concurrent chemoradiotherapy for esophageal carcinoma

    International Nuclear Information System (INIS)

    Objective: To define the maximum-tolerated dose (MTD) and observe the side effect of escalating cisplatin with 5-fluorouracil in concurrent chemoradiotherapy for esophageal carcinoma in Chinese, with toxicity studied. Methods: Previously untreated fifteen Chinese patients suffering from esophageal carcinoma received conventional fractionation radiotherapy, with 5 daily fractions of 2.0 Gy per week. The total radiation dose was 60 Gy. Concurrent chemotherapy dose escalation was given by the relatively safe and kidney-sparing modified Fibonacci sequence. The starting dose was cisplatin 37.5 mg/m2 D1 and 5-fluorouracil 500 mg/m2 D1-5, respectively. This regimen was repeated 4 times every 28 days. Escalation dose was cisplatin 7.5 mg/m2 and 5- fluorouracil 100 mg/m2. Every. cohort contained at least 3 patients. If no dose-limiting toxicity(DLT) was observed, the next dose level was opened for entry. These courses were repeated until DLT appeared. MTD was declared as one dose level below which DLT appeared. Results: DLT was defined as grade 3 radiation-induced esophagitis at the level of cisplatin 60 mg/m2, 5-fluorouracil 700 mg/m2. MTD was defined as cisplatin 52.5 mg/m2, 5- fiuorouracil 700 mg/m2. The major side effect were radiation-induced esophagitis, leucopenia, nausea, vomiting and anorexia. Conclusion: Maximun tolerated dose of cisplatin with 5-fiuorouracil in concurrent ehemoradiotherapy in the Chinese people with esophageal carcinoma were eisplatin 52.5 mg/m2 D1,5-fluorouracil 700 mg/m2 D1-5, repeated 4 times every 28 days. (authors)

  9. PHASE II STUDY OF GEMCITABINE AND CISPLATIN IN ADVANCED NON-SMALL CELL LUNG CANCER

    Directory of Open Access Journals (Sweden)

    M. Hoseinzadeh Mollayosefy

    2006-06-01

    Full Text Available Cisplatin-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC. Many novel drugs have been used in combination with cisplatin in this setting. Of these drugs, gemcitabine is reported to have a high response rate and acceptable toxicity. The aim of this study was to evaluate the efficacy and safety of gemcitabine and cisplatin combination. Twentythree patients with NSCLC were enrolled from January 2001 till September 2003. All of them were confirmed by histology and were in advanced stage, i.e. stage IIIB or stage IV. Cisplatin with the dose of 70 mg/m2 was given every 21 days, in combination with gemcitabine at a dose of 1250 mg/m2 administered on days 1, 8 of a 21-day cycle. Of the 23 patients, 1 showed complete remission, 5 achieved partial remission and 7 had stable disease and 2 patients showed progressive disease, 8 patients were not evaluable for response. The overall response in 15 evaluable patients was 40% (95% CI., median survival was 13.5 months (95% CI, 3.5-27.4 months, and median progression free survival was 11 months (95% CI, 1.04-20.9 months. Hematological toxicity’s included anemia, neutropenia and thrombocytopenia. Non-hematological toxicities included nausea/vomiting, peripheral neuropathy, skin rashes, mild renal impairment and one case of acute respiratory distress syndrome;another case developed transient acute psychosis. The regimen of combined gemcitabine with cisplatin is safe and effective and well tolerated in patients. In this combination, a lower dose of cisplatin seems to have an efficacy similar to that seen in previous reports.

  10. Evaluation of drug loading, pharmacokinetic behavior, and toxicity of a cisplatin-containing hydrogel nanoparticle.

    Science.gov (United States)

    Kai, Marc P; Keeler, Amanda W; Perry, Jillian L; Reuter, Kevin G; Luft, J Christopher; O'Neal, Sara K; Zamboni, William C; DeSimone, Joseph M

    2015-04-28

    Cisplatin is a cytotoxic drug used as a first-line therapy for a wide variety of cancers. However, significant renal and neurological toxicities limit its clinical use. It has been documented that drug toxicities can be mitigated through nanoparticle formulation, while simultaneously increasing tumor accumulation through the enhanced permeation and retention effect. Circulation persistence is a key characteristic for exploiting this effect, and to that end we have developed long-circulating, PEGylated, polymeric hydrogels using the Particle Replication In Non-wetting Templates (PRINT®) platform and complexed cisplatin into the particles (PRINT-Platin). Sustained release was demonstrated, and drug loading correlated to surface PEG density. A PEG Mushroom conformation showed the best compromise between particle pharmacokinetic (PK) parameters and drug loading (16wt.%). While the PK profile of PEG Brush was superior, the loading was poor (2wt.%). Conversely, the drug loading in non-PEGylated particles was better (20wt.%), but the PK was not desirable. We also showed comparable cytotoxicity to cisplatin in several cancer cell lines (non-small cell lung, A549; ovarian, SKOV-3; breast, MDA-MB-468) and a higher MTD in mice (10mg/kg versus 5mg/kg). The pharmacokinetic profiles of drug in plasma, tumor, and kidney indicate improved exposure in the blood and tumor accumulation, with concurrent renal protection, when cisplatin was formulated in a nanoparticle. PK parameters were markedly improved: a 16.4-times higher area-under-the-curve (AUC), a reduction in clearance (CL) by a factor of 11.2, and a 4.20-times increase in the volume of distribution (Vd). Additionally, non-small cell lung and ovarian tumor AUC was at least twice that of cisplatin in both models. These findings suggest the potential for PRINT-Platin to improve efficacy and reduce toxicity compared to current cisplatin therapies. PMID:25744827

  11. The involvement of XPC protein in the cisplatin DNA damaging treatment-mediated cellular response

    Institute of Scientific and Technical Information of China (English)

    Gan WANG; Alan DOMBKOWSKI; Lynn CHUANG; Xiao Xin S XU

    2004-01-01

    Recognition of DNA damage is a critical step for DNA damage-mediated cellular response. XPC is an important DNA damage recognition protein involved in nucleotide excision repair (NER). We have studied the XPC protein in cisplatin DNA damaging treatment-mediated cellular response. Comparison of the microarray data from both normal and XPCdefective human fibroblasts identified 861 XPC-responsive genes in the cisplatin treatment (with minimum fold change≥1.5).The cell cycle and cell proliferation-related genes are the most affected genes by the XPC defect in the treatment. Many other cellular function genes, especially the DNA repair and signal transduction-related genes, were also affected by the XPC defect in the treatment. To validate the microarray data, the transcription levels of some microarray-identified genes were also determined by an RT-PCR based real time PCR assay. The real time PCR results are consistent with the microarray data for most of the tested genes, indicating the reliability of the microarray data. To further validate the microarray data, the cisplatin treatment-mediated caspase-3 activation was also determined. The Western blot hybridization results indicate that the XPC defect greatly attenuates the cisplatin treatment-mediated Caspase-3 activation. We elucidated the role of p53 protein in the XPC protein DNA damage recognition-mediated signaling process. The XPC defect reduces the cisplatin treatment-mediated p53 response. These results suggest that the XPC protein plays an important role in the cisplatin treatment-mediated cellular response. It may also suggest a possible mechanism of cancer cell drug resistance.

  12. HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer.

    Science.gov (United States)

    Sun, Yi; Guan, Zhenfeng; Liang, Liang; Cheng, Yongyi; Zhou, Jiancheng; Li, Jing; Xu, Yonggang

    2016-03-01

    Bladder cancer (BCa) is the 9th most common malignant tumor and the 13th leading cause of death due to cancer. The development of surgery and target drugs bring new challenges for the traditional concept for BCa therapy, and chemotherapy is still the final option for many BCa patients, and cisplatin-containing regimen the most effective one. However, the ubiquitous application of cisplatin-containing regimen in BCa results in the cisplatin-resistance, in addition, the cisplatin‑resistant BCa manifests enhanced malignant behavior, the mechanism of which is unclear. In the present study, we used BCa cell lines to to clarify this point. BCa cell lines T24/J82 were pretreated with cisplatin >3 months to construct stable cisplatin-resistant cell lines (tagged T24Cis-R and J82Cis-R), which manifested as enhanced capacity of proliferation and malignant behavior in vivo and in vitro, accompanied by cisplatin, and even doxorubicin resistance. The following mechanism dissection revealed that prolonged treatment time of T24/J82 cells led to elevated expression of HIF-1α, which targeted the increased expression of MDR1 on the one hand, and contributed to BCa cell proliferation, migration/invasion on the other hand. Finally, IHC staining of human BCa tissue supported our conclusion that the expression of HIF-1α and MDR1 was higher in chemoresistant tissue vs. chemosensitive tissue. Our results provided a new view of HIF-1α in chemotherapy. PMID:26717965

  13. Silence of fibronectin 1 increases cisplatin sensitivity of non-small cell lung cancer cell line.

    Science.gov (United States)

    Gao, Weiwei; Liu, Ying; Qin, Ruiling; Liu, Daijian; Feng, Qingqing

    2016-07-15

    Fibronectin 1 (FN1) is a member of the glycoprotein family which is widely expressed by multiple cell types and involved in cellular adhesion and migration processes. Recent studies have reported that FN1 might have a role in regulating chemoresistance in tumors. However, the regulation of FN1 on cisplatin resistance in non-small cell lung cancer (NSCLC) has not been investigated. The present study aims to illustrate the effect of FN1 on cisplatin resistance in NSCLC and explore potential mechanisms. In the present study, the mRNA and protein expression levels of FN1 were investigated by RT-PCR and Western blot analysis, respectively, and the 50% inhibitory concentration (IC50) value of cisplatin was measured by MTT assay. Apoptotic ratio and migration were determined using an annexin V-FITC/PI detection kit and a Transwell assay, respectively. The interaction between FN1 and integrin-β1 was evaluated by co-immunoprecipitation assay. The protein expression of β-catenin, cyclin D1 and c-myc were tested using Western blot analysis. The results showed that FN1 was more highly expressed in A549/DDP than in A549 cells, and significantly upregulated by cisplatin treatment in H1299 cells. Knockdown of FN1 reduced the IC50 value of cisplatin, inhibited cell migration and promoted apoptosis. FN1 and integrin-β1 protein directly interacted with each other both in A549 and A549/DDP cells. FN1 silencing suppressed the Wnt/β-catenin signaling pathway, and this effect was dampened by integrin-β1-blocking antibody. Taken together, our findings first suggest that FN1 plays a role in the development of cisplatin resistance in NSCLC, possibly by modulation of β-catenin signaling through interaction with integrin-β1 in NSCLC. PMID:27207836

  14. In vitro toxicity assay of cisplatin on mouse acute lymphoblastic leukaemia and spermatogonial stem cells.

    Science.gov (United States)

    Shabani, R; Ashtari, K; Behnam, B; Izadyar, F; Asgari, H; Asghari Jafarabadi, M; Ashjari, M; Asadi, E; Koruji, M

    2016-06-01

    Testicular cancer is the most common cancer affecting men in reproductive age, and cisplatin is one of the major helpful chemotherapeutic agents for treatment of this cancer. In addition, exposure of testes cancer cells to cisplatin could potentially eliminate tumour cells from germ cells in patients. The aim of this study was to evaluate the effect of cisplatin on viability of mouse acute lymphoblastic leukaemia cell line (EL-4) and neonatal mouse spermatogonial cells in vitro. In this study, the isolated spermatogonial stem cells (SSC) and EL-4 were divided into six groups including control (received medium), sham (received DMSO in medium) and experimental groups which received different doses of cisplatin (0.5, 5, 10 and 15 μg ml(-1) ). Cells viability was evaluated with MTT assay. The identity of the cultured cells was confirmed by the expression of specific markers. Our finding showed that viability of both SSC and EL-4 cells was reduced with the dose of 15 μg/ml when compared to the control group (P ≤ 0.05). Also, the differences between the IC50 in doses 10 and 15 μg/ml at different time were significant (P ≤ 0.05). The number of TUNEL-positive cells was increased, and the BAX and caspase-3 expressions were upregulated in EL4 cells for group that received an effective dose of cisplatin). In conclusion, despite the dramatic effects of cisplatin on both cells, spermatogonial stem cells could form colony in culture. PMID:26428408

  15. Cisplatin-mediated radiosensitization of non-small cell lung cancer cells is stimulated by ATM inhibition

    International Nuclear Information System (INIS)

    Background and purpose: Cisplatin activates ataxia-telangiectasia-mutated (ATM), a protein with roles in DNA repair, cell cycle progression and autophagy. We investigated the radiosensitizing effect of cisplatin with respect to its effect on ATM pathway activation. Material and methods: Non-small cell lung cancer cells (NSCLC) cell lines (A549, H460) and human fibroblast (ATM-deficient AT5, ATM-proficient 1BR3) cells were used. The effects of cisplatin combined with irradiation on ATM pathway activity, clonogenicity, DNA double-strand break (DNA-DSB) repair and cell cycle progression were analyzed with Western blotting, colony formation and γ-H2AX foci assays as well as FACS analysis, respectively. Results: Cisplatin radiosensitized H460 cells, but not A549 cells. Radiosensitization of H460 cells was not due to impaired DNA-DSB repair, increased apoptosis or cell cycle dysregulation. The lack of radiosensitization demonstrated for A549 cells was associated with cisplatin-mediated stimulation of ATM (S1981) and AMPKα (T172) phosphorylation and autophagy. However, in both cell lines inhibition of ATM and autophagy by KU-55933 and chloroquine diphosphate (CQ) respectively resulted in a significant radiosensitization. Combined treatment with the AMPK inhibitor compound-C led to radiosensitization of A549 but not of H460 cells. As compared to the treatment with KU-55933 alone, radiosensitivity of A549 cells was markedly stimulated by the combination of KU-55933 and cisplatin. However, the combination of CQ and cisplatin did not modulate the pattern of radiation sensitivity of A549 or H460 cells. In accordance with the results that cisplatin via stimulation of ATM activity can abrogate its radiosensitizing effect, ATM deficient cells were significantly sensitized to ionizing radiation by cisplatin. Conclusion: The results obtained indicate that ATM targeting can potentiate cisplatin-induced radiosensitization

  16. The Role of Epigenetics in Resistance to Cisplatin Chemotherapy in Lung Cancer

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    O' Byrne, Kenneth J.; Barr, Martin P.; Gray, Steven G., E-mail: sgray@stjames.ie [Trinity College Dublin, Department of Clinical Medicine, Trinity Centre for Health Sciences, St James Hospital, James Street, Dublin 8 (Ireland)

    2011-03-17

    Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20–30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC.

  17. Characterization of iron oxide nanoparticles adsorbed with cisplatin for biomedical applications

    International Nuclear Information System (INIS)

    The aim of this study was to characterize the behaviour of cisplatin adsorbed magnetic nanoparticles (cis-MNPs) for minimal invasive cancer treatments in preliminary in vitro investigations. Cisplatin was adsorbed to magnetic nanoparticles (MNPs) by simple incubation. For stability determinations, cis-MNPs were incubated in dH2O, phosphate-buffered saline (PBS) and fetal calf serum (FCS) at 4-121 deg. C up to 20 weeks. Hydrodynamic diameters were measured using laser diffraction. The extent of cisplatin linkage was determined by atomic absorption spectrometry. The magnetite core size was assessed by vibrating sample magnetometry and transmission electron microscopy. The specific loss power (SLP) was measured in an alternating magnetic field. Our results showed that a maximum of 10.3 ± 1.6 (dH2O), 10 ± 1.6 (PBS) and 13.4 ± 2.2 (FCS) mg cisplatin g-1 Fe could be adsorbed to MNPs. With hyperthermal (42 deg. C) or thermal ablative (60 deg. C) temperatures, used for therapeutic approaches, cisplatin did not desorb from cis-MNPs in dH2O during incubation times of 180 or 30 min, respectively. In PBS and FCS, cisplatin amounts adsorbed to MNPs decreased rapidly to approximately 50% and 25% at these temperatures. This cisplatin release will be necessary for successful chemotherapeutic activity and should increase the therapeutic effect of magnetic heating treatment in medicinal applications. The hydrodynamic diameters of MNPs or cis-MNPs were around 70 nm and magnetization data showed superparamagnetic behaviour. The obtained mean core diameter was around 12 nm. The SLP of the sample was calculated to be 75.5 ± 1.6 W g-1. In conclusion, cis-MNPs exhibit advantageous features for a facilitated desorption of cisplatin in biological media and the heating potential is adequate for hyperthermic treatments. Therefore, even though further detailed investigations are still necessary, tentative use in local tumour therapies aiming at a specific chemotherapeutic release in

  18. Characterization of iron oxide nanoparticles adsorbed with cisplatin for biomedical applications

    Science.gov (United States)

    Kettering, Melanie; Zorn, Heike; Bremer-Streck, Sibylle; Oehring, Hartmut; Zeisberger, Matthias; Bergemann, Christian; Hergt, Rudolf; Halbhuber, Karl-Jürgen; Kaiser, Werner A.; Hilger, Ingrid

    2009-09-01

    The aim of this study was to characterize the behaviour of cisplatin adsorbed magnetic nanoparticles (cis-MNPs) for minimal invasive cancer treatments in preliminary in vitro investigations. Cisplatin was adsorbed to magnetic nanoparticles (MNPs) by simple incubation. For stability determinations, cis-MNPs were incubated in dH2O, phosphate-buffered saline (PBS) and fetal calf serum (FCS) at 4-121 °C up to 20 weeks. Hydrodynamic diameters were measured using laser diffraction. The extent of cisplatin linkage was determined by atomic absorption spectrometry. The magnetite core size was assessed by vibrating sample magnetometry and transmission electron microscopy. The specific loss power (SLP) was measured in an alternating magnetic field. Our results showed that a maximum of 10.3 ± 1.6 (dH2O), 10 ± 1.6 (PBS) and 13.4 ± 2.2 (FCS) mg cisplatin g-1 Fe could be adsorbed to MNPs. With hyperthermal (42 °C) or thermal ablative (60 °C) temperatures, used for therapeutic approaches, cisplatin did not desorb from cis-MNPs in dH2O during incubation times of 180 or 30 min, respectively. In PBS and FCS, cisplatin amounts adsorbed to MNPs decreased rapidly to approximately 50% and 25% at these temperatures. This cisplatin release will be necessary for successful chemotherapeutic activity and should increase the therapeutic effect of magnetic heating treatment in medicinal applications. The hydrodynamic diameters of MNPs or cis-MNPs were around 70 nm and magnetization data showed superparamagnetic behaviour. The obtained mean core diameter was around 12 nm. The SLP of the sample was calculated to be 75.5 ± 1.6 W g-1. In conclusion, cis-MNPs exhibit advantageous features for a facilitated desorption of cisplatin in biological media and the heating potential is adequate for hyperthermic treatments. Therefore, even though further detailed investigations are still necessary, tentative use in local tumour therapies aiming at a specific chemotherapeutic release in combination

  19. Characterization of iron oxide nanoparticles adsorbed with cisplatin for biomedical applications

    Energy Technology Data Exchange (ETDEWEB)

    Kettering, Melanie; Zorn, Heike; Kaiser, Werner A; Hilger, Ingrid [Institute of Diagnostic and Interventional Radiology, University Hospital Jena, Erlanger Allee 101, 07747 Jena (Germany); Bremer-Streck, Sibylle [Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Jena, Erlanger Allee 101, 07747 Jena (Germany); Oehring, Hartmut; Halbhuber, Karl-Juergen [Institute of Anatomy II, University Hospital Jena, Teichgraben 7, 07743 Jena (Germany); Zeisberger, Matthias; Hergt, Rudolf [Institute of Photonic Technology, Albert-Einstein-Strasse 9, 07745 Jena (Germany); Bergemann, Christian [Chemicell GmbH, Eresburgstrasse 22-23, 12103 Berlin (Germany)], E-mail: melanie.kettering@med.uni-jena.de, E-mail: ingrid.hilger@med.uni-jena.de

    2009-09-07

    The aim of this study was to characterize the behaviour of cisplatin adsorbed magnetic nanoparticles (cis-MNPs) for minimal invasive cancer treatments in preliminary in vitro investigations. Cisplatin was adsorbed to magnetic nanoparticles (MNPs) by simple incubation. For stability determinations, cis-MNPs were incubated in dH{sub 2}O, phosphate-buffered saline (PBS) and fetal calf serum (FCS) at 4-121 deg. C up to 20 weeks. Hydrodynamic diameters were measured using laser diffraction. The extent of cisplatin linkage was determined by atomic absorption spectrometry. The magnetite core size was assessed by vibrating sample magnetometry and transmission electron microscopy. The specific loss power (SLP) was measured in an alternating magnetic field. Our results showed that a maximum of 10.3 {+-} 1.6 (dH{sub 2}O), 10 {+-} 1.6 (PBS) and 13.4 {+-} 2.2 (FCS) mg cisplatin g{sup -1} Fe could be adsorbed to MNPs. With hyperthermal (42 deg. C) or thermal ablative (60 deg. C) temperatures, used for therapeutic approaches, cisplatin did not desorb from cis-MNPs in dH{sub 2}O during incubation times of 180 or 30 min, respectively. In PBS and FCS, cisplatin amounts adsorbed to MNPs decreased rapidly to approximately 50% and 25% at these temperatures. This cisplatin release will be necessary for successful chemotherapeutic activity and should increase the therapeutic effect of magnetic heating treatment in medicinal applications. The hydrodynamic diameters of MNPs or cis-MNPs were around 70 nm and magnetization data showed superparamagnetic behaviour. The obtained mean core diameter was around 12 nm. The SLP of the sample was calculated to be 75.5 {+-} 1.6 W g{sup -1}. In conclusion, cis-MNPs exhibit advantageous features for a facilitated desorption of cisplatin in biological media and the heating potential is adequate for hyperthermic treatments. Therefore, even though further detailed investigations are still necessary, tentative use in local tumour therapies aiming at a

  20. Cisplatin and Oxaliplatin Toxicity: Importance of Cochlear Kinetics as a Determinant for Ototoxicity

    OpenAIRE

    Hellberg, Victoria; Wallin, Inger; Eriksson, Sofi; Hernlund, Emma; Jerremalm, Elin; Berndtsson, Maria; Eksborg, Staffan; Arnér, Elias S. J.; Shoshan, Maria; Ehrsson, Hans; Laurell, Göran

    2009-01-01

    Background Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained. Methods In HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8....

  1. Distribution of platinum in patients treated with cisplatin determined by radiochemical neutron activation analysis

    DEFF Research Database (Denmark)

    Heydorn, K.; Rietz, B.; Krarup-Hansen, A.

    1998-01-01

    Cisplatin is used in a successful treatment of testicular cancer and some related conditions, but several toxic effects have been observed. Knowledge about the distribution of platinum in the human body after treatment with massive doses of cisplatin might provide clues to the origin of side...... effects, and a study was initiated to provide such information by the analysis of postmortem samples by our method of radiochemical neutron activation analysis (RNAA). Autopsy samples of kidney, liver, lung, muscle, and pancreas were taken with stainless steel scalpels together with samples of nerve...

  2. Severe reversible toxic encephalopathy induced by cisplatin in a patient with cervical carcinoma receiving combined radiochemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Sterzing, F.; Grehn, C.; Dinkel, J.; Krempien, R.; Hartung, G.; Debus, J.; Harms, W. [University of Heidelberg Medical School (Germany). Dept. of Radiation Oncology

    2007-09-15

    Case Report: A 45-year-old patient with cervix carcinoma received combined radiochemotherapy including cisplatin. After a cumulative dose of 240 mg/m{sup 2} the patient suddenly became somnolent and developed a severe tetraparesis and generalized seizures. After ruling out intracranial bleeding, cerebral metastases as well as infectious and metabolic causes of this condition, a severe toxic encephalopathy was diagnosed based on the clinical findings and MRI scans. After symptomatic treatment on the intensive care unit all symptoms were completely reversible. Conclusion: Toxic encephalopathy is a rare but dramatic complication of various cytostatic drugs. With the widespread use of cisplatin this rare disorder should be kept in mind. (orig.)

  3. The Protective Effect of mammalian Target of Rapamycin (mTOR in Cisplatin Induced Nephropathy

    Directory of Open Access Journals (Sweden)

    Kultigin Turkmen

    2009-05-01

    Full Text Available "nCisplatin, a simple inorganic compound, has been one of the leading antitumor drugs especially for solid tumors for near 30 years. The mechanisms of cisplatin include denaturation of DNA and cell mitochondria, arresting cell cycle in the G2 phase and eventually causing apoptosis, inflammation, necrosis and death in cells. Apoptosis is a process of programmed cell death through cystein proteases named ‘caspases'. Pathways of caspase-mediated apoptosis can classified as ‘mitochondrial' pathway and ‘death receptor' pathway Especially caspase-3 plays a crucial role in cisplatin-induced nephrotoxicity through the pathways of apoptosis. The mammalian target of rapamycin (mTOR, is a serine/threonine kinase that regulates both cell growth and cell cycle progression through the phosphotidyl 3 kinase (PI3K/protein kinase B (Akt signaling pathway. mTOR regulates both cell growth, cell cycle progression and angiogenesis. By targeting mTOR, the immunsuppressant and antiproliferative agent Rapamycin inhibits signals required for cell cycle progression, cell growth, cell proliferation and angiogenesis. Angiogenesis is extremely important in tumor progression and metastasis. Although rapamycin is proapoptotic agent especially in cancers, there is an evidence that rapamycin can also have antiapoptotic properties through pleiotropic function in the regulation of cell death depending on the cell type and activation state as well as downstream targets of antiapoptotic molecules such as p53 and Bcl-2 proteins. Activation of caspase signaling pathways and dysregulation of pro- and antiapoptotic Bcl-2 proteins have been described previously. So there are links between the mTOR and caspase signaling pathways. Despite its effectiveness, the dose of cisplatin that can be administered is limited by its nephrotoxicity such as acute tubuler necrosis (ATN causing acute renal failure (ARF. Several agents have been tested to see whether they could

  4. An investigation of the effect of thiamine pyrophosphate on cisplatin-induced oxidative stress and DNA damage in rat brain tissue compared with thiamine: thiamine and thiamine pyrophosphate effects on cisplatin neurotoxicity.

    Science.gov (United States)

    Turan, M I; Cayir, A; Cetin, N; Suleyman, H; Siltelioglu Turan, I; Tan, H

    2014-01-01

    This study investigated the effects of thiamine pyrophosphate (TPP) at dosages of 10 and 20 mg/kg on oxidative stress induced in rat brain tissue with cisplatin and compared this with thiamine. Cisplatin neurotoxicity represents one of the main restrictions on the drug being given in effective doses. Oxidative stress is considered responsible for cisplatin toxicity. Our results showed that cisplatin increased the levels of oxidant parameters such as lipid peroxidation (thio barbituric acid reactive substance (TBARS)) and myeloperoxidase (MPO) in brain tissue and suppressed the effects of antioxidants such as total glutathione (GSH) and superoxide dismutase (SOD). TPP, especially at a dosage of 20 mg/kg, significantly reduced TBARS and MPO levels that increase with cisplatin administration compared with the thiamine group, while TPP significantly increases GSH and SOD levels. In addition, the level of 8-Gua (guanine), a product of DNA damage, was 1.7 ± 0.12 8-hydroxyl guanine (8-OH Gua)/105 Gua in brain tissue in the control group receiving cisplatin, compared with 0.97 ± 0.03 8-OH Gua/105 Gua in the thiamine pyrophosphate (20 mg/kg) group and 1.55 ± 0.11 8-OH Gua/105 Gua in the thiamine (20 mg/kg) group. These results show that thiamine pyrophosphate significantly prevents oxidative damage induced by cisplatin in brain tissue, while the protective effect of thiamine is insignificant. PMID:23632005

  5. Comparison of the effects of cisplatin and a new generation platinum derivative on parental and cisplatin-resistant ovarian cancer cell lines A2780 and A2780cis

    Czech Academy of Sciences Publication Activity Database

    Šindlerová, Lenka; Horváth, Viktor; Souček, Karel; Chramostová, Kateřina; Sova, P.; Kroutil, A.; Turánek, J.; Hofmanová, Jiřina; Kozubík, Alois

    Bratislava : Ústav molekulárnej fyziológie a genetiky SAV, 2003 - (Breier, A.). s. 128-129 [Xenobiochemické sympózium /22./. 09.06.2003-11.06.2003, Smolenice] R&D Projects: GA MPO PZ-Z2/29; GA ČR GA305/01/0418 Institutional research plan: CEZ:AV0Z5004920 Keywords : cisplatin * LA-12 * cellcycle Subject RIV: BO - Biophysics

  6. The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice

    International Nuclear Information System (INIS)

    Cisplatin (cis-diaminedichloroplatinum (II) or CDDP) (a widely used platinum-containing anticancer drug) is nephrotoxic and has a low percentage of tolerance in patients during chemotherapy. The active hexose correlated compound (AHCC) is an extract of Basidiomycotina marketed as a supplement for cancer patients due to its nutrients and fibre content and its ability to strengthen and optimize the capacity of the immune system. The possibility that AHCC could reduce the side effects of cisplatin was assessed in the tumor-bearing BALB/cA mice on the basis of the ability to ameliorate the cisplatin-induced body weight loss, anorexia, nephrotoxicity and hematopoietic toxicity. Although cisplatin (8 mg/kg body weight) reduced the size and weight of the solid tumors, supplementation with AHCC significantly enhanced cisplatin-induced antitumor effect in both the size (p < 0.05) and weight (p < 0.05). Food intake in the cisplatin-treated mice were decreased following commencement of treatment and this remained low compared with the cisplatin-untreated group (control) throughout the experiment period. Supplementation with AHCC increased the food intake in the cisplatin-treated mice. The blood urea nitrogen and serum creatinine concentrations, and the ratio of blood urea nitrogen to serum creatinine were significantly increased in the cisplatin alone treated group compared to the control group. Their increased levels were mitigated by supplementation with AHCC (100 mg/kg body weight) in the cisplatin-treated group. AHCC was also able to modulate the suppression of bone marrow due to cisplatin and the improvement was statistically significant. The histopathological examination of the kidney revealed the presence of cisplatin-induced damage and this was modulated by AHCC treatment. The potential for AHCC to ameliorate the cisplatin-evoked toxicity as well as the chemotherapeutic effect could have beneficial economic implications for patients undergoing chemotherapy with

  7. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    Energy Technology Data Exchange (ETDEWEB)

    Aburto, Andrés [Program of M.Sc., Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Barría, Agustín [School of Biochemistry, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Cárdenas, Areli [Ph.D. Program, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Carpio, Daniel; Figueroa, Carlos D. [Department of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia (Chile); Burgos, Maria E. [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Ardiles, Leopoldo, E-mail: leopoldoardiles@gmail.com [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile)

    2014-10-15

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity.

  8. NOXA-induced alterations in the Bax/Smac axis enhance sensitivity of ovarian cancer cells to cisplatin.

    Directory of Open Access Journals (Sweden)

    Chao Lin

    Full Text Available Ovarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarian cancer. NOXA, a pro-apoptotic BH3-only protein, is identified as a transcription target of p53 and/or p73. In this study, we found that genetic variants of Bcl-2 proteins exist among cisplatin-sensitive and -resistant ovarian cancer cells, and the responses of NOXA and Bax to cisplatin are regulated mainly by p53. We further evaluated the effect of NOXA on cisplatin. NOXA induced apoptosis and sensitized A2780s and SKOV3 cells to cisplatin in vitro and in vivo. The effects were mediated by elevated Bax expression, enhanced caspase activation, release of Cyt C and Smac into the cytosol. Furthermore, gene silencing of Bax or Smac significantly attenuated NOXA and/or cisplatin-induced apoptosis in chemosensitive A2780s cells, whereas overexpression of Bax or addition of Smac-N7 peptide significantly increased NOXA and/or cisplatin-induced apoptosis in chemoresistant SKOV3 cells. To our knowledge, these data suggest a new mechanism by which NOXA chemosensitized ovarian cancer cells to cisplatin by inducing alterations in the Bax/Smac axis. Taken together, our findings show that NOXA is potentially useful as a chemosensitizer in ovarian cancer therapy.

  9. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    International Nuclear Information System (INIS)

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity

  10. Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers.

    Science.gov (United States)

    Li, Feng; Shanmugam, Muthu K; Siveen, Kodappully Sivaraman; Wang, Fan; Ong, Tina H; Loo, Ser Yue; Swamy, Mahadeva M M; Mandal, Somnath; Kumar, Alan Prem; Goh, Boon Cher; Kundu, Tapas; Ahn, Kwang Seok; Wang, Ling Zhi; Hui, Kam Man; Sethi, Gautam

    2015-03-10

    Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated whether garcinol, a polyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin. We found that garcinol inhibited the viability of a panel of diverse HNSCC cell lines, enhanced the apoptotic effect of cisplatin, suppressed constitutive as well as cisplatin-induced NF-κB activation, and downregulated the expression of various oncogenic gene products (cyclin D1, Bcl-2, survivin and VEGF). In vivo study showed that administration of garcinol alone (0.5 mg/kg body weight, i.p. five times/week) significantly suppressed the growth of the tumor, and this effect was further increased by cisplatin. Both the markers of proliferation index (Ki-67) and microvessel density (CD31) were downregulated in tumor tissues by the combination of cisplatin and garcinol. The pharmacokinetic results of garcinol indicated that good systemic exposure was achievable after i.p. administration of garcinol at 0.5 mg/kg and 2 mg/kg with mean peak concentration (Cmax) of 1825.4 and 6635.7 nM in the mouse serum, respectively. Overall, our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers. PMID:25762616

  11. Poly(ADP-ribose) polymerase activation induces high mobility group box 1 release from proximal tubular cells during cisplatin nephrotoxicity.

    Science.gov (United States)

    Kim, J

    2016-06-20

    Cisplatin is one of the most potent chemotherapy drugs against cancer, but its major side effect such as nephrotoxicity limits its use. Inhibition of poly(ADP-ribose) polymerase (PARP) protects against various renal diseases via gene transactivation and/or ADP-ribosylation. However, the role of PARP in necrotic cell death during cisplatin nephrotoxicity remains an open question. Here we demonstrated that pharmacological inhibition of PARP by postconditioning dose-dependently prevented tubular injury and renal dysfunction following cisplatin administration in mice. PARP inhibition by postconditioning also attenuated ATP depletion during cisplatin nephrotoxicity. Systemic release of high mobility group box 1 (HMGB1) protein in plasma induced by cisplatin administration was significantly diminished by PARP inhibition by postconditioning. In in vitro kidney proximal tubular cell lines, PARP inhibition by postconditioning also diminished HMGB1 release from cells. These data demonstrate that cisplatin-induced PARP1 activation contributes to HMGB1 release from kidney proximal tubular cells, resulting in the promotion of inflammation during cisplatin nephrotoxicity. PMID:26447520

  12. Extremely low frequency electromagnetic field sensitizes cisplatin-resistant human ovarian adenocarcinoma cells via P53 activation.

    Science.gov (United States)

    Baharara, Javad; Hosseini, Nasrin; Farzin, Tayebe Ramezani

    2016-08-01

    In the following study, extremely low frequency electromagnetic fields (EL-EMF) radiation was used to restore sensitivity in the cisplatin-resistant A2780 ovarian cancer cells. For this purpose A2780 cells were treated with different doses of cisplatin and EL-EMF (50 Hz, 200 gauss, and 2 h) alone. Cytotoxicity was the measurement using MTT assay. After calculating IC50 for cisplatin (90 µg/ml) a lower concentration from IC50 (30 and 60 µg/ml) was used to be combined with EL-EMF. We compare the effects of each cisplatin, EL-EMF and combination groups using acridine orange-propidium iodide (AO/PI) and DAPI staining, caspase 3/9 activation assay and Annexin/PI assay. We also assessed changes in P53 and Matrix metalloproteinases 2 (MMPs) gene expression with semi-quantitative RT-PCR. Results indicated an EL-EMF-dependent proliferative decrease which was found <10 %, and occurred independently of cisplatin. The decreased proliferation rate for 30 and 60 µg/ml cisplatin was about 20 and 40 %, respectively, while for synergistic groups 30 and 60 µg/ml cisplatin with 2 h EL-EMF exposer, showed 47 and 71 % decrease in viability in rats. DAPI staining indicated that chromatin break down significantly increased in synergistic groups. Acridine orange staining also confirmed MTT assay results. Caspase activity significantly increased in the combined groups. Semi-quantitative RT-PCR showed that in synergistic groups of cisplatin and EL-EMF, expression of P53 was increased but the expression level of MPP-2 gene decreased. Results from this study showed that changes generated by the non-invasive EL-EMF can make resistant cells sensitive to cisplatin. PMID:26370097

  13. Cisplatin/gemcitabine or oxaliplatin/gemcitabine in the treatment of advanced biliary tract cancer: a systematic review

    International Nuclear Information System (INIS)

    Cisplatin/gemcitabine association has been a standard of care for first-line regimen in advanced biliary tract cancer nevertheless oxaliplatin/gemcitabine regimen is frequently preferred. Because comparative effectiveness in clinical outcomes of cisplatin- versus oxaliplatin-containing chemotherapy is not available, a systematic review of studies assessing cisplatin/gemcitabine or oxaliplatin/gemcitabine chemotherapies in advanced biliary tract cancer was performed. Published studies evaluating cisplatin/gemcitabine or oxaliplatin/gemcitabine in advanced biliary tract cancer were included. Each study was weighted according to the number of patients included. The primary objective was to assess weighted median of medians overall survival (mOS) reported for both regimens. Secondary goals were to assess weighted median of medians progression-free survival (mPFS) and toxic effects were pooled and compared within each arm. Thirty-three studies involving 1470 patients were analyzed. In total, 771 and 699 patients were treated by cisplatin/gemcitabine and oxaliplatin/gemcitabine, respectively. Weighted median of mOS was 9.7 months in cisplatin group and 9.5 months in oxaliplatin group. Cisplatin-based chemotherapy was significantly associated with more grade 3 and 4 asthenia, diarrhea, liver toxicity, and hematological toxicity. Sensitivity analysis including only the studies with the standard regimen of cisplatin (25–35 mg/m2 administered on days 1 and 8) showed that the weighted median of mOS increased from 9.7 to 11.7 months but Gem/CDDP regimen remained more toxic than Gemox regimen. These results suggest that the Gem/CDDP regimen with cisplatin (25–35 mg/m2) administered on days 1 and 8 is associated with survival advantage than Gemox regimen but with addition of toxicity

  14. Histological Study of Toxic Effects of Cisplatin Single Dose Injection on Rat Kidney

    Directory of Open Access Journals (Sweden)

    Mashhadi

    2014-07-01

    Full Text Available Background Cisplatin, as an antineoplastic drug widely used for treatment of solid tumors, induces renal toxicity by free radical formation. Objectives The aim of the present study was to identify the histological changes of renal parenchyma after a single dose injection of cisplatin in rat, as an experimental model. Patients and Methods Twenty adult male Sprague Dawley rats, weighting about 210 ± 30 g, were randomly divided into experimental (10 and control (10 groups. The experimental group received a single dose injection of cisplatin intraperitoneally (5 mg/kg. One week after the injection, rats of both groups received deep anesthesia and were scarified. The tissue samples were removed and the prepared sections were stained by H&E and periodic acid–Schiff (PAS methods. The slides were used for both histopathological and morphometric studies. The collected data were analyzed by SPSS. Results Statistical analysis by Mann-Whitney test showed that there was a significant difference in the height of epithelium between the proximal convoluted tubule (PCT and the distal convoluted tubule (DCT of the experimental and control groups (P < 0.001. There was no significant difference in the urinary space diameter between the experimental and control groups. Focal tubular necrosis and vacuolar and eosinophilic degenerations were more prominent in the experimental group. Conclusions It seems that cisplatin can induce many quantitative and qualitative changes in proximal and distal convoluted tubules of nephron in rats.

  15. Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer

    NARCIS (Netherlands)

    Koster, Roelof; di Pietro, Alessandra; Timmer-Bosscha, Hetty; Gibcus, Johan H.; van den Berg, Anke; Suurmeijer, Albert J.; Bischoff, Rainer; Gietema, Jourik A.; de Jong, Steven

    2010-01-01

    Platinum-based chemotherapies such as cisplatin are used as first-line treatment for many cancers. Although there is often a high initial responsiveness, the majority of patients eventually relapse with platinum-resistant disease. For example, a subset of testicular cancer patients still die even th

  16. Reversion by ozone treatment of acute nephrotoxicity induced by cisplatin in rats

    Directory of Open Access Journals (Sweden)

    Ricardo González

    2004-01-01

    Full Text Available BACKGROUND: Ozone therapy has become a useful treatment for pathological processes, in which the damage mediated by reactive oxygen species is involved. Several lines of evidence suggest that cisplatin-induced acute nephrotoxicity is partially mediated by reactive oxygen species.

  17. Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer.

    Science.gov (United States)

    Roh, Jong-Lyel; Kim, Eun Hye; Park, Jin Young; Kim, Ji Won; Kwon, Minsu; Lee, Byung-Heon

    2014-10-15

    Adaptation to cellular stress is not a vital function of normal cells but is required of cancer cells, and as such might be a sensible target in cancer therapy. Piperlongumine is a naturally occurring small molecule selectively toxic to cancer cells. This study assesses the cytotoxicity of piperlongumine and its combination with cisplatin in head-and-neck cancer (HNC) cells in vitro and in vivo. The effect of piperlongumine, alone and in combination with cisplatin, was assessed in human HNC cells and normal cells by measuring growth, death, cell cycle progression, reactive oxygen species (ROS) production, and protein expression, and in tumor xenograft mouse models. Piperlongumine killed HNC cells regardless of p53 mutational status but spared normal cells. It increased ROS accumulation in HNC cells, an effect that can be blocked by the antioxidant N-acetyl-L-cysteine. Piperlongumine induced selective cell death in HNC cells by targeting the stress response to ROS, leading to the induction of death pathways involving JNK and PARP. Piperlongumine increased cisplatin-induced cytotoxicity in HNC cells in a synergistic manner in vitro and in vivo. Piperlongumine might be a promising small molecule with which to selectively kill HNC cells and increase cisplatin antitumor activity by targeting the oxidative stress response. PMID:25193861

  18. Study of feasibility of the treatment with procainamide hydrochloride and cisplatin in pregnant mice

    Czech Academy of Sciences Publication Activity Database

    Ognio, E.; Chiavarina, B.; Peterka, Miroslav; Mariggió, M.A.; Viale, M.

    2006-01-01

    Roč. 164, č. 3 (2006), s. 232-240. ISSN 0009-2797 R&D Projects: GA MŠk OC B23.001 Institutional research plan: CEZ:AV0Z50390512 Keywords : Cisplatin * Embryotoxicity * Chemioprotection Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.800, year: 2006

  19. Up-regulation of fas reverses cisplatin resistance of human small cell lung cancer cells

    Directory of Open Access Journals (Sweden)

    Wu Wei

    2010-05-01

    Full Text Available Abstract Background/Aim Fas/FasL system is a major regulator of apoptosis. The mechanisms by which Fas mediates cisplatin resistance remain unclear. The aim of this study is to explore the effect of Fas over-expression on cisplatin resistance of small cell lung cancer cells and its possible mechanisms. Materials and methods Fas was over-expressed in H446/CDDP cells by infection with the adenoviruses containing Fas. Sensitivity of Fas-overexpressed H446/CDDP cells to cisplatin was evaluated using MTT assay. Expressions of Fas, GST-π and ERCC1 were detected by RT-PCR and Western blot analysis. Apoptosis rate was examined by FACS. Results Over-expression of Fas in H446/CDDP cells significantly decreased the expressions of GST-π and ERCC1 at mRNA and protein levels, and increased the cell apoptosis. Furthermore, up-regulation of Fas significantly decreased the tolerance of H446/CDDP cells to cisplatin. Conclusion Over-expression of Fas reverses drug resistance of H446/CDDP cells, possibly due to the increased cell sensitivity to apoptosis and the decreased expressions of GST-π and ERCC1.

  20. Pinpointing differences in cisplatin-induced apoptosis in adherent and non-adherent cancer cells

    DEFF Research Database (Denmark)

    Tastesen, Hanne Sørup; Holm, Jacob Bak; Poulsen, Kristian Arild;

    2010-01-01

    have previously been demonstrated to protect cells from apoptosis. We find, however, that increase or decrease in the cellular content of glutathione and taurine has no effect on cisplatin-induced cell death in EATC and ELA. Nevertheless, knock-down of the taurine transporter TauT leads to a...

  1. Role of metallothionein in cisplatin sensitivity of germ-cell tumours

    NARCIS (Netherlands)

    Meijer, C.; Timmer, A.; Vries, E.G.E.de; Groten, J.P.; Knol, A.; Zwart, N.; Dam, W.A.; Sleijfer, D.Th.; Mulder, N.H.

    2000-01-01

    Cisplatin (CDDP) is an extremely active drug in the treatment of germ- cell tumours. Earlier, we found an unexpected inverse correlation between the total amount of sulfhydryl groups and CDDP sensitivity in a panel of 3 human germ-cell tumour and 3 colon-carcinoma cell lines. Major components of the

  2. Intravenous or oral administration of vinorelbine in adjuvant chemotherapy with cisplatin and vinorelbine for resected NSCLC

    DEFF Research Database (Denmark)

    Sorensen, Steffen Filskov; Carus, Andreas; Meldgaard, Peter

    2015-01-01

    OBJECTIVES: Cisplatin and vinorelbine given intravenously is a well-established adjuvant chemotherapy regimen after surgery for early-stage NSCLC. Vinorelbine can also be administered orally. However, the efficacy of orally administrated vinorelbine in adjuvant treatment of NSCLC is unknown. We a...... conclusion we observed that intravenous or oral administration of vinorelbine in combination with cisplatin after surgery for NSCLC appear equally effective in terms of overall and disease-free survival.......OBJECTIVES: Cisplatin and vinorelbine given intravenously is a well-established adjuvant chemotherapy regimen after surgery for early-stage NSCLC. Vinorelbine can also be administered orally. However, the efficacy of orally administrated vinorelbine in adjuvant treatment of NSCLC is unknown. We...... assessed the overall survival (OS) and disease-free survival (DFS) of patients treated with adjuvant i.v. vinorelbine or p.o. vinorelbine, in combination with i.v. cisplatin. MATERIALS AND METHODS: We reviewed two time-separated cohorts of patients referred to the Department of Oncology at Aarhus...

  3. Anatomical and physiological basis for the allometric scaling of cisplatin clearance in dogs.

    Science.gov (United States)

    Achanta, S; Sewell, A; Ritchey, J W; Broaddus, K; Bourne, D W A; Clarke, C R; Maxwell, L K

    2016-06-01

    Cisplatin is a platinum-containing cytotoxic drug indicated for the treatment of solid tumors in veterinary and human patients. Several of the algorithms used to standardize the doses of cytotoxic drugs utilize allometry, or the nonproportional relationships between anatomical and physiological variables, but the underlying basis for these relationships is poorly understood. The objective of this proof of concept study was to determine whether allometric equations explain the relationships between body weight, kidney weight, renal physiology, and clearance of a model, renally cleared anticancer agent in dogs. Postmortem body, kidney, and heart weights were collected from 364 dogs (127 juveniles and 237 adults, including 51 dogs ≥ 8 years of age). Renal physiological and cisplatin pharmacokinetic studies were conducted in ten intact male dogs including two juvenile and eight adult dogs (4-55 kg). Glomerular filtration rate (GFR), effective renal plasma flow, effective renal blood flow, renal cisplatin clearance, and total cisplatin clearance were allometrically related to body weight with powers of 0.75, 0.59, 0.61, 0.71, and 0.70, respectively. The similar values of these diverse mass exponents suggest a common underlying basis for the allometry of kidney size, renal physiology, and renal drug handling. PMID:26440900

  4. Overcoming tumor resistance to cisplatin by cationic lipid-assisted prodrug nanoparticles.

    Science.gov (United States)

    Cao, Zhi-Ting; Chen, Zhi-Yao; Sun, Chun-Yang; Li, Hong-Jun; Wang, Hong-Xia; Cheng, Qin-Qin; Zuo, Zu-Qi; Wang, Ji-Long; Liu, Yang-Zhong; Wang, Yu-Cai; Wang, Jun

    2016-07-01

    Chemotherapy resistance has become a major challenge in the clinical treatment of lung cancer which is the leading cancer type for the estimated deaths. Recent studies have shown that nanoparticles as drug carriers can raise intracellular drug concentration by achieving effectively cellular uptake and rapid drug release, and therefore reverse the acquired chemoresistance of tumors. In this context, nanoparticles-based chemotherapy represents a promising strategy for treating malignancies with chemoresistance. In the present study, we developed cationic lipid assisted nanoparticles (CLAN) to deliver polylactide-cisplatin prodrugs to drug resistant lung cancer cells. The nanoparticles were formulated through self-assembly of a biodegradable poly(ethylene glycol)-block-poly(lactide) (PEG-PLA), a hydrophobic polylactide-cisplatin prodrug, and a cationic lipid. The cationic nanoparticles were proven to significantly improve cell uptake of cisplatin, leading to an increased DNA-Pt adduct and significantly promoted DNA damage in vitro. Moreover, our study reveals that cationic nanoparticles, although are slightly inferior in blood circulation and tumor accumulation, are more effective in blood vessel extravasation. The CLANs ultimately enhances the cellular drug availability and leads to the reversal of cisplatin resistance. PMID:27088406

  5. Autophagy and hypertrophy in glioma cells escaping early death in cultures treated with cisplatin

    Czech Academy of Sciences Publication Activity Database

    Krajčí, D.; Mareš, Vladislav; Lisá, Věra

    Dresden: European Life Scientist Organization, 2007. s. 371-371. [ELSO 2007 - Frontiers of cellular, developmental and molecular biology. 01.09.2007-04.09.2007, Dresden] Institutional research plan: CEZ:AV0Z50110509 Keywords : spo2 * autophagy * glioma cels * cisplatin Subject RIV: ED - Physiology

  6. Cell cycle perturbations induced by Cisplatin in normal and tumor transformed cells

    Czech Academy of Sciences Publication Activity Database

    Mareš, Vladislav; Mazzini, G.; Lisá, Věra; Ferrari, C.; Malík, Radek; Šedo, A.

    2001-01-01

    Roč. 5, - (2001), s. 23-29. ISSN 1212-3137 Grant ostatní: GA UK(XC) 58/1999/C; LF UK(XC) 206019-2-"Oncology" Institutional research plan: CEZ:AV0Z5011922 Keywords : cell cycle * cisplatin * DNA content Subject RIV: FD - Oncology ; Hematology

  7. Recent advances in analytical determination of cisplatin and its hydrolysis products

    International Nuclear Information System (INIS)

    Cisplatin (cis-diaminedichloroplatinum [II] is a coordination compound, used in the treatment of several solid tumors. Cisplatin and its hydrolysis products exhibit a great pharmacological effect but are very toxic and probably carcinogenic. The present review summarizes the most important advances in the last years in the techniques employed for the detection and quantification of cisplatin and its hydrolysis products and in the different matrixes studied. The new emerging techniques and their modifications recently developed, fundamentally the combined use of detection and separation techniques for the analysis of platinum species and their impact on the speed, sensitivity and specificity of the analytical determination, with regard to the techniques used in the last century are discussed. High-Performance Liquid Chromatography and Capillary Electrophoresis, coupled with detection methods such as Mass Spectrometry, Inductively Coupled Plasma-Mass Spectrometry, Atomic Absorption Spectrometry and more recently, High-Field Asymmetric Waveform Ion Mobility Spectrometry are the methods more employed. The analysis of cisplatin and its hydrolysis products in new and more complex matrixes is also presented

  8. Platinum(IV) complex with adamantylamine overcomes intrinsic resistance to cisplatin in ovarian cancer cells

    Czech Academy of Sciences Publication Activity Database

    Horváth, Viktor; Blanářová, Olga; Šindlerová, Lenka; Souček, Karel; Hofmanová, Jiřina; Sova, P.; Kroutil, A.; Fedoročko, P.; Kozubík, Alois

    2006-01-01

    Roč. 102, č. 1 (2006), s. 32-40. ISSN 0090-8258 R&D Projects: GA MPO(CZ) PZ-Z2/29 Institutional research plan: CEZ:AV0Z50040507 Keywords : ovarian cancer * cisplatin * adamantylamine Subject RIV: BO - Biophysics Impact factor: 2.319, year: 2006

  9. Sialic acid changes in Dalton's lymphoma-bearing mice after cyclophosphamide and cisplatin treatment

    Directory of Open Access Journals (Sweden)

    Nicol B.M.

    2002-01-01

    Full Text Available Sialic acid changes in Dalton's lymphoma cells and other tissues of 10-12-week-old Swiss albino mice were investigated in relation to tumour growth in vivo and following cyclophosphamide (ip, 200 mg/kg body weight or cisplatin (ip, 8 mg/kg body weight treatment. Three to four animals of both sexes were used in each experimental group. The sialic acid level of tumour cells (0.88 µmol/g increased with tumour progression (1.44-1.59 µmol/g; P<=0.05 in mice. Sialic acid concentration in other tissues (liver, kidney, testes and brain also increased (~40, 10, 30 and 58%, respectively in the tumour-bearing hosts as compared with that in the respective tissues of normal mice. In vivo cyclophosphamide or cisplatin treatment resulted in an overall decrease of sialic acid contents in the tissues. Cyclophosphamide was more efficient in lowering tissue sialic acid than cisplatin (P<=0.01, ANOVA. It is suggested that sialic acid residues could be an important factor contributing to the manifestation of malignant properties in cancer cells in general and Dalton's lymphoma cells in particular. A significant decrease in the sialic acid content of Dalton's lymphoma cells after cisplatin or cyclophosphamide treatment may bring about specific changes in tumour cells which could be associated with tumour regression.

  10. Paclitaxel, cisplatin and gemcitabine in treatment of carcinomas of unknown primary site, a phase II study

    DEFF Research Database (Denmark)

    Møller, Anne Kirstine Hundahl; Pedersen, Karen Damgaard; Gothelf, A.;

    2010-01-01

    Background. The present study was conducted to evaluate the efficacy and toxicity of a combination of paclitaxel, cisplatin and gemcitabine in patients with carcinoma of unknown primary site (CUP). Patients and methods. Patients with CUP, ECOG performance status 0-1 and age between 18 and 65 years...... old were treated with paclitaxel 175 mg/m...

  11. Cleavage enhancement of specific chemical bonds in DNA-Cisplatin complexes induced by X-rays

    International Nuclear Information System (INIS)

    The chemical bond transformation of cisplatin-DNA complexes can be probed efficiently by XPS which provides a concomitant X-ray irradiation source as well. The presence to Pt could considerably increase formation of the SE induced by X-ray and that the further interaction of these LEE with DNA leads to the enhancement of bond cleavages.

  12. Global phosphoproteome profiling reveals unanticipated networks responsive to cisplatin treatment of embryonic stem cells

    DEFF Research Database (Denmark)

    Pines, Alex; Kelstrup, Christian D; Vrouwe, Mischa G;

    2011-01-01

    (stable isotope labeling by amino acids in cell culture)-labeled murine embryonic stem cells with the anticancer drug cisplatin. Network and pathway analyses indicated that processes related to the DNA damage response and cytoskeleton organization were significantly affected. Although the ATM (ataxia...

  13. Radiological study of gastrointestinal motor activity after acute cisplatin in the rat. Temporal relationship with pica.

    Science.gov (United States)

    Cabezos, Pablo Antonio; Vera, Gema; Castillo, Mónica; Fernández-Pujol, Ramón; Martín, María Isabel; Abalo, Raquel

    2008-08-18

    Nausea and vomiting are amongst the most severe dose-limiting side effects of chemotherapy. Emetogenic activity in rats can only be evaluated by indirect markers, such as pica (kaolin intake), or delay in gastric emptying. The aim of this work was to study, by radiological methods, the alterations in gastrointestinal motility induced by acute cisplatin in the rat, and to compare them with the development of pica. Rats received cisplatin (0-6 mg kg(-1)) at day 0. In the pica study, individual food ingestion and kaolin intake were measured each day (from day -3 to day 3). In the radiological study, conscious rats received an intragastric dose of medium contrast 0, 24 or 48 h after cisplatin injection, and serial X-rays were taken 0-24 h after contrast. Cisplatin dose-dependently induced both gastric stasis and stomach distension, showing a strict temporal relationship with the induction of both acute and delayed pica. Radiological methods, which are non-invasive and preserve animals' welfare, are useful to study the effect of emetogenic drugs in the different gastrointestinal regions and might speed up the search for new anti-emetics. PMID:18579450

  14. Expression of proteins correlated with the unique cisplatin-sensitivity of testicular cancer

    NARCIS (Netherlands)

    de Graaf, Trude; de Jong, Steven; deVries, EGE; Mulder, NH

    1997-01-01

    Cisplatin (CDDP) has a curative effect in approximately 80% of patients with testicular cancer, in contrast to the frequent development of resistance in patients with small cell lung cancer and ovarian cancer, and to the natural resistance of colon cancer. At present it is unknown which factors expl

  15. Evaluation of nephroprotective and immunomodulatory activities of antioxidants in combination with cisplatin against murine visceral leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Meenakshi Sharma

    Full Text Available BACKGROUND: Most available drugs against visceral leishmaniasis are toxic, and growing limitations in available chemotherapeutic strategies due to emerging resistant strains and lack of an effective vaccine against visceral leishmaniasis deepens the crisis. Antineoplastic drugs like miltefosine have in the past been effective against the parasitic infections. An antineoplastic drug, cisplatin (cis-diamminedichloroplatinum II; CDDP, is recognized as a DNA-damaging drug which also induces alteration of cell-cycle in both promastigotes and amastigotes leading to cell death. First in vivo reports from our laboratory revealed the leishmanicidal potential of cisplatin. However, high doses of cisplatin produce impairment of kidney, which can be reduced by the administration of antioxidants. METHODOLOGY/PRINCIPAL FINDINGS: The present study was designed to evaluate the antileishmanial effect of cisplatin at higher doses (5 mg and 2.5 mg/kg body weight and its combination with different antioxidants (vitamin C, vitamin E and silibinin so as to eliminate the parasite completely and reduce the toxicity. In addition, various immunological, hematological and biochemical changes induced by it in uninfected and Leishmania donovani infected BALB/c mice were investigated. CONCLUSION/SIGNIFICANCE: A significant reduction in parasite load, higher IgG2a and lower IgG1 levels, enhanced DTH responses, and greater concentration of Th1 cytokines (IFN-γ, IL-2 with a concomitant down regulation of IL-10 and IL-4 pointed towards the generation of the protective Th1 type of immune response. A combination of cisplatin with antioxidants resulted in successful reduction of nephrotoxicity by normalizing the enzymatic levels of various liver and kidney function tests. Reduction in parasite load, increase in Th1 type of immune responses, and normalization of various biochemical parameters occurred in animals treated with cisplatin in combination with various antioxidants as

  16. The Sensitivity of Hela Kyoto Cell Line Transfected with Sensor HyPer2 to Cisplatin

    Directory of Open Access Journals (Sweden)

    Belova A.S.

    2014-12-01

    Full Text Available The aim of the investigation is to compare by means of MTT assay cytotoxic effect of cisplatin on the cells of HeLa Kyoto line and HeLa Kyoto line containing genetically-encoded sensor of hydrogen peroxide HyPer2 (HeLa Kyoto–HyPer2 line, and using staining by trypan blue to identify the doses of cisplatin causing cell death at different exposure time. Materials and Methods. A HeLa Kyoto cell line of human cervical carcinoma and HeLa Kyota line transfected with the cytoplasmic sensor of hydrogen peroxide (HeLa Kyoto–HyPer2 were used in the study. The analysis of cytotoxic and antiproliferative action of cisplatin in relation to the given cells was performed using MTT assay. Cell viability was determined after 24 h of incubation with the preparation at concentrations from 0 to 50 μmol/L, then within the period from 0 to 24 h with an interval of 2 h at concentration of IC50; and also after 2, 4, 6, 8 h at concentrations from 9.3 to 833.3 μmol/L a quantity of live and destructed cells was counted using staining by trypan blue. Results. After cisplatin expose the dose-response curves for cell viability of Hela Kyoto and HeLa Kyoto–HyPer2 cell lines were built according to MTT assay data. It was established that concentration of IC50 corresponding to the dose causing a loss of viability of 50% of cells is 1.3 times lower for HeLa Kyoto–HyPer2 compared to HeLa Kyoto. The results of staining by a vital agent trypan blue showed that inhibiting effects of cisplatin in concentration of IC50 by 24 h are mainly linked with the delay of cell division but not with their death. At concentrations up to 52 μmol/L damage of the membranes does not occur during 8 h, and at superhigh concentrations — 416.7 μmol/L — the damage is possible already 4 h after the exposure. Conclusion. Comparison of sensibility of the two cell lines to the effect of cisplatin showed that transfection of the cells with the fluorescent protein results in the increase of the

  17. Hepatoprotective effect of curcumin and alpha-tocopherol against cisplatin-induced oxidative stress

    Science.gov (United States)

    2014-01-01

    Background cis-Diammineplatinum (II) dichloride (cisplatin) is the important anti-cancer agent useful in treatment of various cancers. Unfortunately, it can produce unwanted side effects in various tissues, including the liver. The present study investigated the possible protective role of curcumin and α-tocopherol against oxidative stress-induced hepatotoxicity in rats upon cisplatin treatment. Methods Male Wistar rats were divided into five groups (n = 5). Saline and Cis groups, rats were intraperitoneal (i.p.) injected with normal saline and cisplatin [20 mg/kg body weight (b.w.)], respectively. Cis + α-tocopherol group, Cis + Cur group and Cis + α-tocopherol + Cur group, rats were pre-treated with a single dose of α-tocopherol (250 mg/kg b.w.), curcumin (200 mg/kg b.w.) and combined α-tocopherol with curcumin, respectively, for 24 h prior the administration of cisplatin. After 72 h of first injection, specimens were collected. Liver enzyme, lipid peroxidation biomarker, liver histopathology and gene expression of liver nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were investigated. Results Cisplatin revealed a significant increase of hepatic malondialdehyde (MDA) levels and a significant reduction of hepatic superoxide dismutase (SOD) and catalase activities compared to the saline group. It elicited a marked increase of the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and demonstrated the liver pathologies including liver congestion, disorganization of hepatic cords and ground glass appearance of hepatocytes. It also demonstrated a significant increase of NADPH oxidase gene expression compared to saline group. Pre-treatment with combined curcumin and α-tocopherol improved the liver enzymes, lipid peroxidation biomarker, liver histopathology and gene expression of liver NADPH oxidase in cisplatin-treated rats. Conclusions The findings indicate that pre-treatment with combined curcumin

  18. Feasibility and Efficacy of Induction Docetaxel, Cisplatin, and 5-Fluorouracil Chemotherapy Combined With Cisplatin Concurrent Chemoradiotherapy for Nonmetastatic Stage IV Head-and-Neck Squamous Cell Carcinomas

    International Nuclear Information System (INIS)

    Purpose: To report the experience of treating selected fit patients with locally advanced head-and-neck squamous cell carcinoma with three cycles of induction TPF (docetaxel 75 mg/m2, cisplatin 75 mg/m2, 5-fluorouracil 750 mg/m2, Days 2–5) followed by concurrent three-weekly bolus cisplatin 100 mg/m2 chemoradiotherapy. Methods and Materials: Between March 2006 and February 2010, 66 patients with nonmetastatic Stage IV head-and-neck squamous cell carcinoma were treated in a single institution with three cycles of induction TPF, followed by radical radiotherapy with concurrent cisplatin 100 mg/m2. Results: Median age was 54 years (range, 33–69 years). Median follow-up was 21 months (range, 4–55 months). During TPF, Grade 3 toxicity occurred in 18 patients (27%), dose modifications in 10 (15%), delays in 3 (5%), and unplanned admissions in 6 (9%); a clinical tumor response was documented in 60 patients (91%). Median time from the final cycle of TPF to commencing radiotherapy was 22 days. Sixty-two patients (94%) received radical radiotherapy, and all completed treatment with no delays ≥3 days. One, two, and three cycles of concurrent cisplatin were delivered to 18 patients (29%), 38 patients (61%), and 3 patients (5%), respectively. Ninety-two percent of patients received enteral feeding; median weight loss during treatment was 7%. Forty-two patients (68%) had unplanned admissions with no on-treatment deaths. Three unrelated deaths occurred after treatment. At 1 year after treatment, 21% of patients without disease progression remained gastrostomy dependent. Of 58 assessable patients, 50 (86%) achieved a complete response after treatment. One- and 2-year progression-free survival, cause-specific survival, and overall survival were 88%, 92%, and 86% and 80%, 85%, and 80%, respectively. Conclusion: The combination of induction TPF with concurrent cisplatin chemoradiotherapy in patients with locally advanced head and neck squamous cell carcinoma is tolerable

  19. Feasibility and Efficacy of Induction Docetaxel, Cisplatin, and 5-Fluorouracil Chemotherapy Combined With Cisplatin Concurrent Chemoradiotherapy for Nonmetastatic Stage IV Head-and-Neck Squamous Cell Carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Prestwich, Robin J., E-mail: Robin.Prestwich@leedsth.nhs.uk [Department of Clinical Oncology, St. James' s Institute of Oncology, Leeds (United Kingdom); Oeksuez, Didem Colpan; Dyker, Karen; Coyle, Catherine; Sen, Mehmet [Department of Clinical Oncology, St. James' s Institute of Oncology, Leeds (United Kingdom)

    2011-11-15

    Purpose: To report the experience of treating selected fit patients with locally advanced head-and-neck squamous cell carcinoma with three cycles of induction TPF (docetaxel 75 mg/m{sup 2}, cisplatin 75 mg/m{sup 2}, 5-fluorouracil 750 mg/m{sup 2}, Days 2-5) followed by concurrent three-weekly bolus cisplatin 100 mg/m{sup 2} chemoradiotherapy. Methods and Materials: Between March 2006 and February 2010, 66 patients with nonmetastatic Stage IV head-and-neck squamous cell carcinoma were treated in a single institution with three cycles of induction TPF, followed by radical radiotherapy with concurrent cisplatin 100 mg/m{sup 2}. Results: Median age was 54 years (range, 33-69 years). Median follow-up was 21 months (range, 4-55 months). During TPF, Grade 3 toxicity occurred in 18 patients (27%), dose modifications in 10 (15%), delays in 3 (5%), and unplanned admissions in 6 (9%); a clinical tumor response was documented in 60 patients (91%). Median time from the final cycle of TPF to commencing radiotherapy was 22 days. Sixty-two patients (94%) received radical radiotherapy, and all completed treatment with no delays {>=}3 days. One, two, and three cycles of concurrent cisplatin were delivered to 18 patients (29%), 38 patients (61%), and 3 patients (5%), respectively. Ninety-two percent of patients received enteral feeding; median weight loss during treatment was 7%. Forty-two patients (68%) had unplanned admissions with no on-treatment deaths. Three unrelated deaths occurred after treatment. At 1 year after treatment, 21% of patients without disease progression remained gastrostomy dependent. Of 58 assessable patients, 50 (86%) achieved a complete response after treatment. One- and 2-year progression-free survival, cause-specific survival, and overall survival were 88%, 92%, and 86% and 80%, 85%, and 80%, respectively. Conclusion: The combination of induction TPF with concurrent cisplatin chemoradiotherapy in patients with locally advanced head and neck squamous cell

  20. The physical and chemical stability of cisplatin (Teva) in concentrate and diluted in sodium chloride 0.9%

    OpenAIRE

    Karbownik, Agnieszka; Szałek, Edyta; Urjasz, Hanna; Głęboka, Aleksandra; Mierzwa, Emilia; Grześkowiak, Edmund

    2012-01-01

    Aim of the study The subject of study was the stability of cisplatin in concentrate in glass vials and diluted in polyethylene (PE) bags stored at 15–25°C for up to 30 days. Material and methods Original vials of cisplatin injection (1 mg/ml, Teva) were stored at room temperature and subjected to re-piercing after 1, 2, 3, 7, 14, 21, 28 and 30 days following the initial piercing. Cisplatin infusions at nominal concentrations of 0.1 mg/ml were prepared in 0.9% sodium chloride (1000 ml) in PE b...

  1. Evaluation of protective effects of water extract of Spirulina platensis (blue green algae on cisplatin-induced lipid peroxidation

    Directory of Open Access Journals (Sweden)

    Ray S

    2007-01-01

    Full Text Available Attempt has been made to evaluate free radical scavenging activity of water extract of Spirulina platensis on cisplatin-induced lipid peroxidation using some common laboratory markers. In this present study goat liver has been used as lipid source. This in vitro evaluation was done by measuring the malondialdehyde, 4-hydroxy-2-nonenal, reduced glutathione and nitric oxide content of tissue homogenates. The results suggest that cisplatin could induce lipid peroxidation to a significant extent and it was also found that water extract of the algae has the ability to suppress the cisplatin-induced toxicity.

  2. Comparison of vinorelbine with cisplatin in concomitant chemoradiotherapy in head and neck carcinoma

    Directory of Open Access Journals (Sweden)

    Devleena

    2010-03-01

    Full Text Available Aim: Head and neck cancer is one of the most commonly occurring malignancies in the world. In India, the most commonly occurring head and neck cancers are those of the oral cavity and the pharynx. The majority of these cancers present with stage III/IV disease. Surgery and radiation therapy are the main treatment modalities. Concomitant chemoradiation is being investigated with the goal of improved local control that translates into improved survival. In this background, we have started this prospective randomized trial to ascertain the dose, schedule and sequence of therapy and to note whether Vinorelbine as radiosensitizer is equally effective as Cisplatin, comparing compliance, local control and toxicity. Patients and Methods: Forty patients of advanced head and neck cancer were randomized into two arms. Arm A received weekly injection Cisplatin 40mg/m 2 along with radiation. Arm B received weekly injection of Vinorelbine 6mg/m 2 along with radiation. Radiotherapy was delivered at a dose of 6,600-7,000 Gy in conventional fractionation in a telecobalt machine. Results: The complete response (CR rate was higher in arm B (90% than in arm A (70%. Major toxicities included neutropenia, anemia, mucositis and nausea. Conclusion: Concomitant chemoradiation with Vinorelbine produced more CR than chemoradiation with Cisplatin in advanced head and neck cancer. Toxicities were more in the Cisplatin arm, but they were manageable. Although a majority of the study was performed using Cisplatin as the radiosensitizer, Vinorelbine can be recommended as radiosensitizer in advanced head and neck malignancy.

  3. Improved efficacy of cisplatin in combination with a nano-formulation of pentacyclic triterpenediol.

    Science.gov (United States)

    Alam, Noor; Qayum, Arem; Kumar, Ashok; Khare, Vaibhav; Sharma, Parduman Raj; Andotra, Samar Singh; Singh, Shashank K; Koul, Surinder; Gupta, Prem N

    2016-11-01

    Cisplatin is widely used for the treatment of various cancers including cervical, ovarian, lung and head and neck, however, its clinical success is limited owing to the dose-dependent adverse effects, mainly nephrotoxicity and neurotoxicity. In order to address this limitation, the present study was undertaken to investigate growth inhibitory effect of cisplatin in combination with a triterpenediol (3a, 24-dihydroxyurs-12-ene and 3a, 24-dihydroxyolean-12-ene, TPD) on human ovarian cancer cell line. Poly(dl-lactic-co-glycolic) acid nanoparticles loaded with TPD (TPD-PLGA-NPs) were successfully developed by emulsion solvent evaporation method. The TPD-PLGA-NPs were characterized for size distribution and zeta potential which was in order of 152.56±3.01nm and -17.36±0.37mV respectively. The morphological evaluation was carried out by transmission electron microscopy and the formulation was also characterized using Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The drug loading of the optimized formulation was 51.03±1.52μg/mg and the formulation exhibited sustained drug release profile. The in vitro cellular uptake study of coumarin-6 loaded PLGA nanoparticles in OVCAR-5 cells demonstrated a time dependent increase in uptake efficiency. Further, growth inhibitory effect of cisplatin was investigated in combination with TPD-PLGA-NPs. The combination index (CI) was <1, indicating a synergistic interaction. Further, at 75% of cell growth inhibition (ED75) the dose of cisplatin was reduced to 3.8 folds using this combination. The results indicated the potential of cisplatin and TPD-PLGA-NPs combination in order to reduce to dose limiting toxicities of the former. PMID:27524002

  4. Synergistic effect of cisplatin and synchrotron irradiation on F98 gliomas growing in nude mice

    International Nuclear Information System (INIS)

    Synchrotron photoactivation therapy of cisplatin relies on a synergistic effect of synchrotron X-rays and platinum and leads to tumor-cell-killing effects and reduction of the tumor blood perfusion. Among brain tumors, glioblastoma multiforme appears as one of the most aggressive forms of cancer with poor prognosis and no curative treatment available. Recently, a new kind of radio-chemotherapy has been developed using synchrotron irradiation for the photoactivation of molecules with high-Z elements such as cisplatin (PAT-Plat). This protocol showed a cure of 33% of rats bearing the F98 glioma but the efficiency of the treatment was only measured in terms of overall survival. Here, characterization of the effects of the PAT-Plat on tumor volume and tumor blood perfusion are proposed. Changes in these parameters may predict the overall survival. Firstly, changes in tumor growth of the F98 glioma implanted in the hindlimb of nude mice after the PAT-Plat treatment and its different modalities have been characterized. Secondly, the effects of the treatment on tumor blood perfusion have been observed by intravital two-photon microscopy. Cisplatin alone had no detectable effect on the tumor volume. A reduction of tumor growth was measured after a 15 Gy synchrotron irradiation, but the whole therapy (15 Gy irradiation + cisplatin) showed the largest decrease in tumor growth, indicating a synergistic effect of both synchrotron irradiation and cisplatin treatment. A high number of unperfused vessels (52%) were observed in the peritumoral area in comparison with untreated controls. In the PAT-Plat protocol the transient tumor growth reduction may be due to synergistic interactions of tumor-cell-killing effects and reduction of the tumor blood perfusion

  5. Synergistic effect of cisplatin and synchrotron irradiation on F98 gliomas growing in nude mice

    Energy Technology Data Exchange (ETDEWEB)

    Ricard, Clement; Fernandez, Manuel [Grenoble Institut des Neurosciences, Grenoble (France); Université Joseph Fourier, Grenoble (France); Requardt, Herwig [European Synchrotron Radiation Facility, Grenoble (France); Wion, Didier [Grenoble Institut des Neurosciences, Grenoble (France); Université Joseph Fourier, Grenoble (France); Vial, Jean-Claude [Université Joseph Fourier, Grenoble (France); Laboratoire Interdisciplinaire de Physique, St Martin d’Hères (France); Segebarth, Christoph; Sanden, Boudewijn van der, E-mail: boudewijn.vandersanden@ujf-grenoble.fr [Grenoble Institut des Neurosciences, Grenoble (France); Université Joseph Fourier, Grenoble (France)

    2013-09-01

    Synchrotron photoactivation therapy of cisplatin relies on a synergistic effect of synchrotron X-rays and platinum and leads to tumor-cell-killing effects and reduction of the tumor blood perfusion. Among brain tumors, glioblastoma multiforme appears as one of the most aggressive forms of cancer with poor prognosis and no curative treatment available. Recently, a new kind of radio-chemotherapy has been developed using synchrotron irradiation for the photoactivation of molecules with high-Z elements such as cisplatin (PAT-Plat). This protocol showed a cure of 33% of rats bearing the F98 glioma but the efficiency of the treatment was only measured in terms of overall survival. Here, characterization of the effects of the PAT-Plat on tumor volume and tumor blood perfusion are proposed. Changes in these parameters may predict the overall survival. Firstly, changes in tumor growth of the F98 glioma implanted in the hindlimb of nude mice after the PAT-Plat treatment and its different modalities have been characterized. Secondly, the effects of the treatment on tumor blood perfusion have been observed by intravital two-photon microscopy. Cisplatin alone had no detectable effect on the tumor volume. A reduction of tumor growth was measured after a 15 Gy synchrotron irradiation, but the whole therapy (15 Gy irradiation + cisplatin) showed the largest decrease in tumor growth, indicating a synergistic effect of both synchrotron irradiation and cisplatin treatment. A high number of unperfused vessels (52%) were observed in the peritumoral area in comparison with untreated controls. In the PAT-Plat protocol the transient tumor growth reduction may be due to synergistic interactions of tumor-cell-killing effects and reduction of the tumor blood perfusion.

  6. Hyperthermia and PARP1-inhibition for sensitization of radiation and cisplatin treatment of cervical carcinoma cells

    International Nuclear Information System (INIS)

    Ionizing radiation causes single and double strand breaks (SSBs and DSBs). DSBs are among the most critical DNA lesions and can be repaired via either non-homologous end joining (NHEJ) in which PARP1, Ku70 and DNA-PKcs are important, or homologous recombination (HR), where BRCA2 and Rad51 are essential. Hyperthermia disturbs HR by temporary inactivation of BRCA2. Cisplatin disrupts NHEJ and PARP1-inhibitor blocks Poly-(ADP-ribose)polymerase- 1, which is important in SSB repair, NHEJ and backup-NHEJ. Our goal was to investigate the additional effectiveness of hyperthermia and PARP1-inhibition on radiation and/or cisplatin treatment. Cervical carcinoma cells (SiHa) were treated at different temperature levels levels (41.0-43.0℃, PARP1-inhibitor (100 μM; NU1025), gamma-irradiation doses (0-8 Gy) or cisplatin (1'R for 1 h). Clonogenic assays were carried out to measure survival and γH2AX staining was used to visualize DSBs. To elucidate mechanisms of action expression levels of DNA repair proteins BRCA2 and DNA-PKcs were investigated after 42.0℃ (1 h) using western blot. Combined hyperthermia and radiation resulted in an increased number of γH2AX foci as compared to radiation alone. Hyperthermia treatment in combination with cisplatin and PARP1 inhibitor and with radiation and PARP1 inhibitor significantly decreased cell survival. Western blot demonstrated a decreased expression of BRCA2 protein at 30 min after hyperthermia treatment. Adding PARP1-inhibitor significantly improves the effectiveness of combined hyperthermia radiotherapy and combined hyperthermia-cisplatin treatment on cervical carcinoma cells. Hyperthermia affects DNA-DSB repair as is indicated by increased γH2AX foci numbers and decreased BRCA2 expression. (author)

  7. Metformin synergistically enhances antiproliferative effects of cisplatin and etoposide in NCI-H460 human lung cancer cells

    Directory of Open Access Journals (Sweden)

    Sarah Fernandes Teixeira

    2013-12-01

    Full Text Available OBJECTIVE: To test the effectiveness of combining conventional antineoplastic drugs (cisplatin and etoposide with metformin in the treatment of non-small cell lung cancer in the NCI-H460 cell line, in order to develop new therapeutic options with high efficacy and low toxicity.METHODS: We used the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay and calculated the combination index for the drugs studied.RESULTS: We found that the use of metformin as monotherapy reduced the metabolic viability of the cell line studied. Combining metformin with cisplatin or etoposide produced a synergistic effect and was more effective than was the use of cisplatin or etoposide as monotherapy.CONCLUSIONS: Metformin, due to its independent effects on liver kinase B1, had antiproliferative effects on the NCI-H460 cell line. When metformin was combined with cisplatin or etoposide, the cell death rate was even higher.

  8. Phase I trial of concomitant hyperfractionated radiotherapy with docetaxel and cisplatin for locally advanced head and neck cancer

    OpenAIRE

    Allal, Abdelkarim Said; Zwahlen, Daniel; Becker, Minerva; Dulguerov, Pavel; Mach, Nicolas

    2006-01-01

    This study was conducted to determine the maximum tolerated dose of docetaxel when administered concomitantly with radical hyperfractionated radiotherapy and cisplatin in patients with locally advanced head and neck cancer.

  9. Anthocyanin - Rich Red Dye of Hibiscus Sabdariffa Calyx Modulates Cisplatin-induced Nephrotoxicity and Oxidative Stress in Rats.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Agbebi, Oluwaseun J; Akinyemi, Ayodele J

    2013-12-01

    This study sought to investigate the protective effect of dietary inclusion of Hibiscus sabdariffa calyx red dye on cisplatin-induced nephrotoxicity and antioxidant status in rats. Adult male rats were randomly divided into four groups of six animals each. Groups I and II were fed basal diet while groups III and IV were fed diets containing 0.5% and 1% of the dye respectively for 20 days prior to cisplatin administration. Nephrotoxicity was induced by a single dose intraperitoneal administration of cisplatin (7 mg/kg b.w) and the experiment was terminated 3 days after. The kidney and plasma were studied for nephrotoxicity and oxidative stress indices. Cisplatin administration caused a significant (Psabdariffa dye could be attributed to its anthocyanin content. PMID:24711761

  10. Hsp90 inhibitor Geldanamycin increases the sensitivity of resistant ovarian adenocarcinoma cell line A2780cis to cisplatin

    Czech Academy of Sciences Publication Activity Database

    Solár, P.; Horváth, Viktor; Kleban, J.; Koval, J.; Solárová, Z.; Kozubík, Alois; Fedoročko, P.

    2007-01-01

    Roč. 54, č. 2 (2007), s. 127-130. ISSN 0028-2685 Institutional research plan: CEZ:AV0Z50040702 Keywords : chemoresistance * cisplatin * Geldanamycin Subject RIV: BO - Biophysics Impact factor: 1.208, year: 2007

  11. Arctigenin enhances chemosensitivity to cisplatin in human nonsmall lung cancer H460 cells through downregulation of survivin expression.

    Science.gov (United States)

    Wang, Huan-qin; Jin, Jian-jun; Wang, Jing

    2014-01-01

    Arctigenin, a dibenzylbutyrolactone lignan, enhances cisplatin-mediated cell apoptosis in cancer cells. Here, we sought to investigate the effects of arctigenin on cisplatin-treated non-small-cell lung cancer (NSCLC) H460 cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and annexin-V/propidium iodide staining were performed to analyze the proliferation and apoptosis of H460 cells. Arctigenin dose-dependently suppressed cell proliferation and potentiated cell apoptosis, coupled with increased cleavage of caspase-3 and poly(ADP-ribose) polymerase. Moreover, arctigenin sensitized H460 cells to cisplatin-induced proliferation inhibition and apoptosis. Arctigenin alone or in combination with cisplatin had a significantly lower amount of survivin. Ectopic expression of survivin decreased cell apoptosis induced by arctigenin (P arctigenin (P arctigenin has a therapeutic potential in combina-tion with chemotherapeutic agents for NSLC. PMID:24395429

  12. Tunable Biodegradable Nanocomposite Hydrogel for Improved Cisplatin Efficacy on HCT-116 Colorectal Cancer Cells and Decreased Toxicity in Rats.

    Science.gov (United States)

    Abdel-Bar, Hend Mohamed; Osman, Rihab; Abdel-Reheem, Amal Youssef; Mortada, Nahed; Awad, Gehanne A S

    2016-02-01

    This work describes the development of a modified nanocomposite thermosensitive hydrogel for controlled cisplatin release and improved cytotoxicity with decreased side effects. The system was characterized in terms of physical properties, morphological architecture and in vitro cisplatin release. Cytotoxicity was tested against human colorectal carcinoma HCT-116. In vivo studies were conducted to evaluate the acute toxicity in terms of rats' survival rate and body weight loss. Nephro and hepatotoxicities were evaluated followed by histopathological alterations of various tissue organs. Nanocomposite thermosensitive hydrogel containing nanosized carrier conferred density and stiffness allowing a zero order drug release for 14 days. Enhanced cytotoxicity with 2-fold decrease in cisplatin IC50 was accomplished. A linear in vivo-in vitro correlation was proved for the system degradation. Higher animal survival rate and lower tissue toxicities proved the decreased toxicity of cisplatin nanocomposite compared to its solution. PMID:26709447

  13. Cordycepin enhances cisplatin apoptotic effect through caspase/MAPK pathways in human head and neck tumor cells

    Directory of Open Access Journals (Sweden)

    Chen YH

    2013-07-01

    Full Text Available Ying-Hui Chen,1,2,* Jo-Yu Wang,3,* Bo-Syong Pan,3,4 Yi-Fen Mu,3 Meng-Shao Lai,3,4 Edmund Cheung So,5 Thian-Sze Wong,6 Bu-Miin Huang3,4 1Department of Anesthesia, Chi-Mei Medical Center, Liouying, 2Department of Nursing, Min-Hwei College of Health Care Management, 3Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, 4The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 5Department of Anesthesia, An Nan Hospital, China Medical University, Tainan, Taiwan; 6Department of Surgery, University of Hong Kong Medical Center, Faculty of Medicine, The University of Hong Kong, Hong Kong *Authors contributed equally to this work Purpose: The present study aims to investigate whether the combination treatment of cordycepin (an extracted pure compound from Cordyceps sinensis and cisplatin (a platinum-based chemotherapy drug has better apoptotic effect in head and neck squamous cell carcinoma (HNSCC. Methods: The apoptotic influences of cordycepin and/or cisplatin treatments to human OC3, OEC-M1, and FaDu HNSCC cells were investigated by morphological observations, viability assay, flow cytometry assay, and Western blotting methods. Results: Data showed that the cell death phenomenon increased as the dosage of cordycepin or cisplatin increased, and it appeared more in cordycepin plus cisplatin cotreatment among three cell lines. Cell survival rates significantly decreased as the dosage of cordycepin or cisplatin increased, and the better apoptotic effects were observed in cotreatment. Cell cycle analysis further demonstrated that percentages of subG1 cells in cordycepin or cisplatin treatments significantly increased, suggesting that cells underwent apoptosis, and cordycepin plus cisplatin induced many more subG1 cells. Furthermore, cordycepin or cisplatin induced caspase-8, caspase-9, caspase-3, and poly adenosine diphosphate-ribose polymerase protein cleavages, and stimulated c

  14. L-Carnitine Protection Against Cisplatin Nephrotoxicity In Rats: Comparison with Amifostin Using Quantitative Renal Tc 99m DMSA Uptake

    Directory of Open Access Journals (Sweden)

    Yakup Yürekli

    2011-04-01

    Full Text Available Objective: In this study, we aimed to investigate the cytoprotective effect of L-carnitine against cisplatin-induced nephrotoxicity and to compare its efficacy with that of amifostin by quantitative renal Tc 99m DMSA uptake. Material and Methods: Male Wistar rats were randomly divided into six groups of six animals each. 1 Control (saline; 5 ml/kg intraperitoneally; 2 L-carnitine (CAR; 300 mg/kg intraperitoneally; 3 Amifostine (AMI; 200 mg /kg intraperitoneally; 4 Cisplatin (CIS;7 mg/kg intraperitoneally; 5 Cisplatin plus L-carnitine (CIS + CAR; 6 Cisplatin plus amifostine (CIS + AMI. L-carnitine and amifostine were injected 30 minutes before cisplatin in Group 5 and 6. Tc 99m DMSA, 7.4 MBq/0.2 ml, was injected through the tail vein 72 hours after the drug administration. Rats were killed and kidneys removed by dissection 2 hours after the injection of the radiopharmaceutical. The percentage of the injected dose per gram of kidney tissue (%ID/g was calculated. Renal function was monitored by measuring BUN and plasma levels of creatinine. Lipid peroxidation and glutathione content were determined by measuring malondialdehyde (MDA and reduced glutathione (GSH in kidney tissue homogenates. Results: Tc 99m DMSA uptake per gram tissue of the kidney as %ID/g was 29.54±4.72, 29.86 ± 7.47 and 26.37 ± 4.54 in the control, CAR and AMI groups respectively. %ID/g was the lowest of all the groups, 11.60±3.59 (p<0.01, in the cisplatin group. Carnitine or amifostine administration 30 minutes before cisplatin injection resulted a significant increase in %ID/g, 21.28±7.73 and 18.97±3.24 respectively, compared to those of cisplatin-treated rats (p<0.002. A marked increase in plasma BUN and creatinine indicating nephrotoxicity and acute renal failure was observed in the cisplatin-treated group. MDA and GSH levels were concordant with cisplatin-induced oxidative stress in the kidney tissue. Conclusion: The results showed that L-carnitine significantly

  15. Additive Renoprotection by Pioglitazone and Fenofibrate against Inflammatory, Oxidative and Apoptotic Manifestations of Cisplatin Nephrotoxicity: Modulation by PPARs.

    Directory of Open Access Journals (Sweden)

    Mai M Helmy

    Full Text Available Nephrotoxicity is a major side effect for the antineoplastic drug cisplatin. Here, we employed pharmacological, biochemical, and molecular studies to investigate the role of peroxisome proliferator-activated receptors (PPARs in cisplatin nephrotoxicity. Rats were treated with a single i.p. dose of cisplatin (5 mg/kg alone or combined with pioglitazone (PPARγ agonist, fenofibrate (PPARα agonist, pioglitazone plus fenofibrate, or thalidomide (Tumor necrosis factor-α inhibitor; TNF-α. Cisplatin nephrotoxicity was evidenced by rises in renal indices of functional (blood urea nitrogen, BUN, and creatinine, inflammatory (TNF-α, interleukin 6, IL-6, oxidative (increased malondialdehyde, MDA, and decreased superoxide dismutase, SOD and nitric oxide metabolites, NOx, apoptotic (caspase 3, and histological (glomerular atrophy, acute tubular necrosis and vacuolation profiles. Cisplatin effects were partly abolished upon concurrent exposure to pioglitazone, fenofibrate, or thalidomide; more renoprotection was observed in rats treated with pioglitazaone plus fenofibrate. Immunostaining showed that renal expressions of PPARα and PPARγ were reduced by cisplatin and restored to vehicle-treated values after simultaneous treatment with pioglitazone or fenofibrate. Fenofibrate or pioglitazone renoprotection remained unaltered after concurrent blockade of PPARα (GW6471 and PPARγ (GW9662, respectively. To complement the rat studies, we also report that in human embryonic kidney cells (HEK293 cells, increases caused by cisplatin in inflammatory, apoptotic, and oxidative biomarkers were (i partly improved after exposure to pioglitazone, fenofibrate, or thalidomide, and (ii completely disappeared in cells treated with a combination of all three drugs. These data establish that the combined use of pioglitazone and fenofibrate additively improved manifestations of cisplatin nephrotoxicity through perhaps GW6471/GW9662-insensitive mechanisms.

  16. A Phase II Study of Docetaxel, Cisplatin and 5- Fluorouracil (TPF) In Patients with Locally Advanced Head and Neck Carcinomas

    OpenAIRE

    Ansari, M.; Omidvari, S; Mosalaei, A.; Ahmadloo, N; Mosleh-Shirazi, M. A.; Mohammadianpanah, M.

    2011-01-01

    Background The combination of cisplatin and 5-fluorouracil (PF) is currently considered a standard and effective regimen for the treatment of advanced head and neck carcinomas. The aim of this study was to evaluate the efficacy and safety of docetaxel, cisplatin and 5-fluorouracil (TPF) in patients with unresectable head and neck carcinomas. Methods Forty-six patients with previously untreated non-metastatic stage IV head and neck carcinomas were enrolled. All patients received three cycles o...

  17. Combination of Taxanes, Cisplatin and Fluorouracil as Induction Chemotherapy for Locally Advanced Head and Neck Cancer: A Meta-Analysis

    OpenAIRE

    Hao Qin; Jie Luo; Yuan-Ping Zhu; Hai-Li Xie; Wei-Qiang Yang; Wen-Bin Lei

    2012-01-01

    BACKGROUND: Some investigations have suggested that induction chemotherapy with a combination of taxanes, cisplatin and fluorouracil (TPF) is effective in locally advanced head and neck cancer. However, other trials have indicated that TPF does not improve outcomes. The objective of this study was to compare the efficacy and safety of TPF with a cisplatin and fluorouracil (PF) regimen through a meta-analysis. METHODS: Four randomized clinical trials were identified, which included 1,552 patie...

  18. Specific antioxidant compounds differentially modulate cytotoxic activity of doxorubicin and cisplatin: in vitro and in vivo study

    OpenAIRE

    Panchuk, Rostyslav; Skorokhyd, Nadia; Chumak, Vira; Lehka, Lilya; Omelyanchik, Sofya; Gurinovich, Valery; Moiseenok, Andrey; Heffeter, Petra; Berger, Walter; Stoika, Rostyslav

    2014-01-01

    Aim To use the antioxidant compounds (sodium selenite, selenomethionine, D-pantethine) for modulation of cytotoxic effect of doxorubicin and cisplatin toward wild type and drug-resistant mutants of several human tumor cells. Similar treatments were applied in vivo toward adult male Wistar rats. Methods Human tumor cells of different lines (HCT-116, Jurkat and HL-60) with various mechanisms of drug-resistance were treated with doxorubicin or cisplatin, alone or in combination with sodium selen...

  19. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression.

    Science.gov (United States)

    Li, Dan; Williams, Jon I; Pietras, Richard J

    2002-04-25

    Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status

  20. Reactive oxygen species-mediated apoptosis contributes to chemosensitization effect of saikosaponins on cisplatin-induced cytotoxicity in cancer cells

    Directory of Open Access Journals (Sweden)

    He Fan

    2010-12-01

    Full Text Available Abstract Background Saikosaponin-a and -d, two naturally occurring compounds derived from Bupleurum radix, have been shown to exert anti-cancer activity in several cancer cell lines. However, the effect of combination of saikosaponins with chemotherapeutic drugs has never been addressed. Thus, we investigated whether these two saikosaponins have chemosensitization effect on cisplatin-induced cancer cell cytotoxicity. Methods Two cervical cancer cell lines, HeLa and Siha, an ovarian cancer cell line, SKOV3, and a non-small cell lung cancer cell line, A549, were treated with saikosaponins or cisplatin individually or in combination. Cell death was quantitatively detected by the release of lactate dehydrogenase (LDH using a cytotoxicity detection kit. Cellular ROS was analyzed by flow cytometry. Apoptosis was evaluated by AO/EB staining, flow cytometry after Anexin V and PI staining, and Western blot for caspase activation. ROS scavengers and caspase inhibitor were used to determine the roles of ROS and apoptosis in the effects of saikosaponins on cisplatin-induced cell death. Results Both saikosaponin-a and -d sensitized cancer cells to cisplatin-induced cell death in a dose-dependent manner, which was accompanied with induction of reactive oxygen species (ROS accumulation. The dead cells showed typical apoptotic morphologies. Both early apoptotic and late apoptotic cells detected by flow cytometry were increased in saikosaponins and cisplatin cotreated cells, accompanied by activation of the caspase pathway. The pan-caspase inhibitor z-VAD and ROS scanvengers butylated hydroxyanisole (BHA and N-acetyl-L-cysteine (NAC dramatically suppressed the potentiated cytotoxicity achieved by combination of saikosaponin-a or -d and cisplatin. Conclusions These results suggest that saikosaponins sensitize cancer cells to cisplatin through ROS-mediated apoptosis, and the combination of saikosaponins with cisplatin could be an effective therapeutic strategy.

  1. Gemcitabine, cisplatin and methylprednisolone (GEM-P) is an effective salvage regimen in patients with relapsed and refractory lymphoma

    OpenAIRE

    Ng, M; Waters, J; Cunningham, D.; Chau, I; Horwich, A.; Hill, M; Norman, A R; Wotherspoon, A; Catovsky, D.

    2005-01-01

    There is currently no standard salvage chemotherapy regimen in relapsed and refractory lymphoma. Gemcitabine is a novel nucleoside analogue, which acts synergistically with cisplatin both in vitro and in clinical studies. We evaluated the combination of gemcitabine, cisplatin and methylprednisolone (GEM-P) in 41 heavily pretreated patients with relapsed and refractory Hodgkin's and non-Hodgkin's lymphoma. The best-achieved response rate (RR) was 79% (95% CI 64–91), with a complete RR of 21%. ...

  2. Evaluation of the Role of Cisplatin-conjugated-soluble Gelatin Sponge: Feasibility Study in a Swine Model

    International Nuclear Information System (INIS)

    PurposeTo evaluate the safety and the delivery function of cisplatin-conjugated-soluble gelatin sponge in a swine model.MethodsFifteen healthy young swine were assigned into three groups: transarterial cisplatin infusion group, transarterial chemoembolization (TACE) with cisplatin-conjugated 120-min soluble gelatin sponge (TACE-120) group, and TACE with cisplatin-conjugated 360-min soluble gelatin sponge (TACE-360) group. A total volume of 0.8 mL/kg cisplatin in each group and 8 mg/kg soluble gelatin sponge in TACE-120 and TACE-360 groups were injected from the left hepatic artery in small increments for 10 min. Common hepatic angiography and whole-blood sampling via the left hepatic vein were conducted to explore recanalization immediately after the procedure and again at 10, 30, 60, 90, 120, 180, 240, 300, 360, and 420 min later. The area under the plasma concentration curve (AUC) of non-protein-bound platinum was compared among the three groups. Each liver was removed and cut into 10-cm-thick sections for calculating liver-damaged volume ratio.ResultsSequential angiography depicted gradual recanalization of the occluded hepatic artery and total recanalization at 120 and 360 min after embolization in the TACE-120 and TACE-360 groups, respectively. Of the three groups, AUC0–30, AUC30–120, and AUC120–420 were significantly highest in the transarterial cisplatin infusion group (p < 0.001), the TACE-120 group (p < 0.001), and the TACE-360 group (p < 0.001), respectively. The liver-damaged volume ratio in the TACE-360 group was small (8.20 %) but significantly higher than that in the TACE-120 group (2.67 %, p = 0.014).ConclusionCisplatin-conjugated soluble gelatin sponge functions as a cisplatin carrier and is associated with tolerable liver damage

  3. Berberine in combination with cisplatin suppresses breast cancer cell growth through induction of DNA breaks and caspase-3-dependent apoptosis.

    Science.gov (United States)

    Zhao, Yuwan; Jing, Zuolei; Li, Yan; Mao, Weifeng

    2016-07-01

    Berberine (BBR) is an isoquinoline alkaloid extracted from medicinal plants such as Hydrastis canadensis, Berberis aristata and Coptis chinensis. BBR displays a number of beneficial roles in the treatment of various types of cancers, yet the precise mechanisms of its action remain unclear. Cisplatin is an effective cancer chemotherapeutic agent and functions by generating DNA damage, promoting DNA damage-induced cell cycle arrest and apoptosis; however, its efficacy is challenged by the resistance of tumor cells in clinical application. The aim of the present study was to investigate the effects of BBR in combination with cisplatin on human breast cancer cells. MTT assay showed that BBR inhibited breast cancer MCF-7 cell growth with a 50% inhibitory concentration (IC50) value of 52.178±1.593 µM and the IC50 value of cisplatin was 49.541±1.618 µM, while in combination with 26 µM BBR, the IC50 value of cisplatin was 5.759±0.76 µM. BBR sensitized the MCF-7 cells to cisplatin in a time- and dose-dependent manner. After treatment of BBR and cisplatin, the cellular pro-apoptotic capase-3 and cleaved capspase-3 and caspase-9 were upregulated and the anti-apoptotic Bcl-2 was downregulated. Importantly, BBR restrained the expression of cellular PCNA, and immunofluoresence analysis of γH2AX showed that BBR increased the DNA damages induced by cisplatin. Taken together, the results demonstrated that BBR sensitized MCF-7 cells to cisplatin through induction of DNA breaks and caspase-3-dependent apoptosis. PMID:27177238

  4. Balance between MKK6 and MKK3 mediates p38 MAPK associated resistance to cisplatin in NSCLC.

    Directory of Open Access Journals (Sweden)

    Eva M Galan-Moya

    Full Text Available The p38 MAPK signaling pathway has been proposed as a critical mediator of the therapeutic effect of several antitumor agents, including cisplatin. Here, we found that sensitivity to cisplatin, in a system of 7 non-small cell lung carcinoma derived cell lines, correlated with high levels of MKK6 and marked activation of p38 MAPK. However, knockdown of MKK6 modified neither the response to cisplatin nor the activation of p38 MAPK. Deeper studies showed that resistant cell lines also displayed higher basal levels of MKK3. Interestingly, MKK3 knockdown significantly decreased p38 phosphorylation upon cisplatin exposure and consequently reduced the response to the drug. Indeed, cisplatin poorly activated MKK3 in resistant cells, while in sensitive cell lines MKK3 showed the opposite pattern in response to the drug. Our data also demonstrate that the low levels of MKK6 expressed in resistant cell lines are the consequence of high basal activity of p38 MAPK mediated by the elevated levels of MKK3. This finding supports the existence of a regulatory mechanism between both MAPK kinases through their MAPK. Furthermore, our results were also mirrored in head and neck carcinoma derived cell lines, suggesting our observations boast a potential universal characteristic in cancer resistance of cisplatin. Altogether, our work provides evidence that MKK3 is the major determinant of p38 MAPK activation in response to cisplatin and, hence, the resistance associated with this MAPK. Therefore, these data suggest that the balance between both MKK3 and MKK6 could be a novel mechanism which explains the cellular response to cisplatin.

  5. Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat.

    Science.gov (United States)

    Chtourou, Yassine; Aouey, Baktha; Aroui, Sonia; Kebieche, Mohammed; Fetoui, Hamadi

    2016-01-01

    Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. Naringin, a natural flavonoid, plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the involvement of ROS overproduction and inflammation in cisplatin-induced nephrotoxicity in aged rats, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after treatment with naringin (20, 50 or 100 mg/kg body weight). Cisplatin resulted in an increase of renal markers, lipid peroxidation, protein and DNA oxidation, and ROS formation. Renal tumor necrosis factor-α (TNF-α) and nitrite levels were also elevated. Expressions of nuclear factor-kappa B (NF-κB), inductible nitric oxide synthase (iNOS), caspase-3 and p53 were up-regulated in renal tissues of Cis-treated rats compared with the normal control group. Histopathological changes were also observed in cisplatin group. Adminstration of naringin at different doses (25, 50 and 100 mg/kg) was able to protect against the deterioration in kidney function, abrogate the decline in antioxidant enzyme activities and suppressed the increase in TBARS, nitrite and TNF-α concentrations. Moreover, naringin inhibited NF-κB and iNOS pathways, caspase-3 and p53 activation and improved the histological changes induced by cisplatin. In conclusion, our studies suggest that oxidative stress and inflammation might play important roles in the development of cisplatin-induced nephrotoxicity and naringin might become an effective therapeutic strategy for this disease. PMID:26612654

  6. D-Methionine attenuated cisplatin-induced vestibulotoxicity through altering ATPase activities and oxidative stress in guinea pigs

    International Nuclear Information System (INIS)

    Cisplatin has been used as a chemotherapeutic agent to treat many kinds of malignancies. Its damage to the vestibulo-ocular reflex (VOR) system has been reported. However, the underlying biochemical change in the inner ear or central vestibular nervous system is not fully understood. In this study, we attempted to examine whether cisplatin-induced vestibulotoxicity and D-methionine protection were correlated with the changes of ATPase activities and oxidative stress of ampullary tissue of vestibules as well as cerebellar cortex (the inhibitory center of VOR system) of guinea pigs. By means of a caloric test coupled with electronystagmographic recordings, we found that cisplatin exposure caused a dose-dependent (1, 3, or 5 mg/kg) vestibular dysfunction as revealed by a decrease of slow phase velocity (SPV). In addition, cisplatin significantly inhibited the Na+, K+-ATPase and Ca2+-ATPase activities in the ampullary tissue with a good dose-response relationship but not those of cerebellar cortex. Regression analysis indicated that a decrease of SPV was well correlated with the reduction of Na+, K+-ATPase and Ca2+-ATPase activities of the ampullary tissue. D-Methionine (300 mg/kg) reduced both abnormalities of SPV and ATPase activities in a correlated manner. Moreover, cisplatin exposure led to a significant dose-dependent increase of lipid peroxidation and nitric oxide concentrations of the vestibules, which could be significantly suppressed by D-methionine. However, cisplatin did not alter the levels of lipid peroxidation and nitric oxide of the cerebellum. In conclusion, cisplatin inhibited ATPase activities and increased oxidative stress in guinea pig vestibular labyrinths. D-Methionine attenuated cisplatin-induced vestibulotoxicity associated with ionic disturbance through its antioxidative property

  7. Neoadjuvant and postoperative chemotherapy with paclitaxel plus cisplatin for the treatment of FIGO stage IB cervical cancer in pregnancy

    OpenAIRE

    Kong, Tae-Wook; Lee, Eun Ju; Lee, Yonghee; Chang, Suk-Joon; Son, Joo Hyuk; Ryu, Hee-Sug

    2014-01-01

    Cervical cancer is one of the most common malignancy diagnosed during pregnancy. The experience of the use of neoadjuvant chemotherapy (NACT) with paclitaxel plus cisplatin during pregnancy is limited. Three pregnant women with International Federation of Gynecology and Obstetrics (FIGO) stage IB cervical cancer received NACT with paclitaxel plus cisplatin until fetal lung maturity, and then underwent cesarean delivery and radical hysterectomy. Two of our patients had intermediate pathologic ...

  8. Role of Metallothionein1H in Cisplatin Resistance of Non-Small Cell Lung Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    Xin-fang Hou; Qing-xia Fan; Liu-xing Wang; Shi-xin Lu

    2009-01-01

    Objective: Despite platinum-based adjuvant chemotherapy has improved greatly patients' outcomes, drug resistance poses a major impediment to the successful use of such an effective agent. Metallothioneins(MTs) are known to play putative roles in cancer cell proliferation, apoptosis, differentiation, drug resistance and prognosis. The present studiy was to investigte the role of metallethioein1H(MT1H) in cisplatin resistance of human non-small cell lung cancer(NSCLC) cell lines in vitro or its possible molecular mechanisms. Methods: MT1H mRNA expression in A549 and A549/DDP cells was detected by RT-PCR. A recombinant eukaryotic expression plasmid pcDNA3.1(-)-MT1H was constructed and transfected into A549 cells which express no MT1H. MT1H siRNA was transfected into A549/DDP cells which express MT1H highly. MT1H expression was detected by RT-PCR and Immunoblot. The chemosensitivity to cisplatin was assessed by MTT assay. Apoptosis rate was determined by Tunel and FCM. Bcl-2 and Bax were determined by immunohistochemistry. Results: MT1H mRNA was expressed in A549/DDP but not in A549. After transfection of MT1H, MT1H expression was enhanced and the chemosensitivity to cisplatin was decreased in A549 cells. Inversely, after transfection of MT1H siRNA, MT1H expression was decreased and the chemosensitivity to cisplatin was increased in A549/DDP. The apoptosis rate induced by cisplatin was increased and Bcl-2 was down-regulated but Bax showed little change in A549/DDP cells interferred with MT1H siRNA. Conclusion: MT1H overexpression can promote drug resistance in A549 cells . Down-regulation of MT1H interfered with siRNA can effectively reverses the drug resistance in A549/DDP cells by down-regulating the expression of Bcl-2 and increasing cisplatin induced apoptosis. SiRNA targeting MT1H combined with chemotherapy may be a very promising strategy for treatment of lung cancer.

  9. Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of Cisplatin-induced neuropathy

    Directory of Open Access Journals (Sweden)

    Egensperger Rupert

    2009-07-01

    Full Text Available Abstract Background Cisplatin mediates its antineoplastic activity by formation of distinct DNA intrastrand cross links. The clinical efficacy and desirable dose escalations of cisplatin are restricted by the accumulation of DNA lesions in dorsal root ganglion (DRG cells leading to sensory polyneuropathy (PNP. We investigated in a mouse model by which mechanism recombinant erythropoietin (rhEPO protects the peripheral nervous system from structural and functional damage caused by cisplatin treatment with special emphasis on DNA damage burden. Results A cumulative dose of 16 mg cisplatin/kg resulted in clear electrophysiological signs of neuropathy, which were significantly attenuated by concomitant erythropoietin (cisplatin 32,48 m/s ± 1,68 m/s; cisplatin + rhEPO 49,66 m/s ± 1,26 m/s; control 55,01 m/s ± 1,88 m/s; p Conclusion The protective effect of recombinant erythropoietin is not mediated by reducing the burden of DNA platination in the target cells, but it is likely to be due to a higher resistance of the target cells to the adverse effect of DNA damage. The increased frequency of intact mitochondria might also contribute to this protective role.

  10. Radiation with cisplatin or carboplatin for locally advanced cervix cancer: the experience of a tertiary cancer centre

    International Nuclear Information System (INIS)

    Definitive treatment with concurrent cisplatin and radiation is the standard of care for locally advanced cervix cancer. The optimal management of patients with a contraindication to cisplatin has not been established. We conducted a retrospective audit of concurrent chemotherapy in a cohort of patients with locally advanced cervix cancer. All patients with locally advanced cervix cancer treated with definitive radiation were entered into a prospective database. Information regarding their demographics, stage, histology, recurrence and survival were recorded. Pharmacy records were reviewed to determine concurrent chemotherapy use. A total of 442 patients were included in the audit. Two hundred sixty-nine patients received cisplatin, 59 received carboplatin and 114 received no concurrent chemotherapy. Overall survival was significantly improved with the use of concurrent cisplatin compared with radiation alone (adjusted hazard ratio 0.53, P=0.001), as was disease-free survival and rate of distant failure. The use of carboplatin was not associated with any significant benefit in terms of overall survival or disease-free survival. The results of this audit are consistent with the known significant survival benefit with concurrent cisplatin chemotherapy. However, there did not appear to be any significant benefit with carboplatin although there were potential confounding factors. The available evidence in the literature would favour the use of non-platinum chemotherapy rather than carboplatin in patients with contraindications to cisplatin.

  11. Cisplatin-Induced Non-Oliguric Acute Kidney Injury in a Pediatric Experimental Animal Model in Piglets.

    Directory of Open Access Journals (Sweden)

    Maria José Santiago

    Full Text Available To design an experimental pediatric animal model of acute kidney injury induced by cisplatin.Prospective comparative observational animal study in two different phases. Acute kidney injury was induced using three different doses of cisplatin (2, 3 and 5 mg/kg. The development of nephrotoxicity was assessed 2 to 4 days after cisplatin administration by estimating biochemical parameters, diuresis and renal morphology. Analytical values and renal morphology were compared between 15 piglets treated with cisplatin 3 mg/kg and 15 control piglets in the second phase of the study.41 piglets were studied. The dose of 3 mg/kg administered 48 hours before the experience induced a significant increase in serum creatinine and urea without an increase in potassium levels. Piglets treated with cisplatin 3 mg/kg had significantly higher values of creatinine, urea, phosphate and amylase, less diuresis and lower values of potassium, sodium and bicarbonate than control piglets. Histological findings showed evidence of a dose-dependent increase in renal damage.a dose of 3 mg/kg of cisplatin induces a significant alteration in renal function 48 hours after its administration, so it can be used as a pediatric animal model of non-oliguric acute kidney injury.

  12. Cisplatin-Induced Non-Oliguric Acute Kidney Injury in a Pediatric Experimental Animal Model in Piglets

    Science.gov (United States)

    Lázaro, Alberto; González, Rafael; Urbano, Javier; López, Jorge; Solana, Maria José; Toledo, Blanca; del Castillo, Jimena; Tejedor, Alberto; López-Herce, Jesús

    2016-01-01

    Objective To design an experimental pediatric animal model of acute kidney injury induced by cisplatin. Methods Prospective comparative observational animal study in two different phases. Acute kidney injury was induced using three different doses of cisplatin (2, 3 and 5 mg/kg). The development of nephrotoxicity was assessed 2 to 4 days after cisplatin administration by estimating biochemical parameters, diuresis and renal morphology. Analytical values and renal morphology were compared between 15 piglets treated with cisplatin 3 mg/kg and 15 control piglets in the second phase of the study. Results 41 piglets were studied. The dose of 3 mg/kg administered 48 hours before the experience induced a significant increase in serum creatinine and urea without an increase in potassium levels. Piglets treated with cisplatin 3 mg/kg had significantly higher values of creatinine, urea, phosphate and amylase, less diuresis and lower values of potassium, sodium and bicarbonate than control piglets. Histological findings showed evidence of a dose-dependent increase in renal damage. Conclusions a dose of 3 mg/kg of cisplatin induces a significant alteration in renal function 48 hours after its administration, so it can be used as a pediatric animal model of non-oliguric acute kidney injury. PMID:26871589

  13. Three-Dimensional Morphology by Multiphoton Microscopy with Clearing in a Model of Cisplatin-Induced CKD.

    Science.gov (United States)

    Torres, Richard; Velazquez, Heino; Chang, John J; Levene, Michael J; Moeckel, Gilbert; Desir, Gary V; Safirstein, Robert

    2016-04-01

    Traditional histologic methods are limited in their ability to detect pathologic changes of CKD, of which cisplatin therapy is an important cause. In addition, poor reproducibility of available methods has limited analysis of the role of fibrosis in CKD. Highly labor-intensive serial sectioning studies have demonstrated that three-dimensional perspective can reveal useful morphologic information on cisplatin-induced CKD. By applying the new technique of multiphoton microscopy (MPM) with clearing to a new mouse model of cisplatin-induced CKD, we obtained detailed morphologic and collagen reconstructions of millimeter-thick renal sections that provided new insights into pathophysiology. Quantitative analysis revealed that a major long-term cisplatin effect is reduction in the number of cuboidal cells of the glomerular capsule, a change we term the "uncapped glomerulus lesion." Glomerulotubular disconnection was confirmed, but connection remnants between damaged tubules and atubular glomeruli were observed. Reductions in normal glomerular capsules corresponded to reductions in GFR. Mild increases in collagen were noted, but the fibrosis was not spatially correlated with atubular glomeruli. Glomerular volume and number remained unaltered with cisplatin exposure, but cortical tubulointerstitial mass decreased. In conclusion, new observations were made possible by using clearing MPM, demonstrating the utility of this technique for studies of renal disease. This technique should prove valuable for further characterizing the evolution of CKD with cisplatin therapy and of other conditions. PMID:26303068

  14. Assessing cisplatin-induced ototoxicity and otoprotection in whole organ culture of the mouse inner ear in simulated microgravity.

    Science.gov (United States)

    Tropitzsch, Anke; Arnold, Heinz; Bassiouni, Mohamed; Müller, Andrea; Eckhard, Andreas; Müller, Marcus; Löwenheim, Hubert

    2014-06-16

    Cisplatin is a widely used anti-cancer drug. Ototoxicity is a major dose-limiting side-effect. A reproducible mammalian in-vitro model of cisplatin ototoxicity is required to screen and validate otoprotective drug candidates. We utilized a whole organ culture system of the postnatal mouse inner ear in a rotating wall vessel bioreactor under "simulated microgravity" culture conditions. As previously described this system allows whole organ culture of the inner ear and quantitative assessment of ototoxic effects of aminoglycoside induced hair cell loss. Here we demonstrate that this model is also applicable to the assessment of cisplatin induced ototoxicity. In this model cisplatin induced hair cell loss was dose and time dependent. Increasing exposure time of cisplatin led to decreasing EC50 concentrations. Outer hair cells were more susceptible than inner hair cells, and hair cells in the cochlear base were more susceptible than hair cells in the cochlear apex. Initial cisplatin dose determined the final extent of hair cell loss irrespective if the drug was withdrawn or continued. Dose dependant otoprotection was demonstrated by co-administration of the antioxidant agent N-acetyl l-cysteine. The results support the use of this inner ear organ culture system as an in vitro assay and validation platform for inner ear toxicology and the search for otoprotective compounds. PMID:24709139

  15. Mitomycin, cisplatin, and vindesine followed by radiotherapy combined with cisplatin in stage III nonsmall cell lung cancer: long-term results

    International Nuclear Information System (INIS)

    Purpose: To assess the tolerance, response rate, pattern of failure, and long-term survival of patients with unresectable nonsmall cell lung cancer treated with one cycle of induction chemotherapy followed by concurrent cisplatin and radiotherapy. Methods and Materials: From 1986 to 1988, 45 patients with histologically proven nonsmall cell lung cancer clinical Stage III (29 IIIA and 16 IIIB) were included in this study. Patients received one cycle of Mitomycin C 10 mg/m2 day 1, Cisplatin 120 mg/m2 day 1, and Vindesine 3 mg/m2 days 1, 8, 15, and 22, by i.v. bolus injection. Radiotherapy was started within 4-6 weeks after completion of chemotherapy, with a total tumor dose of 60 Gy, at 2 Gy/day. Cisplatin, 20 mg/m2/day by i.v. continuous infusion was administered for days 1-5 of radiation treatment. Results: The main toxic acute effects were nausea-vomiting grade 1-3 in 38 patients (85%). Ten patients (22%) developed esophagitis grade 3. Leukopenia grade 1-2 was observed in 18 patients (40%), grade 3 in 12 (27%), and grade 4 in 4 (9%). Three patients (6.6%) died by granulocytopenia and sepsis. A bronchoscopic proven complete response was achieved in 9 patients (21.5%) and partial response in 28 patients (67%). With a minimum follow-up of 65 months, overall median survival was 13 months, 2-year survival was 21%, and 5-year survival was 7%, with no statistical difference between Stage IIIA and IIIB. Median survival of patients with complete response was 23.2 months, and 5-year survival was 33%. Conclusion: This treatment scheme produced a severe toxicity and in spite of a high response rate, long-term survival is poor, similar to previous studies with radiotherapy alone

  16. Role of electrolytes disturbances and Na(+)-K(+)-ATPase in cisplatin - induced renal toxicity and effects of ethanolic extract of Cichorium intybus.

    Science.gov (United States)

    Noori, Shafaq; Mahboob, Tabassum

    2012-10-01

    Cisplatin is known by its toxicity by disturbing electrolytes homeostasis. Thus we aimed to find out the role of herbal plant Cichorium intybus on Cisplatin - induced toxicity. 24 male Albino Wistar rats were randomly divided into 4 groups: Group I is termed as untreated control; Group II is Cisplatin control and received 3 mg/ kg b.w.; i.p.; Group III received C. intybus ethanolic extract at a dose of 500 mg/kg b.w. orally for 10 consecutive days and Group IV is Cisplatin + C. intybus pretreated group. C. intybus is given 30 minutes prior to Cisplatin. Cisplatin - induced electrolytes disturbances is indicated by increase Intra - erythrocyte sodium content, decreased plasma magnesium, calcium and Intra-erythrocyte Na(+)-K(+)-ATPase which implicates the renal toxicity. At a dose of 500 mg/kg b.w. of C. Intybus pretreatment showed partial counter action on the electrolytes imbalances and Na(+)-K(+)-ATPase activity. PMID:23010005

  17. Evaluation of cisplatin plasma levels in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

    Science.gov (United States)

    Fleres, Francesco; Saladino, Edoardo; Catanoso, Rosaria; Arcoraci, Vincenzo; Mandolfino, Tommaso; Cucinotta, Eugenio; Macrì, Antonio

    2016-02-01

    Introduction Peritoneal surface malignancies have long been regarded as incurable, however, they can be treated with cytoreductive surgery in addition to hyperthermic intraperitoneal chemotherapy. This approach is associated with an increase in morbidity and mortality, unless hyperhydration is provided in a timely manner. Methods Cisplatin (CDDP) is the most widely used chemotherapeutic agent. Plasma levels of cisplatin (CDDP), a widely used chemotherapeutic agent, were measured before, during, and after the procedure. This was done in order to identify the window of highest risk as a function of drug concentrations, assuming a dose-dependent effect. Results Plasma levels of CDDP peak during perfusion. The concentration remains high until the 4th post-operative day and returns to pre-operative levels by the 7th post-operative day. Conclusions Our findings suggest that ensuring hyperhydration as well as infusing albumin and fresh frozen plasma may be of particular value for at least the first 4 days after the procedure. PMID:27385136

  18. Pulmonary Function in Patients With Germ Cell Cancer Treated With Bleomycin, Etoposide, and Cisplatin

    DEFF Research Database (Denmark)

    Lauritsen, Jakob; Kier, Maria Gry Gundgaard; Bandak, Mikkel; Mortensen, Mette Saksø; Thomsen, Frederik Birkebæk; Mortensen, Jann; Daugaard, Gedske

    2016-01-01

    significantly influenced baseline PFT results. Pulmonary surgery, pulmonary embolism, IGCCCG poor prognosis, and smoking influenced PFT during follow-up. Mediastinal primary, pulmonary metastases, age, or doses of cisplatin and etoposide had no influence on follow-up PFT, and renal function did not influence...... PFT. CONCLUSION: After 5 years of follow-up, pulmonary impairment in patients with germ cell cancer who were treated with BEP was limited. Exceptions were patients treated with pulmonary surgery, those who suffered pulmonary embolism, and those in the IGCCCG poor prognostic group.......PURPOSE: For patients with germ cell cancer, various pulmonary toxicity risk factors have been hypothesized for treatment with bleomycin, etoposide, and cisplatin (BEP). Because existing studies have shortcomings, we present a large, unselected cohort of patients who have undergone close monitoring...

  19. Case report of cold-weather-induced radiation recall dermatitis after chemoradiotherapy with cisplatin

    International Nuclear Information System (INIS)

    The radiation recall reaction (RRR) is an inflammatory reaction that occurs in previously irradiated areas. The phenomenon is probably due to an idiosyncratic hypersensitivity reaction, in which a second agent can recall the inflammatory reaction. This case report documents a cold-weather-induced radiation recall dermatitis (RRD). We observed a severe RRD in a patient after chemoradiotherapy treatment with cisplatin for a nasopharyngeal carcinoma, precipitated by cold temperatures, which developed 9 days after completion of therapy. In the medical literature, RRD following extreme cold temperatures seems to be a peculiar event. Until further information on the interaction is available, future studies on combined chemotherapy with cisplatin should be carefully monitored and any side effects clearly documented. This case suggests that environmental conditions may play a contributing role in the development of RRD. This case also implies that neither fraction size nor total radiation dose is a determining factor in the development of the dermatologic reaction. (orig.)

  20. Thrombosis of abdominal aorta during cisplatin-based chemotherapy of testicular seminoma - a case report

    Directory of Open Access Journals (Sweden)

    Gehrckens Ralf

    2009-12-01

    Full Text Available Abstract Background Vascular complications occurring during cisplatin-based chemotherapy of germ cell tumours are inadequately recognized to date. Case Presentation A 49 year old man with advanced seminoma underwent two courses of chemotherapy according to the PEB regimen. Upon restaging, two thrombotic deposits were noted in the descending part of the thoracic aorta and in the infrarenal abdominal aorta, respectively. Although thrombotic plaques caused aortic occlusion of about 30%, no clinical signs of malperfusion of limbs were registered. The patient was placed on anticoagulant therapy. Six months after completion of chemotherapy, thrombotic deposits had completely resolved. In the absence of other predisposing factors, it must be assumed that cisplatin-based chemotherapy represented a strong stimulus for arterial thrombosis in the aorta. Conclusions This is the first case of endo-aortic thrombosis during chemotherapy for testicular germ cell cancer. Providers of chemotherapy must be aware of arterial thrombosis even in young patients with testicular cancer.

  1. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

    International Nuclear Information System (INIS)

    Highlights: ► miR-199a-5p levels were significantly decreased after cisplatin treatment. ► Cisplatin treatment induced autophagy activation. ► Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  2. Human germ cell tumours: expression of γ-glutamyl transpeptidase and sensitivity to cisplatin

    OpenAIRE

    Hanigan, M H; Frierson, H F; Abeler, V. M.; Kaern, J; Taylor, P T

    1999-01-01

    Previous studies have shown that the enzyme γ-glutamyl transpeptidase (GGT) is essential for the nephrotoxicity of cisplatin. This study was designed to determine whether GGT activity is necessary for the therapeutic effect of the drug. The relationship between GGT expression and clinical response to platinum-based chemotherapy was examined in 41 human germ cell tumours. Sections of formalin-fixed, paraffin-embedded tumours were immunohistochemically stained with an antibody directed against ...

  3. Metformin Enhances Anti-proliferative Effect of Cisplatin in Cervical Cancer Cell Line

    OpenAIRE

    Ratih D. Yudhani; Riza N. Pesik; Dono Indarto

    2016-01-01

    Cervival cancer is one of the top rank of gynecological malignancy in the world, leading to high morbidity and mortality rates. Cisplatin is a chemotherapeutic agent that is generally used to treat cervical cancer but the use of this drug is limited because of serious side effects. Metformin, a diabetic drug, decreases not only blood glucose levels but also cell viability of some cancer cells. The aim of this study was to investigate the anti-proliferative effect of combination metformin and ...

  4. Exosomes: Decreased Sensitivity of Lung Cancer A549 Cells to Cisplatin

    OpenAIRE

    Xia Xiao; Shaorong Yu; Shuchun Li; Jianzhong Wu; Rong Ma; Haixia Cao; Yanliang Zhu; Jifeng Feng

    2014-01-01

    Exosomes are small extracellular membrane vesicles of endocytic origin released by many cells that could be found in most body fluids. The main functions of exosomes are cellular communication and cellular waste clean-up. This study was conducted to determine the involvement of exosomes in the regulation of sensitivity of the lung cancer cell line A549 to cisplatin (DDP). When DDP was added to A549 cells, exosomes secretion was strengthened. Addition of the secreted exosomes to other A549 cel...

  5. Case report of cold-weather-induced radiation recall dermatitis after chemoradiotherapy with cisplatin

    Energy Technology Data Exchange (ETDEWEB)

    Kindts, Isabelle; Stellamans, Karin; Planckaert, Nikie; Goethals, Laurence [AZ Groeninge Hospital, Department of Radiation Oncology, Kortrijk (Belgium); Bonny, Michiel [AZ Groeninge Hospital, Department of Dermatology, Kortrijk (Belgium)

    2014-08-15

    The radiation recall reaction (RRR) is an inflammatory reaction that occurs in previously irradiated areas. The phenomenon is probably due to an idiosyncratic hypersensitivity reaction, in which a second agent can recall the inflammatory reaction. This case report documents a cold-weather-induced radiation recall dermatitis (RRD). We observed a severe RRD in a patient after chemoradiotherapy treatment with cisplatin for a nasopharyngeal carcinoma, precipitated by cold temperatures, which developed 9 days after completion of therapy. In the medical literature, RRD following extreme cold temperatures seems to be a peculiar event. Until further information on the interaction is available, future studies on combined chemotherapy with cisplatin should be carefully monitored and any side effects clearly documented. This case suggests that environmental conditions may play a contributing role in the development of RRD. This case also implies that neither fraction size nor total radiation dose is a determining factor in the development of the dermatologic reaction. (orig.) [German] Die ''Radiation-Recall-Reaktion'' (RRR) ist eine Entzuendungsreaktion, die in zuvor bestrahlten Bereichen auftritt. Das Phaenomen wird wahrscheinlich durch eine spezifische Ueberempfindlichkeitsreaktion verursacht, bei der ein zweites Agens die Entzuendungsreaktion hervorruft. Dieser Fallbericht beschreibt eine kaltwetterinduzierte RR-Hautentzuendung. Wir beobachteten bei dem Patienten nach einer Radiochemotherapie mit Cisplatin aufgrund eines Nasopharynxkarzinoms eine heftige RR-Dermatitis (RRD) aufgrund kalter Temperaturen, die sich 9 Tage nach Therapiebeendigung entwickelte. In der medizinischen Literatur scheint eine RRD infolge extrem kalter Temperaturen ein besonderes Ereignis. Bis weitere Informationen zu der Interaktion verfuegbar sind, sollten zukuenftige Studien zur Kombinationstherapie mit Cisplatin sorgfaeltig ueberwacht und Nebenwirkungen eindeutig dokumentiert

  6. Simultaneous Treatment of Cancer Cells Lines with the Anticancer Drug Cisplatin and the Antioxidant Fucoxanthin

    OpenAIRE

    Takeshi Mised; Takeshi Yasumoto

    2011-01-01

    The anti-oxidative properties and the other health benefits of fucoxanthin (Fx) make it a good candidate for a health food supplement. However, the use of antioxidant supplements in patients undergoing chemotherapy has been widely debated because of concerns that the antioxidants may interfere with the mechanisms of the anticancer drugs. To investigate this concern, we studied the effect of Fx on the anticancer drug cisplatin. Fucoxanthinol (Fxol), which is a deacetylated product produced dur...

  7. Evaluation of drug loading, pharmacokinetic behavior, and toxicity of a cisplatin-containing hydrogel nanoparticle

    OpenAIRE

    Kai, Marc P.; Keeler, Amanda W.; Perry, Jillian L.; Reuter, Kevin G.; Luft, J. Christopher; O’Neal, Sara K.; Zamboni, William C.; DeSimone, Joseph M.

    2015-01-01

    Cisplatin is a cytotoxic drug used as a first-line therapy for a wide variety of cancers. However, significant renal and neurological toxicities limits it clinical use. It has been documented that drug toxicities can be mitigated through nanoparticle formulation, while simultaneously increasing tumor accumulation through the enhanced permeation and retention effect. Circulation persistence is a key characteristic for exploiting this effect, and to that end we have developed long-circulating, ...

  8. Gap Junction Enhancer Increases Efficacy of Cisplatin to Attenuate Mammary Tumor Growth

    OpenAIRE

    Shishido, Stephanie N.; Nguyen, Thu A.

    2012-01-01

    Cisplatin treatment has an overall 19% response rate in animal models with malignant tumors. Increasing gap junction activity in tumor cells provides the targets to enhance antineoplastic therapies. Previously, a new class of substituted quinolines (PQs) acts as gap junction enhancer, ability to increase the gap junctional intercellular communication, in breast cancer cells. We examined the effect of combinational treatment of PQs and antineoplastic drugs in an animal model, showing an increa...

  9. An upconversion nanoplatform for simultaneous photodynamic therapy and Pt chemotherapy to combat cisplatin resistance.

    Science.gov (United States)

    Ai, Fujin; Sun, Tianying; Xu, Zoufeng; Wang, Zhigang; Kong, Wei; To, Man Wai; Wang, Feng; Zhu, Guangyu

    2016-08-16

    Platinum-based antineoplastic drugs are among the first-line chemotherapeutic agents against a variety of solid tumors, but toxic side-effects and drug resistance issues limit their clinical optimization. Novel strategies and platforms to conquer cisplatin resistance are highly desired. Herein, we assembled a multimodal nanoplatform utilizing 808 nm-excited and biocompatible core-shell-shell upconversion nanoparticles (UCNPs) [NaGdF4:Yb/Nd@NaGdF4:Yb/Er@NaGdF4] that were covalently loaded with not only photosensitizers (PSs), but also Pt(iv) prodrugs, which were rose bengal (RB) and c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2NH2)2], respectively. The UCNPs had the capability to convert near infrared (NIR) light to visible light, which was further utilized by RB to generate singlet oxygen. At the same time, the nanoplatform delivered the Pt(iv) prodrug into cancer cells. Thus, this upconversion nanoplatform was able to carry out combined and simultaneous photodynamic therapy (PDT) and Pt chemotherapy. The nanoplatform was well characterized and the energy transfer efficiency was confirmed. Compared with free cisplatin or UCNPs loaded with RB only, our nanoplatform showed significantly improved cytotoxicity upon 808 nm irradiation in both cisplatin-sensitive and -resistant human ovarian cancer cells. A mechanistic study showed that the nanoparticles efficiently delivered the Pt(iv) prodrug into cancer cells, resulting in Pt-DNA damage, and that the nanoplatform generated cellular singlet oxygen to kill cancer cells. We, therefore, provide a comprehensive strategy to use UCNPs for combined Pt chemotherapy and PDT against cisplatin resistance, and our nanoplatform can also be used as a theranostic tool due to its NIR bioimaging capacity. PMID:27430044

  10. Long-term platinum retention after treatment with cisplatin and oxaliplatin

    OpenAIRE

    Beijnen Jos H; Huitema Alwin DR; Brouwers Elke EM; Schellens Jan HM

    2008-01-01

    Abstract Background The aim of this study was to evaluate long-term platinum retention in patients treated with cisplatin and oxaliplatin. Methods 45 patients, treated 8–75 months before participating in this study, were included. Platinum levels in plasma and plasma ultrafiltrate (pUF) were determined. In addition, the reactivity of platinum species in pUF was evaluated. Relationships between platinum retention and possible determinants were evaluated. Results Platinum plasma concentrations ...

  11. Long-term platinum retention after treatment with cisplatin and oxaliplatin

    OpenAIRE

    Brouwers, Elke EM; Huitema, Alwin DR; Beijnen, Jos H.; Schellens, Jan HM

    2008-01-01

    Background The aim of this study was to evaluate long-term platinum retention in patients treated with cisplatin and oxaliplatin. Methods 45 patients, treated 8–75 months before participating in this study, were included. Platinum levels in plasma and plasma ultrafiltrate (pUF) were determined. In addition, the reactivity of platinum species in pUF was evaluated. Relationships between platinum retention and possible determinants were evaluated. Results Platinum plasma concentrations ranged be...

  12. Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

    OpenAIRE

    Srivastava, Amit Kumar; Han, Chunhua; Zhao, Ran; Cui, Tiantian; Dai, Yuntao; Mao, Charlene; Zhao, Weiqiang; Zhang, Xiaoli; Yu, Jianhua; Wang, Qi-En

    2015-01-01

    Cancer stem cells (CSCs) exhibit enhanced chemo/radiotherapy resistance, and their survival following cancer treatment is believed to be responsible for tumor recurrence and metastasis. Thus, understanding the mechanisms through which CSCs survive conventional chemotherapy is essential for identification of new therapeutic strategies to prevent tumor relapse. Our findings that ovarian CSCs survive cisplatin treatment through elevated expression of polymerase η represent an opportunity to erad...

  13. CD147 and MCT1-potential partners in bladder cancer aggressiveness and cisplatin resistance.

    Science.gov (United States)

    Afonso, Julieta; Santos, Lúcio L; Miranda-Gonçalves, Vera; Morais, António; Amaro, Teresina; Longatto-Filho, Adhemar; Baltazar, Fátima

    2015-11-01

    The relapsing and progressive nature of bladder tumors, and the heterogeneity in the response to cisplatin-containing regimens, are the major concerns in the care of urothelial bladder carcinoma (UBC) patients. The metabolic adaptations that alter the tumor microenvironment and thus contribute to chemoresistance have been poorly explored in UBC setting. We found significant associations between the immunoexpressions of the microenvironment-related molecules CD147, monocarboxylate transporters (MCTs) 1 and 4, CD44 and CAIX in tumor tissue sections from 114 UBC patients. The presence of MCT1 and/or MCT4 expressions was significantly associated with unfavorable clinicopathological parameters. The incidence of CD147 positive staining significantly increased with advancing stage, grade and type of lesion, and occurrence of lymphovascular invasion. Similar associations were observed when considering the concurrent expression of CD147 and MCT1. This expression profile lowered significantly the 5-year disease-free and overall survival rates. Moreover, when selecting patients who received platinum-based chemotherapy, the prognosis was significantly worse for those with MCT1 and CD147 positive tumors. CD147 specific silencing by small interfering RNAs (siRNAs) in UBC cells was accompanied by a decrease in MCT1 and MCT4 expressions and, importantly, an increase in chemosensitivity to cisplatin. Our results provide novel insights for the involvement of CD147 and MCTs in bladder cancer progression and resistance to cisplatin-based chemotherapy. We consider that the possible cooperative role of CD147 and MCT1 in determining cisplatin resistance should be further explored as a potential theranostics biomarker. PMID:25263481

  14. The Impact of Interstrand Cross-link of Cisplatin or Transplatin on Thermodynamic Stability of DNA

    Czech Academy of Sciences Publication Activity Database

    Hofr, Ctirad; Brabec, Viktor

    Brno: Biofyzikální ústav AV ČR, 2001, s. 26. [Biophysics of the Genome and Its Interactions. Hlohovec (CZ), 15.10.2001-17.10.2001] R&D Projects: GA ČR GA305/99/0695; GA ČR GA301/00/0556 Institutional research plan: CEZ:AV0Z5004920 Keywords : DNA * cross-link * cisplatin Subject RIV: BO - Biophysics

  15. Knockdown of Akt Sensitizes Osteosarcoma Cells to Apoptosis Induced by Cisplatin Treatment

    OpenAIRE

    Changwei Yang; Yushu Bai; Guoyou Zhang; Xiaodong Zhu; Ming Li

    2011-01-01

    Akt plays an important role in the inhibition of apoptosis induced by chemotherapy and other stimuli. We therefore investigated if knockdown of Akt2 promoted drug-induced apoptosis in cultured osteosarcoma cells in vitro. SAOS-2 cells were transfected with Akt2 siRNA. The sensitivity of the transformed cell line to the chemotherapeutic drug cisplatin was assessed. Reduced expression of Akt2 did not directly inhibit the growth rate of the transfected cells; however, it significantly increased ...

  16. Mesoporous Silica Nanoparticles Loaded with Cisplatin and Phthalocyanine for Combination Chemotherapy and Photodynamic Therapy in vitro

    OpenAIRE

    Vivero-Escoto, Juan L.; Maram Elnagheeb

    2015-01-01

    Mesoporous silica nanoparticles (MSNs) have been synthesized and loaded with both aluminum chloride phthalocyanine (AlClPc) and cisplatin as combinatorial therapeutics for treating cancer. The structural and photophysical properties of the MSN materials were characterized by different spectroscopic and microscopic techniques. Intracellular uptake and cytotoxicity were evaluated in human cervical cancer (HeLa) cells by confocal laser scanning microscopy (CLSM) and 3-(4,5-dimethylthiazol-2-yl)-...

  17. Effects of a piperidine ligand on DNA modification by antitumor cisplatin analogues

    Czech Academy of Sciences Publication Activity Database

    Kašpárková, Jana; Nováková, Olga; Najajreh, Y.; Gibson, D.; Perez, J.M.; Brabec, Viktor

    2003-01-01

    Roč. 16, č. 11 (2003), s. 1424-1432. ISSN 0893-228X R&D Projects: GA ČR GA305/02/1552; GA AV ČR KJB5004301; GA AV ČR IBS5004009 Institutional research plan: CEZ:AV0Z5004920 Keywords : DNA * piperidine ligand * antitumor cisplatin analogues Subject RIV: BO - Biophysics Impact factor: 3.332, year: 2003

  18. Intra-Arterial Chemotherapy with Doxorubicin and Cisplatin Is Effective for Advanced Hepatocellular Cell Carcinoma

    OpenAIRE

    Ming-Chun Ma; Yen-Yang Chen; Shau-Hsuan Li; Yu-Fan Cheng; Chih-Chi Wang; Tai-Jan Chiu; Sung-Nan Pei; Chien-Ting Liu; Tai-Lin Huang; Chen-Hua Huang; Yu-Li Su; Yen-Hao Chen; Sheng-Nan Lu; Kun-Ming Rau

    2014-01-01

    Advanced hepatocellular carcinoma (HCC) remains a fatal disease even in the era of targeted therapies. Intra-arterial chemotherapy (IACT) can provide therapeutic benefits for patients with locally advanced HCC who are not eligible for local therapies or are refractory to targeted therapies. The aim of this retrospective study was to analyze the effect of IACT with cisplatin and doxorubicin on advanced HCC. Methods. Patients with advanced HCC who were not eligible for local therapies or were r...

  19. The Protective Role of Galium Aparine on Cisplatin – Induced Nephrotoxicity in Male Rats

    OpenAIRE

    SH Zahiri; AR Dezfulian; F Dehghani

    2006-01-01

    ABSTRACT: Introduction & Objective: Cisplatin is a potent antineoplastic drug. The beneficial effects of the drug are limited by its nephrotoxicity. The purpose of this study is to introduce sterological meothds (Estimation of mean glomerular volume) to determine the toxicity of drug & examine the Galium aparine (a traditional herbal plant) as a protective agent. Materials & Methods: This experimental study was done in histology department in Ahwaz University of medical sciences in 13...

  20. Proteome of leukaemic cells after cisplatin treatment - comparison of three independent analytical techniques

    Czech Academy of Sciences Publication Activity Database

    Martinková, Jiřina; Skalníková, Helena; Hrabáková, Rita; Novák, Petr; Man, Petr; Pompach, Petr; Strohalm, Martin; Havlíček, Vladimír; Džubák, P.; Hajdúch, M.; Kovářová, Hana

    Budapest : Hungarian proteomic society, 2009, s. 56-56. ISBN 978-963-9319-99-8. [3rd Central and Eastern European Proteomics Conference. Budapešť (HU), 06.10.2009-09.10.2009] R&D Projects: GA MŠk LC07017 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z50450515 Keywords : Proteomics * Cis-platin * Leukaemic cells Subject RIV: FK - Gynaecology, Childbirth

  1. The effects of Ginkgo biloba on nephrotoxicity induced by cisplatin-based chemotherapy protocols in rats

    OpenAIRE

    OKUYAN, BETÜL; Izzettin, Fikret Vehbi; Bingöl-Ozakpinar, Özlem; Turan, Pınar; Ozdemir, Zarife Nigar; Sancar, Mesut; Cirakli, Zeynep; Clark, Philip Martin; Ercan, Feriha

    2012-01-01

    The study was aimed at investigating the possible renoprotective effects of Ginkgo biloba on nephrotoxicity induced by cisplatin w/wo other antineoplastic agents (etoposide and gemcitabine) in rats. The animals were randomly divided into eight groups each consisting of six rats. Serum blood urea nitrogen (BUN) and creatinine values at baseline and after drug administration, kidney malondialdehyde (MDA), glutathione (GSH) levels, and myeloperoxidase activity (MPO) were measured, an...

  2. Rikkunshito, a traditional Japanese medicine, suppresses cisplatin-induced anorexia in humans

    OpenAIRE

    Ohno T; Yanai M; Ando H; Toyomasu Y; Ogawa A; Morita H; Ogata K; Mochiki E; Asao T; Kuwano H

    2011-01-01

    Tetsuro Ohno, Mitsuhiro Yanai, Hiroyuki Ando, Yoshitaka Toyomasu, Atsushi Ogawa, Hiroki Morita, Kyoichi Ogata, Erito Mochiki, Takayuki Asao, Hiroyuki KuwanoDepartment of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, JapanBackground: The aim of this study was to investigate the effects of Rikkunshito on ghrelin secretion and on cisplatin-induced anorexia in humans.Methods: The study was performed as a crossover design, and ten unresectable or relapsed gastri...

  3. Radiochemotherapy With Cetuximab, Cisplatin, and Amifostine for Locally Advanced Head and Neck Cancer: A Feasibility Study

    International Nuclear Information System (INIS)

    Purpose: Radiotherapy (RT) combined with cisplatin or cetuximab is the standard of care for patients with locally advanced head/neck cancer (LA-HNC). The feasibility of radiochemotherapy with cisplatin and cetuximab, supported with amifostine, was herein investigated. Methods and Materials: Forty-three patients with LA-HNC were recruited. Conformal hypofractionated/accelerated RT with amifostine cytoprotection (2.7 Gy/fraction, 21 fractions in 4 weeks) was combined with cisplatin (30 mg/m2/week) and cetuximab (standard weekly regimen) therapy. The dose of amifostine was individualized according to tolerance. Results: A high daily amifostine dose (750-1,000 mg) was tolerated by 41.8% of patients, and a standard dose (500 mg) was tolerated by 34.9% of patients. A high amifostine dose was linked to reduced RT delays (p = 0.0003). Grade 3 to 4 (3-4) mucositis occurred in 7/43 (16.2%) patients, and fungal infections occurred in 18/43 (41.8%) patients. Radiation dermatitis was not aggravated. Interruption of cetuximab due to acneiform rash was necessary in 23.3% of patients, while amifostine-related fever and rash were not observed. Severe late radiation sequelae consisted of laryngeal edema (9% laryngeal cases) and cervical strictures (33% of hypopharyngeal cases). Good salivary function was preserved in 6/11 (54.5%) nasopharyngeal cancer patients. The complete response rate was 68.5%, reaching 77.2% in patients with minor radiotherapy delays. The 24-month local control and survival rates were 72.3% and 91%, respectively (median follow-up was 13 months.). Conclusions: In this feasibility study, weekly administration of cisplatin and cetuximab was safely combined with accelerated RT, supported with amifostine, at the cost of a high incidence of acneiform rash but a reduced incidence of amifostine-related fever/rash. A high daily dose of amifostine allows completion of therapy with minor delays.

  4. Functional and histopathological changes in dog kidneys after administration of cisplatin

    DEFF Research Database (Denmark)

    Daugaard, G; Abildgaard, U; Larsen, S;

    1987-01-01

    significantly. The histological changes are in agreement with the physiological data which point to the proximal tubules as the more severely damaged segment. In conclusion, the depressed renal function 48-72 h after administration of cisplatin can be attributed to impairment of proximal as well as distal...... tubular reabsorptive capacities associated with increased renal vascular resistance. The polyuria seems to be due to impaired reabsorption rates in the distal nephron segments, which will affect the concentration mechanism....

  5. The results of accelerated radiotherapy and concomitant cisplatin administration in advanced oropharyngeal cancer

    International Nuclear Information System (INIS)

    The accelerated radiotherapy and concomitant infusion of cisplatin in low doses was evaluated in 15 patients with advanced squamous cell carcinoma of the oral cavity and oral part of pharynx. Clinical complete response was seen in 6 of 15 patients (40%) and 4 patients (26.6%) were alive 12 months with no evidence of disease, of all group of 15 patients 9 (60%) were alive 12 months after treatment. (author)

  6. Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin.

    Science.gov (United States)

    Cervia, Davide; Assi, Emma; De Palma, Clara; Giovarelli, Matteo; Bizzozero, Laura; Pambianco, Sarah; Di Renzo, Ilaria; Zecchini, Silvia; Moscheni, Claudia; Vantaggiato, Chiara; Procacci, Patrizia; Clementi, Emilio; Perrotta, Cristiana

    2016-05-01

    The sphingolipid metabolising enzyme Acid Sphingomyelinase (A-SMase) has been recently shown to inhibit melanoma progression and correlate inversely to tumour grade. In this study we have investigated the role of A-SMase in the chemo-resistance to anticancer treatmentusing mice with melanoma allografts and melanoma cells differing in terms of expression/activity of A-SMase. Since autophagy is emerging as a key mechanism in tumour growth and chemo-resistance, we have also investigated whether an action of A-SMase in autophagy can explain its role. Melanoma sensitivity to chemotherapeutic agent cisplatin in terms of cell viability/apoptosis, tumour growth, and animal survival depended directly on the A-SMase levels in tumoural cells. A-SMase action was due to inhibition of autophagy through activation of Akt/mammalian target of rapamycin (mTOR) pathway. Treatment of melanoma-bearing mice with the autophagy inhibitor chloroquine restored sensitivity to cisplatin of tumours expressing low levels of A-SMase while no additive effects were observed in tumours characterised by sustained A-SMase levels. The fact that A-SMase in melanomas affects mTOR-regulated autophagy and plays a central role in cisplatin efficacy encourages pre-clinical testing on the modulation of A-SMase levels/activity as possible novel anti-neoplastic strategy. PMID:27107419

  7. Experience with gemcitabine and cisplatin in the therapy of inoperable and metastatic cholangiocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Chaiyut Charoentum; Sumitra Thongprasert; Busyamas Chewaskulyong; Sutthirak Munprakan

    2007-01-01

    AIM:To study the activity of gemcitabine and cisplatin in a cohort of patients with inoperable or metastatic cholangiocarcinoma.METHODS: Chemotherapy-naive patients with pathologically proven cholangiocarcinoma, receiving treatment that consisted of gemcitabine at 1250 mg/m2in a 30-min infusion on d 1 and 8, and cisplatin at 75 mg/m2 at every 21-d cycle, were retrospectively analyzed.RESULTS: From June 2003 to December 2005, 42patients were evaluated. Twelve patients (28%) had unresectable disease and 30 (72%) had metastatic disease. There were 28 males and 14 females with a median age of 51 years (range 33-67) and median ECOG PS of 1 (range 0-2). A total of 171 cycles were given with a median number of cycles of 4 (range 1-6).There were 0 CR, 9 PR, 11 SD and 13 PD (response rate 21%). Grade 3-4 hematologic toxicities were: anemia in 33%, neutropenia in 22% and thrombocytopenia in 5%.Non-hematologic toxicity was generally mild. No cases of febrile neutropenia or treatment-related death were noted. The median survival was 10.8 mo (range 8.4-13mo) and progression free survival was 8.5 mo. One-year survival rate was 40%.CONCLUSION: Our results indicate that the combination of gemcitabine and cisplatin had consistent efficacy in patients with unresectable or metastatic cholangiocarcinoma.

  8. Intraarterial chemotherapy with gemcitabine and cisplatin in locally advanced or recurrent penile squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jian-Ye Liu; Yong-Hong Li; Zhuo-Wei Liu; Zhi-Ling Zhang; Yun-Lin Ye; Kai Yao; Hui Han; Zi-Ke Qin; Fang-Jian Zhou

    2013-01-01

    The prognosis of locally advanced or recurrent squamous cell carcinoma (SCC) of the penis after conventional treatment is dismal. This study aimed to evaluate the therapeutic effects of intraarterial chemotherapy with gemcitabine and cisplatin on local y advanced or recurrent SCC of the penis. Between April 1999 and May 2011, we treated 5 patients with locally advanced penile SCC and 7 patients with recurrent disease with intraarterial chemotherapy. The response rate and toxicity data were analyzed, and survival rates were calculated. After 2 to 6 cycles of intraarterial chemotherapy with gemcitabine and cisplatin, 1 patients with locoregional y advanced disease achieved a complete response, and 4 achieved partial response. Of the 7 patients with recurrent disease, 2 achieved complete response, 3 achieved partial response, 3 had stable disease, and 1 developed progressive disease. An objective tumor response was therefore achieved in 10 of the 12 patients. The median overal survival for the patients was 24 months (range, 10-50 months). Three out of 10 patients who responded were long-term survivors after intraarterial chemotherapy. Intraarterial chemotherapy with gemcitabine and cisplatin may be effective and potential y curative in locoregional y advanced or recurrent penile SCC. The contribution of this therapy in the primary management of advanced or recurrent penile SCC should be prospectively investigated.

  9. Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea.

    Science.gov (United States)

    De Jonghe, Bart C; Holland, Ruby A; Olivos, Diana R; Rupprecht, Laura E; Kanoski, Scott E; Hayes, Matthew R

    2016-01-01

    While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments. PMID:26522737

  10. Mesoporous Silica Nanoparticles Loaded with Cisplatin and Phthalocyanine for Combination Chemotherapy and Photodynamic Therapy in vitro

    Directory of Open Access Journals (Sweden)

    Juan L. Vivero-Escoto

    2015-12-01

    Full Text Available Mesoporous silica nanoparticles (MSNs have been synthesized and loaded with both aluminum chloride phthalocyanine (AlClPc and cisplatin as combinatorial therapeutics for treating cancer. The structural and photophysical properties of the MSN materials were characterized by different spectroscopic and microscopic techniques. Intracellular uptake and cytotoxicity were evaluated in human cervical cancer (HeLa cells by confocal laser scanning microscopy (CLSM and 3-(4,5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H-tetrazolium (MTS assays, respectively. The CLSM experiments showed that the MSN materials can be readily internalized in HeLa cells. The cytotoxic experiments demonstrated that, after light exposure, the combination of both AlClPc and cisplatin compounds in the same MSN platform potentiate the toxic effect against HeLa cells in comparison to the control AlClPc-MSN and cisplatin-MSN materials. These results show the potential of using MSN platforms as nanocarriers for combination photodynamic and chemotherapies to treat cancer.

  11. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery

    International Nuclear Information System (INIS)

    Seventy patients with muscle-invading bladder carcinoma (clinical stages T2 to T4) who were not candidates for cystectomy were treated with combined cisplatin and full-dose external-beam radiation on a multi-institutional prospective protocol from 1980 through 1985. Thirty-six patients are alive, all but three without evidence of cancer. The complete response rate is 77% in the 62 patients completing planned irradiation and 70% for all patients. Among the complete responders, 73% are currently maintained, and this group has a significantly higher four-year survival than those not having a complete response and those with recurrence of disease - 57% vs 11%. The observed high complete response rates in patients in all stages and the high survival rates suggest irradiation plus cisplatin therapy offers an important therapeutic gain over radiation therapy alone for invasive cancer of the bladder. These results encourage further evaluation of combining cisplatin-based, multidrug chemotherapy with irradiation in patients with locally very-advanced bladder tumors who are not suited for surgery

  12. Attenuation of cisplatin-induced acute renal failure is associated with less apoptotic cell death.

    Science.gov (United States)

    Zhou, H; Miyaji, T; Kato, A; Fujigaki, Y; Sano, K; Hishida, A

    1999-12-01

    To clarify the pathophysiologic role of apoptosis in acute renal failure (ARF), we examined whether the attenuation of cisplatin-induced ARF is associated with the change in the degree of apoptotic cell death. The administration of cisplatin (CDDP) (6 mg/kg body weight) in rats induced ARF at day 5, as manifested by a significant increase in serum creatinine (Scr) and tubular damage. CDDP-induced apoptotic cell death was confirmed by electron microscopic examination, agarose gel electrophoresis, and increased cells positive for TaT-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) in the outer medulla of the kidney. Treatment with dimethylthiourea (DMTU)--a scavenger of hydroxyl radicals--or glycine abrogated CDDP-induced increases in Scr, the tubular damage score, and the number of TUNEL-positive cells. Pretreatment with uranyl acetate (UA) induced a significant expression of Bcl-2 in the kidney and ameliorated CDDP-induced increases in Scr, the tubular damage score, and TUNEL-positive cells in the outer stripe of the outer medulla. Our findings indicate (1) that the attenuation of CDDP-induced ARF was associated with less apoptotic cell death and (2) that the induction of the anti-apoptotic protein Bcl-2 attenuated apoptosis and tubular damage. Our results suggest that apoptotic cell death may play an important role in the development of cisplatin-induced ARF. PMID:10595794

  13. Cisplatin-induced premature senescence with concomitant reduction of gap junctions in human fibroblasts

    Institute of Scientific and Technical Information of China (English)

    Wei ZHAO; Zhong Xiang LIN; Zhi Qian ZHANG

    2004-01-01

    To examine the role of gap junctions in cell senescence,the changes of gap junctions in cisplatin-induced premature senescence of primary cultured fibroblasts were studied and compared with the replicative senescent human fibroblasts.Dye transfer assay for gap junction function and immunofluorescent staining for connexin 43 protein distribution were done respectively. Furthermore,cytofluorimetry and DAPI fluorescence staining were performed for cell cycle and apoptosis analysis. p53 gene expression level was detected with indirect immunofluorescence. We found that cisplatin (10 mM) treatment could block cell growth cycle at G1 and induced premature senescence. The premature senescence changes included high frequency of apoptosis,elevation of p53 expression,loss of membranous gap junctions and reduction of dye-transfer capacity. These changes were comparable to the changes of replicative senescence of human fibroblasts. It was also concluded that cisplatin could induce premature senescence concomitant with inhibition of gap junctions in the fibroblasts. Loss of functional gap junctions from the cell membrane may account for the reduced intercellular communication in the premature senescent fibroblasts. The cell system we used may provide a model useful for the study of the gap junction thus promoting agents against premature senescence.

  14. [Transarterial infusion chemotherapy using fine-powder cisplatin in patients with advanced hepatocellular carcinoma].

    Science.gov (United States)

    Hatanaka, Takeshi; Kakizaki, Satoru; Ueno, Takashi; Takeuchi, Suguru; Takizawa, Daichi; Katakai, Kenji

    2014-02-01

    We investigated the therapeutic effects and safety of fine powder cisplatin for patients with advanced hepatocellular carcinoma( HCC). From January 2006 to March 2012, 123 patients with advanced HCC were treated by transarterial infusion chemotherapy(TAI)with fine-powder cisplatin(IA-call®, Nippon Kayaku Co. Ltd., Tokyo, Japan). The drug was infused into the liver through the feeding artery at a dose of 65 mg/m2. The treatment was repeated every 4 to 8 weeks until evidence of either tumor progression or unacceptable toxicity appeared. Treatment responses were classified as complete response(CR), partial response(PR), stable disease(SD), and progressive disease(PD)in 3.2%, 12.0%, 32.2%, and 52.4% of patients, respectively. The median survival durations were as follows: overall, 12.2 months; CR/PR patients, 23.8 months; and SD/PD patients, 10.6 months. The cumulative survival rates of CR/PR patients were significantly higher than those of SD/PD patients (pPIVKA- II )were predictive factors of survival duration. Problematic adverse events were not observed in any of the patients. Our results suggest that TAI using fine-powder cisplatin can be safely administered for advanced HCC and can improve the prognosis of patients with advanced disease. PMID:24743198

  15. Vitamin E protection from/potentiation of the cytogenetic toxicity of cisplatin in Swiss mice.

    Science.gov (United States)

    Choudhury, R C; Jagdale, M B

    2002-08-01

    Possible protection from or potentiation of the cytogenetic toxic effects of cisplatin (CP) 5 mg/kg b.w. in mouse bone marrow, spermatogonia by three different doses of alpha-tocopheryl acetate (vitamin E) 100, 200 and 300 mg/kg, and the transmission of such effects in the male germline, were assessed. CP-induced chromosomal aberrations (CAs) in bone marrow were decreased in vitamin E pretreated mice, but significantly (P enhanced significantly in the mice pretreated with vitamin E 100 mg/kg (P enhancement in the transmission of such effects was not significant in the mice pretreated with vitamin E 300 mg/kg. Besides, there was no significant change in vitamin E-pretreated groups of mice in the transmission of cytogenetic toxicity of CP from spermatogonia to sperm with the manifestation of abnormal sperm morphology. Thus, vitamin E protected bone marrow and spermatogonia from the cytogenetic toxic effects of CP, particularly efficiently at the highest tested dose (300 mg/kg), but it failed to protect from the transmission of such effects in the male germline of mouse and rather potentiated them to some extent. Treatment with vitamin E, an antioxidant, might be capable of protecting noncancerous cells from the oxidative damage caused by cisplatin but it might also reduce the effects of cisplatin on cancerous cells. Thus, the benefits of antioxidant treatment during cancer chemotherapy is yet to be demonstrated clearly. PMID:12420859

  16. Evaluating the effect of zingiber officinalis on nausea and vomiting in patients receiving Cisplatin based regimens.

    Science.gov (United States)

    Fahimi, Fanak; Khodadad, Kian; Amini, Somayeh; Naghibi, Farzaneh; Salamzadeh, Jamshid; Baniasadi, Shadi

    2011-01-01

    Ginger, the rhizome of Zingiber officinalis, has long been used as herbal medicine for its antiemetic effect. For evaluating the effect of zingiber officinalis on nausea and vomiting (N and V) in patients receiving cisplatin based regimens, a randomized double-blind placebo-controlled cross-over clinical trial was carried out in patients receiving cisplatin in combination with other chemotherapeutic agents. The patients were randomly assigned to receive ginger capsules (rhizome of zingiber officinalis) or placebo in their first cycle of the study. All patients received standard antiemetics for chemotherapy induced nausea and vomiting (CINV). The patients were crossed-over to receive ginger or placebo in their next cycle of chemotherapy. Among 36 eligible patients who received both cycles of treatment, there were no difference in prevalence, severity, and duration of both acute and delayed N and V. Addition of ginger to the standard antiemetic regimen has shown no advantage in reducing acute and delayed N and V in patients with cisplatin-based regimen in this study. PMID:24250368

  17. QM/MM studies of cisplatin complexes with DNA dimer and octamer

    KAUST Repository

    Gkionis, Konstantinos

    2012-08-01

    Hybrid QM/MM calculations on adducts of cisplatin with DNA dimer and octamer are reported. Starting from the crystal structure of a cisplatin-DNA dimer complex and an NMR structure of a cisplatin-DNA octamer complex, several variants of the ONIOM approach are tested, all employing BHandH for the QM part and AMBER for MM. We demonstrate that a generic set of molecular mechanics parameters for description of Pt-coordination can be used within the subtractive ONIOM scheme without loss of accuracy, such that dedicated parameters for new platinum complexes may not be required. Comparison of optimised structures obtained with different strategies indicates that electrostatic embedding is vital for proper description of the complex, while inclusion of water molecules as explicit solvent further improves performance. The resulting DNA structural parameters are in good general agreement with the experimental structure obtained, particularly when the inherent variability in NMR-derived parameters is taken into account. © 2012 Elsevier B.V.

  18. Pathologic Response Rates of Gemcitabine/Cisplatin versus Methotrexate/Vinblastine/Adriamycin/Cisplatin Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Franklin C. Lee

    2013-01-01

    Full Text Available Objectives. To compare pathologic outcomes after treatment with gemcitabine and cisplatin (GC versus methotrexate, vinblastine, adriamycin, and cisplatin (MVAC in the neoadjuvant setting. Methods. Data was retrospectively collected on 178 patients with T2-T4 bladder cancer who underwent radical cystectomy between 2003 and 2011. Outcomes of interest included those with complete response (pT0 and any response (≤pT1. Odds ratios were calculated using multivariate logistic regression. Results. Compared to those who did not receive neoadjuvant chemotherapy, there were more patients with complete response (28% versus 9%, OR 3.11 (95% CI: 1.45–6.64, P=0.03 and any response (52% versus 25%, OR 3.23 (95% CI: 1.21–8.64, P=0.01. Seventy-two patients received GC (n=41 or MVAC (n=31. CR was achieved in 29% and 22% of GC and MVAC patients, respectively (multivariate OR 0.39, 95% CI 0.10–1.58. Any response (≤pT1 was achieved in 56% of GC and 45% of MVAC patients (multivariate OR 0.45, 95% CI 0.12–1.71. Conclusions. We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of patients with muscle invasive urothelial cancer (MIBC. Our findings support the use of GC as an alternative regimen in the neoadjuvant setting.

  19. Quercetin-induced inhibition and synergistic activity with cisplatin – a chemotherapeutic strategy for nasopharyngeal carcinoma cells

    Directory of Open Access Journals (Sweden)

    Daker Maelinda

    2012-07-01

    Full Text Available Abstract Background Nasopharyngeal carcinoma (NPC is a unique tumour of epithelial origin with a distinct geographical distribution, genetic predisposition and environmental as well as dietary influence as aetiological factors. Standard NPC treatment regimes, such as radiotherapy and concurrent chemotherapy with cytotoxic drugs, can produce undesirable complications often associated with significant toxicity. Here, we report the effects of a widely distributed flavonoid, quercetin, on cell proliferation, apoptosis and cell cycle arrest. The effects of combining quercetin and cisplatin on human NPC cells were explored. Methods Cell proliferation was monitored by the dynamic, impedance-based cell analyzer (xCELLigence system and the MTS assay. Ki67 proliferation antigen and fatty acid synthase (FASN level was examined by Western blotting. Flow cytometry was also carried out to study the effects of quercetin on cell cycle and apoptosis status. Results At 100 μM, quercetin inhibited cell proliferation and decreased expression of FASN and Ki67 antigen. Cell cycle analysis revealed a substantial increase in the proportion of cells in the G2/M phase. We also demonstrated the enhanced cytotoxic effects of quercetin treatment in concomitant with the chemotherapeutic drug, cisplatin, in cultured NPC cells. The combination index (CI value of quercetin-cisplatin combination was  Conclusions Our study showed that quercetin exhibited synergistic effects with cisplatin against NPC cells. Dose-reduction index (DRI values > 1 implied the possibility of reducing the cisplatin dosage required to treat NPC, with the addition of quercetin. In turn, this could reduce the risk of cisplatin-associated toxicity. The potential of combining quercetin with cisplatin as a chemotherapeutic strategy for treatment of NPC should be explored further.

  20. Combined therapeutic effect and molecular mechanisms of metformin and cisplatin in human lung cancer xenografts in nude mice

    Directory of Open Access Journals (Sweden)

    Yu-Qin Chen

    2015-01-01

    Full Text Available Objective: This work was aimed at studying the inhibitory activity of metformin combined with the commonly used chemotherapy drug cisplatin in human lung cancer xenografts in nude mice. We also examined the combined effects of these drugs on the molecular expression of survivin, matrix metalloproteinase-2 (MMP-2, vascular endothelial growth factor-C (VEGF-C, and vascular endothelial growth factorreceptor-3 (VEGFR-3 to determine the mechanism of action and to explore the potential applications of the new effective drug therapy in lung cancer. Materials and Methods: The nude mice model of lung cancer xenografts was established, and mice were randomly divided into the metformin group, the cisplatin group, the metformin + cisplatin group, and the control group. The animals were killed 42 days after drug administration, and the tumor tissues were then sampled to detect the messenger ribonucleic acid (mRNA and protein expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR. Results: The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the cisplatin group and the combined treatment group were lower than that in the control group (P < 0.05. In the metformin group, the expression of MMP-2 protein and mRNA was lower than that in the control group (P < 0.05. The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the combined treatment group were lower than that in the cisplatin group and the metformin group (P < 0.05. Conclusions: Metformin inhibited the expression of MMP-2, cisplatin and the combined treatment inhibited the expression of survivin, MMP-2, VEGF-C, and VEGFR-3, and the combined treatment of metformin with cisplatin resulted in enhanced anti-tumor efficacy.

  1. Cisplatin superior to carboplatin in adjuvant radiochemotherapy for locally advanced cancers of the oropharynx and oral cavity

    International Nuclear Information System (INIS)

    The optimal radiochemotherapy regimen for squamous cell carcinoma of the head and neck (SCCHN) is controversial. In most cases, platin-based chemotherapy regimens are used. However, uncertainty exists whether cisplatin or carboplatin is the better choice. This retrospective study compared radiochemotherapy with either cisplatin or carboplatin in patients with locally advanced SCC of the oropharynx and oral cavity. Patients and methods Concurrent chemotherapy consisted of two courses of cisplatin (20 mg/m2 on days 1-5 and days 29 - 33; n = 65) or two courses of carboplatin (AUC 1.5 on days 1-5 and days 29 - 33; n = 41). Both regimens were retrospectively compared for locoregional control (LRC), overall survival (OS), and toxicity. Thirteen additional potential prognostic factors were evaluated including age, gender, ECOG performance status, tumor site, histologic grade, T/N category, AJCC stage, year of treatment, extent of resection, interval between surgery and RT, completion of chemotherapy, and radiotherapy breaks. Results The 3-year LRC rates were 85% in the cisplatin group and 62% in the carboplatin group, respectively (p = 0.004). The 3-year OS rates were 78% and 51%, respectively (p = 0.001). Acute toxicity (mucositis, skin toxicity, nausea/vomiting, renal toxicity, hematologic toxicity) and late toxicity (xerostomia, neck fibrosis, skin toxicity, lymph edema) rates were not significantly different between the two groups. On multivariate analysis, better LRC was significantly associated with cisplatin (p < 0.001), an ECOG performance status of 0-1 (p = 0.001), and an interval between surgery and RT of ≤ 6 weeks (p = 0.001). Improved OS was significantly associated with cisplatin (p < 0.001) and completion of chemotherapy (p = 0.002). Conclusion For adjuvant radiochemotherapy of patients with locally advanced cancer of the oropharynx and oral cavity, cisplatin appears preferable to carboplatin as it resulted in better outcomes without increased toxicity

  2. The Effect of Recombinant Human Epidermal Growth Factor on Cisplatin and Radiotherapy Induced Oral Mucositis in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Na, Jae Boem; Kim, Hye Jung; Chai, Gyu Young [Gyeongsang National University School of Medicine, Jinju (Korea, Republic of)

    2007-12-15

    Purpose: To study the effect of recombinant human epidermal growth factor (rhEGF) on oral mucositis induced by cisplatin and radiotherapy in a mouse model. Materials and Methods: Twenty-four ICR mice were divided into three groups. the normal control group, the no rhEGF group (treatment with cisplatin and radiation) and the rhEGF group (treatment with cisplatin, radiation and rhEGF). A model of mucositis induced by cisplatin and radiotherapy was established by injecting mice with cisplatin (10 mg/kg) on day 1 and with radiation exposure (5 Gy/day) to the head and neck on days 1{approx}5. rhEGF was administered subcutaneously on days -1 to 0 (1 mg/kg/day) and on days 3 to 5 (1 mg/kg/day). Evaluation included body weight, oral intake, and histology. Results: For the comparison of the change of body weight between the rhEGF group and the no rhEGF group, a statistically significant difference was observed in the rhEGF group for the 5 days after day 3 of the experiment. The rhEGF group and no rhEGF group had reduced food intake until day 5 of the experiment, and then the mice demonstrated increased food intake after day 13 of the of experiment. When the histological examination was conducted on day 7 after treatment with cisplatin and radiation, the rhEGF group showed a focal cellular reaction in the epidermal layer of the mucosa, while the no rhEGF group did not show inflammation of the oral mucosa. Conclusion: These findings suggest that rhEGF has a potential to reduce the oral mucositis burden in mice after treatment with cisplatin and radiation. The optimal dose, number and timing of the administration of rhEGF require further investigation.

  3. The Effect of Recombinant Human Epidermal Growth Factor on Cisplatin and Radiotherapy Induced Oral Mucositis in Mice

    International Nuclear Information System (INIS)

    Purpose: To study the effect of recombinant human epidermal growth factor (rhEGF) on oral mucositis induced by cisplatin and radiotherapy in a mouse model. Materials and Methods: Twenty-four ICR mice were divided into three groups. the normal control group, the no rhEGF group (treatment with cisplatin and radiation) and the rhEGF group (treatment with cisplatin, radiation and rhEGF). A model of mucositis induced by cisplatin and radiotherapy was established by injecting mice with cisplatin (10 mg/kg) on day 1 and with radiation exposure (5 Gy/day) to the head and neck on days 1∼5. rhEGF was administered subcutaneously on days -1 to 0 (1 mg/kg/day) and on days 3 to 5 (1 mg/kg/day). Evaluation included body weight, oral intake, and histology. Results: For the comparison of the change of body weight between the rhEGF group and the no rhEGF group, a statistically significant difference was observed in the rhEGF group for the 5 days after day 3 of the experiment. The rhEGF group and no rhEGF group had reduced food intake until day 5 of the experiment, and then the mice demonstrated increased food intake after day 13 of the of experiment. When the histological examination was conducted on day 7 after treatment with cisplatin and radiation, the rhEGF group showed a focal cellular reaction in the epidermal layer of the mucosa, while the no rhEGF group did not show inflammation of the oral mucosa. Conclusion: These findings suggest that rhEGF has a potential to reduce the oral mucositis burden in mice after treatment with cisplatin and radiation. The optimal dose, number and timing of the administration of rhEGF require further investigation

  4. Cisplatin superior to carboplatin in adjuvant radiochemotherapy for locally advanced cancers of the oropharynx and oral cavity

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    Rades, D. [Univ. of Luebeck (Germany). Dept. of Radiation Oncology; Ulbricht, T.; Hakim, S.G. [Univ. of Luebeck (Germany). Dept. of Maxillofacial Surgery; Schild, S.E. [Mayo Clinic, Scottsdale, AZ (United States). Dept. of Radiation Oncology

    2012-01-15

    The optimal radiochemotherapy regimen for squamous cell carcinoma of the head and neck (SCCHN) is controversial. In most cases, platin-based chemotherapy regimens are used. However, uncertainty exists whether cisplatin or carboplatin is the better choice. This retrospective study compared radiochemotherapy with either cisplatin or carboplatin in patients with locally advanced SCC of the oropharynx and oral cavity. Patients and methods Concurrent chemotherapy consisted of two courses of cisplatin (20 mg/m{sup 2} on days 1-5 and days 29 - 33; n = 65) or two courses of carboplatin (AUC 1.5 on days 1-5 and days 29 - 33; n = 41). Both regimens were retrospectively compared for locoregional control (LRC), overall survival (OS), and toxicity. Thirteen additional potential prognostic factors were evaluated including age, gender, ECOG performance status, tumor site, histologic grade, T/N category, AJCC stage, year of treatment, extent of resection, interval between surgery and RT, completion of chemotherapy, and radiotherapy breaks. Results The 3-year LRC rates were 85% in the cisplatin group and 62% in the carboplatin group, respectively (p = 0.004). The 3-year OS rates were 78% and 51%, respectively (p = 0.001). Acute toxicity (mucositis, skin toxicity, nausea/vomiting, renal toxicity, hematologic toxicity) and late toxicity (xerostomia, neck fibrosis, skin toxicity, lymph edema) rates were not significantly different between the two groups. On multivariate analysis, better LRC was significantly associated with cisplatin (p < 0.001), an ECOG performance status of 0-1 (p = 0.001), and an interval between surgery and RT of {<=} 6 weeks (p = 0.001). Improved OS was significantly associated with cisplatin (p < 0.001) and completion of chemotherapy (p = 0.002). Conclusion For adjuvant radiochemotherapy of patients with locally advanced cancer of the oropharynx and oral cavity, cisplatin appears preferable to carboplatin as it resulted in better outcomes without increased

  5. Hearing loss due to concurrent daily low-dose cisplatin chemoradiation for locally advanced head and neck cancer

    International Nuclear Information System (INIS)

    Background and purpose: Cisplatin-based chemo-irradiation (CRT) is increasingly used for head and neck squamous cell carcinoma (HNSCC). We aimed to assess hearing deterioration due to low-dose cisplatin chemoradiation and to compare the observed hearing loss with hearing loss in our previously described high-dose cisplatin CRT cohort. Materials and methods: A prospective analysis of hearing thresholds at low and (ultra)-high frequencies obtained before and after treatment in 60 patients. Patients received low-dose cisplatin (6 mg/m2, daily infusions, 20-25 days) with concomitant accelerated radiotherapy (70 Gy). Results: Audiometry up to 16 kHz was performed before therapy and 31 days (median) post-treatment. The total incidence of ototoxicity in CTCAEv3.0 was 31% in audiograms up to 8 kHz, and 5% of ears tested qualified for HAs due to treatment. The mean hearing loss at speech frequencies was 2.6 dB (SD 5.7) and 2.3 dB (SD 9.2) at PTA 1-2-4 kHz air-conduction and bone-conduction, respectively. The mean hearing loss at ultra-high frequencies (PTA AC 8-10-12.5 kHz) was 9.0 dB (SD 8.1). Low-dose cisplatin CRT caused less acute hearing loss (CTCAE 31%), compared to high-dose cisplatin CRT (CTCAE 78%). Conclusions: Low-dose cisplatin chemo-irradiation for HNSCC is a relatively safe treatment protocol with respect to ototoxicity

  6. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer.

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    Zhu, Haiyan; Wu, Jun; Zhang, Wenwen; Luo, Hui; Shen, Zhaojun; Cheng, Huihui; Zhu, Xueqiong

    2016-01-01

    Pyruvate kinase M2 (PKM2) is a key driver of aerobic glycolysis in cancer cells and has been shown to be up-regulated by mTOR in vitro. Our previous proteomic profiling studies showed that PKM2 was significantly upregulated in cervical cancer tissues after treatment with neoadjuvant chemotherapy (NACT). Whether PKM2 expression predicts cisplatin-based NACT sensitivity and is mTOR dependent in cervical cancer patients remains unclear. Using paired tumor samples (pre- and post-chemotherapy) from 36 cervical cancer patients, we examined mTOR, HIF-1α, c-Myc, and PKM2 expression in cervical cancer samples and investigated the response to cisplatin-based NACT. In addition, we established PKM2 suppressed cervical cancer cell lines and evaluated their sensitivity to cisplatin in vitro. We found that the mTOR/HIF-1α/c-Myc/PKM2 signaling pathway was significantly downregulated in post-chemotherapy cervical cancer tissues. High levels of mTOR, HIF-1α, c-Myc, and PKM2 were associated with a positive chemotherapy response in cervical cancer patients treated with cisplatin-based NACT. In vitro, PKM2 knockdown desensitized cervical cancer cells to cisplatin. Moreover, PKM2 had complex interactions with mTOR pathways. mTOR, HIF1α, c-Myc, and PKM2 expression in cervical cancer may serve as predictive biomarkers to cisplatin-based chemotherapy. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer. PMID:27492148

  7. Mitochondrial modulation by Epigallocatechin 3-Gallate ameliorates cisplatin induced renal injury through decreasing oxidative/nitrative stress, inflammation and NF-kB in mice.

    Science.gov (United States)

    Pan, Hao; Chen, Jun; Shen, Kezhen; Wang, Xueping; Wang, Ping; Fu, Guanghou; Meng, Hongzhou; Wang, Yimin; Jin, Baiye

    2015-01-01

    Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG) can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN). EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX) and manganese superoxide dismutase (MnSOD) in mitochondria, inflammation (tumor necrosis factor α and interleukin 1β), increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation). Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS) generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct candidate for

  8. Effect of ionizing radiation and cisplatin on the expression of TOB1 in human lung cancer cell lines

    International Nuclear Information System (INIS)

    Objective: To explore the effect of ionizing radiation and cisplatin on the expression of Transducer of erbB2, 1 (TOB1) in human lung adenocarcinoma SPCA-1 and LTEP-α-2 cell lines. Methods: SPCA-1 and/or LTEP-α-2 cells were respectively irradiated with 2, 4, 6, 8, and 10 Gy X-rays generated by a linear accelerator (with the source skin distance of 100 cm and dose rate of 200 cGy/min). The cell molecular samples were subtracted at 6, 12, 18, and 24 h after 6 Gy irradiation. For X-rays and cisplatin combination treatment, cells were divided into radiation group (6 Gy X-rays), cisplatin group (20 mol/L cisplatin), and combination group (6 Gy X-rays + 20 mol/L cisplatin). SPCA-1 and LTEP-α-2 cells without any treatment were used as control group. The relative levels of TOB1 mRNA and protein expression were detected by rigorously controlled semi-quantitative RT-PCR and Western blot analysis with quantitation of the mRNA/protein bands by densitometry. Results: The expression level of TOB1 was significantly increased in both mRNA and protein level after radiation exposure (t=8.25-24.48, P<0.05). For time-dependent induction of TOB1, the expression was significantly increased 6 h after X-rays exposure (t=14.23-15.82, P<0.05). More significant increase of TOB1 expression was identified after the combination treatment of X-rays and cisplatin, compared to that of the radiation and/or cisplatin treatment alone (t=11.21-13.67, P<0.05). Conclusions: Ionizing radiation and cisplatin could upregulate the expression of TOB1 in lung cancer cells in both mRNA and protein levels. TOB1 may be a molecular target for ionizing radiation and cisplatin treatment in lung cancer and it may have potential implication in evaluating the curative efficiency of chemo-and radio-therapy. (authors)

  9. Chemical conversion of cisplatin and carboplatin with histidine in a model protein crystallized under sodium iodide conditions

    International Nuclear Information System (INIS)

    Crystals of HEWL with cisplatin and HEWL with carboplatin grown in sodium iodide conditions both show a partial chemical transformation of cisplatin or carboplatin to a transiodoplatin (PtI2X2) form. The binding is only at the Nδ atom of His15. A further Pt species (PtI3X) is also seen, in both cases bound in a crevice between symmetry-related protein molecules. Cisplatin and carboplatin are platinum anticancer agents that are used to treat a variety of cancers. Previous X-ray crystallographic studies of carboplatin binding to histidine in hen egg-white lysozyme (HEWL) showed a partial chemical conversion of carboplatin to cisplatin owing to the high sodium chloride concentration used in the crystallization conditions. Also, the co-crystallization of HEWL with carboplatin in sodium bromide conditions resulted in the partial conversion of carboplatin to the transbromoplatin form, with a portion of the cyclobutanedicarboxylate (CBDC) moiety still present. The results of the co-crystallization of HEWL with cisplatin or carboplatin in sodium iodide conditions are now reported in order to determine whether the cisplatin and carboplatin converted to the iodo form, and whether this took place in a similar way to the partial conversion of carboplatin to cisplatin in NaCl conditions or to transbromoplatin in NaBr conditions as seen previously. It is reported here that a partial chemical transformation has taken place to a transplatin form for both ligands. The NaI-grown crystals belonged to the monoclinic space group P21 with two molecules in the asymmetric unit. The chemically transformed cisplatin and carboplatin bind to both His15 residues, i.e. in each asymmetric unit. The binding is only at the Nδ atom of His15. A third platinum species is also seen in both conditions bound in a crevice between symmetry-related molecules. Here, the platinum is bound to three I atoms identified based on their anomalous difference electron densities and their refined occupancies, with

  10. Chemical conversion of cisplatin and carboplatin with histidine in a model protein crystallized under sodium iodide conditions

    Energy Technology Data Exchange (ETDEWEB)

    Tanley, Simon W. M.; Helliwell, John R., E-mail: john.helliwell@manchester.ac.uk [University of Manchester, Brunswick Street, Manchester M13 9PL (United Kingdom)

    2014-08-29

    Crystals of HEWL with cisplatin and HEWL with carboplatin grown in sodium iodide conditions both show a partial chemical transformation of cisplatin or carboplatin to a transiodoplatin (PtI{sub 2}X{sub 2}) form. The binding is only at the N{sup δ} atom of His15. A further Pt species (PtI{sub 3}X) is also seen, in both cases bound in a crevice between symmetry-related protein molecules. Cisplatin and carboplatin are platinum anticancer agents that are used to treat a variety of cancers. Previous X-ray crystallographic studies of carboplatin binding to histidine in hen egg-white lysozyme (HEWL) showed a partial chemical conversion of carboplatin to cisplatin owing to the high sodium chloride concentration used in the crystallization conditions. Also, the co-crystallization of HEWL with carboplatin in sodium bromide conditions resulted in the partial conversion of carboplatin to the transbromoplatin form, with a portion of the cyclobutanedicarboxylate (CBDC) moiety still present. The results of the co-crystallization of HEWL with cisplatin or carboplatin in sodium iodide conditions are now reported in order to determine whether the cisplatin and carboplatin converted to the iodo form, and whether this took place in a similar way to the partial conversion of carboplatin to cisplatin in NaCl conditions or to transbromoplatin in NaBr conditions as seen previously. It is reported here that a partial chemical transformation has taken place to a transplatin form for both ligands. The NaI-grown crystals belonged to the monoclinic space group P2{sub 1} with two molecules in the asymmetric unit. The chemically transformed cisplatin and carboplatin bind to both His15 residues, i.e. in each asymmetric unit. The binding is only at the N{sup δ} atom of His15. A third platinum species is also seen in both conditions bound in a crevice between symmetry-related molecules. Here, the platinum is bound to three I atoms identified based on their anomalous difference electron densities

  11. SOCS-1 gene delivery cooperates with cisplatin plus pemetrexed to exhibit preclinical antitumor activity against malignant pleural mesothelioma.

    Science.gov (United States)

    Iwahori, Kota; Serada, Satoshi; Fujimoto, Minoru; Ripley, Barry; Nomura, Shintaro; Mizuguchi, Hiroyuki; Shimada, Kazuki; Takahashi, Tsuyoshi; Kawase, Ichiro; Kishimoto, Tadamitsu; Naka, Tetsuji

    2013-01-15

    Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis for which an effective therapy remains to be established. This study investigated the therapeutic potential of gene delivery using suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of intracellular signaling pathways, for the treatment of MPM. We infected MPM cells (MESO-4, H28 and H226) with adenovirus-expressing SOCS-1 vector to examine the effect of SOCS-1 overexpression on MPM cells. We evaluated the antitumor effect of SOCS-1 gene delivery combined with cisplatin plus pemetrexed by cell proliferation, apoptosis and invasion assay. We also investigated the regulation of NF-κB and STAT3 signaling related to apoptotic pathways. Furthermore, we evaluated the inhibition of tumor growth by SOCS-1 gene delivery combined with cisplatin plus pemetrexed in vivo. SOCS-1 gene delivery cooperated with cisplatin plus pemetrexed to inhibit cell proliferation, invasiveness and induction of apoptosis in MPM cells. SOCS-1 regulated NF-κB and STAT3 signaling to induce apoptosis in MESO-4 and H226 cells. Furthermore, SOCS-1 gene delivery cooperated with cisplatin plus pemetrexed to regulate NF-κB signaling and significantly inhibit tumor growth of MPM in vivo. These results suggest that SOCS-1 gene delivery has a potent antitumor effect against MPM and a potential for clinical use in combination with cisplatin plus pemetrexed. PMID:22532243

  12. Increased treatment-related mortality with additional cisplatin-based chemotherapy in patients with nasopharyngeal carcinoma treated with standard radiotherapy

    International Nuclear Information System (INIS)

    Background and purposes: We performed a meta-analysis of randomized controlled trials (RCTs) to determine the overall risk of treatment-related death associated with additional cisplatin-based chemotherapy in patients with nasopharyngeal carcinoma treated with standard radiotherapy. Material and methods: Eligible studies included RCTs in which cisplatin-based chemotherapy in combination with radiotherapy was compared with radiotherapy alone. Statistical analyses were conducted to calculate the summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) using fixed- or random-effects models based on the heterogeneity of included studies. Results: A total of 2829 patients from 13 RCTs were included in this study. The overall incidence for treatment-related death in chemoradiotherapy and radiotherapy treated patients was 1.7% and 0.8%. Compared to radiotherapy alone, radiotherapy plus cisplatin-based chemotherapy significantly increased the risk of treatment-related mortality. On subgroup analyses, no difference was found in treatment-related mortality between different timings of chemotherapy and chemotherapeutic agents. Adding cisplatin-based chemotherapy was associated with higher incidences of severe acute toxicity. Conclusions: Cisplatin-based chemotherapy plus radiotherapy increased the risk of treatment-related death and severe acute toxicity, compared with radiotherapy alone. Better management of treatment toxicity might improve the therapeutic gain in patients with nasopharyngeal carcinoma.

  13. The Role of HER2 in Metastatic Breast Cancer Treated with a Combination of Taxanes and Cisplatin

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    Hung-Chih Hsu

    2009-02-01

    Full Text Available Background: A combination of taxanes and cisplatin have shown modest activity as second-line chemotherapy in breast cancer patients who have been exposed toanthracyclines. The purpose of this study was to retrospectively assesswhether HER2 is associated with clinical sensitivity or with prognostic significancein breast cancer patient groups who had received chemotherapywith taxanes and cisplatin.Methods: Patients were treated either with docetaxel 60 mg/m2 or paclitaxel 175 mg/m2in combination with cisplatin 50 mg/m2 every 3 weeks. The tumor specimenswere checked for estrogen receptor (ER, progestrone receptor (PR, andHER2 status by immunohistochemical stain. Prognostic factors such as performancestatus, status of metastases, history of prior anthracycline response,and biomarkers such as ER and HER2 were analyzed.Results: Ninety patients were eligible for HER2 assessment. Only eighty-five patientswere eligible for response assessment. The overall response rate tochemotherapy with the taxanes/cisplatin regimen was 52%. In patients whowere HER2-positive, the response rate was 62% and in HER2-negativepatients, it was 46%, p = 0.17. Univariate analysis showed no prognostic factorswere significant in predicting a response to chemotherapy. In addition, itappeared that there was no difference in time to progression and overall survivalbased on HER2 status.Conclusions: Our results indicated that HER2 status is independent of a response to a taxanes/cisplatin combination and is also not a prognostic factor for survival.

  14. A novel cisplatin mediated apoptosis pathway is associated with acid sphingomyelinase and FAS proapoptotic protein activation in ovarian cancer.

    Science.gov (United States)

    Maurmann, L; Belkacemi, L; Adams, N R; Majmudar, P M; Moghaddas, S; Bose, R N

    2015-07-01

    Platinum-based anticancer drugs, including cisplatin and carboplatin, have been cornerstones in the treatment of solid tumors. We report here that these DNA-damaging agents, particularly cisplatin, induce apoptosis through plasma membrane disruption, triggering FAS death receptor via mitochondrial (intrinsic) pathways. Our objectives were to: quantify the composition of membrane metabolites; and determine the potential involvement of acid sphingomyelinase (ASMase) in the FAS-mediated apoptosis in ovarian cancer after cisplatin treatment. The resulting analysis revealed enhanced apoptosis as measured by: increased phosphocholine, and glycerophosphocholine; elevated cellular energetics; and phosphocreatine and nucleoside triphosphate concentrations. The plasma membrane alterations were accompanied by increased ASMase activity, leading to the upregulation of FAS, FASL and related pro-apoptotic BAX and PUMA genes. Moreover FAS, FASL, BAX, PUMA, CASPASE-3 and -9 proteins were upregulated. Our findings implicate ASMase activity and the intrinsic pathways in cisplatin-mediated membrane demise, and contribute to our understanding of the mechanisms by which ovarian tumors may become resistant to cisplatin. PMID:25846011

  15. Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation

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    Ploner Ferdinand

    2006-01-01

    Full Text Available Abstract Background Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. Case presentation We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m2 of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. Conclusion To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects.

  16. Antioxidant and anti-inflammatory potential of pomegranate rind extract to ameliorate cisplatin-induced acute kidney injury.

    Science.gov (United States)

    Karwasra, Ritu; Kalra, Prerna; Gupta, Yogendra Kumar; Saini, Deepika; Kumar, Ajay; Singh, Surender

    2016-07-13

    Cisplatin is a chemotherapeutic agent, but the therapeutic utility is limited due to its dose dependent nephrotoxicity. The aim of the present study was to evaluate the nephroprotective effect of pomegranate in cisplatin-induced acute kidney injury. Wistar rats were allocated into six groups as follows: the normal control, cisplatin-induced, pomegranate rind extract treatment (50, 100 and 200 mg kg(-1)) and pomegranate rind extract per se group. All the experimental test drugs/vehicle were administered orally for a period of ten days. Intraperitoneal injection of cisplatin (8 mg kg(-1)) was administered on day 7 to all the groups except the normal control and pomegranate per se group. On day 10, cisplatin resulted in significant nephrotoxicity in Wistar rats with a drastic elevation of serum creatinine and BUN, a decline in the concentrations of GSH, MDA and superoxide dismutase (SOD), and an elevation in the TNF-α level in renal tissues. Pathological changes in renal tissues were examined by histopathology and dysfunction in mitochondria and proximal tubule cells was detected by transmission electron microscopy. The rate of apoptosis and the expression of caspase-3, Il-1β and IL-6 in rat renal tissues were detected by immunohistochemistry. The administration of pomegranate at a dose of 200 mg per kg body weight significantly (p stress and inflammation. PMID:27273121

  17. Comparative Efficacy of Cisplatin vs. Gemcitabine as Concurrent Chemotherapy for Untreated Locally Advanced Cervical Cancer: A Randomized Trail

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    Dr. Manoj Srivastava

    2007-01-01

    Full Text Available Cisplatin based chemo-radiation is considered the standard of care for most patients with locally advanced cervical cancer. Gemcitabine is a new pyrimidire analogue with high radio sensitizing potency in vitro. This study was undertaken to compare the anti-tumor activity and toxicity of the two drugs. It is a prospective randomized study of 60 patients histologically confirmed locally advanced cervical cancer, FIGO stage IIB - IIIB with no previous treatment. Patients were randomized to receive either weekly Cisplatin 40mg/m2 intravenously or Gemcitabine 100mg/m2 intravenously for 5 cycles concurrent with external beam radiation therapy 50Gy/25# as 5# / weeks, followed by single application of medium does rate intracavitory brachytherapy to deliver 20 Gy at point A, 2 weeks after completion of external beam radiation therapy (EBRT. Toxicity was graded according to WHO criteria. Both subjective and objective responses were measured six weeks after completion of treatment. In Cisplatin arm 28/30 (93.33% patients showed complete clinical regression of tumor whereas in Gemcitabine arm only 21/30 (70% patients showed complete clinical response. Thus immediate response was significantly higher in the cisplatin group as compared to the gemcitabine group (p=0.01. All toxicities except nausea and vomiting were more common and severe in patients receiving Gemcitabine with radiation. To conclude, Cisplatin appears to be better than Gemcitabine when used as a radio sensitizer for untreated locally advanced cervical cancer in terms of response and toxicity.

  18. Squalene Selectively Protects Mouse Bone Marrow Progenitors Against Cisplatin and Carboplatin-Induced Cytotoxicity In Vivo Without Protecting Tumor Growth

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    Bikul Das

    2008-10-01

    Full Text Available Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II (cisplatin-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato platinum(II (carboplatin-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin-treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage. Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathione peroxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity.

  19. Anion exchange chromatography for the determination of 5-methyl-2'-deoxycytidine: application to cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines.

    Science.gov (United States)

    Iglesias, Tamara; Espina, Marta; Montes-Bayón, María; Sierra, Luisa María; Blanco-González, Elisa

    2015-03-01

    Epigenetic alterations are increasingly implicated in the initiation and progression of cancer. Genome-wide (global) hypomethylation seems to occur in early neoplasia and is a feature of genomic DNA derived from solid tumour tissues like ovarian cancer. Thus, analytical methods that provide sensitive and quantitative information about cytosine methylation in DNA are currently required. In this work, we compare two different anion-exchange columns for the separation of methylated cytosine from the other DNA nucleotides: a silica-based (Tracer Extrasil SAX) column and a polystyrene/divinyl benzene-based (Mono-Q™) column. Under the optimised conditions, linearity range, precision and detection limits of the developed high-performance liquid chromatography (HPLC) method were evaluated and compared using conventional ultraviolet (UV) absorbance detection at 270 nm. Good separation of the five target nucleotides, including 5-methyl-2'-deoxycytidine monophosphate (5mdCMP) and 2'-deoxycytidine monophosphate (dCMP) was achieved on the Mono-Q™ column with a gradient elution of ammonium acetate buffer (1 M, pH 6.9) at a flow rate of 1 mL min(-1). The coupling of this column to inductively coupled plasma mass spectrometry (ICP-MS) permitted also phosphorous ((31)P) specific detection of the nucleotides. Both detection systems offered adequate analytical performance characteristics, with detection limits of 30 and 40 μg L(-1) for 5mdCMP by HPLC-UV and HPLC-ICP-MS, respectively. However, the latter method allowed the determination of the global DNA methylation level (%) without the need for external calibration. Different genomic DNA samples were analysed including calf thymus DNA and DNA from two human cancer cell lines (adenocarcinoma epithelial A549 and ovarian carcinoma A2780) using the proposed strategy. In the line A2780, the cisplatin-sensitive and cisplatin-resistant variants were analysed, finding no significant differences in the methylation percentage after

  20. Combined modality treatment of the rhabdomyosarcoma R1H of the rat: tumor and normal tissue response after cisplatin and conventional or accelerated irradiation treatment

    International Nuclear Information System (INIS)

    Purpose: To test the importance of the sequence of cisplatin and irradiation, either conventional or accelerated fractionated. Methods and Materials: 30 fractions of 2 Gy were given in 6 or 3 weeks preceded or followed by (time interval between cisplatin and radiotherapy: 3 days) a single IP dose of 5 mg/kg cisplatin in the rhabdomyosarcoma R1H of the rat. Survival curves were generated, and comparisons were made by the log-rank test. Results: After 60 Gy in 6 weeks, no local tumor controls were observed. If cisplatin was injected 3 days before start of 60 Gy/6 weeks, 11 ± 10% (mean ± SE) of the tumors were controlled. Cisplatin after radiotherapy resulted in 50 ± 14% local controls. The difference was significant (p 0.01) for cisplatin after radiotherapy in comparison to radiotherapy alone where no local controls were observed. After accelerated fractionation, 57 ± 19% of the animals were cured with or without cisplatin before radiotherapy. If the drug was injected after end of 60 Gy/3 weeks, 86 ± 13% survived recurrence free. The difference to accelerated radiotherapy alone was not significant. Accelerated radiotherapy produced significantly higher control rates than conventional radiotherapy (p < 0.001). Conclusions: Accelerated radiotherapy resulted in higher local tumor control rates as compared to conventional fractionated irradiation. Cisplatin combined with radiotherapy showed significantly better results if given after but not before irradiation, either conventional or accelerated fractionated

  1. The cytotoxic activity of cisplatin, carboplatin and teniposide alone and combined determined on four human small cell lung cancer cell lines by the clonogenic assay

    DEFF Research Database (Denmark)

    Roed, H; Vindeløv, L L; Christensen, I J; Spang-Thomsen, M; Hansen, H H

    1988-01-01

    Using the clonogenic assay to compare the cytotoxic activity of cisplatin and carboplatin on four human small cell lung cancer cell lines, cisplatin was shown to be equally or more potent than carboplatin at equitoxic doses with 1 h incubation. Increased potency of carboplatin was revealed when the...

  2. N′1,N′3-Dimethyl-N′1,N′3-bis(phenylcarbonothioyl Propanedihydrazide (Elesclomol Selectively Kills Cisplatin Resistant Lung Cancer Cells through Reactive Oxygen Species (ROS

    Directory of Open Access Journals (Sweden)

    Niramol Savaraj

    2009-12-01

    Full Text Available Cisplatin is an important chemotherapeutic agent in lung cancer treatment. The mechanism of drug resistance to cisplatin is complex and historically has been difficult to overcome. We report here that cisplatin resistant lung cancer cell lines possess high basal levels of reactive oxygen species (ROS when compared to normal cells and their parental cell counterparts. These resistant cells also have low thioredoxin (TRX levels which may be one of the contributory factors to high ROS. N′1,N′3-dimethyl-N′1,N'3-bis(phenylcarbonothioyl propanedihydrazide (elesclomol, an agent known to increase ROS is selectively toxic to cisplatin-resistant cells, while sparing normal cells and the parental counterpart. The cytotoxic effect of elesclomol in resistant cells is accompanied by further decreases in TRX and glutathione (GSH antioxidant systems, while opposite results were found in parental cells. The ID50 of elesclomol in cisplatin-resistant cells ranged from 5–10 nM, which is well within clinically achievable ranges. N-Acetylcysteine (NAC, which is known to neutralize ROS, can abolish the cytotoxic effect of elesclomol, suggesting that the cytotoxic effect results from increased ROS. Overall, our data suggest that elesclomol selectively kills cisplatin-resistant tumor cells through increased ROS. This agent may hold potential to overcome cisplatin resistance and should be further explored to treat patients who have failed cisplatin therapy.

  3. Real-time in situ monitoring via europium emission of the photo-release of antitumor cisplatin from a Eu-Pt complex.

    Science.gov (United States)

    Li, Hongguang; Lan, Rongfeng; Chan, Chi-Fai; Jiang, Lijun; Dai, Lixiong; Kwong, Daniel W J; Lam, Michael Hon-Wah; Wong, Ka-Leung

    2015-09-25

    A water-soluble light-responsive antitumor agent, PtEuL, based on a cisplatin-linked europium-cyclen complex has been synthesized and evaluated for controlled cisplatin release by linear/two-photon excitation in vitro with concomitant turn-on and long-lived europium emission as a responsive traceable signal. PMID:26257074

  4. SIRT1 overexpression decreases cisplatin-induced acetylation of NF-{kappa}B p65 subunit and cytotoxicity in renal proximal tubule cells

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    Jung, Yu Jin; Lee, Jung Eun; Lee, Ae Sin [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Lee, Sang Yong [Department of Diagnostic Radiology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Han, Myung Kwan [Department of Microbiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kim, Duk Hoon [Division of Forensic Medicine, National Forensic Service, Seoul (Korea, Republic of); Kim, Won, E-mail: kwon@jbnu.ac.kr [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of)

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer Cisplatin increases acetylation of NF-{kappa}B p65 subunit in HK2 cells. Black-Right-Pointing-Pointer SIRT1 overexpression decreases cisplatin-induced p65 acetylation and -cytotoxicity. Black-Right-Pointing-Pointer Resveratrol decreased cisplatin-induced cell viability through deacetylation of p65. -- Abstract: As the increased acetylation of p65 is linked to nuclear factor-{kappa}B (NF-{kappa}B) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-{kappa}B p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-{kappa}B during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-{kappa}B p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-{kappa}B through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.

  5. Use of an automated capillary DNA sequencer to investigate the interaction of cisplatin with telomeric DNA sequences.

    Science.gov (United States)

    Paul, Moumita; Murray, Vincent

    2012-03-01

    The determination of the sequence selectivity of DNA-damaging agents is very important in elucidating the mechanism of action of anti-tumour drugs. The development of automated capillary DNA sequencers with fluorescent labelling has enabled a more precise method for DNA sequence specificity analysis. In this work we utilized the ABI 3730 capillary sequencer with laser-induced fluorescence to examine the sequence selectivity of cisplatin with purified DNA sequences. The use of this automated machine enabled a higher degree of precision of both position and intensity of cisplatin-DNA adducts than previously possible with manual and automated slab gel procedures. A problem with artefact bands was overcome by ethanol precipitation. It was found that cisplatin strongly formed adducts with telomeric DNA sequences. PMID:21678458

  6. Decreased sensitivity of multidrug-resistant tumor cells to cisplatin is correlated with sorcin gene co-amplification

    International Nuclear Information System (INIS)

    A set of multidrug resistant (MDR) murine leukemia P388 sublines possessing 30-50-fold mdr1 gene amplification was obtained as a result of experimental chemotherapy with rubomycin, ruboxyl, vinblastine, vincristine, or combination of rubomycin and vincristine. Significant differences of developed MDR sublines in response to treatment with cisplatin, tiophosphamide, sarcolysin, and dopad were found. Strong correlation between drug sensitivity and a copy number of gene coding for 19-22 kDa calcium-binding sorcin gene co-amplification were hypersensitive to cisplatin and alkylating agents, the cell sublines showing amplification of sorcin DNA sequences did not possess such collateral sensitivity and even acquired cross-resistance. The dependence of sensitivity to cisplatin on sorcin gene co-amplification was confirmed by analysis of Djungarian hamster DM15 cell sublines that selected for MDR in vitro by colchicine. (author)

  7. Combined chemoradiotherapy with daily low-dose cisplatin in stage III non-small cell lung cancer. An interim report

    International Nuclear Information System (INIS)

    To improve the local control of stage III non-small cell lung cancer, we tried concurrent chemoradiotherapy with daily low-dose cisplatin during the first 5 weeks conventional radiotherapy. Ten consecutive patients with stage III non-small cell lung cancer were treated with chemoradiotherapy with 66 Gy in conventional fractionation and concurrent daily low-dose cisplatin (4 mg/m2), which was given 5 days per week (from Monday to Friday) for the first 5 weeks. There was no case with ≥grade 3 toxicity. The median survival was 14.6 months, and the 2-year local progression-free survival rate was 35%. Daily low-dose cisplatin combined with conventional radiotherapy was considered to be feasible and to have the possibility to offer better local control than radiotherapy alone in the treatment of stage III non-small cell lung cancer. (author)

  8. Evaluation of the synergetic radio-chemotherapy effects of the radio labelled cisplatin for the treatment of glioma

    International Nuclear Information System (INIS)

    The proposal of this work was to investigate the effect of the radioactive (NH3)2PtCl2, cis-diamminedichloroplatinum (II) or CDDP* on malignant glioma cells and verify if the low-dose continuous internal radio-chemotherapy would be able to produce additive effects. The antitumoral activity of CDDP* and the non labeled cisplatin, CDDP, were evaluated in glioblastoma. Cisplatin was cytotoxic for glioblastoma cells in a dose dependent manner. Treatment with CDDP*, (IC50 = 1.75 ± 0.07 μM), proved to be more potent than using just CDDP, (IC50 = 4.96 ± 0.40 μM). These results suggest that cisplatin is a very potent radiosensitizer evoking a supra additive effect. Internal radio-chemotherapy treatment based on CDDP* may be useful alternative to reduce the drug concentration required for effective inhibition of glioblastoma growth. (author)

  9. 5-Aminolevulinic acid protects against cisplatin-induced nephrotoxicity without compromising the anticancer efficiency of cisplatin in rats in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Yoshio Terada

    Full Text Available BACKGROUND/AIMS: Nephrotoxicity is a frequent and major limitation in cisplatin (CDDP-based chemotherapy. 5-Aminolevulinic acid (ALA is widely distributed in animal cells, and it is a precursor of tetrapyrole compounds such as heme that is fundamentally important in aerobic energy metabolism. The aim of this study is to evaluate the protective role of ALA in CDDP-induced acute kidney injury (AKI. METHOD: We used CDDP-induced AKI rat model and cultured renal tubular cells (NRK-52E. We divided four groups of rats: control, CDDP only, CDDP + ALA(post;(ALA 10 mg/kg + Fe in drinking water after CDDP, CDDP + ALA(pre & post. RESULT: CDDP increased Cr up to 6.5 mg/dl, BUN up to 230 mg/dl, and ALA significantly reduced these changes. ALA ameliorates CDDP-induced morphological renal damages, and reduced tubular apoptosis evaluated by TUNEL staining and cleaved caspase 3. Protein and mRNA levels of ATP5α, complex(COX IV, UCP2, PGC-1α in renal tissue were significantly decreased by CDDP, and ALA ameliorates reduction of these enzymes. In contrast, Heme Oxigenase (HO-1 level is induced by CDDP treatment, and ALA treatment further up-regulates HO-1 levels. In NRK-52E cells, the CDDP-induced reduction of protein and mRNA levels of mitochondrial enzymes was significantly recovered by ALA + Fe. CDDP-induced apoptosis were ameliorated by ALA + Fe treatment. Furthermore, we evaluated the size of transplantated bladder carcinoma to the rat skin, and ALA did not change the anti cancer effects of CDDP. CONCLUSION: These data suggested that the protective role of ALA in cisplatin-induced AKI is via protection of mitochondrial viability and prevents tubular apoptosis. Also there are no significant effects of ALA on anticancer efficiency of CDDP in rats. Thus, ALA has the potential to prevent CDDP nephrotoxicity without compromising its anticancer efficacy.

  10. An evaluation of the toxicity and bioaccumulation of cisplatin in the marine environment using the macroalga, Ulva lactuca

    International Nuclear Information System (INIS)

    The cytotoxic drug, cisplatin (cis-PtCl2(NH3)2), has been added to cultures of the marine macroalga, Ulva lactuca, under various experimental conditions. Both accumulation and internalisation over a 48 h period was greater when cisplatin was added to coastal sea water (salinity = 33) from a distilled water solution than when added to either sea water or estuarine water (salinity = 16.5) from a saline solution. This effect is attributed to the greater abundance of the more reactive monoaqua complex (cis-PtCl(OH2)(NH3)2+) in the distilled water solution and kinetic constraints on its conversion back to cis-PtCl2(NH3)2 in sea water. Despite its mode of action at the cellular level, cisplatin added up to concentrations of 150 nM did not incur a measurable reduction in the efficiency of photochemical energy conversion under any of experimental conditions tested. - Highlights: → This study is the first to examine the biogeochemistry and toxicity of a cytotoxic drug in the marine environment. → Cisplatin is accumulated and internalised by the marine macroalga, Ulva lactuca. → Accumulation is greater when the drug is administered from a distilled water solution than from a saline solution. → Results are consistent with the greater abundance of the more reactive aquated complexes in pure water. → Cisplatin is not phytotoxic to the alga over the concentration range (<150 nM) studied. - The cytotoxic drug, cisplatin, is accumulated and internalised by the marine macroalga, Ulva lactuca, but is not phytotoxic up to concentrations of 150 nM

  11. Inhibitory effect of celecoxib combined with cisplatin on growth of human tongue squamous carcinoma Tca8113 cell xenograft tumor

    Institute of Scientific and Technical Information of China (English)

    Weizhong Li; Xiaoyan Wang; Zuguo Li; Yanqing Ding

    2010-01-01

    Objective:The aim of this study was to observe the inhibitory effect of application of COX-2 inhibitor,celecoxib,combined with cisplatin on the growth of human tongue squamous carcinoma Tca8113 cell xenograft by animal experiment.Methods:The nude mice were transplanted subcutaneously with Tca 8113 cells,and then were administrated with celecoxib,cisplatin or celecoxib combined with cisplatin respectively,and were sacrificed after 35 days.The weight of xenograft was measured to calculate the tumor inhibition rate.The histological change was studied under light and electron microscope.The COX-2 protein expression was observed by immunohistological staining.And the COX-2 mRNA expression was determined by RT-PCR.Results:Celecoxib,the COX-2 inhibitor,could not only inhibit the growth of Tca8113 cell xenograft tumor and COX-2 protein expression,but also enhance the inhibitory effect cisplatin on xenograft tumor growth significantly.The tumor inhibition rates of celecoxib group,cisplatin group and celecoxib plus cisplatin group were 15.63%,37.50% and 82.81%respectively that was statistically significant compared to control group(P < 0.01).The combined application of celecoxib and dsplatin could inhibit tumor growth more significantly than that of separated application(P < 0.01).The inhibitory effect of celecoxib on COX-2 mRNA expression of Tca 8113 cell was weaker and not significant(P= 0.073).Conclusion:Celecoxib can not only inhibit xenograft tumor growth in nude mice,but also enhance the inhibitory effect of CDDP on Tca 8113 trans planted tumor growth in nude mice.The mechanism maybe related to inhibition of COX-2 protein expression,which offers beneficial reference to further explore the mechanism between inhibition of COX-2 enzyme activity and prevention of head and neck tumor.

  12. FOXO3a reactivation mediates the synergistic cytotoxic effects of rapamycin and cisplatin in oral squamous cell carcinoma cells

    International Nuclear Information System (INIS)

    FOXO3a, a well-known transcriptional regulator, controls a wide spectrum of biological processes. The Phosphoinositide-3-kinase (PI3K)/Akt signaling pathway inactivates FOXO3a via phosphorylation-induced nuclear exclusion and degradation. A loss or gain of FOXO3a activity has been correlated with efficiency of chemotherapies in various cancers including oral squamous cell carcinoma (OSCC). Therefore, in the current study, we have investigated the FOXO3a activity modulating and antitumor effects of rapamycin and cisplatin in OSCC cells. Cisplatin inhibited proliferation and induced apoptosis in a dose-dependent way in OSCC Tca8113 cells. Rapamycin alone had no effect on cell proliferation and apoptosis. Rapamycin downregulated the expression of S-phase kinase associated protein-2 (Skp2) and increased the FOXO3a protein stability but induced the upregulation of feedback Akt activation-mediated FOXO3a phosphorylation. Cisplatin decreased the phosphorylation of FOXO3a via Akt inhibition. Rapamycin combined with cisplatin as its feedback Akt activation inhibitor revealed the most dramatic FOXO3a nuclear localization and reactivation with the prevention of its feedback loop and exposed significant synergistic effects of decreased cell proliferation and increased apoptosis in vitro and decreased tumor size in vivo. Furthermore, the downstream effects of FOXO3a reactivation were found to be accumulation of p27 and Bim. In conclusion, rapamycin/cisplatin combination therapy boosts synergistic antitumor effects through the significant FOXO3a reactivation in OSCC cells. These results may represent a novel mechanism by which rapamycin/cisplatin combination therapy proves to be a potent molecular-targeted strategy for OSCC.

  13. Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance

    International Nuclear Information System (INIS)

    The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study, we have investigated the regulation of PTEN during cisplatin induced apoptosis in A2780, A270-CP (cisplatin resistant), OVCAR-3 and SKOV3 ovarian cancer cell lines. Cells were treated with 10μM of cisplatin for 24h. Transcript and protein levels were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, respectively. Immunofluorescence microscopy was used to assess the intracellular localization of PTEN. Proteasome inhibitor and various caspases inhibitors were used to find the mechanism of PTEN degradation. PTEN protein levels were found to be decreased significantly in A2780 cells; however, there was no change in PTEN protein levels in A2780-CP, OVCAR-3 and SKOV3 cells with cisplatin treatment. The decrease in PTEN protein was accompanied with an increase in the levels of AKT phosphorylation (pAKT) in A2780 cells and a decrease of BCL-2. Cisplatin treatment induced the activation/cleavage of caspase-3, -6, -7, -8, -9 in all cell lines tested in this study except the resistant variant A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-DEVD-FMK (broad range caspases inhibitor) and not with MG132 (proteasome inhibitor) and by overexpression of BCL-2, suggesting that caspases and BCL-2 are involved in the decrease of PTEN protein levels in A2780 cells. The decrease in pro-apoptotic PTEN protein levels and increase in survival factor pAKT in A2780 ovarian cancer cells suggest that cisplatin treatment could further exacerbate drug resistance in A2780 ovarian cancer cells

  14. Betaine supplementation mitigates cisplatin-induced nephrotoxicity by abrogation of oxidative/nitrosative stress and suppression of inflammation and apoptosis in rats.

    Science.gov (United States)

    Hagar, Hanan; Medany, Azza El; Salam, Reem; Medany, Gamila El; Nayal, Omina A

    2015-02-01

    Cisplatin is one of the most potent chemotherapeutic antitumor drugs used in the treatment of a wide range of solid tumors. Its primary dose-limiting side effect is nephrotoxicity. This study aims to investigate the effect of betaine supplementation on cisplatin-induced nephrotoxicity. A single intraperitoneal injection of cisplatin (5mg/kg) deteriorated the kidney functions as reflected by elevated blood urea nitrogen and serum creatinine levels. Oxidative/nitrosative stress was evident in cisplatin group by increased renal thiobarbituric acid-reactive substances (TBARS), an indicator of lipid peroxidation, reduced renal total antioxidant status and increased renal nitrite concentration. Cisplatin resulted in a decline in the concentrations of reduced glutathione, glutathione peroxidase, catalase, and superoxide dismutase in renal tissues. Renal tumor necrosis factor-α (TNF-α) was also elevated. Expressions of nuclear factor-kappa B (NF-κB) and caspase-3 were up-regulated in renal tissues as indicated by immunohistochemical analysis. Histopathological changes were observed in cisplatin group. Betaine supplementation (250 mg/kg/day) orally via gavage for 21 days prior to cisplatin injection was able to protect against deterioration in kidney function, abrogate the decline in antioxidants enzymes and suppressed the increase in TBARS, nitrite and TNF-α concentrations. Moreover, betaine inhibited NF-κB and caspase-3 activation and improved the histological changes induced by cisplatin. Thus, the present study demonstrated the renoprotective nature of betaine by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in kidney tissues of cisplatin treated rats. Betaine could be a beneficial dietary supplement to attenuate cisplatin nephrotoxicity. PMID:25488130

  15. Amniotic Fluid-Derived Mesenchymal Stem Cells Cut Short the Acuteness of Cisplatin-Induced Nephrotoxicity in Sprague-Dawley Rats

    Science.gov (United States)

    Al-Husseiny, Fatma; Sobh, Mohamed Ahmed; Ashour, Rehab H.; Foud, Samah; Medhat, Tarek; El-Gilany, Abdel-Hady; Elghannam, Doaa; Abdel-Ghaffar, Hassan; Saad, Mohamed-Ahdy; Sobh, Mohamed

    2016-01-01

    Background and objectives Cisplatin is a nephrotoxic chemotherapeutic agent. So, preventive measures worth to be evaluated. Human amniotic fluid stem cells (hAFSCs) in prevention or amelioration of cisplatin-induced acute kidney injury (AKI) in Sprague-Dawley rates have been tested. Methods 80 Sprague-Dawley rats (250~300 g) were used and divided into 4 major groups, 20 rats each. Group I: Saline-injected group. Group II: Cisplatin-injected group (5 mg/kg I.P). Group III: Cisplatin-injected and hAFSCs-treated group (5×106 hAFSCs I.V. one day after cisplatin administration). Group IV: Cisplatin-injected and culture media-treated group. Each major group was further divided into 4 equal subgroups according to the timing of sacrifice; 4, 7, 11 and 30 days post-cisplatin injection. Renal function tests were done. Kidney tissue homogenate oxidative stress parameters malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were determined. Histopathological scoring systems for active injury, regenerative and chronic changes were analyzed separately. Results hAFSCs characterization and differentiation was proved. Cisplatin injection resulted in a significant increase in serum creatinine and MDA and decrease in SOD, GSH and creatinine clearance. These changes were attenuated early by day 4 with the use of hAFSCs. Cisplatin injection induced tubular necrosis, atrophy, inflammatory cells infiltration and fibrosis. The use of hAFSCs was associated with significantly lowered injury score at day 4, 7, 11 and 30 with marked regenerative changes starting from day 4. Conclusion hAFSCs have both a protective and regenerative activities largely through an antioxidant activity. This activity cut short the acuteness of cisplatin nephrotoxicity. PMID:27426088

  16. Improvement in intraperitoneal intraoperative cisplatin exposure based on pharmacokinetic analysis in patients with ovarian cancer.

    Science.gov (United States)

    Royer, Bernard; Delroeux, Delphine; Guardiola, Emmanuel; Combe, Marielle; Hoizey, Guillaume; Montange, Damien; Kantelip, Jean-Pierre; Chauffert, Bruno; Heyd, Bruno; Pivot, Xavier

    2008-03-01

    Ovarian cancer is the leading cause of gynecological cancer-related death in Western countries. The present treatment standards for ovarian cancer are based on the association of debulking surgery with platinum-based chemotherapy. Another strategy that could be further investigated is intraperitoneal chemotherapy (IP). We previously described that the 2-h administration of intraoperative IP cisplatin did not reach satisfactory concentrations. In the present study, we present the results of a pharmacokinetic analysis performed after two consecutive 1-h IP 30 mg/l cisplatin administrations. Twenty-seven patients with advanced epithelial cancer classified FIGO stage IIIC were included in the study. Blood and IP samples were taken over a 24-h period, during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentration levels were analyzed. Biological and clinical toxicities were also recorded. With this strategy, IP Pt concentrations stayed above the target concentration (10 mg/l) for a satisfactory length of time. The serum Pt concentrations were higher than those observed with the "one-bath" protocol and they induced the occurrence of recoverable renal toxicities (3 grade 1, 7 grade 2 and 4 grade 3). The best predictive parameter for renal failure was the total Pt 24-h Area Under the Curve (AUC) with a threshold value of 25 mg h/l RR = 0.31 (95% CI 0.13 - 0.49, P amount of cisplatin is feasible and a satisfactory level of IP Pt concentrations is obtained. However, this improvement is associated with an increase in serum Pt levels and resulting renal toxicities. An attractive solution would be to decrease Pt transfer from peritoneum to bloodstream. A phase 1 study using intraoperative IP epinephrine in order to decrease this transfer is presently being carried out. PMID:17503047

  17. 5-Fluorouracil, folinic acid and cisplatin in advanced colorectal cancer: a pilot study.

    Science.gov (United States)

    Tsavaris, N; Tentas, K; Bacoyiannis, C; Katsikas, M; Sakelaropoulos, N; Kosmas, C; Daliani, D; Kosmidis, P

    1995-08-01

    The combination of 5-fluorouracil (5-FU) and folinic acid (FA) has demonstrated activity in colorectal cancer (CC). Cisplatin is reported to have synergistic activity with 5-FU. We examined the combination FA + 5-FU + cisplatin in patients who had previously received chemotherapy with FA + 5-FU and relapsed. Two months after the last dose of FA + 5-FU and documentation of relapse, patients continued with the regimen consisting of cisplatin 20 mg/m2 in 15 min i.v. infusion followed by FA 500 mg/m2 in 1 h i.v. infusion, in the middle of which 5-FU 500 mg/m2 i.v. bolus was administered, with adequate post-hydration. This was repeated weekly for 4 weeks followed by a 2 week rest, for a maximum of six cycles. A total of 30 patients with CC that had relapsed to the combination of FA + 5-FU were treated; 23 had previous surgery and none had radiotherapy. Local recurrence was found in eight patients, metastases in the liver in 21, in lymph nodes in six, lung six and peritoneal metastases in seven. Seven patients responded partially. Toxicity requiring dose reduction or discontinuation of treatment included neutropenia 42% (grade 3:7%), mucositis 28% (grade 1:2), diarrhea 63% (Grade 3:10%), nausea-vomiting 55% (Grade 3:10%), increased creatinine value in three patients and peripheral neuropathy in two patients. We conclude that evaluation of this regimen shows substantial toxicity, with satisfactory response as a second line chemotherapy in these heavily pretreated patients. PMID:7579565

  18. Transarterial infusion chemotherapy with cisplatin plus S-1 for hepatocellular carcinoma treatment: a phase I trial

    International Nuclear Information System (INIS)

    In Japan, transarterial infusion chemotherapy using cisplatin (CDDP-TAI) is frequently used for advanced hepatocellular carcinoma (HCC). Moreover, oral chemotherapy with S-1, an oral fluoropyrimidine derivative, has also elicited promising responses in HCC patients. We determined the recommended dosage for CDDP-TAI plus S-1 combination therapy for advanced HCC. Twelve Child–Pugh class A or B patients with advanced HCC who met the eligibility criteria were enrolled in this phase I trial. Patients received CDDP-TAI (infusion, day 1) plus S-1 (oral administration, days 1–21) every 5 weeks until disease progression. Cisplatin (65 mg/m2) was administered with S-1 at 50 mg · m-2 day-1 (level 1, 3 patients), 60 mg · m-2 day-1 (level 2, 3 patients), or 80 mg · m-2 day-1 (level 3, 6 patients). The total number of treatment courses was 25 (median, 2 courses/patient; range, 1–6 courses). Dose-limiting toxicity was not observed in any patient at any level; therefore, the recommended dosage for cisplatin and S-1 in combination was level 3. Grade 3 adverse events were elevated alanine aminotransferase levels (2 patients), elevated aspartate aminotransferase levels (2 patients), anemia (1 patient), and decreased platelet counts (1 patient). Median progression-free survival and overall survival were 73 days and 328 days, respectively. The disease control rate was 58% (7/12); 17% (2/12) of patients achieved partial response and 42% (5/12) achieved stable disease. CDDP-TAI plus S-1 is safe for the treatment of HCC. The recommended dosage for further evaluation of this combination therapy in phase II studies is 65 mg/m2 CDDP and 80 mg/m2 S-1. UMIN; number: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function

  19. EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Haslehurst Alexandria M

    2012-03-01

    Full Text Available Abstract Background The epithelial to mesenchymal transition (EMT is a molecular process through which an epithelial cell undergoes transdifferentiation into a mesenchymal phenotype. The role of EMT in embryogenesis is well-characterized and increasing evidence suggests that elements of the transition may be important in other processes, including metastasis and drug resistance in various different cancers. Methods Agilent 4 × 44 K whole human genome arrays and selected reaction monitoring mass spectrometry were used to investigate mRNA and protein expression in A2780 cisplatin sensitive and resistant cell lines. Invasion and migration were assessed using Boyden chamber assays. Gene knockdown of snail and slug was done using targeted siRNA. Clinical relevance of the EMT pathway was assessed in a cohort of primary ovarian tumours using data from Affymetrix GeneChip Human Genome U133 plus 2.0 arrays. Results Morphological and phenotypic hallmarks of EMT were identified in the chemoresistant cells. Subsequent gene expression profiling revealed upregulation of EMT-related transcription factors including snail, slug, twist2 and zeb2. Proteomic analysis demonstrated up regulation of Snail and Slug as well as the mesenchymal marker Vimentin, and down regulation of E-cadherin, an epithelial marker. By reducing expression of snail and slug, the mesenchymal phenotype was largely reversed and cells were resensitized to cisplatin. Finally, gene expression data from primary tumours mirrored the finding that an EMT-like pathway is activated in resistant tumours relative to sensitive tumours, suggesting that the involvement of this transition may not be limited to in vitro drug effects. Conclusions This work strongly suggests that genes associated with EMT may play a significant role in cisplatin resistance in ovarian cancer, therefore potentially leading to the development of predictive biomarkers of drug response or novel therapeutic strategies for

  20. Phospholipid flippase associates with cisplatin resistance in plasma membrane of lung adenocarcinoma A549 cells

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The fusion of the liposomes containing N-(7-nitro-2, 1, 3-benzoxadiazol-4-yl)-i ,2-hexadecanoylSn-glycero-3-1abeled phosphatidylethanolamine (NBD-PE) with A549 and A549/DDP cells was performed, and the activity of the phospholipid flippase in the plasma membrane of the cells was measured by fluorescence intensity change of NBDPE in the outer membrane. When A549 or A549/DDP cells containing N BD-PE were incubated at 37 C for 0, 30, 60 and 90 min, the fluorescence intensities in the outer membrane of the cells were 0%, 1.4%, 2.9% and 7.8% for A59cells, and 0%, 10.5 %, 15. 5 % and 18.3 % for A549/DDP cells respectively, demonstrating that the phospholipid flippase was distributed in the plasma membrane of As49 cells, but its activity in the drug-resistant A549/DDP cells was much higher than that in the A549 cells. When the A549/DDP cells were incubated with a multidrug resistance reverse agent, verapamil, for 60 min at 37C, the results showed that the NBD-PE in outer membrane decreased by 25.0% compared with the control's. Furthermore, when A549/DDP cells were incubated with 25 μmol/L cisplatin, which is a specific anticancer drug, the flippase activity decreased by 31.6%, and it further decreased with the increase of cisplatin concentration, suggesting that phospholipid flippase in the membrane might be related to the cisplatin-resistance of human lung adenocarcinoma cancer cells.

  1. siRNA-mediated downregulation of TC21 sensitizes esophageal cancer cells to cisplatin

    Institute of Scientific and Technical Information of China (English)

    Md.Raghibul Hasan; Shyam Singh Chauhan; Rinu Sharma; Ranju Ralhan

    2012-01-01

    AIM:To determine the functional significance of TC21 in esophageal squamous cell carcinoma (ESCC).METHODS:TC21 siRNA transfection was carried out using Hyperfectamine to knock down TC21,and transcripts were analyzed by reverse transcription-polymerase chain reaction and protein by Western blotting.We demonstrated the effect of TC21 downregulation of cell signaling in esophageal cancer cells by assessing the phosphorylation status of its downstream targets,phosphoinositide 3-kinase (PI3K),phosphatase and tensin homolog (PTEN),protein kinase B (pAkt),nuclear factor-κB (NF-κB) and cyclinD1 using specific antibodies.Cell survival analysis after cisplatin treatment was carried out by cell viability assay and cell cycle analysis using flow cytometry.RESULTS:TC21 knockdown in human ESCC cell line TE13 cells,showed only a marginal increase (14.2%) in cell death compared with control cells.The expressions of the signaling proteins PI3K and pAkt,transcription factor NF-κB,and cell cycle protein cyclin D1 were markedly decreased in response to TC21 downregulation,whereas the level of pPTEN,an antagonist of PI3K,was increased.In addition,we evaluated the potential of TC21 as a putative target for sensitizing ESCC cells to the chemotherapeutic agent dsplatin.Increased cell death (38.4%) was observed in cells treated with cisplatin after TC21 knockdown compared with cells which were treated with cisplatin alone (20% cell death).CONCLUSION:Results suggest that TC21 mediates its effects via the PI3K-Akt pathway,NF-κB and cydin D1,and enhances chemoresistance in esophageal cancer cells.

  2. Attenuation of cisplatin induced ototoxicity by sound preonditioning through NO pathway

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective:To explore the protective effect of sound preconditioning against ototoxicity induced by cisplatin and its possible mechanism with respect to the nitric oxide (NO) pathway. Methods:Albino guinea pigs were divided into silent control, CDDP,sound preconditioning and sound preconditioning+CDDP groups. The animals of the CDDP group were injected with cisplatin intravenously 8 mg/kg b.w. The animals in the sound preconditioning were exposed to white noise at 85dB SPL, 5h/d, for 10 d (sound preconditioning). The animals in the sound preconditioning+CDDP group were treated with sound preconditioning first and then administrated with cisplatin intravenously 8 mg/kg b.w. Hearing thresholds of auditory brainstem responses (ABRs) of all animals were measured to evaluate hearing function. Hair cell loss was estimated via surface preparation. Cochlear tissue was assayed for measurement of NO level and immunohistochemistry method was used for inducible nitric oxide synthase (iNOS) analysis. Results:There was no significant difference between the silent control and sound preconditioning animals with respect to either functional or histological measures. Among the animals in the CDDP group, there was a significant elevation of threshold at the high test frequencies after administration compared with the silent control group (P<0.05). Morphological examination showed that there was obvious loss of the OHC, especially in the third row of the basal turn. The NO level and immunoreactivity to iNOS in this group were higher and more intensive than those of the silent control group (P<0.05). The ABR thresholds in the sound preconditioning + CDDP group were much lower than those of the CDDP group (P<0.05). Slight sporadic loss of OHC was found in this group. The immunoreactivity to iNOS and the level of NO in cochlea decreased significantly compared with the CDDP group (P<0. 05). Conclusion:It is suggested that sound preconditioning, to some extent, provides protective

  3. Identification of platform-independent gene expression markers of cisplatin nephrotoxicity.

    OpenAIRE

    Thompson, Karol L.; Afshari, Cynthia A; Amin, Rupesh P; Bertram, Timothy A; Car, Bruce; Cunningham, Michael; Kind, Clive; Kramer, Jeffrey A; Lawton, Michael; Mirsky, Michael; Naciff, Jorge M; Oreffo, Victor; Pine, P Scott; Sistare, Frank D.

    2004-01-01

    Within the International Life Sciences Institute Committee on Genomics, a working group was formed to focus on the application of microarray technology to preclinical assessments of drug-induced nephrotoxicity. As part of this effort, Sprague-Dawley rats were treated with the nephrotoxicant cisplatin at doses of 0.3-5 mg/kg over a 4- to 144-hr time course. RNA prepared from these animals was run on a variety of microarray formats at multiple sites. A set of 93 differentially expressed genes a...

  4. /sup 131/I-Orthoiodohippurate clearance in the detection of cisplatin nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Hengst, W.; Wieler, H.; Rabs, U.; Buerger, R.A.

    1985-06-01

    In this study, 26 patients were treated with 20 mg cisplatin (CP)/m/sup 2/ body surface daily for 5 days as part of a combination therapy for testicular cancer. Simultaneously a vigorous hyperhydration (3000 ml daily) was applied to reduce the nephrotoxic effect induced by the drug. sup(/sup 131/I)-orthoiodophippurate clearance values obtained by the modified method of Oberhausen did not show any significant evidence of tubular dysfunction after therapy. These results may have been due to the vigorous hydration as well as to the youth of the patients.

  5. 131I-orthoiodohippurate clearance in the detection of cisplatin nephrotoxicity

    International Nuclear Information System (INIS)

    In this study, 26 patients were treated with 20 mg cisplatin (CP)/m2 body surface daily for 5 days as part of a combination therapy for testicular cancer. Simultaneously a vigorous hyperhydration (3000 ml daily) was applied to reduce the nephrotoxic effect induced by the drug. sup(131I)-orthoiodophippurate clearance values obtained by the modified method of Oberhausen did not show any significant evidence of tubular dysfunction after therapy. These results may have been due to the vigorous hydration as well as to the youth of the patients. (orig.)

  6. A Randomized Trial Comparing Cisplatin Plus 5-fluorouracil With or Without Levamisole in Operable Gastric Cancer

    OpenAIRE

    Choi, Jong Soo; Lee, Kyoo Hyung; Ahn, Myung Ju; Lee, Jung Shin; Lee, Je Han; ZANG, DAE YOUNG; Suh, Chel Won; Kim, Sang We; Kim, Woo Gun; Kim, Jin Cheon; Kim, SukKoo; Park, Kun Choon; Lee, Moo Song; Kim, Sang-Hee

    1997-01-01

    Objectives To determine the effectiveness and toxicity when levamisole was added to the adjuvant combination chemotherapy in patients with operable gastric cancer. Methods After en bloc resection of gastric cancer without gross or microscopic evidence of residual disease from April 1991 to December 1992, 100 patients were randomized to 6 months of 5-fluorouracil 1,000mg/m2/day administered as continous infusion for 5 days, cisplatin 60mg/m2/day as intravenous infusion for 1 day with or withou...

  7. 4-Aminoantipyrine reduces toxic and genotoxic effects of doxorubicin, cisplatin, and cyclophosphamide in male mice.

    Science.gov (United States)

    Berno, Claudia Rodrigues; Rós, Barbara de Toledo; da Silveira, Ingridhy Ostaciana Maia Freitas; Coelho, Henrique Rodrigues; Antoniolli, Andréia Conceição Milan Brochado; Beatriz, Adilson; de Lima, Dênis Pires; Monreal, Antônio Carlos Duenhas; Sousa, Fabricio Garmus; da Silva Gomes, Roberto; Oliveira, Rodrigo Juliano

    2016-07-01

    The analgesic drug dipyrone is used to treat side effects (including pain and fever) of cancer chemotherapeutic agents. Dipyrone is metabolized to 4-aminoantipyrine (4-AA), a PGE2-dependent blocker and inhibitor of cyclooxygenase (COX). We evaluated the genotoxic, mutagenic, apoptotic, and immunomodulatory activities of 4-AA in vivo and the effects of its combination with the antineoplastic drugs doxorubicin, cisplatin, and cyclophosphamide. 4-AA did not cause genotoxic/mutagenic damage, splenic phagocytosis, or leukocyte alterations. However, when combined with the antineoplastic agents, 4-AA decreased their genotoxic, mutagenic, apoptotic, and phagocytic effects. These results suggest that 4-AA might interfere with DNA damage-mediated chemotherapy. PMID:27402479

  8. L-shell x-ray fluorescence computed tomography (XFCT) imaging of Cisplatin

    International Nuclear Information System (INIS)

    X-ray fluorescence computed tomography (XFCT) imaging has been focused on the detection of K-shell x-rays. The potential utility of L-shell x-ray XFCT is, however, not well studied. Here we report the first Monte Carlo (MC) simulation of preclinical L-shell XFCT imaging of Cisplatin. We built MC models for both L- and K-shell XFCT with different excitation energies (15 and 30 keV for L-shell and 80 keV for K-shell XFCT). Two small-animal sized imaging phantoms of 2 and 4 cm diameter containing a series of objects of 0.6 to 2.7 mm in diameter at 0.7 to 16 mm depths with 10 to 250 µg mL−1 concentrations of Pt are used in the study. Transmitted and scattered x-rays were collected with photon-integrating transmission detector and photon-counting detector arc, respectively. Collected data were rearranged into XFCT and transmission CT sinograms for image reconstruction. XFCT images were reconstructed with filtered back-projection and with iterative maximum-likelihood expectation maximization without and with attenuation correction. While K-shell XFCT was capable of providing an accurate measurement of Cisplatin concentration, its sensitivity was 4.4 and 3.0 times lower than that of L-shell XFCT with 15 keV excitation beam for the 2 cm and 4 cm diameter phantom, respectively. With the inclusion of excitation and fluorescence beam attenuation correction, we found that L-shell XFCT was capable of providing fairly accurate information of Cisplatin concentration distribution. With a dose of 29 and 58 mGy, clinically relevant Cisplatin Pt concentrations of 10 µg mg−1 could be imaged with L-shell XFCT inside a 2 cm and 4 cm diameter object, respectively. (paper)

  9. Electrochemical activity of cis-platinated DNA and its utilization in protein-DNA binding studies

    Czech Academy of Sciences Publication Activity Database

    Pivoňková, Hana; Havran, Luděk; Vidláková, Pavlína; Horáková Brázdilová, Petra; Těsnohlídková, Lucie; Fojta, Miroslav

    Glasgow, 2009. S205_009. [42nd IUPAC Congress - Chemistry Solutions. 02.08.2009-07.08.2009, Glasgow] R&D Projects: GA ČR(CZ) GP204/07/P476; GA MŠk(CZ) LC06035; GA AV ČR(CZ) IAA500040701; GA AV ČR(CZ) 1QS500040581 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : cis-platin * DNA modification * electrochemical technique Subject RIV: BO - Biophysics

  10. Effect of Smac in combination with cisplatin on esophageal cancer cell line ECA109

    OpenAIRE

    Hou, Liang; Chen, Kang; Hao, Yingtao; Zhao, Yunpeng; Sun, Qifeng; Zhao, Xiaogang; Peng, Chuanliang

    2015-01-01

    Objective: This study was to investigate inhibiting effect of structurally unique Second mitochondria-derived activator of caspase (Smac) in combination with cisplatin on esophageal cancer cell line ECA109. Methods: PcDNA3.1-Smac (ECA109/Smac group), pcDNA3.1 (ECA109/neo group) and PBS (ECA109 or control group) were transfected into ECA109 cells respectively, and transfected cells which expressed Smac stably were got. Smac protein expression was analyzed by Western blot. The invasive ability ...

  11. Platinum(IV) complex with adamantylamine overcomes intrinsic resistance to cisplatin in ovarian cancer cells

    Czech Academy of Sciences Publication Activity Database

    Horváth, Viktor; Blanářová, Olga; Šindlerová, Lenka; Souček, Karel; Hofmanová, Jiřina; Sova, Petr; Kroutil, Aleš; Fedoročko, P.; Kozubík, Alois

    Bratislava : Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, 2006 - (Boháčová, V.; Breier, A.; Zbyňovská, D.; Zliechovec, J.). s. 296-296 ISBN 80-969532-6-5. [Biochemický zjazd /20./. 12.09.2006-16.09.2006, Piešťany] R&D Projects: GA AV ČR(CZ) 1QS500040507; GA MPO(CZ) PZ-Z2/29 Institutional research plan: CEZ:AV0Z50040507 Keywords : ovarian cancer * cisplatin * resistance Subject RIV: BO - Biophysics

  12. Adducts of cisplatin formed in human telomeric sequences destabilize G-quadruplexes

    Czech Academy of Sciences Publication Activity Database

    Heringová, Pavla; Kašpárková, Jana; Brabec, Viktor

    Debrecen, 2009. s. 80. ISBN 978-963-473-307-2. [10th International Symposium on Applied Bioinorganic Chemistry. 25.09.2009-28.09.2009, Debrecen] R&D Projects: GA MŠk(CZ) LC06030; GA MŠk(CZ) ME08017; GA AV ČR(CZ) 1QS500040581; GA AV ČR(CZ) KAN200200651; GA AV ČR(CZ) IAA400040803 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : cisplatin * G-quadruplex * telomere Subject RIV: BO - Biophysics

  13. Gemcitabine and cisplatin in locally advanced and metastatic bladder cancer; 3- or 4-week schedule?

    DEFF Research Database (Denmark)

    Als, Anne Birgitte; Sengeløv, Lisa; Von Der Maase, Hans

    2008-01-01

    BACKGROUND: Chemotherapy with gemcitabine and cisplatin (GC) is an active regimen in advanced transitional cell carcinoma (TCC). Traditionally, GC has been administered as a 4-week schedule. However, an alternative 3-week schedule may be more feasible. Long-term survival data for the alternative 3......-week schedule and comparisons of the feasibility and toxicity between the two schedules have not previously been published. MATERIAL AND METHODS: We performed a retrospective analysis of patients with stage IV TCC, treated with GC by a standard 4-week or by an alternative 3-week schedule. RESULTS: A...

  14. Epigallocatechin-3-gallate protects against cisplatin nephrotoxicity by inhibiting the apoptosis in mouse

    OpenAIRE

    Zou, Peimei; Song, Jian; Jiang, Bei; Pei, Fei; Chen, Binbin; Yang, Xiangdong; Liu, Guangyi; HU, ZHAO

    2014-01-01

    Cisplatin (CP) is a commonly used anticancer drug, but its notable side effect of nephrotoxicity limits its use in clinic. Epigallocatechin-3-gallate (EGCG), an anti-oxidant, anti-inflammatory, and anti-tumorigenic green tea polyphenol, has been available on the market for its beneficial effects. The aim of this study was to investigate whether EGCG can prevent the nephrotoxic effect of CP and the involved mechanisms. Male C57/BL6 mice were randomly divided into four groups: control group, EG...

  15. Vinorelbine and cisplatin combined with endostatin as the first-line therapy for metastatic pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Objective Systemic chemotherapy for metastatic pancreatic cancer is still a difficult problem in clinical practice.The standard chemotherapy of pancreatic cancer has been gemcitabine,but the response rate is low.Therefore,it is in urgent need to explore an effective clinical therapy for this cancer.This paper,a case report,is aimed at discussing the effectiveness of vinorelbine and cisplatin combined with endostatin as the first-line therapy for metastatic pancreatic cancer.Methods A 52-year-old female pati...

  16. Potential Antitumor Dendrimers: Synthesis and Characterizations of Rhenium(Ⅰ) and Cis-platin Containing Dendrimers

    Institute of Scientific and Technical Information of China (English)

    Zhao Xinxin; Chit-Kay Chu

    2005-01-01

    @@ 1Introduction The chemistry of dendrimers is a fast developing field and has brought about a tsunami of research activity since Vogtle reported the first preparation in 1978. These hyperbranched macromolecules have grown out of chemists' imagination and have challenged synthetic chemists with their architectural complexity and intriguity. The potentials of these macromolecules are extensive and are synthesized using both organic and inorganic cores from which different scaffoldings are built, and upon which functionalities are attached for specific applications. The synthesis and characterizations of cisplatin and rhenium(Ⅰ) containing PAMAM derivatives will be discussed.

  17. The effects of aspirin plus cisplatin on SGC7901/CDDP cells in vitro

    OpenAIRE

    DONG, HANZHANG; LIU, GAOGAO; Jiang, Biao; GUO, JIUBING; TAO, GUOQUAN; YIU, WEI; Zhou, Jingsong; Li, Guoxin

    2014-01-01

    The purpose of this study was to determine the effect of aspirin plus cisplatin (CDDP) in the chemotherapy of gastric cancer. We cultured SGC7901/CDDP cells by long-term exposure of SGC7901 cells to small doses of CDDP in vitro. The cells were treated with aspirin, CDDP or aspirin plus CDDP for 24 h and cell growth was assessed by the MTT assay, the apoptotic rate by flow cytometry, the survivin mRNA expression by RT-PCR and the survivin protein expression by western blotting. The results rev...

  18. Core-shell polymer nanoparticles for prevention of GSH drug detoxification and cisplatin delivery to breast cancer cells

    Science.gov (United States)

    Surnar, Bapurao; Sharma, Kavita; Jayakannan, Manickam

    2015-10-01

    Platinum drug delivery against the detoxification of cytoplasmic thiols is urgently required for achieving efficacy in breast cancer treatment that is over expressed by glutathione (GSH, thiol-oligopeptide). GSH-resistant polymer-cisplatin core-shell nanoparticles were custom designed based on biodegradable carboxylic functional polycaprolactone (PCL)-block-poly(ethylene glycol) diblock copolymers. The core of the nanoparticle was fixed as 100 carboxylic units and the shell part was varied using various molecular weight poly(ethylene glycol) monomethyl ethers (MW of PEGs = 100-5000 g mol-1) as initiator in the ring-opening polymerization. The complexation of cisplatin aquo species with the diblocks produced core-shell nanoparticles of 75 nm core with precise size control the particles up to 190 nm. The core-shell nanoparticles were found to be stable in saline solution and PBS and they exhibited enhanced stability with increase in the PEG shell thickness at the periphery. The hydrophobic PCL layer on the periphery of the cisplatin core behaved as a protecting layer against the cytoplasmic thiol residues (GSH and cysteine) and exhibited polycaprolactone (PCL)-block-poly(ethylene glycol) diblock copolymers. The core of the nanoparticle was fixed as 100 carboxylic units and the shell part was varied using various molecular weight poly(ethylene glycol) monomethyl ethers (MW of PEGs = 100-5000 g mol-1) as initiator in the ring-opening polymerization. The complexation of cisplatin aquo species with the diblocks produced core-shell nanoparticles of 75 nm core with precise size control the particles up to 190 nm. The core-shell nanoparticles were found to be stable in saline solution and PBS and they exhibited enhanced stability with increase in the PEG shell thickness at the periphery. The hydrophobic PCL layer on the periphery of the cisplatin core behaved as a protecting layer against the cytoplasmic thiol residues (GSH and cysteine) and exhibited <5% of drug

  19. Co-expression of ING4 and P53 enhances hypopharyngeal cancer chemosensitivity to cisplatin in vivo.

    Science.gov (United States)

    Ren, Xin; Liu, Hao; Zhang, Mingjie; Wang, Mengjun; Ma, Shiyin

    2016-09-01

    Hypopharyngeal cancer is a distinct type of malignant head and neck tumor, which exhibits low sensitivity to anti-cancer drugs. The importance of developing methods for reducing chemotherapy resistance, and improving and enhancing prognosis has previously been emphasized and is considered a challenge for effective clinical treatment of hypopharyngeal cancer. The current study investigated the effects of co‑expression of inhibitor of growth protein 4 (ING4) and P53, a tumor suppressor gene, on chemosensitivity to cisplatin in human hypopharyngeal cancer xenografts in vivo, and the potential molecular mechanisms involved. A tumor model was established by injecting athymic nude mice with FADU human hypopharyngeal cancer cells. Five days after intratumoral and peritumoral injections of an empty adenoviral vector (Ad), Ad‑ING4‑P53, cisplatin, or a combination of Ad‑ING4‑P53 and cisplatin (Ad‑ING4‑P53 + cisplatin) every other day for 5 days, the mice were euthanized and their tumors, livers, and kidneys were removed. The tumor weights were used to calculate the inhibition rate, and the expression levels of ING4 and P53 were detected by reverse transcription‑polymerase chain reaction. Additionally, apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunohistochemistry determined the levels ING4, P53, B‑cell lymphoma‑2 (Bcl‑2) and Bcl‑2 associated X protein (Bax) protein expression. The results demonstrated increased expression of ING4 and P53 in the Ad‑ING4‑P53 groups compared with PBS and Ad groups, indicating successful introduction of the genes into the tumor cells. Notably, the Ad‑ING4‑P53 + cisplatin group exhibited a higher inhibition rate compared with the four other groups. The results of immunohistochemistry analysis demonstrated that Bax expression was increased and Bcl‑2 was decreased in the Ad‑ING4‑P53 + cisplatin group. This suggested that the enhanced

  20. L-Carnitine Protection Against Cisplatin Nephrotoxicity In Rats: Comparison with Amifostin Using Quantitative Renal Tc 99m DMSA Uptake

    OpenAIRE

    Yakup Yürekli; Perihan Ünak; Çiğdem Yenisey; Türkan Ertay; Fazilet Zumrut Biber Müftüler; Emin İlker Medine

    2011-01-01

    Objective: In this study, we aimed to investigate the cytoprotective effect of L-carnitine against cisplatin-induced nephrotoxicity and to compare its efficacy with that of amifostin by quantitative renal Tc 99m DMSA uptake. Material and Methods: Male Wistar rats were randomly divided into six groups of six animals each. 1) Control (saline; 5 ml/kg intraperitoneally); 2) L-carnitine (CAR; 300 mg/kg intraperitoneally); 3) Amifostine (AMI; 200 mg /kg intraperitoneally); 4) Cisplatin (CIS;7 mg/k...

  1. Relative Contributions of Radiation and Cisplatin-Based Chemotherapy to Sensorineural Hearing Loss in Head-and-Neck Cancer Patients

    International Nuclear Information System (INIS)

    Purpose: To investigate the risk of sensorineural hearing loss (SNHL) in patients with head-and-neck cancer and treated with radiation therapy (RT) or concomitant cisplatin-based chemoradiation, the relationship among SNHL and radiation dose to the cochlea, the use of two common cisplatin dose regimens. Methods and Materials: A total of 62 head-and-neck cancer patients treated with curative intent were included in this prospective study. Of the patients, 21 received RT alone, 27 received 40 mg/m2 weekly cisplatin, 13 received 100 mg/m2 every 3 weeks during RT, and 1 received RT with weekly epidermal growth factor receptor inhibitor antibody. The effect of chemotherapy and RT dose on hearing was determined using a model that accounted for the age and variability between each ear for each patient. Results: We constructed a model to predict dose-dependent hearing loss for RT or cisplatin-based chemotherapy either alone or in combination. For patients only receiving RT, no significant hearing loss was found at doses to the cochlea of less than 40 Gy. Patients receiving 100 mg/m2 or 40 mg/m2 of cisplatin chemotherapy had an estimated +21.5 dB and +9.5 dB hearing loss at 8,000 Hz with low radiation doses (10 Gy), which rose to +38.4 dB and +18.9 dB for high radiation doses (40 Gy). Conclusions: Use of RT alone with doses of less than 40 Gy did not result in clinically significant hearing loss. High-frequency SNHL was profoundly damaged in patients who received concomitant cisplatin when doses of 100 mg/m2 were used. The threshold cochlear dose for hearing loss with cisplatin-based chemotherapy and RT was predicted to be 10 Gy. The inner ear radiation dose constraints and cisplatin dose intensity should be considered in the treatment of advanced head-and-neck cancer

  2. Potential implications of GRP58 expression and susceptibility of cervical cancer to cisplatin and thymoquinone-based therapy

    Directory of Open Access Journals (Sweden)

    Hafiza WAGWN

    2014-08-01

    Full Text Available Wan Abd Ghani Wan Nor Hafiza,1,2 Saiful Yazan Latifah1,3 1Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, 2College of Medical Laboratory Technology, Institute for Medical Research, Ministry of Health, Jalan Pahang, Kuala Lumpur, 3Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia Abstract: A new therapeutic approach of looking at the expression of glucose-regulated protein (GRP 58 as an indication of cisplatin sensitivity may eradicate fruitless treatment and side effects in patients with cervical cancer. Thymoquinone, the bioactive compound in Nigella sativa, has been reported to have an antiproliferative effect on cervical cancer cells. This study compared the cytotoxic effects of cisplatin, a drug commonly used in the treatment of cervical cancer, and thymoquinone in cervical cancer (HeLa and SiHa cell lines by 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay, and measured GRP58 expression in the cells by quantitative real-time polymerase chain reaction and Western blotting. Cisplatin had higher antiproliferative activity towards the cervical cancer cell lines than thymoquinone in a dose-dependent and time-dependent manner. However, cisplatin was more toxic to normal 3T3 and Vero cell lines than thymoquinone. The half maximal inhibitory concentration (IC50 of cisplatin in HeLa and SiHa cells at 72 hours was 13.3±2.52 µM and 19.5±2.12 µM, respectively. Meanwhile, the IC50 of thymoquinone in HeLa and SiHa cells was 29.57±5.81 µM and 23.41±1.51 µM, respectively (P<0.05. A significant correlation was found between the cytotoxicity of cisplatin and expression of GRP58, but this relationship was not significant for thymoquinone. Therefore, the response of cervical cancer cells to cisplatin can be predicted on the basis of GRP58 expression. Keywords: glucose-regulated protein 58, cervical cancer, cisplatin

  3. Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer

    DEFF Research Database (Denmark)

    Als, Anne B; Dyrskjøt, Lars; von der Maase, Hans;

    2007-01-01

    and survival. EXPERIMENTAL DESIGN: Affymetrix GeneChip expression profiling was carried out using tumor material from 30 patients. A set of genes with an expression highly correlated to survival time after chemotherapy was identified. Two genes were selected for validation by immunohistochemistry in...... strong independent prognostic factors for response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer.......PURPOSE: Cisplatin-containing chemotherapy is the standard of care for patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The response rate is approximately 50% and tumor-derived molecular prognostic markers are desirable for improved estimation of response...

  4. Dose-response relationship in cisplatin-treated breast cancer xenografts monitored with dynamic contrast-enhanced ultrasound

    OpenAIRE

    Chen, Yao; Han, Feng; Cao, Long-hui; Li, Cheng; Wang, Jian-Wei; Li, Qing; Zheng, Wei; Guo, Zhi-xing; Li, An-Hua; Zhou, Jian-Hua

    2015-01-01

    Background Exactly assessing tumor response to different dose of chemotherapy would help to tailor therapy for individual patients. This study was to determine the feasibility of dynamic contrast-enhanced ultrasound (CEUS) in the evaluation of tumor vascular response to different dose cisplatin. Methods MCF-7 breast cancer bearing mice were treated with different dose of cisplatin in group B (1 mg/kg) and group C (3 mg/kg). A control group A was given with saline. Sequential CEUS was performe...

  5. Selectivity analysis of protein kinase CK2 inhibitors DMAT, TBB and resorufin in cisplatin-induced stress responses

    DEFF Research Database (Denmark)

    Fritz, Gerhard; Issinger, Olaf-Georg; Olsen, Birgitte Brinkmann

    2009-01-01

    DMAT, TBB and resorufin differ in their selectivity against PI3K family members, since PI3K and DNA-PK are subject to inhibition by DMAT and TBB, however, not by resorufin. TBB and DMAT treatment together with cisplatin lead to an inhibition of cisplatin-induced stress signaling (as detected...... by phosphorylation of JNK and H2AX). In the case of resorufin no interference with the stress-signaling pathway is observed, supporting the notion that TBB and DMAT interfere with upstream molecules involved in genotoxic stress signaling. We have also tested the protein kinase CK2 inhibitors with respect to cell...

  6. Short-term health-related quality of life and symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 24971/TAX 323).

    NARCIS (Netherlands)

    Herpen, C.M.L. van; Mauer, M.E.; Mesia, R.; Degardin, M.; Jelic, S.; Coens, C.; Betka, J.; Bernier, J.; Remenar, E.; Stewart, J.S.; Preiss, J.H.; Weyngaert, D. van den; Bottomley, A.; Vermorken, J.B.

    2010-01-01

    BACKGROUND: The EORTC 24971/TAX 323, a phase III study of 358 patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck, showed an improved progression-free and overall survival (OS) with less toxicity when docetaxel (T) was added to cisplatin and 5-fluorouracil

  7. MUS81 is associated with cell proliferation and cisplatin sensitivity in serous ovarian cancer.

    Science.gov (United States)

    Xie, Suhong; Zheng, Hui; Wen, Xuemei; Sun, Jiajun; Wang, Yanchun; Gao, Xiang; Guo, Lin; Lu, Renquan

    2016-08-01

    The dysfunction of DNA damage repair (DDR) pathway contributes to tumorigenesis and drug-resistance in cancer. MUS81 is a member of the conserved xeroderma pigmentosum group F (XPF) family protein of endonucleases, which is important to the DDR pathway. However, the role of MUS81 in the development of ovarian cancer remains uncertain. To explore the expression of MUS81 and its association to serous ovarian cancer (SOC), 43 biopsies of SOC patients were detected by qRT-PCR, and 29 specimens were further performed by immunohistochemistry analysis. Here, we observed that MUS81 was over-expressed in SOC tissues at both transcript and protein levels, and the expression level of MUS81 protein in ovarian cancer cell lines was also higher than that in human normal ovarian surface epithelial cell line (HOSEpiC). We also found that down-regulation of MUS81 expression in ovarian cancer cells inhibited cell proliferation and colony formation ability, and influenced cell cycle progression. Moreover, inhibition of MUS81 expression induced cellular senescence and enhanced the antitumor effect of cisplatin. Down-regulation of MUS81 expression could suppress the growth and development of SOC. These results indicate that MUS81 might play important roles in the progression of SOC and influence the antitumor effect of cisplatin. PMID:27255997

  8. Advanced neuroblastoma: improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26.

    Science.gov (United States)

    Shafford, E A; Rogers, D W; Pritchard, J

    1984-07-01

    Forty-two children, all over one year of age, were given vincristine, cyclophosphamide, and sequentially timed cisplatin and VM-26 (OPEC) or OPEC and doxorubicin (OPEC-D) as initial treatment for newly diagnosed stage III or IV neuroblastoma. Good partial response was achieved in 31 patients (74%) overall and in 28 (78%) of 36 patients whose treatment adhered to the chemotherapy protocol, compared with a 65% response rate achieved in a previous series of children treated with pulsed cyclophosphamide and vincristine with or without doxorubicin. Only six patients, including two of the six children whose treatment did not adhere to protocol, failed to respond, but there were five early deaths from treatment-related complications. Tumor response to OPEC, which was the less toxic of the two regimens, was at least as good as tumor response to OPEC-D. Cisplatin-induced morbidity was clinically significant in only one patient and was avoided in others by careful monitoring of glomerular filtration rate and hearing. Other centers should test the efficacy of OPEC or equivalent regimens in the treatment of advanced neuroblastoma. PMID:6539811

  9. The effect of intraarterial high-dose cisplatin on lymph nodes in oral and oropharyngeal cancer

    Directory of Open Access Journals (Sweden)

    A F Kovács

    2012-01-01

    Full Text Available Aim of Study: To assess the effect of strictly local treatment [intraarterial chemotherapy (iaCHT with high-dose cisplatin and parallel neutralization] in the primary oral and oropharyngeal cancer (OOSCC on the dependent cervical lymph nodes. Patients and Methods: Seventeen consecutive patients with OOSCC and clinically positive necks underwent a prospective blinded comparison of two pre-surgical fluor18-deoxyglucose (FDG-positron emission tomography (PET examinations: baseline examination 1 week before and follow-up examination 3 weeks after iaCHT. Maximal standardized uptake (SUVmax values of lymph nodes were measured and compared with each other and histopathology. Results: The SUVmax value of the primary and all neck lymph nodes with uptake decreased significantly. Twelve/17 patients having metastases revealed significant decrease (P = 0.03, and benign lymph nodes showed non-significant decrease of the SUVmax. All neck lymph nodes with uptake and nodal metastases showed a significant reduction (P = 0.004 of standard uptake values (SUV. Conclusion: A regional effect of intraarterial cisplatin is proven. To date, it is not clear whether this is due to decreasing inflammatory reaction or a translymphatic anti-neoplastic effect.

  10. Cadmium and cisplatin damage erythropoietin-producing proximal renal tubular cells

    Energy Technology Data Exchange (ETDEWEB)

    Horiguchi, Hyogo; Oguma, Etsuko; Kayama, Fujio [Jichi Medical School, Division of Environmental Medicine, Center for Community Medicine, Tochigi (Japan); Core Research for Evolutional Science and Technology, Japan Science Technology Corporation (CREST-JST), Saitama (Japan)

    2006-10-15

    The concomitant manifestations of proximal renal tubular dysfunction and anemia with erythropoietin (Epo) deficiency observed in chronic cadmium (Cd) intoxication, such as Itai-itai disease, suggest a close local correlation between the Cd-targeted tubular cells and Epo-producing cells in the kidney. Therefore, we investigated the local relationship between hypoxia-induced Epo production and renal tubular injury in rats injected with Cd at 2 mg/kg twice a week for 8 months. Anemia due to insufficient production of Epo was observed in Cd-intoxicated rats. In situ hybridization detected Epo mRNA expression in the proximal renal tubular cells of hypoxic rats without Cd intoxication, and the Cd-intoxicated rats showed atrophy of Epo-expressing renal tubules and replacement of them with fibrotic tissue. A single dose of cisplatin at 8 mg/kg, which can induce clinical manifestations similar to those of Cd including renal tubular damage along with Epo-deficient anemia, resulted in Epo-expressing renal tubule destruction on day 4. These data indicate that Cd and cisplatin would induce anemia through the direct injury of the proximal renal tubular cells that are responsible for Epo production. (orig.)

  11. Safety and Efficacy of Concurrent Cisplatin and Radiotherapy in Inoperable or Metastatic Squamous Cell Esophageal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Shaleen; Dimri, Kislay; Datta, Niloy R.; Rastogi, Neeraj; Lal, Punita; Das, Koilpillai J. Maria; Ayyagari, Sundar [Sanjay Gandhi Postgraduate Inst. of Medical Sciences, Lucknow (India). Dept of Radiotherapy

    2002-09-01

    Between August 1996 and May 1999, 50 consecutive, previously untreated patients with carcinoma of the esophagus and who were inoperable for various reasons were treated with weekly doses of cisplatin (35 mg/m{sup 2}, maximum 7 cycles) concurrent with either 66 Gy/33 fractions external beam radiotherapy (EBRT) (n=42) or 50 Gy/25 fractions EBRT and two insertions of high-dose-rate intraluminal radiotherapy of 6 Gy each, spaced a week apart (n=8). Eighty-two percent (41/50) of the patients received the stipulated radiotherapy (RT) dose. Seventy-six percent (38/50) received at least 6 cycles of chemotherapy. Neutropenia in the form of WHO grade II-12% (6/50) and grade III-2% (1/50) was observed. Grade III emesis was seen in 8% (4/50). Improvement in the swallowing status was seen in 84% (42/50). Median duration of dysphagia relief was 6 months. The median overall survival was 9 months with 17% estimated to be alive after 4 years. Combined treatment with single agent cisplatin and definitive radiotherapy for inoperable cancer of the esophagus is safe, well tolerated and reasonably efficacious.

  12. Combined therapy of radiotherapy and chemotherapy (cisplatin, methotrexate and peplomycin) for esophageal cancer

    International Nuclear Information System (INIS)

    Between January 1984 and June 1989, 39 patients with esophageal cancer were treated with radiotherapy and 1-3 courses of cisplatin (80 mg/m2 iv day 1), methotrexate (40 mg/m2 iv day 2), and peplomycin (10 mg/body day 24 hours continuous subcutaneous infusion days 2-5) (Group 1). Results were compared with 35 patients treated between January 1984 and June 1989 with radiotherapy alone (Group 2). Group 1 patients had 35.9% complete response (CR) compared to Group 2 (28.6%). In stage 2, CR rate of Group 1 and Group 2 were 100% and 46.2% respectively (p<0.05). Median survival time (MST) for Group 1 (11 months) was longer than for Group 2 (7 months). Especially in stage 3, MST of Group 1 and Group 2 were 11 months and 5 months respectively (p<0.05). Radiation esophagitis and pneumonitis of Group 1 was more severe and more frequently than Group 2, but no fatal reaction occurred. These data suggest that radiotherapy with chemotherapy (cisplatin, methotrexate, and peplomycin) for esophageal cancer may improve response rate and survival. (author)

  13. Cisplatin sensitization to radiotherapy of squamous cell carcinomas of the head and neck

    Energy Technology Data Exchange (ETDEWEB)

    Leipzig, B.

    1983-10-01

    A combined modality of treatment utilizing cisplatin as a radiosensitizing agent concomitantly with full-course radical irradiation has been studied in 14 patients. Cisplatin at a dose of 15 mg/M2 body surface area was given intravenously on days 1 through 5 and 21 through 25 of the radiation therapy course. Among the 14 patients so treated, 11 patients had evidence of complete clinical regression of their tumors. Most remained in remission without evidence of recurrent disease for as long as 18 months. Recurrence in the field of treatment was even more rare. Symptomatic improvement was very encouraging in these patients. Most of them have had a significant improvement in their tolerance of pain and in the ability to swallow foods and maintain weight without a nasogastric feeding tube. Decannulation of the tracheostomy is usual. Problems included four patients with renal toxicity, one of whom died with renal failure. No patient required interruption of therapy due to mocositis or dysphagia. Nausea was rare. This encouraging data in our pilot study of a new therapeutic regimen justifies a full-scale clinical trial.

  14. Radiotherapy with concomitant carboplatin (CBDCA) vs cisplatin (CDDP) and superselective arterial infusion of decadose CDDP

    International Nuclear Information System (INIS)

    We compared the effectiveness between carboplatin (CBDCA) and cisplatin (CDDP) as a single-agent chemotherapy and concomitant radiotherapy in operable head and neck cancer by a prospective randomized trial. The CBDCA-treated group (n=60) showed significantly better 5-year local control rate (56.2%) than the CDDP-treated group (n=59, 35.5%, p=0.03). There was no difference in toxicities, which were considered acceptable. We suggest choosing weekly CBDCA rather than daily low-dose CDDP as a chemotherapeutic agent for concomitant chemoradiotherapy in patients with operable cancer, although a dose of CDDP may be too small. Superselective arterial infusion for patients with advanced head and neck cancer has increasingly applied in Japan. We analyzed our experiences and evaluated the efficacy and safety of this treatment. Twenty nine patients received superselective intra-arterial infusion therapy of cisplatin (100-120 mg/m2/week) and conventional concomitant extrabeam radiotherapy. Two year overall survival rate was 42.9%. The primary lesions were well controlled in 21 patients (72.4%). High-frequent acute toxic effects were leukopenia and mucositis. Severe toxic events occurred in three cases, namely, methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, sepsis, and tetraplasia. We confirmed the effectiveness and safety of superselective arterial infusion and concomitant radiotherapy. Furthermore, we must establish the optimal procedures and schedule, as well as the indications for this treatment. This treatment protocol expected the cure of patients with unresectable disease and patients rejecting surgical treatment. (author)

  15. Experimental study of the effect of cisplatin combined with indomethacin and its derivatives for the treatment of lewis lung carcinoma with '18FDG-PET/CT

    International Nuclear Information System (INIS)

    Background: Non-steroidal anti-inflammatory drug Indomethacin have been used in the treatment of fever, pain, inflammation and rheumatic disease. In recent years, some researches have confirmed that Indomethacin have the ability of assistant therapy on many kinds of malignant tumors, such as colon cancer; gastric cancer and lung cancer: Purpose: To evaluate the effect of Cisplatin combined with Indomethacin and Histamine-Indomethacin to Lewis lung cancer. Methods: 40 male Kunming mice were used to establish Lewis lung cancer model. They were randomly divided into four groups: Cisplatin treatment group, Cisplatin+Indomethacin treatment group, Cisplatin+Histamine-Indomethacin treatment group and control group. Each mouse was given the PET/CT imaging and taken orbital blood for 0.2 mL before and after the treatment. Histological detection was given. Results: Ratio of targets were significantly different after the treatment, especially in Cisplatin+Histamine-Indomethacin treatment group. Each group TNF-α levels were increased after treatment and the Cisplatin+Histamine-Indomethacin treatment group was the most obvious. There was no obvious difference in tumor inhibiting rates. Conclusions: The results showed that Cisplatin combined with Histamine-Indomethacin could inhibit tumor growth and promote apoptosis of tumor cells better. The changes of the ratio of targets could reflect the effect of the chemotherapy drugs earlier. (authors)

  16. The comparison between weekly and three-weekly cisplatin delivered concurrently with radiotherapy for patients with postoperative high-risk squamous cell carcinoma of the oral cavity

    International Nuclear Information System (INIS)

    The aim of this study was to compare the outcomes of postoperative adjuvant concomitant chemoradiotherapy using two different schedules of cisplatin for patients with high-risk oral squamous cell carcinoma (OSCC). From Feb. 2008 to Aug. 2010, 55 patients with high-risk OSCC were included in this study. Patients were randomized into treatment groups that either received 100 mg/m2 cisplatin once every 3 weeks (arm A) or 40 mg/m2 cisplatin once per week (arm B). All patients were irradiated with 66 Gy in 33 fractions. Of the 50 eligible patients, 26 were assigned to arm A, and 24 were assigned to arm B. Both groups of patients received the same mean doses of radiotherapy and cisplatin. However, 88.5% of patients in arm A and 62.5% of those in arm B (p = 0.047) received ≥ 200 mg/m2 of cisplatin in total. The overall toxicity was significantly greater in arm B (p = 0.020), and all of the grade 4 toxicities occurred in patients in arm B. Three-weekly high-dose cisplatin treatment showed higher compliance, and lower acute toxicity compared to weekly low-dose cisplatin treatment

  17. Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis.

    Science.gov (United States)

    Aloe, L; Manni, L; Properzi, F; De Santis, S; Fiore, M

    2000-12-28

    In this study we investigate the neurotoxic action of Cisplatin (6 micrograms/g body weight for 5 treatment cycles during 15 weeks with a total dose of 30 micrograms/g), an antitumor drug, and its effect on the level of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in peripheral tissues. We found that Cisplatin in adult rodents impairs peripheral sensory function and both sympathetic and sensory peripheral innervation as shown by the hot-plate response, catecholamine distribution and substance P immunoreactivity respectively. These changes are associated with decreased NGF in intestine, paws, and bladder while NGF increased in the spinal cord. Also BDNF decreased in bladder and paws and increased in spinal cord and intestine. To further investigate the role of NGF in the pathogenesis of Cisplatin-induced peripheral neuropathies a group of animals was injected with NGF (1 microgram/g every 4 days for 4 times) following Cisplatin treatment and evaluated for sensory function, sympathetic and sensory innervation and BDNF levels. Data demonstrated that exogenous NGF administration is able to restore biochemical, structural and functional changes induced by Cisplatin. These findings suggest that the reduction of NGF availability could be a cause of Cisplatin-induced peripheral neuropathies and that NGF exogenous administration could prevent or reduce Cisplatin neurotoxicity also in cancer patients, reducing the side effects of chemotherapy. PMID:11269929

  18. Rigosertib Is a More Effective Radiosensitizer Than Cisplatin in Concurrent Chemoradiation Treatment of Cervical Carcinoma, In Vitro and In Vivo

    International Nuclear Information System (INIS)

    Purpose: To compare rigosertib versus cisplatin as an effective radiosensitizing agent for cervical malignancies. Methods and Materials: Rigosertib and cisplatin were tested in cervical cancer cell lines, HeLa and C33A. A 24-hour incubation with rigosertib and cisplatin, before irradiation (2-8 Gy), was used for clonogenic survival assays. Cell cycle analysis (propidium iodide staining) and DNA damage (γ-H2AX expression) were evaluated by fluorescence-activated cell sorter cytometry. Rigosertib was also tested in vivo in tumor growth experiments on cervical cancer xenografts. Results: Rigosertib was demonstrated to induce a G2/M block in cancer cells. Survival curve comparison revealed a dose modification factor, as index of radiosensitization effect, of 1.1-1.3 for cisplatin and 1.4-2.2 for rigosertib. With 6-Gy irradiation, an increase in DNA damage of 15%-25% was achieved in both HeLa and C33A cells with cisplatin pretreatment, and a 71-108% increase with rigosertib pretreatment. In vivo tumor growth studies demonstrated higher performance of rigosertib when compared with cisplatin, with 53% longer tumor growth delay. Conclusions: Rigosertib was more effective than cisplatin when combined with radiation and caused minimal toxicity. These data support the need for clinical trials with rigosertib in combination therapy for patients with cervical carcinoma

  19. Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice.

    Science.gov (United States)

    Garcia, Jose M; Chen, Ji-an; Guillory, Bobby; Donehower, Lawrence A; Smith, Roy G; Lamb, Dolores J

    2015-07-01

    Cisplatin administration induces DNA damage resulting in germ cell apoptosis and subsequent testicular atrophy. Although 50 percent of male cancer patients receiving cisplatin-based chemotherapy develop long-term secondary infertility, medical treatment to prevent spermatogenic failure after chemotherapy is not available. Under normal conditions, testicular p53 promotes cell cycle arrest, which allows time for DNA repair and reshuffling during meiosis. However, its role in the setting of cisplatin-induced infertility has not been studied. Ghrelin administration ameliorates the spermatogenic failure that follows cisplatin administration in mice, but the mechanisms mediating these effects have not been well established. The aim of the current study was to characterize the mechanisms of ghrelin and p53 action in the testis after cisplatin-induced testicular damage. Here we show that cisplatin induces germ cell damage through inhibition of p53-dependent DNA repair mechanisms involving gamma-H2AX and ataxia telangiectasia mutated protein kinase. As a result, testicular weight and sperm count and motility were decreased with an associated increase in sperm DNA damage. Ghrelin administration prevented these sequelae by restoring the normal expression of gamma-H2AX, ataxia telangiectasia mutated, and p53, which in turn allows repair of DNA double stranded breaks. In conclusion, these findings indicate that ghrelin has the potential to prevent or diminish infertility caused by cisplatin and other chemotherapeutic agents by restoring p53-dependent DNA repair mechanisms. PMID:26019260

  20. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China); Xia, Qiang, E-mail: xiaqiang1@yahoo.com.cn [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer miR-199a-5p levels were significantly decreased after cisplatin treatment. Black-Right-Pointing-Pointer Cisplatin treatment induced autophagy activation. Black-Right-Pointing-Pointer Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  1. Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression

    Directory of Open Access Journals (Sweden)

    Kaina Bernd

    2010-09-01

    Full Text Available Abstract Background Cisplatin based chemotherapy cures over 80% of metastatic testicular germ cell tumours (TGCT. In contrast, almost all other solid cancers in adults are incurable once they have spread beyond the primary site. Cell lines derived from TGCTs are hypersensitive to cisplatin reflecting the clinical response. Earlier findings suggested that a reduced repair capacity might contribute to the cisplatin hypersensitivity of testis tumour cells (TTC, but the critical DNA damage has not been defined. This study was aimed at investigating the formation and repair of intrastrand and interstrand crosslinks (ICLs induced by cisplatin in TTC and their contribution to TTC hypersensitivity. Results We observed that repair of intrastrand crosslinks is similar in cisplatin sensitive TTC and resistant bladder cancer cells, whereas repair of ICLs was significantly reduced in TTC. γH2AX formation, which serves as a marker of DNA breaks formed in response to ICLs, persisted in cisplatin-treated TTC and correlated with sustained phosphorylation of Chk2 and enhanced PARP-1 cleavage. Expression of the nucleotide excision repair factor ERCC1-XPF, which is implicated in the processing of ICLs, is reduced in TTC. To analyse the causal role of ERCC1-XPF for ICL repair and cisplatin sensitivity, we over-expressed ERCC1-XPF in TTC by transient transfection. Over-expression increased ICL repair and rendered TTC more resistant to cisplatin, which suggests that ERCC1-XPF is rate-limiting for repair of ICLs resulting in the observed cisplatin hypersensitivity of TTC. Conclusion Our data indicate for the first time that the exceptional sensitivity of TTC and, therefore, very likely the curability of TGCT rests on their limited ICL repair due to low level of expression of ERCC1-XPF.

  2. Concurrent versus Sequential Chemoradiotherapy with Cisplatin and Vinorelbine in Locally Advanced Non-Small Cell Lung Cancer: A Randomized Study

    Czech Academy of Sciences Publication Activity Database

    Zatloukal, P.; Petruželka, L.; Zemanová, M.; Havel, L.; Janků, F.; Judas, L.; Kubík, A.; Křepela, E.; Fiala, P.; Pecen, Ladislav

    2004-01-01

    Roč. 46, - (2004), s. 87-98. ISSN 0169-5002 Institutional research plan: CEZ:AV0Z1030915 Keywords : concurrent chemoradiotherapy * sequential chemoradiotherapy * locally advanced non-small cell lung cancer * cisplatin * vinorelbine Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.914, year: 2004

  3. Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate.

    Science.gov (United States)

    Wintzell, My; Löfstedt, Lina; Johansson, Joel; Pedersen, Anne B; Fuxe, Jonas; Shoshan, Maria

    2012-12-01

    Cisplatin is used in treatment of several types of cancer, including epithelial ovarian carcinoma (EOC). In order to mimic clinical treatment and to investigate longterm effects of cisplatin in surviving cancer cells, two EOC cell lines were repeatedly treated with low doses. In the SKOV-3 cell line originating from malignant ascites, but not in A2780 cells from a primary tumor, this led to emergence of a stable population (SKOV-3-R) which in the absence of cisplatin showed increased motility, epithelial-mesenchymal transition (EMT) and expression of cancer stem cell markers CD117, CD44 and ALDH1. Accordingly, the cells formed self-renewing spheres in serum-free stem cell medium. Despite upregulation of mitochondrial mass and cytochrome c, and no upregulation of Bcl-2/Bcl-xL, SKOV-3-R were multiresistant to antineoplastic drugs. Cancer stem cells, or tumor-initiating cells (TICs) are highly chemoresistant and are believed to cause relapse into disseminated and resistant EOC. Our second aim was therefore to target resistance in these TIC-like cells. Resistance could be correlated with upregulation of hexokinase-II and VDAC, which are known to form a survival-promoting mitochondrial complex. The cells were thus sensitive to 3-bromopyruvate, which dissociates hexokinase-II from this complex, and were particularly sensitive to combination treatment with cisplatin at doses down to 0.1 x IC 50. 3-bromopyruvate might thus be of use in targeting the especially aggressive TIC populations. PMID:22954696

  4. Influence of interstrand cross-links of antitumor cisplatin and clinically ineffective transplatin on thermodynamics of DNA duplex

    Czech Academy of Sciences Publication Activity Database

    Hofr, Ctirad; Brabec, Viktor

    New Jersey : Reutgers (The State University of New Jersey ), 2002. s. 26. [CALCON 2002: Annual Calorimetry Conference /57./. 11.08.2002-15.08.2002, New Brunswick] R&D Projects: GA ČR GP202/01/D110; GA ČR GA305/02/1552 Keywords : cisplatin * transplatin * cross-link Subject RIV: BO - Biophysics

  5. A novel time-course cDNA microarray analysis method identifies genes associated with the development of cisplatin resistance.

    Science.gov (United States)

    Whiteside, Martin A; Chen, Dung-Tsa; Desmond, Renee A; Abdulkadir, Sarki A; Johanning, Gary L

    2004-01-22

    In recent years, most cDNA microarray studies of chemotherapeutic drug resistance have not considered the temporal pattern of gene expression. The objective of this study was to examine systematically changes in gene expression of NCI-H226 and NCI-H2170 lung cancer cells treated weekly with IC10 doses of cisplatin. NCI-H226 lung cancer cells were treated weekly with an IC10 dose of cisplatin. Candidate genes with a fold change of 2.0 or more were identified from this study. A second experiment was conducted by exposing NCI-H2170 cells to cisplatin doses that were increased in week 4 and decreased in week 5. Overall, 44 genes were differentially expressed in both the NCI-H226 and NCI-H2170 cell lines. In the NCI-H2170 cell line, 24 genes had a twofold gene expression change from weeks 3 to 4. Real-time PCR found a significant correlation of the gene expression changes for seven genes of interest. This small time-ordered series identified novel genes associated with cisplatin resistance. This kind of analysis should be viewed as a first step towards building gene-regulatory networks. PMID:14737109

  6. [Pt(O,O'-acac)(γ-acac)(DMS)] versus cisplatin: apoptotic effects in B50 neuroblastoma cells.

    Science.gov (United States)

    Grimaldi, Maddalena; Santin, Giada; Insolia, Violetta; Dal Bo, Veronica; Piccolini, Valeria Maria; Veneroni, Paola; Barni, Sergio; Verri, Manuela; De Pascali, Sandra Angelica; Fanizzi, Francesco Paolo; Bernocchi, Graziella; Bottone, Maria Grazia

    2016-05-01

    Cisplatin is one of the most active chemotherapeutic agents used in the treatment of childhood and adult malignancies. Cisplatin induces cell death through different pathways. Despite its effectiveness, the continued clinical use of cisplatin is limited by onset of severe side effects (nephrotoxicity, ototoxicity and neurotoxicity) and drug resistance. Therefore, one of the main experimental oncology purpose is related to the search for new platinum-based drugs to create different types of adducts or more specific and effective subcellular targets. Thus, [Pt(O,O'-acac)(γ-acac)(DMS)], which reacts preferentially with protein thiols or thioether, was synthesized. In our research, different approaches were used to compare cisplatin and [Pt(O,O'-acac)(γ-acac)(DMS)] effects in B50 rat neuroblastoma cells. Our results, using immunocytochemical, cytometric and morphological techniques, showed that these compounds exert a cytostatic action and activate apoptosis with different pathways. Long-term effects demonstrated that [Pt(O,O'-acac)(γ-acac)(DMS)] exerts cytotoxic effects in neuronal B50 cell line not inducing drug resistance. Analysis was performed both to compare the ability of these platinum compounds to induce cell death and to investigate the intracellular mechanisms at the basis of their cytotoxicity. PMID:26748644

  7. Mutations in cockayne syndrome-associated genes (Csa and Csb) predispose to cisplatin-induced hearing loss in mice

    NARCIS (Netherlands)

    R.N. Rainey (Robert N.); S.-Y. Ng (Sum-Yan); J. Llamas (Juan); G.T.J. van der Horst (Gijsbertus); N. Segil (Neil)

    2016-01-01

    textabstractCisplatin is a common and effective chemotherapeutic agent, yet it often causes permanent hearing loss as a result of sensory hair cell death. The causes of sensitivity to DNA-damaging agents in nondividing cell populations, such as cochlear hair and supporting cells, are poorly understo

  8. Proteomic Analyses Reveal that Sky1 Modulates Apoptosis and Mitophagy in Saccharomyces cerevisiae Cells Exposed to Cisplatin

    Directory of Open Access Journals (Sweden)

    Silvia Rodríguez-Lombardero

    2014-07-01

    Full Text Available Sky1 is the only member of the SR (Serine–Arginine protein kinase family in Saccharomyces cerevisiae. When yeast cells are treated with the anti-cancer drug cisplatin, Sky1 kinase activity is necessary to produce the cytotoxic effect. In this study, proteome changes in response to this drug and/or SKY1 deletion have been evaluated in order to understand the role of Sky1 in the response of yeast cells to cisplatin. Results reveal differential expression of proteins previously related to the oxidative stress response, DNA damage, apoptosis and mitophagy. With these precedents, the role of Sky1 in apoptosis, necrosis and mitophagy has been evaluated by flow-cytometry, fluorescence microscopy, biosensors and fluorescence techniques. After cisplatin treatment, an apoptotic-like process diminishes in the ∆sky1 strain in comparison to the wild-type. The treatment does not affect mitophagy in the wild-type strain, while an increase is observed in the ∆sky1 strain. The increased resistance to cisplatin observed in the ∆sky1 strain may be attributable to a decrease of apoptosis and an increase of mitophagy.

  9. Photodynamic action of LED-activated pyropheophorbide-α methyl ester in cisplatin-resistant human ovarian carcinoma cells

    International Nuclear Information System (INIS)

    Cisplatin-resistance is a major obstacle for the successful therapy to ovarian cancer, and exploring novel approach to deactivate cisplatin-resistant ovarian cells will improve the clinical outcomes. Our present study showed that there was no dark cytotoxicity of MPPa in the COC1/DDP cells at the dose of 0.25 – 4 μM, and LED-activated MPPa resulted in drug dose- and light-dependent cytotoxicity. Apoptotic rate 6 h after LED-activated MPPa (2 μM) increased to 16.71% under the light energy of 1 J/cm2. Confocal laser scanning microscopy showed that MPPa mainly localized in the intracellular membrane system, namely the endoplasmic reticulum, Golgi apparatus, lysosomes and mitochondria in the COC1/DDP cells. Mitochondrial membrane potential (ΔΨm) was collapsed when COC1/DDP cells were exposed to 2 μM MPPa for 20 h and then 1 J/cm2 irradiation of LED source. These data demonstrated that LED-activated MPPa significantly deactivated cisplatin-resistant ovarian cell line COC1/DDP cells and enhanced apoptosis and decreased ΔΨm, which suggests LED is an efficient light source for PDT and LED-activated MPPa can be developed as new modality for treating cisplatin-resistant ovarian

  10. The effects of an ACTH (4-9) analogue on development of cisplatin neuropathy in testicular cancer: A randomized trial

    NARCIS (Netherlands)

    J. van Gerven (Joop); A. Hovestadt (Ad); J.W.B. Moll (Wibe); C.J. Rodenburg (C.); T.A.W. Splinter (Ted); A.T. van Oosterom (Allan); L. Keizer (L.); T.E. Drogendijk (T.); C.M. Groenhout (C.); C.J. Vecht (Charles); J.P. Neijt (J.)

    1994-01-01

    textabstractThe efficacy of the ACTH (4-9) analogue Org 2766 in the prevention of subclinical cisplatin neuropathy was assessed in a double-blind placebo-controlled multi-centre study in patients with testicular cancer or adenocarcinoma of unknown primary. Forty-two patients received at least four c

  11. Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival

    DEFF Research Database (Denmark)

    Zimling, Zarah Glad; Sørensen, Jens Benn; Gerds, Thomas Alexander; Bech, Cecilia; Andersen, Claus Bøgelund; Santoni-Rugiu, Eric

    2012-01-01

    The relationship between excision repair cross-complementation group 1 (ERCC1) expression and outcome, in patients with malignant pleural mesothelioma (MPM), treated with cisplatin/vinorelbine combination-therapy, was retrospectively evaluated in a patient population from a previously published...

  12. No significant role for beta tubulin mutations and mismatch repair defects in ovarian cancer resistance to paclitaxel/cisplatin

    International Nuclear Information System (INIS)

    The mechanisms of chemoresistance in ovarian cancer patients remain largely to be elucidated. Paclitaxel/cisplatin combination is the standard chemotherapeutic treatment for this disease, although some patients do not respond to therapy. Our goals were to investigate whether TUBB mutations and mismatch repair defects underlie paclitaxel and cisplatin resistance. Thirty-four patients with primary ovarian carcinomas (26 serous and eight clear cell carcinomas) treated with paclitaxel/cisplatin were analysed. TUBB exon 4 was analysed by nested PCR after a first round PCR using intronic primers. Microsatellite analysis was performed with the quasimonomorphic markers BAT 26 and BAT 34. Twenty-two of the 34 ovarian cancers (64.7%) presented residual tumour after surgery, seven of which (7/22; 31.8%) were shown to be chemoresistant (five serous and two clear cell tumours). Sequence analysis did not find any mutation in TUBB exon 4. Microsatellite instability was not detected in any of the ovarian carcinomas. We conclude that TUBB exon 4 mutations and mismatch repair defects do not play a significant role in paclitaxel/cisplatin resistance

  13. Cisplatin induced gamma-glutamyltransferase up-regulation, hypertrophy and differentiation in astrocytic glioma cells in culture

    Czech Academy of Sciences Publication Activity Database

    Mareš, Vladislav; Lisá, Věra; Malík, Radek; Kozáková, Hana; Šedo, A.

    2003-01-01

    Roč. 18, č. 3 (2003), s. 687-693. ISSN 0213-3911 R&D Projects: GA ČR GA301/02/0962 Institutional research plan: CEZ:AV0Z5020903; CEZ:AV0Z5011922 Keywords : glioma * cisplatin * gamma-glutamytranspeptidase Subject RIV: FD - Oncology ; Hematology Impact factor: 1.830, year: 2003

  14. MiRNA 17 family regulates cisplatin-resistant and metastasis by targeting TGFbetaR2 in NSCLC.

    Directory of Open Access Journals (Sweden)

    Zeyong Jiang

    Full Text Available MicroRNAs (miRNAs have been proven to play crucial roles in cancer, including tumor chemotherapy resistance and metastasis of non-small-cell lung cancer (NSCLC. TGFβ signal pathway abnormality is widely found in cancer and correlates with tumor proliferation, apoptosis and metastasis. Here, miR-17, 20a, 20b were detected down-regulated in A549/DDP cells (cisplatin resistance compared with A549 cells (cisplatin sensitive. Over-expression of miR-17, 20a, 20b can not only decrease cisplatin-resistant but also reduce migration by inhibiting epithelial-to-mesenchymal transition (EMT in A549/DDP cells. These functions of miR-17, 20a, 20b may be caused at least in part via inhibition of TGFβ signal pathway, as miR-17, 20a, 20b are shown to directly target and repress TGF-beta receptor 2 (TGFβR2 which is an important component of TGFβ signal pathway. Consequently, our study suggests that miRNA 17 family (including miR-17, 20a, 20b can act as TGFβR2 suppressor for reversing cisplatin-resistant and suppressing metastasis in NSCLC.

  15. Retrospective study of irinotecan/cisplatin followed by etoposide/cisplatin or the reverse sequence in extensive-stage small cell lung cancer

    Science.gov (United States)

    Xiao, Xiaoguang; Wang, Shujing; Xia, Shu; Zou, Man; Li, Yang; Wei, Yao; Mei, Qi; Chen, Yuan

    2015-01-01

    Background Much research has confirmed the favorable effect of irinotecan/cisplatin (IP) and etoposide/cisplatin (EP) on extensive-stage small cell lung cancer (E-SCLC). This study investigated two sequential orders of IP and EP in the treatment of E-SCLC. We also compared the efficacy and safety of IP and EP in first-line chemotherapy in E-SCLC. Methods Ninety-three untreated patients with E-SCLC were randomly allocated to two groups. Group A received IP as first-line therapy until progression and then changed to EP; group B received EP as first-line therapy until tumor progression followed by IP. The primary endpoints were overall survival and time to second tumor progression. The secondary endpoints were first progression-free survival (PFS), ie, time from randomization to first occurrence of tumor progression after first-line treatment with IP or EP, tumor response, and safety of the different sequential treatment orders of IP and EP. Results Median overall survival was 15.4 months in group A (IP followed by EP) versus 15.7 months in group B (EP followed by IP; P=0.483). The median time to second tumor progression was 9.5 months in group A versus 9.9 months in group B (P=0.361). As first-line and second-line therapy, IP achieved a 95.9% and 60% disease control rate, respectively, and EP achieved 95.6% and 59% disease control rate. The median first PFS was not significantly different between group A and group B (6.5 months and 6.3 months, respectively; P=0.256). Grade 3/4 diarrhea appeared to be significantly more frequent with IP than with EP. The probability of anemia and thrombocytopenia was not significantly different between the two groups. However, significantly more patients who received the IP regimen as second-line treatment developed grade 3/4 neutropenia than those who received the IP regimen as first-line therapy. Conclusion There were no statistically significant differences in between the two sequences of IP and EP in the treatment of E

  16. Retrospective study of irinotecan/cisplatin followed by etoposide/cisplatin or the reverse sequence in extensive-stage small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Xiao XG

    2015-08-01

    Full Text Available Xiaoguang Xiao, Shujing Wang, Shu Xia, Man Zou, Yang Li, Yao Wei, Qi Mei, Yuan Chen Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China Background: Much research has confirmed the favorable effect of irinotecan/cisplatin (IP and etoposide/cisplatin (EP on extensive-stage small cell lung cancer (E-SCLC. This study investigated two sequential orders of IP and EP in the treatment of E-SCLC. We also compared the efficacy and safety of IP and EP in first-line chemotherapy in E-SCLC. Methods: Ninety-three untreated patients with E-SCLC were randomly allocated to two groups. Group A received IP as first-line therapy until progression and then changed to EP; group B received EP as first-line therapy until tumor progression followed by IP. The primary endpoints were overall survival and time to second tumor progression. The secondary endpoints were first progression-free survival (PFS, ie, time from randomization to first occurrence of tumor progression after first-line treatment with IP or EP, tumor response, and safety of the different sequential treatment orders of IP and EP. Results: Median overall survival was 15.4 months in group A (IP followed by EP versus 15.7 months in group B (EP followed by IP; P=0.483. The median time to second tumor progression was 9.5 months in group A versus 9.9 months in group B (P=0.361. As first-line and second-line therapy, IP achieved a 95.9% and 60% disease control rate, respectively, and EP achieved 95.6% and 59% disease control rate. The median first PFS was not significantly different between group A and group B (6.5 months and 6.3 months, respectively; P=0.256. Grade 3/4 diarrhea appeared to be significantly more frequent with IP than with EP. The probability of anemia and thrombocytopenia was not significantly different between the two groups. However, significantly more patients who received the IP regimen as

  17. Near infrared light-actuated gold nanorods with cisplatin-polypeptide wrapping for targeted therapy of triple negative breast cancer

    Science.gov (United States)

    Feng, Bing; Xu, Zhiai; Zhou, Fangyuan; Yu, Haijun; Sun, Qianqian; Wang, Dangge; Tang, Zhaohui; Yu, Haiyang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2015-09-01

    Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR) laser illumination, the resulting FA-GNR@Pt hybrid nanoparticles are able to significantly inhibit the growth of the TNBC tumor when administered systemically. In particular, they can extensively suppress the dissemination of TNBC cells from the primary tumor to the lung by eliminating the peripheral tumor blood vessels. Collectively, our studies demonstrate that the combined PT therapy and chemotherapy using cisplatin-loaded GNRs with FA conjugation might imply a promising strategy for targeted treatment of TNBC.Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR

  18. Chemotherapy with cisplatin and vinorelbine for elderly patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC)

    International Nuclear Information System (INIS)

    Although modest improvements in the survival of patients with non-small cell lung cancer (NSCLC) can be achieved with cisplatin-based chemotherapy (CT), its value is disputed in the geriatric setting. In this study, we evaluate the feasibility of vinorelbine/cisplatin CT for elderly NSCLC patients. In this pilot phase I/II trial, all patients received CT with vinorelbine 25 mg/m2, on day 1 and 8, and cisplatin on day 1, in 28 days-cycles. After stratification for age (up to 75 years), younger patients were sequentially allocated to moderate cisplatin doses (80 mg/m2 or 90 mg/m2), and older patients were allocated to lower cisplatin doses (60 mg/m2 or 70 mg/m2). We recruited patients aged over 70 years with newly diagnosed NSCLC, clinical stage III or IV, Karnofsky performance status ≥ 70%, normal serum creatinine, peripheral neuropathy ≤ grade 1, and no prior cancer therapy. Analysis was by intention to treat. Main toxicities (grade 3–4) was as follows: neutropenia, 20%; anemia, 11%; and thrombocytopenia, 2%; alopecia, 55%; fatigue, 11%; and peripheral neurotoxicity, 2%. No grade 3–4 emesis or renal toxicity occurred. Global median time to progression (TTP) and overall survival (OS) were 27.0 (95% CI: 10.1 to 43.7) weeks and 30.1 (95% CI: 24.4 to 35.8) weeks; 1- and 2-year survival rates were 36.3% and 13.2%, respectively. Overall response rate was 50.0% (95% CI: 35.4% to 64.5%), with 1 complete response; no difference on response rate was noticed according to cisplatin dose. Median overall survival was 30.1 weeks, with 1- and 2-year survival rates of 36.3% and 13.2%, respectively. Age does not preclude assessment on the role of cisplatin-vinorelbine CT for elderly NSCLC patients with good performance status and adequate bodily functions

  19. Antioxidantes da dieta como inibidores da nefrotoxicidade induzida pelo antitumoral cisplatina Dietary antioxidants as inhibitors of cisplatin-induced nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Lusânia Maria Greggi Antunes

    2004-03-01

    Full Text Available A cisplatina é uma droga antineoplásica altamente efetiva contra vários tipos de cânceres humanos, tais como tumores do testículo e ovário, câncer da cabeça e pescoço e câncer do pulmão. Entretanto, a nefrotoxicidade é um dos principais efeitos colaterais da terapia com a cisplatina. A gravidade da nefrotoxicidade induzida pela cisplatina está relacionada com a concentração de platina nos rins. As evidências mostram que a nefrotoxicidade induzida pela cisplatina é atribuída ao dano oxidativo resultante da geração de radicais livres, e que a administração de antioxidantes é eficiente na inibição destes efeitos colaterais. Uma abordagem alternativa para proteger os roedores dos efeitos colaterais da cisplatina é o uso de conhecidos antioxidantes da dieta. Alguns estudos têm sido realizados para diminuir a peroxidação lipídica e os efeitos citotóxicos induzidos pela cisplatina, com o emprego de antioxidantes da dieta, tais como, selenito de sódio, vitaminas C e E, curcumina e o carotenóide bixina. Nós sugerimos que aqueles antioxidantes da dieta têm efeito nefroprotetor, e que os mecanismos antioxidantes destes compostos deveriam ser explorados durante a quimioterapia com a cisplatina.Cisplatin is a highly effective antineoplastic drug used against several types of human cancers, such as testicular and ovarian tumors; head and neck; and lung cancer. However, nephrotoxicity is one of the most important side-effects of cisplatin therapy. The severity of cisplatin nephrotoxicity is related to platinum concentration in the kidneys. There is a growing amount of evidence that cisplatin-induced nephrotoxicity is ascribed to oxidative damage resulting from free radical generation and that the administration of antioxidants is efficient in inhibiting these side effects. An alternative approach aiming to protect rodents against cisplatin side-effects is the introduction of known dietary antioxidants. Some studies have been

  20. Assessment of D-methionine protecting cisplatin-induced otolith toxicity by vestibular-evoked myogenic potential tests, ATPase activities and oxidative state in guinea pigs.

    Science.gov (United States)

    Lo, Wu-Chia; Chang, Chih-Ming; Liao, Li-Jen; Wang, Chi-Te; Young, Yi-Ho; Chang, Yih-Leong; Cheng, Po-Wen

    2015-01-01

    To date, inadequate study has been devoted to the toxic vestibular effects caused by cisplatin. In addition, no electrophysiological examination has been conducted to assess cisplatin-induced otolith toxicity. The purposes of this study are thus two-fold: 1) to determine whether cervical vestibular-evoked myogenic potentials (VEMPs) and ocular VEMPs are practical electrophysiological methods of testing for cisplatin-induced otolith toxicity and 2) to examine if D-methionine (D-met) pre-injection would protect the otolith organs against cisplatin-induced changes in enzyme activities and/or oxidative status. Guinea pigs were intraperitoneally treated once daily with the following injections for seven consecutive days: sterile 0.9% saline control, cisplatin (5 mg/kg) only, D-met (300 mg/kg) only, or a combination of d-met (300 mg/kg) and cisplatin (5 mg/kg), respectively, with a 30 minute window in between. Each animal underwent the oVEMP and cVEMP tests before and after treatment. The changes in the biochemistry of the otolith organs, including membranous Na(+), K(+)-ATPase and Ca(2+)-ATPase, lipid peroxidation (LPO) levels and nitric oxide (NO) levels, were also evaluated. In the cisplatin-only treated guinea pigs, the mean amplitudes of the oVEMP tests were significantly (ppigs receiving both D-met and cisplatin, the amplitudes of their oVEMP tests were significantly larger (p<0.05) than those of the cisplatin-only group, but smaller (p<0.05) than those of the saline control or D-met-only group. However, no significant difference of the amplitudes of cVEMP tests was noted among the four groups. In comparison with the other three groups, the cisplatin-only group had the lowest (ps<0.05) mean Na(+), K(+)-ATPase and Ca(2+)-ATPase, and the highest (ps<0.05) LPO and NO levels. The oVEMP tests were feasible for the evaluation of cisplatin-related otolith dysfunction. D-Met attenuated the reduced ATPase activities and increased oxidative stress induced by cisplatin