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Sample records for concomitant weekly cisplatin

  1. A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas.

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    Medina, José Antonio; Rueda, Antonio; de Pasos, Antonio Sacchetti; Contreras, Jorge; Cobo, Manuel; Moreno, Paloma; Benavides, Manuel; Villanueva, Asunción; Alba, Emilio

    2006-04-01

    This phase II study evaluated the efficacy and toxicity of weekly cisplatin along with concomitant boost accelerated radiation regimen in patients with locally advanced unresectable head and neck carcinoma. A total of 94 patients (median age, 58 years) with UICC stage III (n = 19) and IV (n = 75) cancer of the oropharynx, larynx, hypopharynx and oral cavity were included. Patients received radiotherapy with a concomitant boost scheme (1.8 Gy on days 1-40 and 1.5 Gy boost on days 25-40 with a total dose of 72 Gy) and concurrent cisplatin, 40 mg/m(2) weekly, for the first 4 weeks. Most patients (95%) received both radiation and chemotherapy according to protocol. Toxicity was manageable with grade III mucositis and pharyngeal-oesophageal toxicity in 85 and 50% of patients, respectively. Haematological toxicity was mild. Four patients (4%) died due to complications. With a median follow of 41 months, median overall survival and time to progression were 27 and 25 months, respectively. The estimated overall survival at 4 years was 41%. Concomitant boost accelerated radiation plus concurrent weekly cisplatin is a feasible schedule in patients with locally advanced unresectable head and neck carcinoma, with acceptable toxicity and survival data.

  2. Palonosetron and prednisolone for the prevention of nausea and emesis during fractionated radiotherapy and 5 cycles of concomitant weekly cisplatin-a phase II study

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    Ruhlmann, Christina H; Belli, Charlotte; Dahl, Tina;

    2013-01-01

    Recommendations for antiemetic prophylaxis supportive to radiotherapy and concomitant chemotherapy are not evidence-based. The purpose of this study was to evaluate the efficacy of the antiemetic regimen concurrent to fractionated radiotherapy and concomitant weekly cisplatin in two Danish depart...

  3. MMP9 but Not EGFR, MET, ERCC1, P16, and P-53 Is Associated with Response to Concomitant Radiotherapy, Cetuximab, and Weekly Cisplatin in Patients with Locally Advanced Head and Neck Cancer

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    George Fountzilas

    2009-01-01

    Full Text Available Concomitant administration of radiotherapy with cisplatin or radiotherapy with cetuximab appear to be the treatment of choice for patients with locally advanced head and neck cancer. In the present retrospective analysis, we investigated the predictive role of several biomarkers in an unselected cohort of patients treated with concomitant radiotherapy, weekly cisplatin, and cetuximab (CCRT. We identified 37 patients treated with this approach, of which 13 (35% achieved a complete response and 10 (27% achieved a partial response. Severe side effects were mainly leucopenia, dysphagia, rash, and anemia. Tumor EGFR, MET, ERCC1, and p-53 protein and/or gene expression were not associated with treatment response. In contrast, high MMP9 mRNA expression was found to be significantly associated with objective response. In conclusion, CCRT is feasible and active. MMP9 was the only biomarker tested that appears to be of predictive value in cetuximab treated patients. However, this is a hypothesis generating study and the results should not be viewed as definitive evidence until they are validated in a larger cohort.

  4. Induction chemotherapy with cisplatin, epirubicin, and paclitaxel (CEP), followed by concomitant radiotherapy and weekly paclitaxel for the management of locally advanced nasopharyngeal carcinoma. A hellenic cooperative oncology group phase II study

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    Fountzilas, G.; Kalogera-Fountzila, A.; Karanikiotis, C.; Nicolaou, A.; Plataniotis, G.; Daniilidis, J. [AHEPA Hospital, Aristotle Univ. of Thessaloniki, Thessaloniki (Greece); Tolis, C.; Bai, M.; Tsekeris, P. [Univ. of Ioannina Medical School, Ioannina (Greece); Misailidou, D. [' ' Papageorgiou' ' Hospital, Thessaloniki (Greece); Samantas, E.; Athanassiou, E. [' ' Agii Anargiri' ' Cancer Hospital, Athens (Greece); Papamichael, D.; Catodritis, N. [Bank of Cyprus Oncology Center, Nicosia (Cyprus); Makatsoris, T. [' ' Rio' ' Hospital, Univ. of Patras Medical School, Rio, Patras (Greece); Papakostas, P. [' ' Ippokration' ' Hospital, Athens (Greece); Zamboglou, N. [Dept. of Radiotherapy, Klinikum Offenbach, Offenbach (Germany)

    2005-04-01

    Background: clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control. Patients and methods: untreated patients with stage IIB-IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m{sup 2} followed by paclitaxel 175 mg/m{sup 2} as 3-h infusion on day 1 and cisplatin 75 mg/m{sup 2} on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m{sup 2}. Results: from November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet. Conclusion: IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions. (orig.)

  5. New potential for enhancing concomitant chemoradiotherapy with FDA approved concentrations of cisplatin via the photoelectric effect.

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    Altundal, Yucel; Cifter, Gizem; Detappe, Alexandre; Sajo, Erno; Tsiamas, Panagiotis; Zygmanski, Piotr; Berbeco, Ross; Cormack, Robert A; Makrigiorgos, Mike; Ngwa, Wilfred

    2015-02-01

    We predict, for the first time, that by using United States Food and Drug Administration approved concentrations of cisplatin, major radiosensitization may be achieved via photoelectric mechanism during concomitant chemoradiotherapy (CCRT). Our analytical calculations estimate that radiotherapy (RT) dose to cancer cells may be enhanced via this mechanism by over 100% during CCRT. The results proffer new potential for significantly enhancing CCRT via an emerging clinical scenario, where the cisplatin is released in-situ from RT biomaterials loaded with cisplatin nanoparticles.

  6. COMPARATIVE STUDY OF WEEKLY VERSUS THREE WEEKLY CISPLATIN IN ADVANCED CASES OF CARCINOMA CERVIX ALONG WITH RADIOTHERAPY

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    Preety

    2015-10-01

    Full Text Available : OBJECTIVE: To determine the clinical response and compliance of patients with external radiation therapy with concomitant weekly inj. CISPLATIN (30mg/m2 versus external radiation therapy with three weekly inj.CISPLATIN (100mg/m2. MATERIALS & METHODS: This prospective study was conducted in the Department of Radiation oncology, GOVT. CANCER HOSPITAL. M.G.M. MEDICAL COLLEGE INDORE (M. P. A total of 50 patients were enrolled in study from April 2013 to October 2013 after obtaining written and informed consent. The patients were randomized into two arms. Arm 1- Concurrent weekly cisplatin with Radiotherapy. Arm 2 - Concurrent 3 Weekly Cisplatin with Radiotherapy. All the patients received external beam radiotherapy (EBRT along with 2-3 sittings of intracavitary radiotherapy (ICR with concurrent weekly/ 3 weekly cisplatin. All the patients were simulated in supine position with proper immobilisation. Pelvic EBRT was given using COBALT 60 THERATRON 780C by two parallel opposed AP-PA portals or by four field techniques. A mid plane dose of 46 Gy 20#. RESULTS: out of 25 patients, 19 patients from Arm A and 21 from Arm B had a complete response to treatment, whereas partial and progressive diseases responses were not observed in either of the patients of Arm A and Arm B. On the other hand 12 to 8 percent patients had a stable disease. However, from the whole lot, only 2(8% patients of Arm B had a recurrence of the diseases. Statistically the responses to the different treatment plans on the patients in Arm A and Arm B did not differ significantly from each other. CONCLUSION: this study showed that tri-weekly cispiatin 100mg/m2 concurrent with radiation is feasible and more effective than the conventional weekly cispiatin 40mg/m2- based regimen in achieving local control of the disease at 1 month follow up, however this difference was not sustained over prolonged follow-up. Longer follow-up is required to assess the delayed toxicity, overall survival

  7. Inoperable nonmetastatic squamous cell carcinoma of the esophagus managed by concomitant chemotherapy (5-fluorouracil and cisplatin) and radiation therapy

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    Seitz, J.F.; Giovannini, M.; Padaut-Cesana, J.; Fuentes, P.; Giudicelli, R.; Gauthier, A.P.; Carcassonne, Y. (Institut J. Paoli-I. Calmettes, Marseilles (France))

    1990-07-15

    Thirty-five patients with nonmetastatic squamous cell carcinoma of the esophagus were treated with chemotherapy (5-fluorouracil, cisplatin) and concomitant split-course radiation therapy. All of the patients presented with dysphagia. Treatment consisted of two courses of chemotherapy with 5-FU (1 g/m2/day in continuous infusion for 5 days (days 1 to 5 and days 29 to 33) ) and cisplatin (70 mg/m2 intravenous bolus at days 2 and 30). Radiation therapy was concomitant in two courses delivering 20 Gy in 5 days (days 1 to 5 and days 29 to 33). On the first day of treatment, endoscopic peroral dilation or Nd-YAG laser therapy was usually carried out. At the end of the treatment, all of the patients were capable of oral nutrition. Histoendoscopic confirmation was made 8 weeks after the beginning of the therapy. Twenty-five of the 35 patients had a complete response with negative biopsy findings. There was only one serious complication (fatal myelosuppression) in the only patient who received more than two courses of chemotherapy. Sixteen patients died and 19 were still alive at 3 to 42 months after the beginning of treatment. Overall median survival for the 35 patients is 17 months. Actuarial survival was 55 +/- 18% at 1 year and 41 +/- 21% at 2 years. The median survival of the Stage I and II patients is 28 months. These results confirm that concomitant chemoradiotherapy is capable of producing a very high histoendoscopic complete response rate and improved 1-year and 2-year survival. The use of concentrated split-course radiotherapy enabled the authors to reduce the total length of the treatment to two periods of 5 days, with results that are similar to previous studies using classic radiotherapy for a 5-week to 7-week period.

  8. A comparison of weekly versus 3-weekly cisplatin during adjuvant radiotherapy for high-risk head and neck cancer

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    Oosting, Sjoukje F.; Chen, Tom W. W.; Huang, Shao H.; Wang, Lisa; Waldron, John; Gilbert, Ralph; Goldstein, David; Halmos, Gyorgy B.; Witjes, Max J. H.; Gietema, Jourik A.; O'Sullivan, Brian; Langendijk, Johannes A.; Siu, Lillian L.; Hansen, Aaron R.

    2016-01-01

    Objectives: To compare cumulative cisplatin dose and toxicity between patients who received 3-weekly versus weekly cisplatin during adjuvant radiotherapy for high-risk head and neck squamous cell carcinoma (HNSCC). Materials and methods: Consecutive HNSCC patients with involved resection margins and

  9. Cisplatin-induced premature senescence with concomitant reduction of gap junctions in human fibroblasts

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    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.

  10. Weekly Cisplatin during cranial irradiation for malignant melanoma metastatic to brain

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    Stewart, D.J.; Feun, L.G.; Maor, M.; Leavens, M.; Burgess, M.A.; Benjamin, R.S.; Bodey, G.P. Sr.

    1983-01-01

    Because Cisplatin potentiates the effect of radiotherapy in animal tumor systems and because Cisplatin is capable of causing regressions of human malignant melanomas, a study was initiated in patients with malignant melanoma metastatic to brain to investigate the feasibility of administering Cisplatin once a week during cranial irradiation. Cisplatin 40 mg/m2/week (three doses) was given I.V. to 18 patients during whole brain irradiation, 3 000 rads in 12 fractions over 21/2 weeks. Eleven patients also received Cisplatin 120 mg/m2 every three weeks, starting three weeks after cranial irradiation. Median survival was ten weeks, and only one of 13 patients whose brain metastases had not been resected experienced neurological and CT scan improvement. Thirteen patients have died, and brain metastases were a major cause. No regression of extracerebral tumor was seen in 15 patients with evaluable extracerebral lesions. During weekly low-dose Cisplatin administration, nausea and vomiting were moderate to severe. No granulocytopenia was noted, although three courses were associated with mild thrombocytopenia. Mucositis, peri orbital swelling, vertigo, and headache were each noted in two of 51 courses of treatment and seizures, ototoxicity, pancreatitis, and hiccups were each noted in one course. Renal toxicity and ototoxicity each developed in three of the 11 patients receiving Cisplatin 120 mg/m2, and nausea and vomiting were severe.

  11. Cost analysis of cetuximab (Erbitux) plus radiotherapy (ERT) versus concomitant cisplatin plus radiotherapy (CRT) within an NHS oncology unit (single institution): a pilot study.

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    Caroline, Brammer; Sundus, Yahya; Dawn, Dawson; Carol, Glaister; Susan, Merrick

    2016-12-01

    The aim of this feasibility study is to define the resource effectiveness of cetuximab vs cisplatin given concomitantly with radiotherapy for squamous cell carcinoma within a National Health Service clinical oncology unit. 20 patients with Stage 3 or 4 head and neck squamous cell cancers were randomized to receive either cetuximab with radiotherapy (ERT) or cisplatin with radiotherapy concurrent with external beam radiotherapy 70 Gy in 35 fractions on a 1 : 1 basis over a 12-month duration. The study compared the resource utilization of ERT vs cisplatin with radiotherapy taking into account drug costs, clinical management and the costs of managing treatment-related toxicity from first fraction of radiotherapy to 6 months after the completion of therapy. Outcome measures were quality of life (recorded at the entry, end of radiotherapy, 6 weeks post treatment and 6 months post treatment), admissions to hospital, delays to radiotherapy, locoregional control and survival. Total drug costs including cost of nutritional supplements for patients treated with cetuximab were £7407.45 compared with £3959.07 for patients treated with cisplatin. Unscheduled admissions for toxicity management were significantly more common in the ERT arm. Healthcare personnel spent significantly more time delivering unscheduled outpatient care for patients receiving cisplatin than for those receiving cetuximab (p = 0.01). No significant difference in the quality of life was suggested at baseline, 6 weeks and 6 months. The mean time to removal of percutaneous gastrostomy (PEG) after completion of radiotherapy was 49.7 weeks in the cisplatin arm and 18.5 weeks in the cetuximab arm (p = 0.04). There was a statistically significant difference in patient-reported use of PEG between the cisplatin and cetuximab arms at 6 months following completion of treatment (p = 0.04). At 21 months, overall survival was 80% in the cisplatin arm vs 50% in the cetuximab (p = 0.332), with

  12. Concurrent Chemoradiation with Low-Dose Weekly Cisplatin in Locally Advanced Stage IV Head and Neck Squamous Cell Carcinoma

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    Kang, Myoung Hee; Kang, Jung Hun; Song, Haa-Na; Jeong, Bae Kwon; Chai, Gyu Young; Kang, Kimun; Woo, Seung Hoon; Park, Jung Je; Kim, Jin Pyeong

    2014-01-01

    Purpose Concurrent chemoradiation (CRT) with 3-weekly doses of cisplatin is a standard treatment for loco-regionally advanced head and neck squamous cell carcinoma (HNSCC). However, treatment with 3-weekly doses of cisplatin is often associated with several adverse events. Therefore, we conducted this retrospective analysis to determine the efficacy and tolerance of CRT with a low weekly dose of cisplatin in stage IV HNSCC patients. Materials and Methods Medical records of patients who were d...

  13. A phase II randomized trial comparing radiotherapy with concurrent weekly cisplatin or weekly paclitaxel in patients with advanced cervical cancer

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    Charafeddine Maya

    2010-09-01

    Full Text Available Abstract Purpose/Objective This is a prospective comparison of weekly cisplatin to weekly paclitaxel as concurrent chemotherapy with standard radiotherapy for locally advanced cervical carcinoma. Materials/Methods Between May 2000 and May 2004, 31 women with FIGO stage IB2-IVA cervical cancer or with postsurgical pelvic recurrence were enrolled into this phase II study and randomized to receive on a weekly basis either 40 mg/m2 Cisplatin (group I; 16 patients or 50 mg/m2 paclitaxel (group II; 15 patients concurrently with radiotherapy. Median total dose to point A was 74 Gy (range: 66-92 Gy for group I and 66 Gy (range: 40-98 Gy for group II. Median follow-up time was 46 months. Results Patient and tumor characteristics were similar in both groups. The mean number of chemotherapy cycles was also comparable with 87% and 80% of patients receiving at least 4 doses in groups I and II, respectively. Seven patients (44% of group I and 8 patients (53% of group II developed tumor recurrence. The Median Survival time was not reached for Group I and 53 months for group II. The proportion of patients surviving at 2 and 5 years was 78% and 54% for group I and 73% and 43% for group II respectively. Conclusions This small prospective study shows that weekly paclitaxel does not provide any clinical advantage over weekly cisplatin for concurrent chemoradiation for advanced carcinoma of the cervix.

  14. Concomitant radiochemotherapy with 5-FU and cisplatin for invasive bladder cancer. Acute toxicity and first results

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    Birkenhake, S.; Leykamm, S.; Sauer, R. [Friedrich-Alexander Univ., Erlangen-Nuernberg (Germany). Dept. of Radiooncology; Martus, P. [Friedrich-Alexander Univ., Erlangen-Nuernberg (Germany). Dept. of Medical Statistics

    1999-03-01

    Purpose: To evaluate acute toxicity and efficacy of simultaneous radiochemotherapy for invasive urothelial cancer of the bladder. Patients and Methods: From September 1993 to July 1997, 61 patients with invasive bladder cancer were treated with a transurethral resection (TURB) followed by radiochemotherapy (RCT). Twenty-five received a combination of 5-FU and cisplatin. The prescribed doses were 600 mg/m{sup 2} 5-FU daily as continuous infusion over 5 days each in the 1st and 5th treatment week and 20 mg/m{sup 2} cisplatin daily at the same days as a short infusion. The pelvis was irradiated with 54 Gy, the bladder with 59.4 Gy and the paraortic nodes in 7 cases with 45 Gy, respectively. Six to 8 weeks after RCT a second TURB was performed for reasons of restaging. Results: Twenty out of 25 patients received at least 80% of the prescribed chemotherapy, in 13 cases the full dose could be given. Gastrointestinal toxicity of Grade I and II occurred in 10 cases, 1 patient developed severe diarrhea (Grade VI). After the 1st course of chemotherapy 7 patients had leuco- or thrombopenia of Grade III. One patient had a leucopenia of Grade IV. After the 2nd course 4 patients developed Grade III leuko- and thrombopenia, 1 of Grade IV. Two Grade II anemia were found. All more severe toxicities and necessary dose reductions were related to radiation of the paraaortic nodes. No life threatening infections, bleedings or cardiotoxicity was found. Restaging TURBs resulted in 22 complete remissions, 1 patient had a de-novo-carcinoma (Tis) at this time, 2 were non-responders (8%). After a median follow-up of 38 months 20 patients are alive (80%). Conclusions: 1. If irradiation of paraaortic nodes is necessary, 5-FU should not be applied, because the gastrointestinal toxicity is too extensive. In all other cases side effects are tolerable and can be managed by supportive care. 2. The first results are promising and should be evaluated in a prospective study. (orig.) [Deutsch

  15. Gemcitabine and cisplatin in locally advanced and metastatic bladder cancer; 3- or 4-week schedule?

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    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...

  16. [SIB-IMRT radiotherapy given concomitantly with cisplatin for locally advanced squamous cell head and neck cancer (SCHNC). Evaluation of the early results and toxicity].

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    Kiprian, Dorota; Jarząbski, Andrzej; Pawłowska, Beata; Michalski, Wojciech; Kawecki, Andrzej

    2011-09-01

    Concomitant radiochemotherapy become the treatment of choice for locally advanced SCHNC. This strategy of treatment has a limitation, which is an acute and late toxicity. The IMRT technique provides the possibility of better sparing of healthy tissue. Radiobiological and clinical data also suggest that accelerated fractionation and higher dose per fraction given in GTV may produce better locoregional control. Therefore it might be expected that concomitant chemotherapy and SIB-IMRT radiotherapy could increase locoregional control and reduce acute and late radiation reactions. The evaluation of early results and toxicity of this treatment modality is presented. The evaluation of the early results and toxicity of SIB-IMRT radiotherapy given concomitantly with cisplatin for locally advanced squamous cell head and neck cancer (SCHNC). SIB-IMRT technique was applied. The boost volume was limited to the GTV + 3mm margin (macroscopic tumor extension was defined on the basis of CT and/or MRI examinations). Dose per fraction given to this volume was 2.25 Gy up to 67.5 Gy of total dose. The PTV-CTV + 3mm - was defined as an area of increased risk of microscopic spread. Dose per fraction given to this volume was 2 Gy up to 60 Gy. The PTV1-ETV+ 3mm (electively irradiated volume) received dose per fraction -1.8 Gy up to 54-56 Gy. Overall treatment time was 6 weeks (5 fractions per week, 30 fractions). Concomitant chemotherapy consisted of cisplatin in daily dose100mg/m2 given two times during irradiation (1 and 22 day of treatment). The evaluation of early tolerance was performed once weekly during the treatment than during the follow up every 2 months. The early reactions were scored according to the EORTC/RTOG scale. Between June 2006 and December 2009 99 patients diagnosed with III and IV clinical stage of SCHNC were treated with this method. 65 patients were diagnosed with oropharyngeal cancer, 18 with laryngeal cancer and 16 with hypopharyngeal cancer. PEG was performed at

  17. Weekly Gemcitabine and Cisplatin in Combination With Radiotherapy in Patients With Locally Advanced Head-and-Neck Cancer: Phase I Study

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    Arruda Viani, Gustavo, E-mail: gusviani@gmail.com [Radiation Oncology Department, Faculty of Medicine of Marilia, Sao Paulo (Brazil); Afonso, Sergio Luis [Clinical Oncology Department, Faculty of Medicine of Marilia, Sao Paulo (Brazil); Cardoso Tavares, Vivian [Head and Neck Oncology Department, Faculty of Medicine of Marilia, Sao Paulo (Brazil); Bernardes Godoi da Silva, Lucas; Stefano, Eduardo Jose [Radiation Oncology Department, Faculty of Medicine of Marilia, Sao Paulo (Brazil)

    2011-11-15

    Purpose: To define the maximum tolerated dose by describing the dose-limiting toxicity (DLT) of weekly gemcitabine and cisplatin in patients with locally advanced head-and-neck (LAHN) cancer concomitant to irradiation. Methods and Materials: Patients with LAHN cancer were enrolled in a prospective, dose-escalation Phase I study. Toxicity was graded according to the Common Toxicity Criteria score. Maximum tolerated dose was defined when DLT developed in 2 of 6 patients. The starting dose of cisplatin was 20 mg/m{sup 2} and that of gemcitabine was 10 mg/m{sup 2} in 3 patients, with a subsequent dose escalation of 10 mg/m{sup 2} of cisplatin only for 3 new patients. In the next levels, only a dose escalation of gemcitabine with 10 mg/m{sup 2} for each new cohort was used (Level 1, 10 mg/m{sup 2} of gemcitabine and 20 mg/m{sup 2} of cisplatin; Level 2, 10 mg/m{sup 2} of gemcitabine and 30 mg/m{sup 2} of cisplatin; and Level 3, 20 mg/m{sup 2} of gemcitabine and 30 mg/m{sup 2} of cisplatin). Radiation therapy was administered by use of a conformal technique over a period of 6 to 7 weeks in 2.0-Gy daily fractions for 5 consecutive days per week to a total dose of 70 Gy. Results: From 2008 to 2009, 12 patients completing 3 dose levels were included in the study. At Dose Level 3, 1 of 3 patients had DLT with Grade 3 mucositis. Of the next 3 required patients, 2 showed DLT with Grade 3 dermatitis. At a follow-up of 3 months, 10 of 12 evaluable patients (83.3%) obtained a complete response and 1 patient (8.3%) obtained a partial response. Among the complete responders, at a median follow-up of 10 months (range, 6-14 months), 9 patients are alive and disease free. Conclusion: Gemcitabine at low doses combined with cisplatin is a potent radiosensitizer effective in patients with LAHN cancer. The recommended Phase II dose is 10 mg/m{sup 2} of gemcitabine and 30 mg/m{sup 2} of cisplatin with an acceptable tolerability profile.

  18. Pooled analysis of phase II trials evaluating weekly or conventional cisplatin as first-line therapy for advanced urothelial carcinoma

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    Maughan, Benjamin L; Agarwal, Neeraj; Hussain, Syed A;

    2013-01-01

    Weekly gemcitabine with GC every 3-4 weeks is considered conventional first-line chemotherapy for advanced urothelial carcinoma (UC). Weekly split-dose cisplatin with wGC might be less toxic and have similar activity, but has not been compared with GC. We pooled published phase II trials of GC...

  19. Concurrent Chemoradiation With Weekly Gemcitabine and Cisplatin in Locally Advanced Cervical Cancer

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    Esmati E

    2011-12-01

    Full Text Available Background: More than 80 years, the standard treatment of locally advanced cervical cancer was radiotherapy. However, based on several phase III randomized clinical trials in the past decade, concurrent cisplatin-based chemoradiotherapy is the current standard of treatment for this disease. Gemcitabine has potent radiosensitizing properties in preclinical and clinical trials, so it can be utilized simultaneously with radiation.Methods: Thirty Women with untreated invasive squamous-cell carcinoma of the cervix of stage IIB to stage IVA were enrolled in the study in Radiation Oncology department of Imam Khomeini Hospital in Tehran from September 2009 to September 2010. Sixty mg/m2 gemcitabine followed by 35 mg/m2 cisplatin were concurrently administered with radiotherapy to the whole pelvic region on day one of each treatment week for five weeks One and three months after treatment, patients underwent a complete physical examination and MRI to determine the response to treatment.Results: The mean age of the participants was 58.13±11.83 (29-78 years. After 3 months of treatment, 73.3% had complete and 26.7% had partial response to treatment. Grade 3 anemia was seen in 10%, grade 3 thrombocytopenia in 3.3% and grade 3 leukopenia in 10% of the patients.Conclusion: According to the positive results of this study in stage IIB, further phase II and III clinical trials are suggested to evaluate the role of chemoradiation by gemcitabine in advanced cervical cancers.

  20. Concurrent Weekly Cisplatin and Radiation Therapy for High risk group of Uterine Cervical Cancer

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    Suh, Hyun Suk; Kang, Seung Hee; Kim, Ju Ree; Lee, Eung Soo; Kim, Yong Bong; Park, Sung Kwan [Inje University College of Medicine, Seoul (Korea, Republic of)

    1992-12-15

    Locally advanced cervical carcinoma has shown high rate of local failure and poor survival rate despite the advances in modern radiation therapy techniques. Combination of chemotherapy and radiation therapy demonstrated benefit in improving local control and possibly the overall survival. Twelve patients with advanced stages(Figo stage III, IV) or 11b with bulky tumors(>5 cm in diameter) were treated with combination of radiation therapy and concurrent weekly cisplatin between May of 1988 and September of 1991 at Inje University Paik Hospital. Cisplatin was administered in bolus injections of 50mg at weekly intervals during the courses of radiation therapy. Median follow-up period was 34 months with ranges from 3 to 53 months. Eleven patients were evaluable for the estimation of response. Response was noted in all the 11 patients: complete response(CR) in 7(64%), partial response (PR) in 4(36%). Of the 7 patients with CR, all maintained local control, whereas only 1 of 4 with PR showed local control. Six of 7 with CR are alive disease free on the completion of follow-up. Eight of 11 patients (73%) maintained local control in the pelvis. The Median survival for CR patient is 27 months and 9 months for the PR patients. Analysis of survival by stage shows 11 b 4/5, III 2/e and IV 1/3. Overall survival rate was 61%. Three patients recurred : 1 at local, 1 in distant site and 1 with local and distant site. Toxicity for the combination therapy was not excessive. These results are preliminary, but definitely encouraging in view of markedly improved response rate compared with the results of historical control group.

  1. Long-term outcomes of a phase II randomized controlled trial comparing intensity-modulated radiotherapy with or without weekly cisplatin for the treatment of locally recurrent nasopharyngeal carcinoma

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    Ying Guan; Shuai Liu; HanYu Wang; Ying Guo; WeiWei Xiao; ChunYan Chen; Chong Zhao; TaiXiang Lu; Fei Han

    2016-01-01

    Background: Salvage treatment for locally recurrent nasopharyngeal carcinoma (NPC) is complicated and relatively limited. Radiotherapy, combined with effective concomitant chemotherapy, may improve clinical treatment out‑comes. We conducted a phase II randomized controlled trial to evaluate the efcacy of intensity‑modulated radio‑therapy with concomitant weekly cisplatin on locally recurrent NPC. Methods: Between April 2002 and January 2008, 69 patients diagnosed with non‑metastatic locally recurrent NPC were randomly assigned to either concomitant chemoradiotherapy group (n = 34) or radiotherapy alone group(n= 35). All patients received intensity‑modulated radiotherapy. The radiotherapy dose for both groups was 60 Gy in 27 fractions for 37 days (range 23–53 days). The concomitant chemotherapy schedule was cisplatin 30 mg/m2 by intravenous infusion weekly during radiotherapy. Results: The median follow‑up period of all patients was 35 months (range 2–112 months). Between concomitant chemoradiotherapy and radiotherapy groups, there was only significant difference in the 3‑year and 5‑year overall survival (OS) rates (68.7% vs. 42.2%, P = 0.016 and 41.8% vs. 27.5%, P = 0.049, respectively). Subgroup analysis showedthat concomitant chemoradiotherapy significantly improved the 5‑year OS rate especially for patients in stage rT3–4 (33.0% vs. 13.2%, P = 0.009), stages III–IV (34.3% vs. 13.2%, P = 0.006), recurrence interval >30 months (49.0% vs. 20.6%,P= 0.017), and tumor volume >26 cm3 (37.6% vs. 0%, P = 0.006). Conclusion: Compared with radiotherapy alone, concomitant chemoradiotherapy can improve OS of the patients with locally recurrent NPC, especially those with advanced T category (rT3–4) and stage (III–IV) diseases, recurrence intervals >30 months, and tumor volume >26 cm3.

  2. Modified Weekly Cisplatin-Based Chemotherapy Is Acceptable in Postoperative Concurrent Chemoradiotherapy for Locally Advanced Head and Neck Cancer

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    Hsueh-Ju Lu

    2015-01-01

    Full Text Available Background. Triweekly cisplatin-based postoperative concurrent chemoradiotherapy (CCRT has high intolerance and toxicities in locally advanced head and neck cancer (LAHNC. We evaluated the effect of a modified weekly cisplatin-based chemotherapy in postoperative CCRT. Methods. A total of 117 patients with LAHNC were enrolled between December 2007 and December 2012. Survival, compliance/adverse events, and independent prognostic factors were analyzed. Results. Median follow-up time was 30.0 (3.1–73.0 months. Most patients completed the entire course of postoperative CCRT (radiotherapy ≥ 60 Gy, 94.9%; ≥6 times weekly chemotherapy, 75.2%. Only 17.1% patients required hospital admission. The most common adverse effect was grade 3/4 mucositis (28.2%. No patient died due to protocol-related adverse effects. Multivariate analysis revealed the following independent prognostic factors: oropharyngeal cancer, extracapsular spread, and total radiation dose. Two-year progression-free survival and overall survival rates were 70.9% and 79.5%, respectively. Conclusion. Modified weekly cisplatin-based chemotherapy is an acceptable regimen in postoperative CCRT for LAHNC.

  3. [A comparative study of S-1 plus cisplatin and S-1 plus weekly cisplatin for unresectable gastric cancer].

    Science.gov (United States)

    Kemmochi, Takeshi; Egawa, Tomohisa; Sato, Aya; Umakoshi, Tomoko; Ito, Yasuhiro; Nagashima, Atsushi; Makino, Hiroyuki; Yamamuro, Wataru

    2012-11-01

    Clinical efficacy and safety were analyzed in patients with unresectable gastric cancer receiving S-1 plus CDDP(CS) therapy or S-1 plus weekly CDDP (w-CS) therapy as first-line treatment between April 2007 and December 2010. Fifteen patients received CS therapy and 17 received w-CS therapy. CS therapy was used according to the SPIRITS regimen, and w-CS therapy of S-1 80 mg/(m2·day) was administered for 2 weeks followed by a 1-week rest, with CDDP 20 mg/m2 being injected intravenously on days 1 and 8. In the CS therapy group and w-CS therapy group, the overall response rates were 33.3% and 70.1%, the median overall survival periods were 135 and 174 days (p=0.113), and the median follow- up times were 196 and 352 days (p=0.196), respectively. The w-CS therapy group showed less adverse events than did the CS therapy group. This study suggested that the w-CS regimen is a useful treatment modality showing clinical efficacy and safety for unresectable gastric cancer.

  4. Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin in the treatment of stage III non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Tianlin XIAO

    2008-02-01

    Full Text Available Background and objective Concurrent chemoradiotherapy is regarded as the standard care for locally advanced non-small cell lung cancer at present. This paper is designed to evaluate the efficacy and toxicity of low-dose weekly docetaxel (DTX with concurrent chemoradiotherapy followed by consolidation chemotherapy with DTX and cisplatin for unresectable stage III non-small cell lung cancer(NSCLC. Methods 44 previously untreated patients with stage III NSCLC were randomized into low-dose weekly DTX group and control group concomitant with radiotherapy. Both groups were treated by the standard fractionation schedule with three-dimensional conformal radiotherapy. An involved-field irradiation technique was performed. Gross tumor and metastatic lymph nodes were irradiated to a total dose of 66 Gy~70 Gy. Patients in the former group received chemotherapy with DTX 20mg. m-2.w-1,and the other group patients received DTX 60 mg/m2 on day 1 and DDP 30 mg/m2 on day 1~3 every 21 days. All patients received consolidation chemotherapy with DP regime after chemoradiotherapy for no more than 4 cycles. Results The overall response rates of patients in the low-dose weekly DTX group and control group were 81.8% with 27.3% CR(complete response and 86.4% with 27.3% CR respectively (Chisquare=0.120, P=0.942. After a median follow-up of 20months, the median survival time was 20 months and 17 months respectively. The 1-, 2- year survival rates of patients in low-dose weekly DTX group and control group were 69.8%, 48.1% versus 66.5%, 40.2% respectively;there was no difference between two groups. Grade 3 or 4 neutropenia and esophagitis occurred in 26.3%, 14.3% and 15.8%, 28.6% respectively (Chiquare=0.765,P =0.382(Chiquare=1.108,P =0.292.Grade 3 and 4 pulmonary toxicity was unusual.Conclusion Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin is highly active with manageable toxicity in patients

  5. A Phase 1 Study of Everolimus + Weekly Cisplatin + Intensity Modulated Radiation Therapy in Head-and-Neck Cancer

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    Fury, Matthew G. [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Medicine, Weill Cornell Medical College, New York, New York (United States); Lee, Nancy Y. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Sherman, Eric; Ho, Alan L. [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Medicine, Weill Cornell Medical College, New York, New York (United States); Rao, Shyam [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Heguy, Adriana [Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Shen, Ronglai [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Korte, Susan; Lisa, Donna [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Ganly, Ian; Patel, Snehal; Wong, Richard J.; Shaha, Ashok; Shah, Jatin [Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Haque, Sofia [Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Katabi, Nora [Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Pfister, David G. [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Medicine, Weill Cornell Medical College, New York, New York (United States)

    2013-11-01

    Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m{sup 2} weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.

  6. A phase II study of weekly docetaxel-cisplatin as first-line treatment for advanced non-small cell lung cancer.

    Science.gov (United States)

    Binder, Daniel; Hackenthal, Matthias; Graseck, Lutz; Schweisfurth, Hans; Schäper, Christoph; Krüll, Matthias; Temmesfeld-Wollbrück, Bettina; Suttorp, Norbert; Beinert, Thomas; Hellriegel, Klaus-Peter

    2009-09-01

    The combination of docetaxel and cisplatin is an effective first-line regimen in patients with advanced non-small cell lung cancer. However, the recommended three-weekly schedule is associated with frequent neutropenia and infections. Because of the toxicity of cisplatin, patients may need to be hospitalized to ensure adequate hydration. The aim of this study was to assess the efficacy and tolerability of a weekly schedule of docetaxel and cisplatin. Patients with inoperable stage International Union Against Cancer IIIB (malignant effusion) or IV non-small cell lung cancer received docetaxel (35 mg/m(2), 30 minutes infusion) and cisplatin (25 mg/m(2), 30 minutes infusion) on days 1, 8, and 15, every 4 weeks for 4 to 6 cycles. Ondansetron (8 mg) and dexamethasone (8 mg) were given intravenously before chemotherapy. The patients received oral dexamethasone 2 x 4 mg daily from the day before until the day after chemotherapy. NK1-antagonists were given at the investigator's discretion. The majority of patients was treated in outpatient departments. Safety was assessed using CTCAE v3.0. The primary end point was response rate (RECIST). Forty-four patients were included. Twelve of 44 patients achieved an objective response (11 partial, 1 complete, intent-to-treat response rate 27%). Median time to progression was 4.4 months (95% confidence interval: 4.0-4.7) and median survival 9.6 months (95% confidence interval: 2.9-16.2). Patients received a median of three full cycles. Four patients (9%) required dose reductions. No cases of febrile neutropenia or grade 2 to 4 thrombocytopenia were observed. One patient (2%) experienced grade 3/4 nausea and vomiting. Weekly docetaxel-cisplatin demonstrated comparable efficacy with three-weekly schedules. Although the frequencies of neutropenia and febrile neutropenia were low, non-neutropenic infections remained a problem. Because of relatively short hydration, the schedule can be safely administered in an outpatient setting.

  7. Locoregionally advanced nasopharyngeal carcinoma treated with intensity-modulated radiotherapy plus concurrent weekly cisplatin with or without neoadjuvant chemotherapy

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    Wee, Chan Woo; Keam, Bhum Suk; Heo, Dae Seog; Sung, Myung Whun; Won, Tae Bin; Wu, Hong Gyun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2015-06-15

    The outcomes of locoregionally advanced nasopharyngeal carcinoma patients treated with concurrent chemoradiation (CCRT) using intensity-modulated radiotherapy (IMRT) with/without neoadjuvant chemotherapy (NCT) were evaluated. Eighty-three patients who underwent NCT followed by CCRT (49%) or CCRT with/without adjuvant chemotherapy (51%) were reviewed. To the gross tumor, 67.5 Gy was prescribed. Weekly cisplatin was used as concurrent chemotherapy. With a median follow-up of 49.4 months, the 5-year local control, regional control, distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival rates were 94.7%, 89.3%, 77.8%, 68.0%, and 81.8%, respectively. In multivariate analysis, the American Joint Committee on Cancer stage (p = 0.016) and N stage (p = 0.001) were negative factors for DMFS and DFS, respectively. Overall, NCT demonstrated no benefit and an increased risk of severe hematologic toxicity. However, compared to patients treated with CCRT alone, NCT showed potential of improving DMFS in stage IV patients. CCRT using IMRT resulted in excellent local control and survival outcome. Without evidence of survival benefit from phase III randomized trials, NCT should be carefully administered in locoregionally advanced nasopharyngeal carcinoma patients who are at high-risk of developing distant metastasis and radiotherapy-related mucositis. The results of ongoing trials are awaited.

  8. A comparative study of low dose weekly paclitaxel versus cisplatin with concurrent radiation in the treatment of locally advanced head and neck cancers

    Directory of Open Access Journals (Sweden)

    R K Jain

    2009-01-01

    Full Text Available Purpose: The purpose of this study was to compare low dose weekly paclitaxel versus cisplatin with concurrent radiation in locally advanced head and neck cancers. Materials and Methods: From August 2005 to July 2006, a total of 100 biopsy proven, locally advanced head and neck cancers were enrolled for the study. All the patients were stratified in two groups, study group A and control group B. Study group patients received injection Paclitaxel 20 mg/m 2 , I/V 1 hr infusion weekly for 6 weeks and control group patients received injection Cisplatin 30 mg/m 2 , I/V 2 hrs infusion weekly for 6 weeks. All patients received 66-70 Gy concurrent radiation at the rate of 2 Gy/day, 5 #/week, in 6-7 weeks by cobalt theratron phoenix - 80 teletherapy units. Result: Complete response achieved in 73% of patients in study group and 64% of patients in control group. There was no statistically significant difference observed between the study group and the control group (χ2 = 1.167, df = 1, level of significance 0.05. On 3-10 months of follow-up 59% of patients in the study group and 42% of patients in the control group are alive and disease free. Local toxicities including mucositis, dysphasia and skin reactions were more in the study group but tolerable. Conclusion: Efficacy of paclitaxel in low dose weekly schedule is comparable to cisplatin in locally advanced head and neck squamous cell carcinoma. Further analysis and follow-up are needed to evaluate if this benefit will translate into prolonged survival.

  9. Three-week schedule of irinotecan plus cisplatin in patients with previously untreated extensive-stage small-cell lung cancer

    Science.gov (United States)

    Hong, Y S; Lee, H R; Park, S; Lee, S C; Hwang, I G; Park, B-B; Lee, J; Ahn, J S; Ahn, M-J; Lim, H Y; Park, K

    2006-01-01

    Irinotecan and cisplatin demonstrated promising outcomes in extensive-stage small-cell lung cancer. According to the dosage and schedule of irinotecan, efficacy and toxicity profiles showed subtle differences. This study was designed to evaluate efficacy and toxicity of 3-week schedule of irinotecan/cisplatin in patients with previously untreated extensive-stage small-cell lung cancer. The primary objective was to evaluate response rate and secondary objectives were overall survival and progression-free survival. Patients with previously untreated extensive-stage small-cell lung cancer were enrolled. Irinotecan 65 mg m−2 was administered on days 1 and 8 and cisplatin 60 mg m−2 on day 1. Treatment was repeated every 3 weeks. Seven out of 54 patients (13.0%) had complete response, and partial response was observed in 33 (61.1%). The overall response rate was 74.1% (95% CI; 62.0–82.2%). Stable disease was observed in eight (14.8%) and no progressive disease was observed. After a median follow-up duration of 28.7 months, the median overall survival and progressive-free survival were 13.6 and 6.5 months, respectively. Major grade 3/4 toxicities were neutropenia (50.0%), anorexia (42.6%), diarrhoea (29.6%), fatigue (29.6%) and vomiting (13.0%). There was one treatment-related death owing to pneumonia. Three-week schedule of irinotecan/cisplatin showed effective antitumour activity and moderate toxicities in patients with previously untreated extensive-stage small-cell lung cancer. PMID:17133266

  10. Concomitant bid radiotherapy with cisplatin and 5-fluorouracil in unresectable carcinoma of the pharynx: 10 year's experience at the Centre Antoine Lacassagne; Radiotherapie bifractionnee et chimiotherapie par cisplatine et 5-fluoro-uracile concomitantes dans les carcinomes epidermoides localement evolues non resecables du pharynx: dix ans d'experience au centre Antoine Lacassagne

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    Magne, N.; Pivot, X.; Marcy, P.Y.; Chauvel, P.; Courdi, A.; Dassonville, O.; Possonnet, G.; Vallicioni, J.; Ettore, F.; Falewee, M.N.; Milano, G.; Santini, J.; Lagrange, J.L.; Schneider, M.; Demard, F.; Bensadoun, R.J. [Centre Antoine-Lacassagne, 06 - Nice (France)

    2001-08-01

    Patients suffering from locally advanced unresectable squamous cell carcinoma of the oropharynx and hypopharynx treated with radiotherapy alone have a poor prognosis. More than 70% of patients die within 5 years mainly due to local recurrences. The aim of this study was to evaluate retrospectively the Antoine Lacassagne Cancer Center's experience in a treatment by concomitant bid radiotherapy and chemotherapy. Evaluation was based on analysis of the toxicity, the response rates, the survival, and the clinical prognostic factors. From 1992 to 2000, 92 consecutive patients were treated in our single institution. All of them had stage IV, unresectable squamous cell carcinoma of the pharynx and they received continuous bid radiotherapy (two daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal internal between fractions). Total radiotherapy dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Two or three chemotherapy courses of cisplatin (CP)-5-fluorouracil (5FU) were given during radiotherapy at 21 -day intervals (third not delivered after the end of the radiotherapy). CP dose was 100 mg/m{sup 2} (day 1) and 5-FU was given as 6-day continuous infusion (750 mg/m{sup 2}/day at 1. course; 430 mg/m{sup 2}/day at 2. and 3. courses). Special attention was paid to supportive care, particularly in terms of enteral nutrition and mucositis prevention by low-level laser energy. Acute toxicity was marked and included WHO grade III/IV mucositis (89%, 16% of them being grade IV), WHO grade III dermatitis (72%) and grade III/IV neutropenia (61%). This toxicity was significant but manageable with optimised supportive care, and never led to interruption of treatment for more than 1 week, although there were two toxic deaths. Complete global response rate at 6 months was 74%. Overall global survival at 1 and 3 years was 72% and 50% respectively, with a median follow-up of 17 months. Prognostic factors for overall were the Karnofsky index (71% survival at 3

  11. Weekly nanoparticle albumin bound-paclitaxel in combination with cisplatin versus weekly solvent-based paclitaxel plus cisplatin as first-line therapy in Chinese patients with advanced esophageal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Wang HY

    2016-09-01

    Full Text Available Hai-ying Wang, Zhi-hua Yao, Hong Tang, Yan Zhao, Xiao-san Zhang, Shu-na Yao, Shu-jun Yang, Yan-yan Liu Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, People’s Republic of China Objective: More effective regimens for advanced esophageal squamous cell carcinoma (ESCC are urgently needed. Therefore, a retrospective study concerning the efficacy and safety of nanoparticle albumin-bound paclitaxel plus cisplatin (nab-TP versus solvent-based paclitaxel plus cisplatin (sb-TP as a first-line therapy was conducted in Chinese patients with advanced ESCC.Methods: From June 2009 to June 2015, 32 patients were treated with nab-paclitaxel (125 mg/m2 on the first and eighth days (30 minutes infusion and cisplatin (75 mg/m2 on the second day every 21 days (nab-TP arm. Also, 43 patients were treated with solvent-based paclitaxel (80 mg/m2 intravenously on the first and eighth days and the same dose of cisplatin (sb-TP arm. The two groups were compared in terms of objective response rate (ORR, disease control rate, progression-free survival (PFS, overall survival (OS, and safety profile. OS and PFS were estimated using Kaplan–Meier methods to determine associations between chemotherapy regimens and survival outcomes.Results: Nab-TP demonstrated a higher ORR (50% vs 30%; P=0.082 and disease control rate (81% vs 65%; P=0.124 than sb-TP. Median OS was similar for nab-TP and sb-TP (12.5 vs 10.7 months; P=0.269. However, nab-TP resulted in a longer median PFS (6.1 months [95% confidence interval: 5.3–6.9] than sb-TP (5.0 months [95% confidence interval: 4.4–5.6] (P=0.029. The most common adverse events included anemia, leukopenia, neutropenia, febrile neutropenia, and thrombocytopenia in both the groups and no statistically significant differences were observed between the groups. With statistically significant differences, significantly less grade ≥3 peripheral neuropathy

  12. Weekly nanoparticle albumin-bound paclitaxel in combination with cisplatin versus weekly solvent-based paclitaxel plus cisplatin as first-line therapy in Chinese patients with advanced esophageal squamous cell carcinoma

    Science.gov (United States)

    Wang, Hai-ying; Yao, Zhi-hua; Tang, Hong; Zhao, Yan; Zhang, Xiao-san; Yao, Shu-na; Yang, Shu-jun; Liu, Yan-yan

    2016-01-01

    Objective More effective regimens for advanced esophageal squamous cell carcinoma (ESCC) are urgently needed. Therefore, a retrospective study concerning the efficacy and safety of nanoparticle albumin-bound paclitaxel plus cisplatin (nab-TP) versus solvent-based paclitaxel plus cisplatin (sb-TP) as a first-line therapy was conducted in Chinese patients with advanced ESCC. Methods From June 2009 to June 2015, 32 patients were treated with nab-paclitaxel (125 mg/m2) on the first and eighth days (30 minutes infusion) and cisplatin (75 mg/m2) on the second day every 21 days (nab-TP arm). Also, 43 patients were treated with solvent-based paclitaxel (80 mg/m2) intravenously on the first and eighth days and the same dose of cisplatin (sb-TP arm). The two groups were compared in terms of objective response rate (ORR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety profile. OS and PFS were estimated using Kaplan–Meier methods to determine associations between chemotherapy regimens and survival outcomes. Results Nab-TP demonstrated a higher ORR (50% vs 30%; P=0.082) and disease control rate (81% vs 65%; P=0.124) than sb-TP. Median OS was similar for nab-TP and sb-TP (12.5 vs 10.7 months; P=0.269). However, nab-TP resulted in a longer median PFS (6.1 months [95% confidence interval: 5.3–6.9]) than sb-TP (5.0 months [95% confidence interval: 4.4–5.6]) (P=0.029). The most common adverse events included anemia, leukopenia, neutropenia, febrile neutropenia, and thrombocytopenia in both the groups and no statistically significant differences were observed between the groups. With statistically significant differences, significantly less grade ≥3 peripheral neuropathy, arthralgia, and myalgia occurred in the nab-TP arm (all Pline therapy were similar between the two regimens. There were no treatment-related deaths in either group. Conclusion Nab-paclitaxel plus cisplatin is found to be an effective and tolerable option for advanced

  13. Combined Chemoradiation Therapy With Twice-Weekly Gemcitabine and Cisplatin for Organ Preservation in Muscle-Invasive Bladder Cancer: Long-Term Results of a Phase 1 Trial

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    Azria, David, E-mail: david.azria@icm.unicancer.fr [Department of Radiation Oncology and Radiophysics Unit, Montpellier Cancer Institute (ICM), Montpellier (France); INSERM, U896, IRCM, Montpellier (France); Riou, Olivier [Department of Radiation Oncology and Radiophysics Unit, Montpellier Cancer Institute (ICM), Montpellier (France); Rebillard, Xavier [Department of Urology, Clinique Beausoleil, Montpellier (France); Thezenas, Simon [Biostatistics Unit, Montpellier Cancer Institute, Montpellier (France); Thuret, Rodolphe [Department of Urology, Montpellier University Hospital, Montpellier (France); Fenoglietto, Pascal [Department of Radiation Oncology and Radiophysics Unit, Montpellier Cancer Institute (ICM), Montpellier (France); Pouessel, Damien; Culine, Stephane [Department of Medical Oncology, AP-HP Saint-Louis, Paris (France)

    2014-03-15

    Purpose: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. Methods and Materials: Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. Results: Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. Conclusions: This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.

  14. Concurrent hyperfractionated accelerated radiotherapy with 5-FU and once weekly cisplatin in locally advanced head and neck cancer. The 10-year results of a prospective phase II trial

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    Budach, V.; Boehmer, D.; Badakhshi, H.; Jahn, U.; Stromberger, C. [Campus Virchow Klinikum, Charite Universitaetsmedizin Berlin, Department for Radiooncology, Clinic for Radiooncology, Berlin (Germany); Becker, E.T. [Charite Universitaetsmedizin, Department of Otorhinolaryngology, Berlin (Germany); Wernecke, K.D. [Sostana Statistics GmbH, Charite Universitaetsmedizin Berlin, Berlin (Germany)

    2014-03-15

    In this study, the acute toxicity and long-term outcome of a hyperfractionated accelerated chemoradiation regimen with cisplatin/5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinomas of head and neck were evaluated. From 2000-2002, 38 patients with stage III (5.3 %) and stage IV (94.7 %) head and neck cancer were enrolled in a phase II study. Patients received hyperfractionated-accelerated radiotherapy with 72 Gy in 15 fractions of 2 Gy followed by 1.4 Gy twice daily with concurrent, continuous infusion 5-FU of 600 mg/m{sup 2} on days 1-5 and 6 cycles of weekly cisplatin (30 mg/m{sup 2}). Acute toxicities (CTCAEv2.0), locoregional control (LRC), metastases-free (MFS), and overall survival (OS) were analyzed and exploratively compared with the ARO 95-06 trial. Median follow-up was 11.4 years (95 % CI 8.6-14.2) and mean dose 71.6 Gy. Of the patients, 82 % had 6 (n = 15) or 5 (n = 16) cycles of cisplatin, 5 and 2 patients received 4 and 3 cycles, respectively. Grade 3 anemia, leukopenia, and thrombocytopenia were observed in 15.8, 15.8, and 2.6 %, respectively. Grade 3 mucositis in 50 %, grade 3 and 4 dysphagia in 55 and 13 %. The 2-, 5-, and 10-year LRC was 65, 53.6, and 48.2 %, the MFS was 77.5, 66.7, and 57.2 % and the OS 59.6, 29.2, and 15 %, respectively. Chemoradiation with 5-FU and cisplatin seems feasible and superior in terms of LRC and OS to the ARO 95-06C-HART arm at 2 years. However, this did not persist at the 5- and 10-year follow-ups. (orig.) [German] Untersuchung der Akuttoxizitaet und des Langzeitueberlebens einer hyperfraktioniert-akzelerierten simultanen Radiochemotherapie mit Cisplatin/5-Fluorouracil (5-FU) bei Patienten mit lokal fortgeschrittenen Kopf-Hals-Tumoren. Von 2000 bis 2002 wurden 38 Patienten mit Plattenepithelkarzinomen der Kopf-Hals-Region im Stadium III (5,3 %) und IV (94,7 %) eingeschlossen. Es erfolgte eine simultane hyperfraktionierte akzelerierte Radiochemotherapie mit 72 Gy in 15 Fraktionen a 2 Gy

  15. Concurrent IMRT and weekly cisplatin followed by GDP chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell lymphoma.

    Science.gov (United States)

    Ke, Q-H; Zhou, S-Q; Du, W; Liang, G; Lei, Y; Luo, F

    2014-12-12

    On the basis of the benefits of frontline radiation in early-stage, extranodal natural killer (NK)/T-cell lymphoma (ENKTL), we conducted the trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of gemcitabine, dexamethasone and cisplatin (GDP). Thirty-two patients with newly diagnosed, stage IE to IIE, nasal ENKTL received CCRT (that is, all patients received intensity-modulated radiotherapy 56 Gy and cisplatin 30 mg/m(2) weekly, 3-5 weeks). Three cycles of GDP (gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4 and cisplatin 75 mg/m(2) i.v. on day 1 (GDP), every 21 days as an outpatient were scheduled after CCRT. All patients completed CCRT, which resulted in 100% response that included 24 complete responses (CRs) and eight partial responses. The CR rate after CCRT was 75.0% (that is, 24 of 32 responses). Twenty-eight of the 32 patients completed the planned three cycles of GDP, whereas four patients did not because they withdrew (n = 1) or because they had an infection (n = 3). The overall response rate and the CR rate were 90.6% (that is, 29 of 32 responses) and 84.4% (that is, 27 of 32 responses), respectively. Only two patient experienced grade 3 toxicity during CCRT (nausea), whereas 13 of the 30 patients experienced grade 4 neutropenia. The estimated 3-year overall survival and progression-free rates were 87.50% and 84.38%, respectively. In conclusion, CCRT followed by GDP chemotherapy can be a feasible and effective treatment strategy for stage IE to IIE nasal ENKTL.

  16. Addition of the Neurokinin-1-Receptor Antagonist (RA) Aprepitant to a 5-Hydroxytryptamine-RA and Dexamethasone in the Prophylaxis of Nausea and Vomiting Due to Radiation Therapy With Concomitant Cisplatin

    Energy Technology Data Exchange (ETDEWEB)

    Jahn, Franziska, E-mail: franziska.jahn@uk-halle.de [Department of Hematology/Oncology, Martin-Luther-University Halle-Wittenberg, Halle (Saale) (Germany); Riesner, Anica [Department of Gastroenterology, Martin-Luther-University Halle-Wittenberg, Halle (Saale) (Germany); Jahn, Patrick [Nursing Research Unit, Martin-Luther-University Halle-Wittenberg, Halle (Saale) (Germany); Sieker, Frank; Vordermark, Dirk [Department of Radiation Oncology, Martin-Luther-University Halle-Wittenberg, Halle (Saale) (Germany); Jordan, Karin [Department of Hematology/Oncology, Martin-Luther-University Halle-Wittenberg, Halle (Saale) (Germany)

    2015-08-01

    Purpose: To assess, in a prospective, observational study, the safety and efficacy of the addition of the neurokinin-1-receptor antagonist (NK1-RA) aprepitant to concomitant radiochemotherapy, for the prophylaxis of radiation therapy–induced nausea and vomiting. Patients and Methods: This prospective observational study compared the antiemetic efficacy of an NK1-RA (aprepitant), a 5-hydroxytryptamine-RA, and dexamethasone (aprepitant regimen) versus a 5-hydroxytryptamine-RA and dexamethasone (control regimen) in patients receiving concomitant radiochemotherapy with cisplatin at the Department of Radiation Oncology, University Hospital Halle (Saale), Germany. The primary endpoint was complete response in the overall phase, defined as no vomiting and no use of rescue therapy in this period. Results: Fifty-nine patients treated with concomitant radiochemotherapy with cisplatin were included in this study. Thirty-one patients received the aprepitant regimen and 29 the control regimen. The overall complete response rates for cycles 1 and 2 were 75.9% and 64.5% for the aprepitant group and 60.7% and 54.2% for the control group, respectively. Although a 15.2% absolute difference was reached in cycle 1, a statistical significance was not detected (P=.22). Furthermore maximum nausea was 1.58 ± 1.91 in the control group and 0.73 ± 1.79 in the aprepitant group (P=.084); for the head-and-neck subset, 2.23 ± 2.13 in the control group and 0.64 ± 1.77 in the aprepitant group, respectively (P=.03). Conclusion: This is the first study of an NK1-RA–containing antiemetic prophylaxis regimen in patients receiving concomitant radiochemotherapy. Although the primary endpoint was not obtained, the absolute difference of 10% in efficacy was reached, which is defined as clinically meaningful for patients by international guidelines groups. Randomized phase 3 studies are necessary to further define the potential role of an NK1-RA in this setting.

  17. GILT - A randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer

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    Flentje, Michael [University Hospital Wuerzburg, Dept. of Radiotherapy, Wuerzburg (Germany); Huber, Rudolf M. [University Hospital Munich, Member of the German Center for Lung Research (DZL CPC-M), Munich (Germany); Engel-Riedel, Walburga [University Hospital Merheim, Dept. of Pneumonology, Cologne (Germany); Andreas, Stefan [Dept. of Pneumonology, Immenhausen (Germany); Kollmeier, Jens [Helios Emil-von-Behring Hospital, Berlin (Germany); Staar, Susanne [Municipal Hospital Bremen-Mitte, Bremen (Germany); Dickgreber, Nicolas [University Hospital Hannover, Hannover (Germany); Vaissiere, Nathalie; Almeida, Cecilia de [Institut de Recherche Pierre Fabre, Boulogne (France); Edlich, Birgit [Pierre Fabre Pharma GmbH, Freiburg (Germany); Fietkau, Rainer [University Hospital Erlangen, Erlangen (Germany)

    2016-04-15

    Concurrent chemoradiotherapy (CRT) is considered standard for inoperable stage III non-small cell lung cancer (NSCLC). Consolidation chemotherapy (CC) following CRT is intended to further improve outcomes, yet studies have shown discordant results. This phase III study assessed CRT followed by best supportive care (BSC) or consolidation with oral vinorelbine and cisplatin. Patients received two cycles of oral vinorelbine (50 mg/m{sup 2} days 1, 8 and 15) + cisplatin (20 mg/m{sup 2} days 1-4) q4w + radiotherapy (RT; 66 Gy). Patients with at least stable disease (SD) were randomised to either two cycles oral vinorelbine (60-80 mg/m{sup 2} days 1 and 8) + cisplatin (80 mg/m{sup 2} day 1) q3w + BSC or BSC alone. Primary endpoint was progression-free survival (PFS). A total of 279 patients were enrolled for CRT and 201 patients were randomised to CC or BSC. Both CRT and CC were well tolerated, with limited radiation-mediated grade 3/4 toxicities (CRT/CC/BSC: oesophagitis-related events 12.9 %/3.1 %/0 %; grade 3 pneumonitis 0 %/0 %/2 %) and chemotherapy-mediated grade 3/4 toxicities (CRT/CC: neutropenia 11.2 %/22.1 %; leukopenia 18.3 %/26.7 %; grade 3 nausea 5.0 %/2.3 %, grade 3 vomiting 3.2 %/3.5 %). Median PFS from randomisation was 6.4 (5.0-8.7) and 5.5 (3.8-7.4) months in the CC and BSC arms (hazard ratio, HR = 0.93 [0.69-1.26]; p = 0.63), respectively; median overall survival (OS) 20.8 (13.5-25.3) and 18.5 (13.6-24.7) months, respectively. Consolidation chemotherapy after concurrent CRT did not prolong PFS or OS. Concurrent RT with oral vinorelbine and cisplatin demonstrated a favourable safety profile and represents a suitable treatment regimen for inoperable stage III NSCLC. (orig.) [German] Simultane Radiochemotherapie (CRT) wird als Standardtherapie beim inoperablen Stadium III des nicht-kleinzelligen Lungenkarzinoms (NSCLC) angesehen. Konsolidierende Chemotherapie (CC) nach der CRT zielt darauf ab, das Therapieergebnis zu verbessern, allerdings zeigen Studien

  18. Hyperfractionated accelerated radiotherapy with concomitant integrated boost of 70-75 Gy in 5 weeks for advanced head and neck cancer. A phase I dose escalation study

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    Cvek, J.; Skacelikova, E.; Otahal, B.; Halamka, M.; Feltl, D. [University Hospital Ostrava (Czech Republic). Dept. of Oncology; Kubes, J. [University Hospital Bulovka, Prague (Czech Republic). Dept. of Radiation Oncology; Kominek, P. [University Hospital Ostrava (Czech Republic). Dept. of Otolaryngology

    2012-08-15

    Background and purpose: The present study was performed to evaluate the feasibility of a new, 5-week regimen of 70-75 Gy hyperfractionated accelerated radiotherapy with concomitant integrated boost (HARTCIB) for locally advanced, inoperable head and neck cancer. Methods and materials: A total of 39 patients with very advanced, stage IV nonmetastatic head and neck squamous cell carcinoma (median gross tumor volume 72 ml) were included in this phase I dose escalation study. A total of 50 fractions intensity-modulated radiotherapy (IMRT) were administered twice daily over 5 weeks. Prescribed total dose/dose per fraction for planning target volume (PTV{sub tumor}) were 70 Gy in 1.4 Gy fractions, 72.5 Gy in 1.45 Gy fractions, and 75 Gy in 1.5 Gy fractions for 10, 13, and 16 patients, respectively. Uninvolved lymphatic nodes (PTV{sub uninvolved}) were irradiated with 55 Gy in 1.1 Gy fractions using the concomitant integrated boost. Results: Acute toxicity was evaluated according to the RTOG/EORTC scale; the incidence of grade 3 mucositis was 51% in the oral cavity/pharynx and 0% in skin and the recovery time was {<=} 9 weeks for all patients. Late toxicity was evaluated in patients in complete remission according to the RTOG/EORTC scale. No grade 3/4 late toxicity was observed. The 1-year locoregional progression-free survival was 50% and overall survival was 55%. Conclusion: HARTCIB (75 Gy in 5 weeks) is feasible for patients deemed unsuitable for chemoradiation. Acute toxicity was lower than predicted from radiobiological models; duration of dysphagia and confluent mucositis were particularly short. Better conformity of radiotherapy allows the use of more intensive altered fractionation schedules compared with older studies. These results suggest that further dose escalation might be possible when highly conformal techniques (e.g., stereotactic radiotherapy) are used.

  19. A biologically competitive 21 days hypofractionation scheme with weekly concomitant boost in breast cancer radiotherapy feasibility acute sub-acute and short term late effects

    Directory of Open Access Journals (Sweden)

    Garelli Stefania

    2010-11-01

    Full Text Available Abstract Background Radiation therapy after lumpectomy is a standard part of breast conserving therapy for invasive breast carcinoma. The most frequently used schedule worldwide is 60 Gy in 30 fractions in 6 weeks, a time commitment that sporadically may dissuade some otherwise eligible women from undertaking treatment. The purpose and primary endpoint of this perspective study is to evaluate feasibility and short-term late toxicity in a hypofractionated whole breast irradiation schedule. Methods Between February and October 2008 we treated 65 consecutive patients with operable invasive early-stage breast cancer with a hypofractionated schedule of external beam radiation therapy. All patients were assigned to 39 Gy in 13 fractions in 3 weeks to the whole breast plus a concomitant weekly boost dose to the lumpectomy cavity of 3 Gy in 3 fractions. Results All the patients had achieved a median follow up of 24 months (range 21-29 months. At the end of treatment 52% presented grade 0 acute toxicity 39% had grade 1 and 9% had grade 2. At 6 months with all the patients assessed there were 34% case of grade 1 subacute toxicity and 6% of grade 2. At 12 months 43% and 3% of patients presented with clinical grade 1 and grade 2 fibrosis respectively and 5% presented grade 1 hyperpigmentation. The remaining patients were free of side effects. At 24 months, with 56 assessed, just 2 patients (3% showed grade 2 of late fibrosis. Conclusions The clinical results observed showed a reasonably good feasibility of the accelerated hypofractionated schedule in terms of acute, subacute and short-term late toxicity. This useful 13 fractions with a concomitant boost schedule seems, in selected patients, a biologically acceptable alternative to the traditional 30 days regime.

  20. Phase Ⅰ / Ⅱ clinical trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy followed by intensity-modulated radiotherapy and concomitant chemotherapy in locally advanced nasopharyngeal carcinoma%局部晚期鼻咽癌调强放疗同期化疗前TPF诱导化疗Ⅰ和Ⅱ期临床研究

    Institute of Scientific and Technical Information of China (English)

    张群; 何妨; 康德华; 王振宇; 文碧秀; 罗伟

    2013-01-01

    Objective To investigate the maximum-tolerated dose (MTD) of cisplatin in docetaxel,cisplatin,and fluorouracil (TPF) induction chemotherapy followed by intensity-modulated radiotherapy (IMRT) and concomitant chemotherapy as well as the safety and short-term efficacy of TPF induction chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma (NPC).Methods Thirtythree patients with locally advanced NPC were enrolled in this trial.The MTD of cisplatin was determined by dose escalation study,and the short-term efficacy and toxicities were evaluated.Results When the doses of docetaxel and fluorouracil were 60 mg/m2 d1 and 550 mg/m2 d1-5,respectively,the MTD of cisplatin was 65 mg/m2 d1.In this regimen (repeated every 3 weeks),grade 3-4 toxicities included neutropenia (67%),febrile neutropenia (9%),diarrhea (21%),and oral mucositis (6%).Except those who experienced dose-limited toxicity,other patients completed the whole treatment schedule.After TPF induction chemotherapy,the overall response rate was 97%,and the complete response rate was 21%.Conclusions In the endemic areas of NPC,induction chemotherapy with docetaxel (60 mg/m2 d1),cisplatin (65 mg/m2 d1),and fluorouracil (550 mg/m2 d1-5),which is repeated every 3 weeks,is proved safe and effective for Asian patients with locally advanced NPC.%目的 探讨局部晚期鼻咽癌调强放疗同期化疗前多西泰索加顺铂加氟尿嘧啶方案诱导化疗中顺铂最大耐受剂量(MTD)及方案安全性、有效性.方法 选取33例局部晚期鼻咽癌患者,通过剂量递增试验确立顺铂MTD并评价临床疗效及不良反应.结果 多西泰索60 mg/m2第1天、氟尿嘧啶550 mg/m2第1~5天剂量下顺铂MTD为65 mg/m2第1天,每3周重复下3、4级不良反应发生率分别为中性粒细胞降低67%,粒细胞缺乏性发热9%,腹泻21%,口腔黏膜炎6%.除剂量限制性毒性患者外,其余均完成了治疗.诱导化疗后有效率为97%,其中完

  1. Accelerated radiotherapy with concomitant boost technique (69.5 Gy/5 weeks). An alternative in the treatment of locally advanced head and neck cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kubes, Jiri; Vondracek, Vladimir; Pala, Miloslav [Prague Univ., Prag (Czech Republic). Inst. of Radiation Oncology; Cvek, Jakub; Feltl, David [Faculty Hospital Ostrava (Czech Republic). Dept. of Oncology

    2011-10-15

    To present the feasibility and results of accelerated radiotherapy with concomitant boost technique (69.5 Gy/5 weeks) in the treatment of locally advanced head and neck cancer. A total of 65 patients were treated between June 2006 and August 2009. The distribution of clinical stages was as follows: II 11%, III 23%, IV 61%, and not defined 5%. The median follow-up was 30.5 months. The treatment plan was completed in 94% of patients. Patients were treated using the conformal or intensity-modulated radiotherapy (IMRT) technique. The median overall treatment time was 37 days (13-45 days). The mean radiotherapy dose was 68.4 Gy (16-74 Gy). Overall survival was 69% after 2 years. Disease-free survival was 62% after 2 years. Acute toxicity {>=} grade 3(RTOG scale) included mucositis (grade 3: 42.6%), pharynx (grade 3: 42.3%), skin (grade 3: 9.5%), larynx (grade 3: 4%), while late toxicity affected skin (grade 3: 6.25%) and salivary glands (grade 3: 3.7%). Accelerated radiotherapy with concomitant boost technique is feasible in patients with locally advanced head and neck cancer, has an acceptable toxicity profile, and yields promising treatment results.

  2. A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial.

    NARCIS (Netherlands)

    Ducreux, M.; Cutsem, E. van; Laethem, J. van; Gress, T.M.; Jeziorski, K.; Rougier, P.; Wagener, T.; Anak, O.; Baron, B.; Nordlinger, B.

    2005-01-01

    Previous small phase II trials have demonstrated that the combination of 5-fluorouracil (5FU) and cisplatin(CDDP) could have clinical activity in metastatic biliary tract cancer. This randomised phase II trial was designed to assess the activity and safety of a high-dose infusional weekly 5FU alone

  3. A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma : results of the 40955 EORTC trial

    NARCIS (Netherlands)

    Ducreux, M; van Cutsem, E; van Laethern, JL; Gress, TM; Jeziorski, K; Rougier, P; Wagener, T; Anak, O; Baron, B; Nordlinger, B

    2005-01-01

    Previous small phase II trials have demonstrated that the combination of 5-fluorouracil (5FU) and cisplatin(CDDP) could have clinical activity in metastatic biliary tract cancer. This randomised phase II trial was designed to assess the activity and safety of a high-dose infusional weekly 5FU alone

  4. Induction chemotherapy with carboplatin-paclitaxel followed by standard radiotherapy with concurrent daily low-dose cisplatin plus weekly paclitaxel for inoperable non-small-cell lung cancer.

    Science.gov (United States)

    Ardizzoni, Andrea; Scolaro, Tindaro; Mereu, Carlo; Cafferata, Mara Argenide; Tixi, Lucia; Bacigalupo, Almalina; Tiseo, Marcello; Monetti, Francesco; Rosso, Riccardo

    2005-02-01

    Both induction chemotherapy and concurrent platinating agents have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study investigated activity and feasibility of a novel chemoradiation regimen, including platinum and paclitaxel, both as induction chemotherapy and concurrently with thoracic radiotherapy. Previously untreated patients with histologically/cytologically proven unresectable stage I-III NSCLC were eligible. Induction chemotherapy consisted of 2 courses of 200 mg/m2 paclitaxel and carboplatin at AUC of 6 mg/mL/min every 3 weeks. From day 43, continuous thoracic irradiation (60 Gy in 30 fractions radiotherapy for 6 weeks) was given concurrently with daily cisplatin at a dose of 5 mg/m2 intravenously and weekly paclitaxel at a dose of 45 mg/m2 for 6 weeks. Fifteen patients were accrued in the first stage of the trial. According to the previous statistical considerations, accrual at the second stage of the study was halted as a result of the achievement an insufficient number of successes. Major toxicity of combined chemoradiation was grade III-IV esophagitis requiring hospitalization for artificial nutrition, which occurred in 58% of patients. Other toxicities included grade II-IV fatigue in 75% of patients and grade I-IV neuromuscular toxicity in 67%. Only 7 patients completed the treatment program as scheduled. Eight patients (53.3%; 95% confidence interval, 26.5-78.7%) had a major response (5 partial response, 3 complete response), 2 patients had disease progression, and 1 was stable at the end of treatment. Four patients died early. With a median follow up of 38 months, the median survival was 12 months. A combined chemoradiation program, including platinum and paclitaxel, appears difficult to deliver at full dose as a result of toxicity, mainly esophagitis. More active and less toxic combined modality treatments need to be developed for inoperable NSCLC.

  5. Superselective arterial infusion and concomitant radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Homma, Akihiro; Suzuki, Fumiyuki; Inuyama, Yukio; Fukuda, Satoshi [Hokkaido Univ., Sapporo (Japan). School of Medicine

    2003-05-01

    Superselective arterial infusion for patients with advanced head and neck cancer has been increasingly applied in Japan. We analyzed our experiences and evaluated the efficacy and safety of this treatment. Through October 1999 to March 2002, 29 patients, ranging in age between 33 and 71 years (median 52 years), received superselective intra-arterial infusion therapy of cisplatin (100-120 mg/m{sup 2}/week) with simultaneous intravenous infusion of thiosulfate for neutralizing cisplatin toxicity, and conventional concomitant extrabeam radiotherapy (65 Gy/26 f/6.5 weeks). Four patients were diagnosed with stage III and 25 with stage IV. Thirteen patients were considered contraindicated for surgery, and the other 16 patients rejected radical surgery. Primary tumor sites included paranasal sinus (11 patients), hypopharynx (7), oropharynx (6), oral cavity (4), and parotid gland (1). During the median follow-up period of 20 months, there was no apparent recurrence in 14 (48.3%) of 29 patients. Eleven (37.9%) patients died of disease, and three (10.3%) were alive with disease. In twenty-one patients (72.4%) the primary lesions were well-controlled. Acute toxic effects were moderate, and severe toxic events occurred in four cases, namely, methicillin-resistant staphylococcus aureus (MRSA) pneumonia, sepsis, tetraplasia, and osteoradionecrosis. 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 may improve the prognosis of patients with unresectable disease and patients rejecting surgical treatment. Further study in this particular area is needed. (author)

  6. Clinical benefit of gemcitabine plus cisplatin 3-week regimen for patients with advanced non-small cell lung cancer:a prospective observational study

    Institute of Scientific and Technical Information of China (English)

    王莉; 廖美琳; 李龙芸; 万欢英; 徐农; 刘基巍; 梁厚杰

    2004-01-01

    Background Platinum-based chemotherapy has been proved effective in patients with advanced non-small cell lung cancer (NSCLC). This study evaluated the effectiveness and safety of first-line chemotherapy with gemcitabine plus cisplatin (GEM-Cis) 3-week regimen in routine care of Chinese patients with advanced NSCLC.Methods Two hundred and twenty-one patients with NSCLC stage IIIb or IV were enrolled and 209 were eligible foreffectiveness and safety analysis. The median age was 58 (range 29 to 79) years. The percents of cases in stage Ⅳ and stage Ⅲb were 52.2% and 47.8%; of Karnofsky performance score (KPS) less than 80 and 80-100 were 37.3% and 62.7% and of adeno-cancer and non-adeno-cancer were 59.8% and 40.2%. The average number of completed chemotherapy cycles was three. Measures of effectiveness included clinical benefit, significant clinical response (SCR) and adverse effects of GEM-Cis in the treatment of NSCLC at stages Ⅲb/Ⅳ.Results KPS increased from 79±9 at baseline to 86±10 after chemotherapy (P<0.01). Lung cancer symptom scale (LCSS) score of pain, dyspnea and cough increased from 77±24, 74±22 and 63±19 to 92±15, 90±14 and 86±15, respectively (P<0.01). The clinical benefit rate was 85.2% [95% confidence interval (CI) 80.3%-90.0%]. The SCR was 89.5% (95% CI 85.3%-93.7%). Median survival time was 7.8 months (95% CI 7.1 months-9.1 months). Sixty-four patients (30.6%) experienced an adverse effect that was deemed clinically significant. Only one patient (0.5%) was hospitalized due to chemotherapy related adverse effects. Life-threatening toxicity was observed in two patients (1.0%).Conclusion First-line chemotherapy with GEM-Cis in the routine care of Chinese patients with advanced NSCLC is effective and safe.

  7. Cisplatin Injection

    Science.gov (United States)

    ... Dilantin), bumetanide (Bumex), ethacrynic acid (Edecrin), furosemide (Lasix), pyridoxine (Vitamin B-6). Your doctor may need to ... looks like coffee grounds Cisplatin may increase the risk that you will develop other cancers. Talk to ...

  8. Long-Term Outcome and Morbidity After Treatment With Accelerated Radiotherapy and Weekly Cisplatin for Locally Advanced Head-and-Neck Cancer: Results of a Multidisciplinary Late Morbidity Clinic

    Energy Technology Data Exchange (ETDEWEB)

    Ruetten, Heidi, E-mail: h.rutten@rther.umcn.nl [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Pop, Lucas A.M.; Janssens, Geert O.R.J. [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Takes, Robert P. [Department of Otorhinolaryngology and Head and Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Knuijt, Simone [Department of Rehabilitation/Speech Pathology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Rooijakkers, Antoinette F. [Department of Oral and Maxillofacial Surgery, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Berg, Manon van den [Department of Gastroenterology-Dietetics, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Merkx, Matthias A. [Department of Oral and Maxillofacial Surgery, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Herpen, Carla M.L. van [Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Kaanders, Johannes H.A.M. [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands)

    2011-11-15

    Purpose: To evaluate the long-term outcome and morbidity after intensified treatment for locally advanced head-and-neck cancer. Methods and Materials: Between May 2003 and December 2007, 77 patients with Stage III to IV head-and-neck cancer were treated with curative intent. Treatment consisted of accelerated radiotherapy to a dose of 68 Gy and concurrent cisplatin. Long-term survivors were invited to a multidisciplinary outpatient clinic for a comprehensive assessment of late morbidity with special emphasis on dysphagia, including radiological evaluation of swallowing function in all patients. Results: Compliance with the treatment protocol was high, with 87% of the patients receiving at least five cycles of cisplatin and all but 1 patient completing the radiotherapy as planned. The 5-year actuarial disease-free survival and overall survival rates were 40% and 47%, respectively. Locoregional recurrence-free survival at 5 years was 61%. The 5-year actuarial rates of overall late Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) Grade 3 and Grade 4 toxicity were 52% and 25% respectively. Radiologic evaluation after a median follow-up of 44 months demonstrated impaired swallowing in 57% of the patients, including 23% with silent aspiration. Subjective assessment using a systematic scoring system indicated normalcy of diet in only 15.6% of the patients. Conclusion: This regimen of accelerated radiotherapy with weekly cisplatin produced favorable tumor control rates and survival rates while compliance was high. However, comprehensive assessment by a multidisciplinary team of medical and paramedical specialists revealed significant long-term morbidity in the majority of the patients, with dysphagia being a major concern.

  9. Results of the Tremplin trial proposing an induction chemotherapy followed by concomitant radiotherapy with cisplatin ou cetuximab in order to protect the larynx; Resultats de l'essai Tremplin proposant une chimiotherapie d'induction suivie d'une radiotherapie concomitante avec cisplatine ou cetuximab dans le but de preserver le larynx

    Energy Technology Data Exchange (ETDEWEB)

    Pointreau, Y.; Calais, G. [Service de radiotherapie, Centre regional universitaire de cancerologie Henry-S.-Kaplan, Hopital Bretonneau, CHU de Tours, 37 (France); Pointreau, Y.; Calais, G. [Universite Francois-Rabelais de Tours, 37 (France); Pointreau, Y. [CNRS, UMR 6239 - Genetique, immunotherapie, chimie et cancer - et Laboratoire de pharmacologie-toxicologie, CHRU de Tours, 37 (France); Rolland, F.; Bardet, E. [Centre Rene-Gauducheau, 44 - Nantes (France); Alfonsi, M. [Clinique Sainte-Catherine, 84 - Avignon (France); Baudoux, A. [Clinique Sainte-Elisabeth, Namur (Belgium); Sire, G. [Centre hospitalier de Lorient, 56 (France); De Raucourt, D. [Centre Francois-Baclesse, 14 - Caen (France); Tuchais, C. [Centre Paul-Papin, 49 - Angers (France); Lefebvre, J.L. [Centre Oscar-Lambret, 59 - Lille (France)

    2010-10-15

    The authors report a randomized phase II trial which aimed at comparing over three months the laryngeal protection after a TPF-based induction chemotherapy followed by radiotherapy in combination with cisplatin or cetuximab. Over two years, 153 patients have been concerned. The TPF-based induction chemotherapy followed by radiotherapy with cetuximab seems to be the less toxic. A longer monitoring is needed to get better information in terms of laryngeal protection rate, life quality, and laryngeal functionality. Short communication

  10. [Preliminary clinical evaluation of low-dose cisplatin and continuous infusion of 5-FU (LFP) chemotherapy after weekly high-dose 5-FU therapy for the treatment of liver metastases from colorectal cancer].

    Science.gov (United States)

    Itoh, Satoshi; Morita, Sojiro; Ohnishi, Takenao; Tsuji, Akihito; Takamatsu, Masahiro; Horimi, Tadashi

    2002-07-01

    In this study, we evaluate the efficacy of low-dose cisplatin and continuous 5-FU infusion systemic chemotherapy (LFP therapy) for the treatment of unresectable and recurrent liver metastases from colorectal cancer after weekly high-dose 5-FU therapy via the hepatic artery (WHF therapy). At the start of chemotherapy, 12 patients with multiple extrahepatic lesions were treated with the LFP therapy (LFP group), and 18 patients with none or a few extrahepatic lesions were treated with the WHF therapy followed by the LFP therapy (LFP after WHF group). In the LFP group, the response rate was 50.0% (PR 6) and the one-year survival rate was 50.0%. On the contrary, in the LFP after WHF group, the response rate was 38.9% (CR 1, PR 6) and the one-year survival rate after LFP started was 46.0%. We conclude that the LFP therapy may be effective for the treatment of liver metastases from colorectal cancer even after the WHF therapy.

  11. Radiotherapy and concomitant chemotherapy by cisplatin, 5-fluorouracil and mitomycin C in locally advanced oropharynx carcinomas: results on a test in phase II. Radiotherapie et chimiotherapie concomitante par cisplatine (CDDP), 5-fluorouracile (5FU) et mitomycine C (MMC) dans les cancers localement evolues de l'oropharynx: resultats d'un essai de phase II

    Energy Technology Data Exchange (ETDEWEB)

    Berger, C.; Chapet, S.; Reynaud-Bougnoux, A.; Calais, G.; Le Floch, O. (Hopital Bretonneau, 37 - Tours (France))

    1994-01-01

    After exclusive irradiation the prognosis of advanced oropharynx carcinomas is bad. To improve the response to the tumoral treatment, a test in phase II was made, associating irradiation and concomitant chemotherapy. The results show that this association allow a high rate of complete remissions at the end of the treatment, but with a severe digestive and hematological toxicity.

  12. Two consecutive days of treatment with liposomal cisplatin in non-small cell lung cancer

    OpenAIRE

    Stathopoulos, G. P.; STATHOPOULOS, J.; Dimitroulis, J.

    2012-01-01

    Liposomal cisplatin (Lipoplatin) is a new agent, a cisplatin formulation that has been investigated in a number of studies and compared with cisplatin with respect to toxicity and effectiveness. It has been administered once weekly and in combination with a second agent, once every two weeks. The main outcome of the studies was that lipoplatin has no renal toxicity and is as equally effective as cisplatin. The present study investigated toxicity and effectiveness when lipoplatin is administer...

  13. 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.

  14. Predictive factors of head and neck squamous cell carcinoma patient tolerance to high-dose cisplatin in concurrent chemoradiotherapy

    OpenAIRE

    Nakano, Kenji; SATO, YASUYOSHI; TOSHIYASU, TAKASHI; SATO, YUKIKO; INAGAKI, LINA; Tomomatsu, Junichi; Sasaki, Toru; SHIMBASHI, WATARU; FUKUSHIMA, HIROFUMI; YONEKAWA, HIROYUKI; Mitani,Hiroki; Kawabata, Kazuyoshi; Takahashi, Shunji

    2015-01-01

    Although high-dose cisplatin is the standard regimen of concurrent chemoradiotherapy (CCRT) for locally advanced head and neck squamous cell carcinoma (HNSCC), varying levels of patient tolerance towards cisplatin have been reported, and the predictive factors of cisplatin tolerance remain to be elucidated. The present study retrospectively reviewed newly diagnosed HNSCC patients who received CCRT. Cisplatin (80 mg/m2) was administered every 3 weeks. The proportion of high-dose cisplatin-tole...

  15. Characterization of Cardiovascular Alterations Induced by Different Chronic Cisplatin Treatments

    Directory of Open Access Journals (Sweden)

    Esperanza Herradón

    2017-05-01

    Full Text Available In the last years, many clinical studies have revealed that some cisplatin-treated cancer survivors have a significantly increased risk of cardiovascular events, being cisplatin-induced cardiovascular toxicity an increasing concern. The aim of the present work was to evaluate the cardiovascular alterations induced by different chronic cisplatin treatments, and to identify some of the mechanisms involved. Direct blood pressure, basal cardiac (left ventricle and coronary arteries and vascular (aortic and mesenteric functions were evaluated in chronic (5 weeks saline- or cisplatin-treated male Wistar rats. Three different doses of cisplatin were tested (1, 2, and 3 mg/kg/week. Alterations in cardiac and vascular tissues were also investigated by immunohistochemistry, Western Blot, and or quantitative RT-PCR analysis. Cisplatin treatment provoked a significant modification of arterial blood pressure, heart rate, and basal cardiac function at the maximum dose tested. However, vascular endothelial dysfunction occurred at lower doses. The expression of collagen fibers and conexin-43 were increased in cardiac tissue in cisplatin-treated rats with doses of 2 and 3 mg/kg/week. The expression of endothelial nitric oxide synthase was also modified in cardiac and vascular tissues after cisplatin treatment. In conclusion, chronic cisplatin treatment provokes cardiac and vascular toxicity in a dose-dependent manner. Besides, vascular endothelial dysfunction occurs at lower doses than cardiac and systemic cardiovascular toxicity. Moreover, some structural changes in cardiac and vascular tissues are also patent even before any systemic cardiovascular alterations.

  16. Radiation-Free Weekend Rescued! Continuous Accelerated Irradiation of 7-Days per Week Is Equal to Accelerated Fractionation With Concomitant Boost of 7 Fractions in 5-Days per Week: Report on Phase 3 Clinical Trial in Head-and-Neck Cancer Patients

    Energy Technology Data Exchange (ETDEWEB)

    Skladowski, Krzysztof, E-mail: skladowski@io.gliwice.pl [Maria Sklodowska-Curie Memorial Cancer Center and the Institute of Oncology, Branch in Gliwice (Poland); Hutnik, Marcin; Wygoda, Andrzej; Golen, Maria; Pilecki, Boleslaw; Przeorek, Wieslawa; Rutkowski, Tomasz; Lukaszczyk-Widel, Beata; Heyda, Alicja; Suwinski, Rafal; Tarnawski, Rafal; Maciejewski, Boguslaw [Maria Sklodowska-Curie Memorial Cancer Center and the Institute of Oncology, Branch in Gliwice (Poland)

    2013-03-01

    Purpose: To report long-term results of randomized trial comparing 2 accelerated fractionations of definitive radiation therapy assessing the need to irradiate during weekend in patients with head and neck squamous cell carcinoma. Methods and Materials: A total of 345 patients with SCC of the oral cavity, larynx, and oro- or hypo-pharynx, stage T2-4N0-1M0, were randomized to receive continuous accelerated irradiation (CAIR: once per day, 7 days per week) or concomitant accelerated boost (CB: once per day, 3 days per week, and twice per day, 2 days per week). Total dose ranged from 66.6-72 Gy, dose per fraction was 1.8 Gy, number of fractions ranged from 37-40 fractions, and overall treatment time ranged from 37-40 days. Results: No differences for all trial end-points were noted. At 5 and 10 years, the actuarial rates of local-regional control were 63% and 60% for CAIR vs 65% and 60% for CB, and the corresponding overall survival were 40% and 25% vs 44% and 25%, respectively. Confluent mucositis was the main acute toxicity, with an incidence of 89% in CAIR and 86% in CB patients. The 5-year rate of grade 3-4 late radiation morbidity was 6% for both regimens. Conclusions: Results of this trial indicate that the effects of accelerated fractionation can be achieve by delivering twice-per-day irradiation on weekday(s). This trial has also confirmed that an accelerated, 6-weeks schedule is a reasonable option for patients with intermediate-stage head-and-neck squamous cell carcinoma because of the associated high cure rate and minimal severe late toxicity.

  17. 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.

  18. Liposomal cisplatin: a new cisplatin formulation.

    Science.gov (United States)

    Stathopoulos, George P

    2010-09-01

    Over the last three decades, cisplatin has been one of the most effective cytotoxic agents, but its administration has been hindered by its nephrotoxicity, neurotoxicity and myelo toxicity. Recently, liposomal cisplatin, lipoplatin, has been formulated and tested thoroughly in preclinical (in vitro) and phase I, II and III trials, as documented in the literature. Experiments in animals showed that lipoplatin is less toxic than cisplatin and that it produces tumour reduction. The histological examination of treated tumours from mouse xenografts was consistent with apoptosis in the tumour cells in a mechanism similar to that of cisplatin. Lipoplatin infusion in patients and measurements of platinum levels in tumour specimens showed 10-50 times higher levels in tumours and metastases than in the adjacent normal specimens. A phase I-II study using a combination of lipoplatin and gemcitabine in pretreated patients (with disease progression or stable disease) with advanced pancreatic cancer was conducted. No nephrotoxicity was observed. With lipoplatin monotherapy the dose-limiting toxicity was determined to be 350 mg/m and the maximum tolerated dose 300 mg/m; when used in combination with paclitaxel the dose-limiting toxicity for lipoplatin was 250 mg/m and for paclitaxel 175 mg/m, and the maximum tolerated dose was 200 and 175 mg/m, respectively. In two phase II randomized studies comparing the lipoplatin combination versus the cisplatin combination, it was found that the former was statistically significantly less toxic than the latter, whereas the response rate and survival were similar. Up to now, the data on lipoplatin treatment in malignant tumours are quite impressive, because of the negligible toxicity and because it is equal if not superior to cisplatin with regard to response rate. This review aims to chronologically document publications relevant to liposomal cisplatin to date.

  19. 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.

  20. Cisplatin triggers platelet activation.

    Science.gov (United States)

    Togna, G I; Togna, A R; Franconi, M; Caprino, L

    2000-09-01

    Clinical observations suggest that anticancer drugs could contribute to the thrombotic complications of malignancy in treated patients. Thrombotic microangiopathy, myocardial infarction, and cerebrovascular thrombotic events have been reported for cisplatin, a drug widely used in the treatment of many solid tumours. The aim of this study is to explore in vitro cisplatin effect on human platelet reactivity in order to define the potentially active role of platelets in the pathogenesis of cisplatin-induced thrombotic complications. Our results demonstrate that cisplatin increases human platelet reactivity (onset of platelet aggregation wave and thromboxane production) to non-aggregating concentrations of the agonists involving arachidonic acid metabolism. Direct or indirect activation of platelet phospholipase A(2) appears to be implicated. This finding contributes to a better understanding of the pathogenesis of thrombotic complications occurring during cisplatin-based chemotherapy.

  1. Enhancement of cisplatin cytotoxicity by benzyl isothiocyanate in HL-60 cells.

    Science.gov (United States)

    Lee, Younghyun; Kim, Yang Jee; Choi, Young Joo; Lee, Joong Won; Lee, Sunyeong; Chung, Hai Won

    2012-07-01

    Cis-diamminedichloroplatinum (II) (cisplatin) is one of the most widely used chemotherapeutic drugs, but its effectiveness is limited by tumor cell resistance and the severe side effects it causes. One strategy for overcoming this problem is the concomitant use of natural dietary compounds as therapeutic agents. Benzyl isothiocyanate (BITC) is a promising chemopreventive agent found in cruciferous vegetables and papaya fruits. The aim of this study was to investigate the effects of BITC on cisplatin-induced cytotoxicity in human promyelocytic leukemia cells and normal human lymphocytes. The combined treatment of HL-60 cells with BITC followed by cisplatin (BITC/cisplatin) caused a significant decrease in cell viability. BITC also increased apoptotic cell death compared to cisplatin treatment alone. In normal human lymphocytes, BITC did not enhance the cytotoxic effects of cisplatin. Cellular exposure to BITC/cisplatin increased reactive oxygen species (ROS) generation but decreased the total glutathione (GSH) level in HL-60 cells. Pretreatment of HL-60 cells with N-acetylcysteine or glutathione monoethyl ester effectively decreased BITC/cisplatin-induced cell death. The addition of the extracellular signal-regulated kinase (ERK) inhibitor PD98059 abolished BITC/cisplatin-induced apoptosis. Taken together, our results suggest that BITC enhances cisplatin-induced cytotoxicity through the generation of ROS, depletion of GSH, and ERK signaling in HL-60 cells.

  2. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone.

    Science.gov (United States)

    Aminian, Atefeh; Javadi, Shiva; Rahimian, Reza; Dehpour, Ahmad Reza; Asadi Amoli, Fahimeh; Moghaddas, Payman; Ejtemaei Mehr, Shahram

    2016-07-01

    Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg), animals received intraperitoneal injections of morphine (5 mg/kg/day) and/or naltrexone (20 mg/kg/day), an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH) concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy.

  3. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone

    Directory of Open Access Journals (Sweden)

    Atefeh Aminian

    2016-07-01

    Full Text Available Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg, animals received intraperitoneal injections of morphine (5 mg/kg/day and/or naltrexone (20 mg/kg/day, an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy.

  4. Concurrent chemoradiotherapy using cisplatin, tegafur, and leucovorin for advanced squamous cell carcinoma of the hypopharynx and oropharynx

    Directory of Open Access Journals (Sweden)

    Hung-Ming Wang

    2014-06-01

    Full Text Available Background: To evaluate the efficacy and adverse events of cisplatin, tegafur, and leucovorin concomitantly with radiotherapy for patients with advanced, non-metastatic squamous cell carcinoma (SCC of the oropharynx and hypopharynx. Methods: The PTL regimen consisted of cisplatin (P 50 mg/m 2 on day 1, oral tegafur (T 800 mg/day plus leucovorin (LV 60 mg/day on days 1 through 14. It was repeated every 2 weeks through the radiotherapy course. Conventional radiotherapy with 1.8-2.0 Gy/day, 5 days per week, was delivered in a total dose of between 70 and 72 Gy. Results: Sixty-five patients with stage III or IV of SCC of the head and neck were consecutively treated between May 2002 and November 2005. Forty-six (70.7% patients had complete response after concomitant chemoradiotherapy (CCRT. With a median follow-up of 54.0 months (range 1-103 months, the 5-year locoregional control, progression-free survival, and overall survival rates were 50.6%, 40.7%, and 59.7%, respectively. Three (4.6% patients had toxic death during treatment. Fifty-one (80.0% patients experienced grade 3-4 mucositis which occurred in about 35% of the CCRT duration. The functional preservation rate among post-CCRT complete responders was 93.5% (43/46. The median cisplatin accumulated dosage was 150 mg, and the rate of hearing impairment among the survivors was 7.8%. Conclusion: CCRT with outpatient-based PTL for advanced SCC of oropharynx and hypopharynx is feasible and has comparative efficacy and acceptable adverse events.

  5. 局部晚期鼻咽癌同期放化疗顺铂单药每周方案剂量递增临床研究%Radiation therapy concurrent with weekly cisplatin therapy for Ioco-regionally advanced nasopharyngeal carcinoma: outcomes of a clinical trial

    Institute of Scientific and Technical Information of China (English)

    Daiyuan Ma; Chunqiao Fu; Bangxian Tan; Mi Liu; Xianfu Li; Yeqin Zhou

    2011-01-01

    Objective: The purpose of this study was to define the maximum tolerated dose (MTD) by describing the doselimiting toxicity (DLT) of weekly cisplatin concurrently with conventional plus 3-dimensional conformal radiotherapy (CT +3DCRT) in patients with loco-regionally advanced nasopharyngeal carcinoma (NPC). Methods: Patients with loco-regionally advanced NPC (Ⅲ/Ⅳa stage) were enrolled into a dose-escalating study. Toxicity was graded according to Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). MTD was defined when 2 of 6 patients developed DLT. The starting dose of cisplatin was 15 mg/m2/w, with a subsequent dose escalation of 5 mg/m2/w in cohorts of 3 new patients. CT +3DCRT was given to the nasopharynx and the upper neck; the lower neck was treated by a single anterior field irradiation. The prescription dose was 70-80 Gy by 35-40 fractions to the nasopharynx gross tumor, and 66-70 Gy by 33-35 fractions to the positive neck lymph nodes. Results: From Jun. 2008 to Sep. 2009, 24 patients received complete chemoradiotherapy, and all of them were eligible for toxicity evaluation. On the first five dose levels of 15 mg/m2/w and 35 mg/m2/w, no patient experienced DLT. On the next dose level of 40 mg/m2/w, 1 patient experienced DLT of grade 3 myelosuppression for 1.4 weeks, and among the additional 3 patients, no one developed DLT. On the seventh dose level of 45 mg/m2/w, all the patients developed grade 3 myelosuppression for more than 1 weeks, and the dose-escalating trial stopped. The 23 (95.8%) patients achieved clinicai complete remission (CR) in the local site; 22 (91.7%) achieved CR in the regional site, and all patients got CR 3 months later. After a median follow-up of 16.4 months, 1 patient developed liver metastases 2 months later, 1 patient developed bone metastases 10 months later and 22 kept disease-free survival. Conclusion: The MTD of cisplatin weekly with concurrent CT + 3DCRT for local advanced NPC is 40 mg/m2/w, with

  6. Chemo radioimmunotherapy with 5-fluorouracil, cisplatin and interferon-{alpha} in pancreatic and peri-ampullary cancer: Results of a feasibility study; Chimioradiotherapie et immunotherapie avec 5-fluoro-uracile, cisplatine et interferon-{alpha} dans les cancers du pancreas et periampullaires: resultats d'une etude de faisabilite

    Energy Technology Data Exchange (ETDEWEB)

    Nitsche, M.; Christiansen, H.; Hermann, R.M.; Hess, C.F. [Goettingen Univ., Dept. of Radiation Oncology (Germany); Horstmann, O.; Becker, H. [Goettingen Univ., Dept. of Surgery (Germany); Pradier, O. [Centre Hospitalier Universitaire, Dept. de cancerologie, 29 - Brest (France); Schmidberger, H. [Mainz Univ., Dept. of Radiation Oncology (Germany)

    2008-12-15

    Background: Recent studies give rise to the hypothesis, that adjuvant chemo radioimmunotherapy with 5-fluorouracil (5-F.U.), cisplatin and interferon-a (I.F.N.-a) might be a possible new treatment of pancreatic cancer in resected patients. We report the up-to-now experience at our institution. Patients and methods: Eleven patients with histological diagnosis of localized carcinoma of the pancreas (n = 7) or peri-ampullary (n = 4) were prospectively analyzed. Four patients were deemed unresectable because of local invasion of adjacent organs (neo-adjuvant setting) and seven patients underwent curative resection (adjuvant setting). Eight patients were classified as T3 carcinomas and three T4 carcinomas. Fifty-five per cent (6/11) of the patients presented with positive lymph node involvement. One histological Grade I, six Grade II and three Grade III were detected. External conformal irradiation to a total dose of 50.4 Gy with 1.8 Gy per day was delivered. All patients received a concomitant chemotherapy with continuous 5-F.U. 200 mg/m{sup 2} per day on 28 treatment days and intravenous bolus cisplatin 30 mg/m{sup 2} per week (Day 2, 9, 16, 23, 30). A recombinant r-I.F.N.-a was administered on three days weekly during Week one to five of the radiotherapy course as subcutaneous injections with 3*3 Mio. I.U. weekly. Results: The four-year overall survival rate for all patients was 55%. In the neo-adjuvant group, three of four patients died due to progressive disease; in the adjuvant group, combined chemo radioimmunotherapy lead to controlled disease in five of seven patients. The overall toxicity was well-managed. Conclusion: Our data strengthens the hypothesis of concomitant chemo radioimmunotherapy with 5-F.U., I.F.N.-a and cisplatin as a possible new treatment of pancreatic cancer in resected patients. (authors)

  7. Protective effect of Panax ginseng in cisplatin-induced cachexia in rats.

    Science.gov (United States)

    Lobina, Carla; Carai, Mauro A M; Loi, Barbara; Gessa, Gian Luigi; Riva, Antonella; Cabri, Walter; Petrangolini, Giovanna; Morazzoni, Paolo; Colombo, Giancarlo

    2014-05-01

    This study investigated the protective effect of a standardized extract of Panax ginseng on multiple cisplatin-induced 'sickness behaviors' (model of cancer-induced cachexia) in rats. Cisplatin was administered twice weekly (1-2 mg/kg, intraperitoneal) for 5 consecutive weeks. Panax ginseng extract (0, 25 and 50 mg/kg, intragastric) was administered daily over the 5-week period of cisplatin exposure. Malaise, bodyweight and temperature, pain sensitivity, and endurance running were recorded at baseline and at 5 weekly intervals. Treatment with cisplatin produced severe signs of malaise, marked loss of bodyweight, hypothermia, hyperalgesia and reduction in running time. Treatment with Panax ginseng extract completely prevented all cisplatin-induced alterations. These data indicate that treatment with Panax ginseng extract exerted a protective effect in a rat model of cachexia and suggest that Panax ginseng extract may be a therapeutic promising tool for supportive care in oncology.

  8. 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.)

  9. N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models.

    Science.gov (United States)

    Muldoon, Leslie L; Wu, Y Jeffrey; Pagel, Michael A; Neuwelt, Edward A

    2015-02-01

    Decreasing oxidative damage with the antioxidant agent N-acetylcysteine (NAC) can block the side effects of chemotherapy, but may diminish anti-tumor efficacy. We tested the potential for interactions of high dose NAC against a minimally effective cisplatin chemotherapy regimen in rat models of human pediatric cancers. Athymic rats received subcutaneous implantation of human SK-N-AS neuroblastoma cells or intra-cerebellar implantation of human D283-MED medulloblastoma cells. Rats were untreated or treated with cisplatin (3 or 4 mg/kg IV) with or without NAC (1,000 mg/kg IV) 30 min before or 4 h after cisplatin treatment. Blood urea nitrogen (BUN) and tumor volumes were measured. Cisplatin decreased the growth of SK-N-AS neuroblastoma subcutaneous tumors from 17.7 ± 4.9 to 6.4 ± 2.5 fold over baseline 2 weeks after treatment (P cisplatin efficacy, while 4 h delayed NAC did not significantly affect cisplatin anti-tumor effects (relative tumor volume 6.8 ± 2.0 fold baseline, P cisplatin efficacy (tumor volume 6.8 ± 8.1 mm(3), P = 0.014 versus control). Cisplatin was minimally nephrotoxic in these models. NAC decreased cisplatin-induced elevations in BUN (P < 0.02). NAC chemoprotection did not alter cisplatin therapy, if delayed until 4 h after chemotherapy. These data support a Phase I/II clinical trial of delayed NAC to reduce ototoxicity in children with localized pediatric cancers.

  10. Combination of Telmisartan with Cisplatin Controls Oral Cancer Cachexia in Rats

    Science.gov (United States)

    Patel, Bhoomika M.; Damle, Deepak

    2013-01-01

    The objective of the present investigation was to study the effect of combination of telmisartan with cisplatin in oral cancer cachexia induced by applying 0.5% 4-nitroquinoline-1-oxide (4-NQO) in propylene glycol to tongue, thrice a week for 8 weeks. From 8th to 22nd week, cisplatin (0.23 mg/kg, i.v.) was administered once in three weeks and telmisartan (5 mg/kg/day, p.o.) was administered daily. 4-NQO produced significant decrease in food intake, body weight, hyperglycemia, dyslipidemia, hypertension, and bradycardia, worsened hemodyanamics, increased cachexia markers like insulin, C-reactive protein, and interleukin-6, and increased tumor markers like lactate dehydrogenase and γ-glutamyl transferase.Treatment with combination of telmisartan with cisplatin produced significant increase in food intake and body weight and controlled hyperglycaemia and dyslipidemia, preserved hemodynamic function, and decreased the cachexia markers while cisplatin alone did not produce any increase in food intake and body weight. Further, the combination of telmisartan with cisplatin significantly reduced tumor marker levels. Combination of telmisartan with cisplatin prevented 4-NQO induced oxidative stress, hyperplasia and hyperkeratosis, premalignant dysplasia, and invasive squamous cell carcinoma in the tongue. Our data suggests that combination of telmisartan with cisplatin treatment is beneficial in controlling cancer cachexia. Telmisartan can be used as an add-on therapy with cisplatin or other traditional chemotherapeutic agents. PMID:24381940

  11. 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...

  12. 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.

  13. 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.

  14. Cisplatin induced paroxysmal supraventricular tachycardia.

    Science.gov (United States)

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

    2013-10-01

    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 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.

  15. Haemolytic anaemia after cisplatin treatment.

    OpenAIRE

    Levi, J A; Aroney, R S; Dalley, D N

    1981-01-01

    Normochromic or normocytic anaemia is a common side effect of treatment with cisplatin. Two patients treated with cisplatin 100 mg/m2 in combination with vinblastine, bleomycin, and actinomycin D developed haemolytic anaemia. Neither patient had evidence of haemolysis before treatment, and in both cases severe haemolytic anaemia developed after several courses of cisplatin and when the cancer had regressed almost completely. The importance of haemolysis in the development of anaemia after cis...

  16. Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells

    DEFF Research Database (Denmark)

    Sørensen, Belinda Halling; Dam, Celina Støving; Stürup, Stefan;

    2016-01-01

    component of volume sensitive channels for organic osmolytes (VSOAC) and volume regulated anion channels (VRAC), which are activated during the apoptotic process. Here we illustrate that cisplatin resistance in human ovarian cancer cells (A2780) correlates with a reduced expression of LRRC8A and copper...... transporter receptor 1 (CTR1), as well as a concomitant increased expression of copper-transporting P-type ATPases (ATP7A/ATP7B). We also find that cisplatin (Pt) accumulation correlates with LRRC8A protein expression and channel activity, i.e., the cellular Pt content is high when VSOAC is activated...... expression in cisplatin-resistant A2780 cells ensures cell survival through limitation in cisplatin accumulation and a concomitant reduction in osmolytes loss via VSOAC/VRAC and hence instigation of the apoptotic process....

  17. 周剂量多西他赛联合顺铂、5-FU治疗晚期食管癌的临床观察%Weekly docetaxel combined with cisplatin and 5-Fu in patients with advanced esophageal carcinoma

    Institute of Scientific and Technical Information of China (English)

    陆向东; 张汀荣

    2011-01-01

    Objective: To evaluate the clinical efficacy and toxicity of weekly docetaxel combined with cisplatin and 5 -FU in patients with advanced esophageal carcinoma.Methods: Total of 47 patients with advanced esophageal carcinoma received docetaxel 30mg/m2 iv d1 ,8,15 , cisplatin 20mg/m2 iv d1-5 , 5 - FU 500mg/m2 iv d1-5.Treatments were repeated every 28 days.The clinical responses were assessed after two cycles.Toxicity was assessed every cycle.Results: All of the 47 patients were assessable for response,3 case of complete response and 21 cases of partial response were confirmed, eith an overall response rate of 51.06%.The median time to progression( TTP ) was 149 days and the median survival time( MST ) was 274 days.The major toxicity was myelosuppression, neutropenia of grade Ⅲ/Ⅳ occurred in 13 patients ( 27.7% ),thrombocytopenia of grade Ⅲ in 3 patients( 6.4% ) and anemia of Ⅲ in 5 patients( 10.6% ).There was no treatment - related death.Conclusion: Weekly docetaxel combined with cisplatin and 5 - FU is effective and well tolerated for patients with advanced esophageal carcinoma.%目的:观察周剂量多西他赛联合顺铂、5-FU治疗晚期食管癌的临床疗效及不良反应.方法:47例晚期食管癌患者,应用多西他赛30mg/m2 静脉滴注第1、8、15天,顺铂20mg/m2 静脉滴注第1-5天,5-FU 500mg/m2 静脉滴注第1-5天,每28天重复.治疗2个周期评价疗效,每周期评价毒性.结果:47例患者均可评价疗效.获CR 3例,PR 21例,总有效率(CR+PR)为51.06%.所有患者中位疾病进展时间为149天,中位生存时间274天.主要不良反应为骨髓抑制,出现Ⅲ/Ⅳ度中性粒细胞减少13例(27.7%),Ⅲ度血小板减少3例(6.4%),Ⅲ度贫血5例(10.6%),无治疗相关性死亡.结论:周剂量多西他赛联合顺铂、5-FU治疗晚期食管癌疗效较好,毒性可以耐受,值得临床进一步研究.

  18. Cisplatin-Induced Eosinophilic Pneumonia

    Directory of Open Access Journals (Sweden)

    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.

  19. Effect of cisplatin on proximal convoluted and straight segments of the rat kidney

    DEFF Research Database (Denmark)

    Daugaard, G; Holstein-Rathlou, N H; Leyssac, P P

    1988-01-01

    The immediate effect of cisplatin on rat proximal tubular function was investigated by two different methods, the lithium clearance method and the occlusion time-transit time method (TT-OT). Within minutes after administration of cisplatin a significant increase in lithium clearance, fractional...... and the late proximal convoluted tubule after cisplatin administration. Concomitantly absolute proximal reabsorption rate was significantly decreased. Intervention by saline loading (2% of body weight) did not prevent the increase in e-TT/OT, but the increase in CLi/Cin was significantly less than...... in the control group. This finding suggests that saline loading protects either the pars recta of the proximal tubule or the juxtamedullary nephrons. Thus, cisplatin-induced nephrotoxicity in the rat is initiated by an acute mainly proximal tubular impairment including both pars convoluta and pars recta...

  20. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma

    NARCIS (Netherlands)

    Perilongo, G.; Maibach, R.; Shafford, E.; Brugieres, L.; Brock, P.; Morland, B.; de Camargo, B.; Zsiros, J.; Roebuck, D.; Zimmermann, A.; Aronson, D.; Childs, M.; Widing, E.; Laithier, V.; Plaschkes, J.; Pritchard, J.; Scopinaro, M.; Czauderna, P.

    2009-01-01

    Background: Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). Methods: Children with standard-risk hepato

  1. 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.

  2. Arterial Emboli Complicating Cisplatin Therapy

    OpenAIRE

    Tait, Campbell D.; Rankin, Elaine M

    2012-01-01

    We report three cases of arterial emboli in patients with lung cancer treated with cisplatin chemotherapy. All three patients were managed without surgical intervention but subsequent oncological treatment was complicated by the sequelae of arterial emboli. We discuss the issues surrounding these patients and the importance of identifying patients at risk of arterial embolic phenomena with cisplatin treatment.

  3. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway

    Directory of Open Access Journals (Sweden)

    Kilic Ulkan

    2013-01-01

    Full Text Available Abstract Background Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo. Methods Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days, cisplatin treatment (7 mg/kg b.w., i.p. and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-κB and AP-1 in Western blot analysis. Results Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin

  4. A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats

    Directory of Open Access Journals (Sweden)

    Mehdi Nematbakhsh

    2013-01-01

    Full Text Available Background: Cisplatin (cis-diamminedichloroplatinum II; CP is used widely as an antitumor drug in clinics, but is accompanied with renal toxicity. Cisplatin induced nephrotoxicity consists of change in kidney weight, histological changes in kidney and increase in serum creatinine (Cr and blood urea nitrogen (BUN. This study was designed to find out a model for prediction of cisplatin induced nephrotoxicity. Materials and Methods: Pathological damage score, kidney weight, BUN, and Cr of 227 rats that were involved in different projects were determined. A total of 187 rats were treated with 7 mg/kg cisplatin and sacrificed 1 week later. Results: There was a good significant correlation between normalized kidney weight and logarithmic scale of BUN and Cr. Relationship between BUN, Cr or normalized kidney weight and pathology damage score was significant. Conclusion: Normalized kidney weight and pathology damage score is a good predictor of renal function in cisplatin induced nephrotoxicity in experimental rats.

  5. 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.

  6. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma.

    OpenAIRE

    Perilongo, G.; Maibach, R; Shafford, E.; Brugieres, L; Brock, P; Morland, B.; de Camargo, B; Zsiros, J.; Roebuck, D; Zimmermann, A; Aronson, D.; Childs, M.; Widing, E.; Laithier, V.; Plaschkes, J.

    2009-01-01

    BACKGROUND: Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). METHODS: Children with standard-risk hepatoblastoma who were younger than 16 years of age were eligible for inclusion in the study. After they received one cycle of cisplatin (80 mg per square meter of body-surface area per 24 hours), we...

  7. Sensitization of Cervical Cancer Cells to Cisplatin by Genistein: The Role of NFB and Akt/mTOR Signaling Pathways

    Directory of Open Access Journals (Sweden)

    K. Sahin

    2012-01-01

    Full Text Available Cervical cancer is among the top causes of death from cancer in women. Cisplatin-based chemotherapy has been shown to improve survival; however, cisplatin treatment is associated with toxicity to healthy cells. Genistein has been used as an adjunct to chemotherapy to enhance the activity of chemotherapeutic agents without causing increased toxicity. The present study was designed to investigate the effect of genistein (25 μM on antitumor activity of cisplatin (250 nM on HeLa cervical cancer cells. We have examined the alterations in expression of NF-B, p-mTOR, p-p70S6K1, p-4E-BP1, and p-Akt protein levels in response to treatment. The combination of 25 μM genistein with 250 nM cisplatin resulted in significantly greater growth inhibition (. Genistein enhanced the antitumor activity of cisplatin and reduced the expression of NF-B, p-mTOR, p-p70S6K1, p-4E-BP1, and p-Akt. The results in the present study suggest that genistein could enhance the activity of cisplatin via inhibition of NF-κB and Akt/mTOR pathways. Genistein is a promising nontoxic nutritional agent that may enhance treatment outcome in cervical cancer patients when given concomitantly with cisplatin. Clinical trials of genistein and cisplatin combination are warranted to test this hypothesis.

  8. Efficacy and safety of fosaprepitant for the prevention of nausea and emesis during 5 weeks of chemoradiotherapy for cervical cancer (the GAND-emesis study)

    DEFF Research Database (Denmark)

    Ruhlmann, Christina H; Christensen, Thomas Broe; Dohn, Line Hammer

    2016-01-01

    3 adverse events none of which were related to the study treatment; the most common grade 3 adverse event during the 5 weeks of treatment was diarrhoea (11 [9%] of 118 patients in the fosaprepitant group vs six [5%] of 116 patients in the placebo group). There was only one report of a grade 4......BACKGROUND: The role of the neurokinin-1 (NK-1) receptor antagonists in the prevention of radiation-induced nausea and vomiting has not been established. The purpose of the GAND-emesis study was to investigate the efficacy and safety of fosaprepitant in combination with palonosetron...... adverse event (neutropenia), in the fosaprepitant group. No deaths were recorded in either group. INTERPRETATION: To our knowledge, this is the first study to investigate safety and efficacy of a NK-1 receptor antagonist during 5 weeks of radiotherapy and concomitant weekly cisplatin. Patients receiving...

  9. Enhanced effects of bleomycin on pulmonary function disturbances in patients with decreased renal function due to cisplatin

    NARCIS (Netherlands)

    Sleijfer, S; vanderMark, TW; Mulder, NH; Schraffordt Koops, H.

    1996-01-01

    We examined whether cisplatin-induced nephrotoxicity augmented bleomycin-induced pulmonary toxicity in patients with testicular cancer treated with etoposide and cisplatin with (BEP) or without bleomycin (EP). Before and at 3-week intervals during chemotherapy, creatinine clearance and lung function

  10. Effect of Cisplatin on Glomerular Filtration Rate and Effective Renal Plasma Flow

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Sang Moo; Hong, Sung Woon; Kim, Young Hyun; Hong, Weon Seon; Song, Jae Kwan; Kim, Young Whan; Lee, Jhin Oh; Kang, Tae Woong [Korea Cancer Canter Hospital, Seoul (Korea, Republic of)

    1989-03-15

    While cisplatin has been widely used in the treatment of a variety of cancers, nephrotoxicity is one of the major problems which frequently limit clinical usefulness of cisplatin. This study has been conducted to investigate nephrotoxicity of cisplatin in terms of changes in glomerular filtration rate (GFR) and effective renal plasma flow (EFPF) measured by the simultaneous use of {sup 99m}Tc-DTPP and {sup 131}I-OIH, before and after administration of cisplatin, in 12 patients with lung cancer and four patients with esophageal cancer. Cisplatin was administrated at total doses of 75-100 mg/m{sup 2} with two hour hydration and diuresis method. GFR determined by the use of {sup 99m}Tc-DTPA had a good correlation with 24-hour creatinine clearance rate (r=0.77, p<0.001). GFR and filtration fraction decreased immediately after administration of cisplatin, however, they showed a tendency to be in completely recovered four weeks after administration. ERPF was not changed immediately after and four weeks after administration of cisplatin. GFR before and immediately after administration of cisplatin were analyzed with regard to age, sex, performance status, previous administration of cisplatin and method of administration. None of these factors had any influence on the rate of decrease in GFR except method of administration. Administration of cisplatin as a single dose lowered GFR more compared with that as divided doses. In this study, we have also demonstrated that the simultaneous use of {sup 99m}Tc-DTPA and {sup 131}I-OIH was a useful tool for the measurement of GFR and ERPF respectively.

  11. Effect of free creatine therapy on cisplatin-induced renal damage.

    Science.gov (United States)

    Genc, Gurkan; Okuyucu, Ali; Meydan, Bilge Can; Yavuz, Oguzhan; Nisbet, Ozlem; Hokelek, Murat; Bedir, Abdulkerim; Ozkaya, Ozan

    2014-08-01

    Abstract Cisplatin is one of the commonly used anticancer drugs and nephrotoxicity limits its use. The aim of this study is to investigate the possible protective effect of creatine supplementation on cisplatin-induced nephrotoxicity. Sixty male Sprague-Dawley rats were divided into three groups: Group I: Cisplatin (n=20) (7 mg/kg cisplatin intraperitoneal (i.p.) single dose), group II: Cisplatin+creatine monohydrate (n=20) (7 mg/kg cisplatin i.p. single dose and 300 mg/kg creatine p.o. daily for 30 days starting on first day of cisplatin injection), group III: Control group (n=20) (Serum physiologic, 2.5 mL/kg i.p.). Sacrifications were performed at first week and 30th day. Blood urea nitrogen (BUN) and serum creatinine levels, histopathological evaluation, mitochondrial deoxyribonucleic acid (mtDNA) common deletion rates, and body weights of rats were evaluated. A significant decrease in body weight, higher values of kidney function tests, histopathological scores, and mtDNA deletion ratios were observed in group I compared to control group at days 7 and 30 (pcreatine significantly reversed kidney functions and pathological findings, this improvement was not sufficient to reach normal control group's results at days 7 and 30. In conclusion, the present study demonstrates that creatine administration is a promising adjuvant protective drug for reducing nephrotoxic effect of cisplatin.

  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. Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes.

    Science.gov (United States)

    Kim, Se-Jin; Ho Hur, Joon; Park, Channy; Kim, Hyung-Jin; Oh, Gi-Su; Lee, Joon No; Yoo, Su-Jin; Choe, Seong-Kyu; So, Hong-Seob; Lim, David J; Moon, Sung K; Park, Raekil

    2015-02-20

    Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH.

  14. Central Diabetes Insipidus and Cisplatin-Induced Renal Salt Wasting Syndrome: A Challenging Combination.

    Science.gov (United States)

    Cortina, Gerard; Hansford, Jordan R; Duke, Trevor

    2016-05-01

    We describe a 2-year-old female with a suprasellar primitive neuroectodermal tumor and central diabetes insipidus (DI) who developed polyuria with natriuresis and subsequent hyponatremia 36 hr after cisplatin administration. The marked urinary losses of sodium in combination with a negative sodium balance led to the diagnosis of cisplatin-induced renal salt wasting syndrome (RSWS). The subsequent clinical management is very challenging. Four weeks later she was discharged from ICU without neurological sequela. The combination of cisplatin-induced RSWS with DI can be confusing and needs careful clinical assessment as inaccurate diagnosis and management can result in increased neurological injury.

  15. CISPLATIN I KAMPEN MOD CANCER

    OpenAIRE

    Hasle Rasmussen, Cecilie; Cohen Pedersen, Sarah; Gamsgaard, Christian; Mads Pedersen, Christoffer; Lindberg, Sanne

    2016-01-01

    This study focuses on the conveying of a teaching material based on the subject of cisplatin, more specifically “Cisplatin as a chemotherapeutic remedy against cancer”. Our paper attempts to analyze the possibility of conveying complex knowledge with regards to e.g. coordination chemistry in an interdisciplinary booklet that incorporates both scientific knowledge of level A chemistry and level B biology, of Danish STX standards. Furthermore, this paper will take into account the governmental ...

  16. 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/cisplatin....Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/cisplatin...in_vivo/Liver/Repeat/cisplatin.Rat.in_vivo.Liver.Repeat.zip ftp://ftp.bioscienced...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 ...

  17. 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.)

  18. 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.

  19. Protective effect of riboflavin on cisplatin induced toxicities: a gender-dependent study.

    Science.gov (United States)

    Naseem, Imrana; Hassan, Iftekhar; Alhazza, Ibrahim M; Chibber, Sandesh

    2015-01-01

    The toxicity exerted by the anticancer drug, cisplatin in vivo is functional to many factors such as dose, duration, gender and age etc. The present study is aimed to investigate if ameliorative potential of riboflavin on cisplatin induced toxicity is gender dependent. Eighty four adult mice from male and female sex were divided into seven groups (n=6) for both sexes. They were treated with riboflavin (2mg/kg), cisplatin (2mg/kg) and their two different combinations (cisplatin at 2mg/kg with 1mg/kg and 2mg/kg of riboflavin) under photoillumination with their respective controls for the combination groups without photoillumination. After treatment, all groups were sacrificed and their kidney, liver and serum were collected for biochemical estimations, comet assay and histopathology. In the present investigation, it was evident from antioxidant and detoxification studies (SOD, CAT, GSH, GST, MDA and carbonyl level) that the female mice exhibited better tolerance towards cisplatin inducted toxicity and the ameliorative effect of riboflavin against cisplatin toxicity was found stronger in their combination groups as compared to the male groups as the activity of all antioxidant enzymes were found better concomitant with lower level of MDA and carbonyl contents in the female combination groups than their male counterparts. Furthermore, single cell gel electrophoresis and histopathological examination confirmed that restoration of normal nuclear and cellular integrity was more prominent in female with respect to the males after treatment in the combination groups in a dose-dependent manner. Hence, this study reveals that cisplatin is more toxic in male mice and the ameliorative effect of riboflavin against cisplatin toxicity is stronger in female mice.

  20. The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity.

    Directory of Open Access Journals (Sweden)

    Kristien J Ledeganck

    Full Text Available Cisplatin-induced hypomagnesemia is described in humans and rats, but the underlying mechanisms are still unclear. Recent studies have shown that epidermal growth factor (EGF stimulates Mg(2+ re-absorption in the distal convoluted tubule via the Mg(2+ channel TRPM6. This study investigates the role of TRPM Mg(2+ channels, claudines, and EGF in the Mg(2+ homeostasis in a rat model of cisplatin-induced nephrotoxicity. Wistar rats were given 2.5 mg/kg cisplatin per week for 3 weeks and were euthanized 4 or 9 weeks after the first administration. The cisplatin treatment significantly increased the fractional excretion of Mg(2+. Real-time RT-PCR and/or Western blots were performed to assess the renal expression TRPM6, TRPM7, claudin-16, claudin-19, EGF, EGF receptor (EGFR and EGFR-pathway components. The renal mRNA expression of TRPM6 and EGF showed a significant decrease after cisplatin treatment, while the TRPM7, claudin-16 and EGFR expressions remained stable. The claudin-19 mRNA expression was significantly upregulated after cisplatin treatment. Western blotting confirmed the mRNA expression data for the claudins, but an showed upregulation of EGFR only at week 9. The role of the EGFR pathway, involving Pi3-AKT-Rac1, in cisplatin-induced nephropathy, could not be substantiated in further detail. This study shows that cisplatin treatment results in EGF and TRPM6 downregulation in the rat kidney, causing renal Mg(2+ loss. Our results are in line with the hypothesis that EGF influences the renal expression or activation of TRPM6 and plays a significant role in Mg(2+ loss in medication-induced nephropathy.

  1. Cisplatin-induced hyperglycaemic hyperosmolar coma

    NARCIS (Netherlands)

    Komdeur, R.; Derksen, J.; Legdeur, M-C.; Hylkema, B. S.

    2007-01-01

    We present a case of severe hyperglycaemic hyperosmolar derangement after treatment with cisplatin in a patient without previous diabetes mellitus. Limited data are available on this adverse reaction, explaining why impaired glucose handling due to cisplatin is not generally recognised.

  2. The effect of Thespesia populnea on cisplatin induced nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Denish Mika

    2013-01-01

    Full Text Available Aim of the Study: To study the effect of Thespesia populnea on Cisplatin induced Nephrotoxicity. Materials and Methods: Experiments were conducted on Male Sprague Dawley Rats (4-6 weeks old weighing 100-120g B.Wt. The drug under study was cisplatin, which is an anticancer drug. Thespesia populnea extract was used to test its ability to alleviate the harmful effects of cisplatin. The animals were divided into three groups: Group I was considered as normal, Group II was given a single dose of cisplatin (6 mg/kg/b.wt., i.p and they constituted the control animals and Group III was treated with cisplatin along with Thespesia populnea (5 mg/kg/b.wt., i.p for 10 consecutive days. Results: Administration of cisplatin resulted in significant (P < 0.05 increase in the levels of serum urea (137 ± 1.6, creatinine (1.69 ± 0.14, ALT (96.18 ± 3.44, AST (80.84 ± 3.34 and bilirubin (4.57 ± 0.08 as compared to normal animals. On the other hand, introduction of Thespesia populnea extract caused a significant (P < 0.05 reduction in the levels of serum markers namely urea (112 ± 2.16, creatinine (0.54 ± 0.004, ALT (76.4 ± 1.45, AST (58.80 ± 1.6 and bilirubin (3.96 ± 0.85. Discussion: Increase in the levels of urea and creatinine in serum as well as ALT, AST and bilirubin is suggestive of both kidney and liver damage. Thespesia populnea extract ameliorated cisplatin induced kidney and liver damage as indicated by reduction in the levels of serum urea, creatinine, AST, ALT and bilirubin. Reduction in the levels of these biochemical markers is an indication of regeneration process. Thus it is concluded that the extract might contain nephroprotective compounds such as flavonoids, alkaloids, etc. which are responsible for alleviating cisplatin induced toxicity.

  3. Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial.

    Science.gov (United States)

    Caponigro, Francesco; Di Gennaro, Elena; Ionna, Franco; Longo, Francesco; Aversa, Corrado; Pavone, Ettore; Maglione, Maria Grazia; Di Marzo, Massimiliano; Muto, Paolo; Cavalcanti, Ernesta; Petrillo, Antonella; Sandomenico, Fabio; Maiolino, Piera; D'Aniello, Roberta; Botti, Gerardo; De Cecio, Rossella; Losito, Nunzia Simona; Scala, Stefania; Trotta, Annamaria; Zotti, Andrea Ilaria; Bruzzese, Francesca; Daponte, Antonio; Calogero, Ester; Montano, Massimo; Pontone, Monica; De Feo, Gianfranco; Perri, Francesco; Budillon, Alfredo

    2016-11-25

    Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to down regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition (EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic disorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may be to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the possible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR. V-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell carcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration of cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from day -14 with a titration strategy in each patient (target serum level of 50-100 μg/ml). Primary end point is the objective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size, calculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit for rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18 responses. Secondary endpoints are time to progression, duration of response

  4. Low toxicity and anticancer activity of a novel liposomal cisplatin (Lipoplatin) in mouse xenografts.

    Science.gov (United States)

    Boulikas, Teni

    2004-07-01

    Cisplatin has been one of the most widely used and most effective cytotoxic agents in the treatment of malignancies but causes severe adverse reactions including nausea/vomiting, renal toxicity, gastrointestinal toxicity, peripheral neuropathy, asthenia, and ototoxicity. A liposomal formulation of cisplatin, Lipoplatin, was developed in order to reduce the systemic toxicity of cisplatin. A single treatment of rats with 30 mg/kg Lipoplatin resulted in no toxicity whereas 2 or 3 weekly administrations at 30 mg/kg to rats gave neutropenia but no nephrotoxicity. On the contrary, a single injection to rats of 5 mg/kg cisplatin resulted in severe nephrotoxicity. Thus, Lipoplatin is less toxic than cisplatin in rats. Intraperitoneal or intravenous injection of Lipoplatin to SCID (severe combined immunodeficient) mice with subcutaneous breast MCF-7 or prostate LNCaP human tumors resulted in size reduction of the tumors; histological examination of the treated tumors in xenografts was consistent with apoptosis in tumor cells; thus, Lipoplatin appears to exert its cytotoxic effects to tumors in a mechanism similar to that of cisplatin. The preclinical studies reported here set the foundation for the clinical use of Lipoplatin as an exciting new drug with lower toxicity than cisplatin, endowed with proapoptotic properties.

  5. Future opportunities in preventing cisplatin induced ototoxicity

    NARCIS (Netherlands)

    J.H. van den Berg; J.H. Beijnen; A.J.M. Balm; J.H.M. Schellens

    2006-01-01

    Cisplatin is one of the most commonly used cytotoxic agents. ototoxicity is an important and dose-limiting side-effect of cisplatin therapy. It is believed that cisplatin suppresses the formation of endogenous anti-oxidants that normally prevent the inner ear against reactive oxygen species (ROS). T

  6. Matricaria chamomilla attenuates cisplatin nephrotoxicity.

    Science.gov (United States)

    Salama, Ragaa H M

    2012-07-01

    Matricaria chamomilla is extensively consumed as a tea or tonic. Despite its widespread use as a home remedy, relatively few trials evaluated its benefits in nephro protection. Hence, this study evaluates the protective role of M. chamomilla in cisplatin nephrotoxicity rat model. The study was conducted on 32 rats divided into four groups. The first group (G1) was injected with saline intra-peritoneally (IP); G2 was injected with 5 mg/kg cisplatin on day 0 of the experiment and repeated four times, with five days free interval. G3 and G4 were injected daily with M. chamomilla (50 mg/kg) IP, starting five days before the experiment (-5 day); in addition, G4 was injected with cisplatin. On day 16, animals were scarified and serum and/or kidney tissue was used to determine: (a) kidney function tests (serum urea, creatinine, gamma glutamyl transferase (GGT), NAG, β-gal), (b) oxidative stress indices (NO, LPO), (c) antioxidant activities (SOD, GSH, total thiols), (d) apoptotic indices (Cathepsin D, DNA fragmentation) and (e) mineral (calcium). M. chamomilla significantly increased the body weight, normalized the kidney functions, improved the apoptotic markers, reduced the oxidative stress markers and corrected the hypo-calcemia that resulted from cisplatin nephrotoxicity. M. chamomilla is a promising nephro-protective compound reducing cisplatin nephrotoxicity most probably by its antioxidant activities and inhibition of gamma glutamyl transferase activity.

  7. Matricaria chamomilla attenuates cisplatin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Ragaa H.M. Salama

    2012-01-01

    Full Text Available Matricaria chamomilla is extensively consumed as a tea or tonic. Despite its widespread use as a home remedy, relatively few trials evaluated its benefits in nephro protection. Hence, this study evaluates the protective role of M. chamomilla in cisplatin nephrotoxicity rat model. The study was conducted on 32 rats divided into four groups. The first group (G1 was injected with saline intra-peritoneally (IP; G2 was injected with 5 mg/kg cisplatin on day 0 of the experiment and repeated four times, with five days free interval. G3 and G4 were injected daily with M. chamomilla (50 mg/kg IP, starting five days before the experiment (-5 day; in addition, G4 was injected with cisplatin. On day 16, animals were scarified and serum and/or kidney tissue was used to determine: (a kidney function tests (serum urea, creatinine, gamma glutamyl transferase (GGT, NAG, β-gal, (b oxidative stress indices (NO, LPO, (c antioxidant activities (SOD, GSH, total thiols, (d apoptotic indices (Cathepsin D, DNA fragmentation and (e mineral (calcium. M. chamomilla significantly increased the body weight, normalized the kidney functions, improved the apoptotic markers, reduced the oxidative stress markers and corrected the hypo-calcemia that resulted from cisplatin nephrotoxicity. M. chamomilla is a promising nephro-protective compound reducing cisplatin nephrotoxicity most probably by its antioxidant activities and inhibition of gamma glutamyl transferase activity.

  8. 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

  9. Cisplatin and cranial irradiation-related hearing loss in children.

    Science.gov (United States)

    Warrier, Rajasekharan; Chauhan, Aman; Davluri, Murali; Tedesco, Sonya L; Nadell, Joseph; Craver, Randall

    2012-01-01

    High doses of cisplatin and cranial radiotherapy (CRT) have been reported to cause irreversible hearing loss. The objective of this study was to examine the influence of cranial irradiation on cisplatin-associated ototoxicity in children with pediatric malignancies. Serial audiograms were obtained for 33 children, age <16 years, treated with cisplatin-based chemotherapy (90-120 mg/m(2) per cycle) with or without CRT. Eligible patients included those with normal baseline audiometric evaluations and without significant exposure to other ototoxic drugs. We defined significant hearing loss as a hearing threshold ≥30 dB at 2,000-8,000 Hz frequencies. The median age of our study population was 4.9 years (range 6 weeks to 16 years), and the male to female ratio was 0.8:1. The study population consisted of 15 Caucasians, 17 African-Americans, and 1 Hispanic. Fourteen patients had brain tumors, and 19 had other solid tumors. Thirteen patients were exposed to CRT, and 20 were not. Bilateral hearing loss was observed in 24/33 (73%) patients, with severe/profound (≥70 dB) impairment in 10/33 (30%) of all patients. Young age (<5 years), CRT, and brain tumors were independent prognostic factors predicting hearing loss. The study demonstrated a high incidence of hearing loss in children treated with cisplatin and CRT. Consequently, we recommend monitoring these children for the early detection of hearing loss.

  10. Taurine protects cisplatin induced cardiotoxicity by modulating inflammatory and endoplasmic reticulum stress responses.

    Science.gov (United States)

    Chowdhury, Sayantani; Sinha, Krishnendu; Banerjee, Sharmistha; Sil, Parames C

    2016-11-12

    Oxidative stress, ER stress, inflammation, and apoptosis results in the pathogenesis of cisplatin-induced cardiotoxicity. The present study was designed to investigate the signaling mechanisms involved in the ameliorating effect of taurine, a conditionally essential amino acid, against cisplatin-mediated cardiac ER stress dependent apoptotic death and inflammation. Mice were simultaneously treated with taurine (150 mg kg(-1) body wt, i.p.) and cisplatin (10 mg kg(-1) body wt, i.p.) for a week. Cisplatin exposure significantly altered serum creatine kinase and troponin T levels. In addition, histological studies revealed disintegration in the normal radiation pattern of cardiac muscle fibers. However, taurine administration could abate such adverse effects of cisplatin. Taurine administration significantly mitigated the reactive oxygen species production, alleviated the overexpression of nuclear factor-κB (NF-κB), and inhibited the elevation of proinflammatoy cytokines, adhesion molecules, and chemokines. Cisplatin exposure resulted in the unfolded protein response (UPR)-regulated CCAAT/enhancer binding protein (CHOP) up-regulation, induction of GRP78: a marker of ER stress and eIF2α signaling. Increase in calpain-1 expression level, activation of caspase-12 and caspase-3, cleavage of the PARP protein as well as the inhibition of antiapoptotic protein Bcl-2 were reflected on cisplatin-triggered apoptosis. Taurine could, however, combat against such cisplatin induced cardiac-abnormalities. The above mentioned findings suggest that taurine plays a beneficial role in providing protection against cisplatin-induced cardiac damage by modulating inflammatory responses and ER stress. © 2016 BioFactors, 42(6):647-664, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

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

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    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.

  12. Pharmacogenomics of cisplatin-induced ototoxicity

    Science.gov (United States)

    Mukherjea, Debashree; Rybak, Leonard P

    2011-01-01

    Cisplatin ototoxicity affects different individuals in a widely variable manner. These variations are likely to be explained by genetic differences among those affected. It would be highly advantageous to identify genetic variants that predispose to cisplatin ototoxicity in order to minimize the risk to susceptible subgroups. Although this area of research is very important, only a few studies have rigorously examined the genetic basis for cisplatin-induced susceptibility to hearing loss. This article addresses recent progress in clarifying the incidence of cisplatin ototoxicity and the risk factors and controversies regarding the identifcation of genetic variants associated with cisplatin-induced hearing loss. PMID:21787192

  13. 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...... 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 distal...

  14. Two consecutive days of treatment with liposomal cisplatin in non-small cell lung cancer.

    Science.gov (United States)

    Stathopoulos, G P; Stathopoulos, J; Dimitroulis, J

    2012-11-01

    Liposomal cisplatin (Lipoplatin) is a new agent, a cisplatin formulation that has been investigated in a number of studies and compared with cisplatin with respect to toxicity and effectiveness. It has been administered once weekly and in combination with a second agent, once every two weeks. The main outcome of the studies was that lipoplatin has no renal toxicity and is as equally effective as cisplatin. The present study investigated toxicity and effectiveness when lipoplatin is administered on two consecutive days, repeated every two weeks. Between January 2011 and November 2011, a total of 21 patients with histologically- or cytologically-confirmed non-small cell lung cancer (NSCLC) were enrolled in the study. All but two patients, who had not been pretreated, had received one or two series of chemotherapy and some had undergone radiotherapy. Lipoplatin monotherapy was infused for 8 h the first and second days and repeated every 2 weeks with the aim of administering 6 cycles. The dose per day was 200 mg/m(2). Eight out of 21 (38.10%) patients had a partial response, 9 (42.86%) had stable disease and 4 (19.05%) had progressive disease. Results showed that there was no renal failure toxicity and no other adverse reactions apart from grade 1 myelotoxicity in only 2 patients who had been heavily pretreated, and grade 1 nausea/vomiting in 4 patients. Liposomal cisplatin is an agent with negligible toxicity and reasonably high effectiveness even when administered to pretreated patients with NSCLC.

  15. The protective role of tetramethylpyrazine against cisplatin-induced ototoxicity.

    Science.gov (United States)

    Bayram, Ali; Kaya, Altan; Akay, Ebru; Hıra, İbrahim; Özcan, İbrahim

    2017-03-01

    The aim of the present study was to investigate the protective effect of tetramethylpyrazine (TMP) on cisplatin-induced ototoxicity in rats. Forty healthy, female, 24-week-old, Sprague-Dawley rats (n = 40) were randomly assigned to four groups as follows: group one (n = 10) received intraperitoneal (i.p.) physiological saline at daily doses of 3 mg/kg for seven days; group two (n = 10) received a single dose of i.p. 15 mg/kg cisplatin; group three (n = 10) received i.p. 140 mg/kg TMP daily for seven days plus a single dose of i.p. 15 mg/kg cisplatin on the fourth day; group four (n = 10) received i.p. 140 mg/kg TMP daily for seven days. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements were obtained from the animals (40 rats, 80 ears) under general anesthesia before and after drug administration. The temporal bulla of animals were bilaterally removed for immunohistopathological examination. In group two, DPOAE and ABR values were significantly deteriorated after drug administration, whereas there was no statistically significant difference between the pre- and posttreatment DPOAE and ABR values for all frequencies for groups one, three and four. The mean scores for external ciliated cells (ECCs), stria vascularis (SV) and spiral ganglion (SG) injuries in hematoxylin and eosin (H&E) staining, and also caspase-3 immunoreactivity were significantly higher in group two than in the other groups. In the present study, the protective effect of TMP on cisplatin ototoxicity was demonstrated through studies of electrophysiology and immunohistopathology. Co-administration of TMP may have potential protective effects against cisplatin-induced ototoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. 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 neur...

  17. Membrane Transition Temperature Determines Cisplatin Response.

    Directory of Open Access Journals (Sweden)

    Krishnan Raghunathan

    Full Text Available 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.

  18. Weekly Performance

    Institute of Scientific and Technical Information of China (English)

    1994-01-01

    There are many retired people living in Beijing. In order to amuse themselves and improve their health, some have formed yangko (folk dance) teams on a voluntary basis. Ordinarily they do the yangko individually and gather to perform on Sundays. Wearing traditional costumes and forming a circle, yangko teams’ members are enthusiastic about their activity, known as a "weekly performance."

  19. 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.

  20. Treatment of small cell lung cancer with TRA-8 in combination with cisplatin and radiation.

    Science.gov (United States)

    Bonner, James A; Willey, Christopher D; Yang, Eddy S; Dobelbower, Michael C; Sanford, Leisa L; Bright, Sheila J; Buchsbaum, Donald J; Raisch, Kevin P

    2011-10-01

    Limited stage small cell lung cancer (SCLC) represents a minority of SCLC. Despite extensive clinical trials, standard treatment remains cisplatin-based chemotherapy and thoracic irradiation (TI). This study focused on the interaction of cisplatin/radiation with the anti-human DR5 monoclonal antibody TRA-8 in SCLC cells. TRA-8 binds specifically to DR5 and has been shown to activate apoptosis. Four human SCLC cell lines were utilized for experimentation (SCLC-41, SCLC-58, SCLC-68, and SCLC-74). Immunoblot analysis was used to determine relative protein levels of DR5, DR4 and pro-caspase 8 for each cell line. Using a tetrazolium-based assay (XTT), the IC(50) values for cisplatin with or without TRA-8 were determined for the SCLC cell lines. Four SCLC lines were assayed with a combination of TRA-8 (10 μg/ml), 2 Gy radiation and various concentrations of cisplatin. Apoptosis was evaluated using Annexin V-FITC and cleaved caspase immunoblotting. Using a SCLC-58 subcutaneous xenograft model, treatment began 21 d after tumor cell injection. Treatment included weekly cisplatin (4 mg/kg) and radiation of 1 Gy (24 h after cisplatin) and TRA-8 (200 μg) was administered i.p. twice weekly for three weeks. Immunoblot analysis showed similar levels of DR5 for all cell lines with variable levels of DR4. Various concentrations of TRA-8 antibody (≤ 10 μg/ml) induced no significant cytotoxicity in the SCLC cell lines. The in vitro combination treatment with TRA-8 (10 μg/ml), 1.25 μg/ml cisplatin and 2 Gy radiation showed increased cytotoxicity when compared to combinations without TRA-8. Furthermore, the triple combination demonstrated the greatest amount of apoptosis as measured by Annexin V staining. The in vivo studies showed the combination of 1G y, cisplatin and TRA-8 extended the tumor doubling time to 44 d as compared to any doublet treatment groups that ranged from 12 to 20 d. Analysis of survival data showed 100% of the combination group (RT+cisplatin+TRA-8) were

  1. Protective effects of sildenafil citrate administration on cisplatin-induced ovarian damage in rats.

    Science.gov (United States)

    Taskin, Mine Islimye; Yay, Arzu; Adali, Ertan; Balcioglu, Esra; Inceboz, Umit

    2015-04-01

    The aim of this study is to evaluate the effects of sildenafil citrate on cisplatin-induced ovarian toxicity. Thirty-two female rats were divided into four groups. Group 1: saline control; group 2: cisplatin; group 3: sildenafil citrate; and group 4: cisplatin plus sildenafil citrate group. In groups 2 and 4, the rats were injected with 5 mg/kg cisplatin intraperitoneally (i.p.). In groups 3 and 4, the rats were injected with 1.4 mg/kg sildenafil citrate i.p. The ovaries were removed two weeks later in all groups. Histopathologic examination, follicle counting and classification were performed. The expression of anti-Müllerian hormone (AMH) was detected immunohistochemically in the ovarian tissues. Sildenafil alleviated cisplatin-induced histopathological changes in the ovarian tissue. Primordial, secondary and tertiary follicles were diminished in group 2 compared with group 1 (p sildenafil citrate preserved primordial follicle count in group 4 compared with group 2, and the difference was statistically significant (p sildenafil citrate is beneficial for protecting the ovaries from cisplatin-induced damage. Sildenafil citrate can be a choice for fertility preservation.

  2. Cisplatin-based chemotherapy: Add high-frequency audiometry in the regimen

    Directory of Open Access Journals (Sweden)

    R Arora

    2009-01-01

    Full Text Available Background : Cisplatin-induced ototoxicity shows high interindividual variability and is often accompanied by transient or permanent tinnitus. It is not possible to identify the susceptible individuals before commencement of the treatment. We conducted a prospective, randomized and observational study in a tertiary care centre and evaluated the effects of different doses of cisplatin on hearing. Materials and Methods : Fifty-seven patients scheduled for cisplatin-based chemotherapy were included in the study. All patients were divided into three groups depending on the dose of cisplatin infused in 3 weeks. Results : The subjective hearing loss was found in seven patients, while six patients had tinnitus during the chemotherapy. The hearing loss was sensorineural, dose dependent, symmetrical, bilateral and irreversible. Higher frequencies were first to be affected in cisplatin chemotherapy. Conclusion : As use of high-frequency audiometry is still limited in research work only, we need a strict protocol of adding high-frequency audiometry in the cisplatin-based chemotherapy regimen.

  3. Modulation of Nrf2/HO-1 by Thymoquinone During Cisplatin-Induced Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Ramazan ULU

    2013-05-01

    Full Text Available OBJECTIVE: Side effects of cisplatin, such as nephrotoxicity, limit its use in chemotherapeutic regimens and indicate an agent that suppresses its toxicity. Thymoquinone (TQ, the predominant bioactive constituent present in black seed oil (Nigella sativa, has antiinfl ammatory, antioxidant and antitumor effects. We propose a protective mechanism of of TQ on cisplatin-nephrotoxicity in rats that is through modulation of Nrf2-mediated antioxidant induction and reduced inflammation. MATERIAL and METHODS: Twenty-eight male Wistar rats (8 weeks-old were divided into four groups; Control (vehicle; 0.9% saline, 1 ml/kg body wt., p.o., TQ (10 mg/kg body weight/day in drinking water for 5 days, cisplatin (a single injection of 7mg/kg body wt, i.p. and TQ for 5 days in drinking water then a single injection of cisplatin. On day 10, all rats were sacrificed by cervical dislocation, kidneys were removed, and serum urea and creatinine were collected. RESULTS: Serum urea and creatinine levels were significantly higher in cisplatin-treated rats compared with control rats. TQ-treatment significantly decreased serum urea and creatinine levels. Cisplatin-treatment caused significant downregulation of the nuclear NF-E2-related factor-2 (Nrf2, heme oxygenase-1(HO-1 and caused an increase in the levels of nuclear factor-kappa B (NF-κB. Interestingly, TQ supplementation significantly improved the changes associated with cisplatin nephrotoxicity by increasing the levels of Nrf-2 and HO-1 and decreasing the levels of NF-κB. CONCLUSION: This study demonstrates the TQ targets NRF2/HO-1 and can be used as a potential agent against cisplatin-induced nephrotoxicity.

  4. Methods of reduction of cisplatin nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Walker, E.M. Jr.; Gale, G.R.

    Cisplatin, an agent widely used in the chemotherapy of a variety of human malignancies, is often dose-limited owing to its nephrotoxicity. Some of the approaches under consideration, regarding the reduction of cisplatin nephrotoxicity, include the use of hydration and osmotic diuresis, pharmacological diuretics, chelating agents or agents which otherwise react with cisplatin or reverse cisplatin-induced deoxyribonucleic acid cross-links, and antioxidants to destroy free radicals, especially superoxide radicals, produced by cisplatin. The effects of each of these and other interventions on cisplatin-induced nephrotoxicity are delineated, along with their proposed mechanisms and effects on therapeutic efficacy. The current status of development of organoplatinum analogs yielding congeners with less nephrotoxicity and greater efficacy is discussed briefly. Finally, a possible role of endogenous and/or exogenous prostaglandins in protecting against or reversing heavy metal nephrotoxicity is suggested.

  5. Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

    Science.gov (United States)

    Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan

    2014-08-01

    Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

  6. Cisplatin- vs. oxaliplatin-based radiosensitizing chemotherapy for squamous cell carcinoma of the esophagus. A comparison of two preoperative radiochemotherapy regimens

    Energy Technology Data Exchange (ETDEWEB)

    Fakhrian, K. [University Clinic of the Ruhr University Bochum, Department of Radiation Oncology, Marien Hospital Herne, Herne (Germany); University of Bochum, Department of Radiation Oncology, Bochum (Germany); Technische Universitaet Muenchen, Department of Radiation Oncology, Klinikum rechts der Isar, Munich (Germany); Ordu, A.D.; Molls, M. [Technische Universitaet Muenchen, Department of Radiation Oncology, Klinikum rechts der Isar, Munich (Germany); Haller, B. [Technische Universitaet Muenchen, Department of Epidemiology and Medical Statistics, Klinikum rechts der Isar, Munich (Germany); Theisen, J. [Technische Universitaet Muenchen, Department of Surgery, Klinikum rechts der Isar, Munich (Germany); Lordick, F. [University Clinic Leipzig, University Cancer Center Leipzig (UCCL), Leipzig (Germany); Technische Universitaet Muenchen, Department of Internal Medicine III (Hematology/Oncology), Klinikum rechts der Isar, Munich (Germany); Bisof, V. [Clinical Hospital Centre Zagreb, Department of Oncology, Zagreb (Croatia); Geinitz, H. [Technische Universitaet Muenchen, Department of Radiation Oncology, Klinikum rechts der Isar, Munich (Germany); Krankenhaus der Barmherzigen Schwestern Linz, Department of Radiation Oncology, Linz (Austria)

    2014-11-15

    To compare the outcomes of two neoadjuvant radiochemotherapy (N-RCT) regimens for squamous cell carcinoma of the esophagus (ESCC). The standard N-RCT regimen for ESCC at our institution between 2002 and 2011 was a total dose of 45 Gy (1.8-Gy fractions) with concomitant cisplatin (20 mg/m{sup 2}, days 1-5 and 29-33) and 5-fluorouracil (5-FU; 225 mg/m{sup 2}, 24 h continuous infusion on days 1-33). During the same period, a phase I/II study comparing the standard ESCC N-RCT protocol with a regimen identical except for the replacement of cisplatin with weekly oxaliplatin (40-50 mg/m{sup 2}) was performed at our center. The standard regimen was used to treat 40 patients; 37 received the oxaliplatin regimen. All patients subsequently underwent radical resection with reconstruction according to tumor location and two-field lymph node dissection. Median follow-up time from the start of N-RCT was 74 months (range 3-116 months). The two patient groups were comparable in terms of demographic and baseline tumor characteristics. R0 resection was achieved in 37/39 patients (95 %) in the cisplatin-based N-RCT group, compared to 24/37 (65 %) in the oxaliplatin-based group (p = 0.002). A pathological complete response (pCR) was seen in the resection specimens from 18/39 patients (46 %) in the cisplatin-based N-RCT group and in 8/37 (22 %) oxaliplatin-group patients. In the cisplatin group, 2- and 5-year overall survival (OS) rates were 67 ± 8 % and 60 ± 8 %, respectively (median OS 103 months), compared to 38 ± 8 % and 32 ± 8 %, respectively, for the oxaliplatin group (median OS 17 months; hazard ratio, HR 0.452; 95 % confidence interval, CI 0.244-0.839; p = 0.012). Oxaliplatin-based N-RCT resulted in poorer outcomes in ESCC patients and should not routinely replace cisplatin-based N-RCT. (orig.) [German] Unser Ziel war es, die Ergebnisse zweier neoadjuvanter Radiochemotherapie- (N-RCT-) Konzepte mit nachfolgender Resektion beim fortgeschrittenen Plattenepithelzellkarzinom des

  7. Concomitant variables in finite mixture models

    NARCIS (Netherlands)

    Wedel, M

    The standard mixture model, the concomitant variable mixture model, the mixture regression model and the concomitant variable mixture regression model all enable simultaneous identification and description of groups of observations. This study reviews the different ways in which dependencies among

  8. Chemopreventive Effect of Tadalafil in Cisplatin-Induced Nephrotoxicity in Rats.

    Science.gov (United States)

    Adeneye, A A; Benebo, A S

    2016-08-30

    Nephrotoxicity remains a common untoward effect of cisplatin therapy with limited effective chemopreventive options available till date. This study aims to evaluate the possible chemopreventive effect and mechanism(s) of action of 2 mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this study, twenty-five male Wistar rats were randomly divided into five groups (n = 5 rats per group) and daily pretreated with oral doses of distilled water (10 mLkg-1), ascorbic acid (100 mgkg-1), Tadalafil (2 mgkg-1 and 5 mgkg-1) for 7 days before cisplatin (5 mgkg-1, intraperitoneal) was administered. 72 hours post-cisplatin injections, rats were sacrificed humanely and blood samples for serum electrolytes, urea and creatinine and renal tissues for reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malonialdehyde dehydrogenase (MAD) assays and histopathology were collected. Results showed that cisplatin injection caused significant decreases in the serum sodium (Na+), potassium (K+), bicarbonate (HCO3-), calcium (Ca2+), phosphate (PO42-) and concomitant significant increases in the serum urea and creatinine levels. In addition, there were significant decreases in the renal tissue GSH, SOD, CAT and increased MAD and GSH-Px levels which were corroborated by histopathological features of tubulonephritis. However, these histo-biochemical alterations were significantly attenuated by ascorbic acid and Tadalafil pretreatments. Overall, results of this study showed the chemopreventive potential of Tadalafil against cisplatin-induced nephrotoxicity which was possibly mediated via antioxidant and anti-lipoperoxidation mechanisms.

  9. Accelerated hyperfractionated radiotherapy combined with induction and concomitant chemotherapy for inoperable non-small-cell lung cancer. Impact of total treatment time

    Energy Technology Data Exchange (ETDEWEB)

    Nyman, J.; Mercke, C. [Sahlgrenska Univ. Hospital, Gothenburg (Sweden). Dept. of Oncology; Bergman, B. [Sahlgrenska Univ. Hospital, Gothenburg (Sweden). Dept. of Respiratory Medicine

    1998-12-31

    Tumour cell proliferation during conventionally fractionated radiotherapy (RT) can negatively influence the treatment outcome in patients with unresectable non-small-cell lung cancer (NSCLC). Accelerated and hyperfractionated RT may therefore have an advantage over conventional RT. Moreover, earlier studies have suggested improved survival with addition of cisplatin-based chemotherapy (CT). We present here the results of combined treatment with induction and concomitant CT and accelerated hyperfractionated RT in a retrospective series of patients with advanced NSCLS. Between August 1990 and August 1995, 90 consecutive patients, aged 42-77 years (median 63 years), with locally advanced unresectable or medically inoperable NSCLC and good performance status were referred for treatment: stage: I 23%, IIIa 37%, IIIb 40%. Patient histologies included: squamous cell carcinoma 52%, adenocarcinoma 34% and large cell carcinoma 13%. The treatment consisted of two courses of CT (cisplatin 100 mg/m{sup 2} day 1 and etoposide 100 mg/m{sup 2} day 1-3 i.v.), the second course given concomitantly with RT. The total RT dose was 61.2-64.6 Gy, with two daily fractions of 1.7 Gy. A one-week interval was introduced after 40.8 Gy to reduce acute toxicity, making the total treatment time 4.5 weeks. Concerning toxicity, 33 patients had febrile neutropenia, 10 patients suffered from grade III oesophagitis and 7 patients had grade III pneumonitis. There were two possible treatment-related deaths, one due to myocardial infarction and the other due to a pneumocystis carinii infection. The 1-, 2- and 3-year overall survival rates were 72%, 46% and 34%, respectively; median survival was 21.3 months. Fifty-nine patients had progressive disease: 21 failed locoregionally, 29 had distant metastases and 9 patients had a combination of these. Pretreatment weight loss was the only prognostic factor found, except for stage. However, the results for stage IIIb were no different from those for stage IIIa

  10. Cisplatin-induced regulation of signal transduction pathways and transcription factors in p53-mutated subclone variants of hepatoma cells: Potential application for therapeutic targeting.

    Science.gov (United States)

    Kuo, Jinn-Rung; Shang, Hung-Sheng; Ho, Chun-Te; Lai, Kun-Goung; Liu, Tsan-Zon; Chen, Yin-Ju; Chiou, Jeng-Fong

    2016-11-01

    Cisplatin is commonly recognized as a DNA-damaging drug; however, its versatile antitumor effects have been demonstrated to extend beyond this narrow functional attribute. The present study determined how cisplatin regulates alternative pathways and transcription factors to exert its additional antitumor actions. Cisplatin was observed to be able to trigger an endoplasmic reticulum stress response through aggravated nitrosative stress coupled to perturbed mitochondrial calcium (Ca(2+)) homeostasis, which substantially downregulated glucose-regulated protein (GRP) 78 expression by suppressing the cleavage of activating transcription factor (ATF) 6α (90 kDa) to its active 50 kDa subunit. Concomitantly, the ATF4-ATF3-C/emopamil binding protein homologous protein axis was activated by cisplatin, which triggered cellular glutathione (GSH) depletion by strongly inhibiting γ-glutamylcysteine synthetase heavy chain (γ-GCSh), a key enzyme in GSH biosynthesis. The present study also demonstrated that cisplatin substantially inhibited β-catenin, causing a marked downregulation of survivin and B-cell lymphoma (Bcl)-2. Taken together, the present results uncovered a novel mechanism of cisplatin that could simultaneously trigger the inhibition of three prominent antiapoptotic effector molecules (Bcl-2, survivin and GRP78) and effectively promote GSH depletion by inhibiting γ-GCSh. These newly discovered functional attributes of cisplatin can provide an avenue for novel combined therapeutic strategies to kill hepatocellular carcinoma cells effectively.

  11. Role of glutathione in cisplatin resistance in osteosarcoma cell lines.

    Science.gov (United States)

    Komiya, S; Gebhardt, M C; Mangham, D C; Inoue, A

    1998-01-01

    This study was designed to examine whether and how glutathione and catalase increase the resistance of osteosarcoma cells to the toxicity of cisplatin. Eight osteosarcoma cell lines were exposed to varying concentrations of cisplatin, and a [3H]thymidine incorporation study then estimated their drug sensitivity. Cells were pretreated with aminotriazole and buthionine sulfoximine to depress catalase and glutathione activities and then entered into the same protocol to assess their sensitivity to cisplatin. Intracytoplasmic levels of catalase and glutathione were measured before and after the treatments. Cisplatin-glutathione conjugates were created to examine how glutathione might depress the toxicity of cisplatin. Although the cell lines differed in the magnitude of their response to cisplatin, there was a statistical correlation between intrinsic glutathione content and cisplatin resistance. Pretreatment with aminotriazole reduced catalase activity by 84% but did not change the sensitivity to cisplatin. Depletion of glutathione activity by 70% increased the sensitivity of the cells to the cytotoxicity of cisplatin. In addition, cisplatin was detoxified following conjugation with glutathione. The increased sensitization to cisplatin toxicity caused by the depletion of glutathione and cisplatin detoxification after the in vitro reaction of glutathione to cisplatin indicated that the formation of the glutathione-cisplatin conjugate was an important mechanism in the cellular resistance to cisplatin. These data also demonstrated that catalase activity did not contribute to resistance to cisplatin and suggested that H2O2-induced oxidative stress did not significantly contribute to the cytotoxicity of cisplatin in osteosarcoma cells.

  12. 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.

  13. Carvedilol alleviates testicular and spermatological damage induced by cisplatin in rats via modulation of oxidative stress and inflammation.

    Science.gov (United States)

    Eid, Ahmed H; Abdelkader, Noha F; Abd El-Raouf, Ola M; Fawzy, Hala M; El-Denshary, Ezz-El-Din S

    2016-12-01

    The clinical application of the anticancer drug cisplatin is limited by its deleterious side effects, including male reproductive toxicity. In this context, the potential protective effect of carvedilol on testicular and spermatological damage induced by cisplatin in male Sprague-Dawley rats was investigated. Carvedilol was orally administered at a dose of 10 mg/kg for 2 weeks, and cisplatin was given as a single intraperitoneal injection of 10 mg/kg on the 12th day to induce toxicity. Cisplatin significantly reduced reproductive organ weight, sperm count and sperm motility, and increased sperm abnormalities and histopathological damage of testicular tissue. In addition, it resulted in a significant decline in serum testosterone as well as levels of testicular enzymatic and non-enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxides, and reduced glutathione). Moreover, cisplatin remarkably augmented malondialdehyde, nitric oxide, tumor necrosis factor-α, and nuclear factor-kappa B contents in testicular tissue. Conversely, carvedilol administration markedly mitigated cisplatin-induced testicular and spermatological injury as demonstrated by suppression of oxidative/nitrosative and inflammatory burden, amendment of antioxidant defenses, enhancement of steroidogenesis and spermatogenesis, and mitigation of testicular histopathological damage. The current study reveals a promising protective action of carvedilol against cisplatin-induced reproductive toxicity by virtue of its anti-inflammatory and antioxidant properties.

  14. Phase I study of the cisplatin analogue 1,1-diamminomethylcyclohexane sulfatoplatinum (TNO-6) (NSC 311056)

    DEFF Research Database (Denmark)

    Sørensen, J B; Groth, S; Hansen, S W;

    1985-01-01

    The cisplatin derivative TNO-6 was evaluated for clinical toxicity in a phase I trial. TNO-6 was given daily for 5 days every 3 weeks as a 30-min IV infusion without hydration. In all, 39 patients with advanced cancer were treated at doses of 2.5-9.0 mg/m2. No dose-limiting nephrotoxicity occurred...

  15. Cytotoxicity of Nanoliposomal Cisplatin Coated with Synthesized ...

    African Journals Online (AJOL)

    The characteristics of the nanoparticles were evaluated by dynamic light ... scanning electron microscopy (SEM). ... that of free cisplatin in human ovarian cancer cell line A2780CP. ... was -20 °C under inert gas stream [12]. The .... Figure 2: SEM image of nanoliposomal cisplatin ... The chemical structure of the synthesized.

  16. Referee: hyperthermia alone or combined with cisplatin in addition to radiotherapy for advanced uterine cervical cancer.

    Science.gov (United States)

    Dahl, O; Mella, O

    2002-01-01

    There are two evidence based therapeutic options for locally advanced cervical cancer: Radiotherapy and concurrent chemotherapy (cisplatin alone or combined with other drugs) or radiation and hyperthermia, documented in randomised trials. The weight of evidence is less for the most advanced stages. Combination of all three options are currently tested in several centres with good clinical response and acceptable toxicity. Based on a pragmatic approach we propose to proceed with a trial selecting cisplatin concurrent with radiation therapy as the standard arm to be compared with the same regimen with the addition of hyperthermia once a week.

  17. The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Cisplatin-Induced Hearing Loss.

    Science.gov (United States)

    Fernandez, Rayne; Harrop-Jones, Anne; Wang, Xiaobo; Dellamary, Luis; LeBel, Carl; Piu, Fabrice

    2016-01-01

    The otoprotective effects of OTO-104 were investigated following both acute and chronic administration of cisplatin. The acute administration of cisplatin to guinea pigs resulted in profound hearing loss (70-80 dB SPL) across all frequencies tested. A single intratympanic injection of 6% OTO-104, but not of lower doses, almost completely protected against cisplatin ototoxicity. In contrast, a dexamethasone solution administered under the same experimental conditions offered no otoprotection. OTO-104 was also very effective in protecting against the progressive hearing loss observed with the chronic administration of cisplatin (3 injections at a weekly interval). The otoprotection was found to be dependent upon the activation of dexamethasone-dependent classical nuclear receptor pathways. © 2016 The Author(s) Published by S. Karger AG, Basel.

  18. 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.

  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. Comparative Efficacy of Cisplatin vs. Gemcitabine as Concurrent Chemotherapy for Untreated Locally Advanced Cervical Cancer: A Randomized Trail

    Directory of Open Access Journals (Sweden)

    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.

  1. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial.

    Science.gov (United States)

    Thatcher, Nick; Hirsch, Fred R; Luft, Alexander V; Szczesna, Aleksandra; Ciuleanu, Tudor E; Dediu, Mircea; Ramlau, Rodryg; Galiulin, Rinat K; Bálint, Beatrix; Losonczy, György; Kazarnowicz, Andrzej; Park, Keunchil; Schumann, Christian; Reck, Martin; Depenbrock, Henrik; Nanda, Shivani; Kruljac-Letunic, Anamarija; Kurek, Raffael; Paz-Ares, Luis; Socinski, Mark A

    2015-07-01

    Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m(2) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash--a class effect of EGFR antibodies--that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients

  2. Successful Treatment of Ptyalism Gravidarum With Concomitant Hyperemesis Using Hypnosis.

    Science.gov (United States)

    Beevi, Zuhrah; Low, Wah Yun; Hassan, Jamiyah

    2015-10-01

    Ptyalism gravidarum, or sialorrhea, is the excessive secretion of saliva during pregnancy. Treatment of ptyalism gravidarum is often challenging due to its unknown etiologies. This article discusses a case of ptyalism gravidarum with concomitant hyperemesis in which the condition was successfully treated with hypnosis. A 28-year-old woman presented with ptyalism 2 months into her pregnancy and hyperemesis 3 months into pregnancy with associated vomiting that occurred following every meal. Hypnosis was administered at week 16 of pregnancy to eliminate ptyalism and hyperemesis, to prepare for childbirth, and to increase overall psychological well-being. Ptyalism resolved by week 36, concurrent with the final hypnosis session.

  3. Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation.

    Science.gov (United States)

    Charest, Gabriel; Paquette, Benoit; Fortin, David; Mathieu, David; Sanche, Léon

    2010-04-01

    Despite significant advances, the radiotherapy and chemotherapy protocols marginally improve the overall survival of patients with glioblastoma. Lipoplatin(TM), and Lipoxal(TM), the liposomal formulations of cisplatin and oxaliplatin respectively, were tested on the F98 glioma cells for their ability to improve the cell uptake and increase the synergic effect when combined with ionizing radiation. The cytotoxicity and synergic effect of platinum compounds were assessed by colony formation assay, while the cellular uptake was measured by Inductively Coupled Plasma Mass Spectrometer (ICP-MS). After 4 h exposure with platinum compounds, cells were irradiated (1.5-6.6 Gy) with a (60)Co source. The liposomal formulations were compared to their liposome-free analogs and to carboplatin. The concomitant treatment of F98 cells with carboplatin and radiation produced the highest radiosensitizing effect (30-fold increase). Among the platinum compounds tested, Lipoplatin(TM) produced the most promising results. This liposomal formulation of cisplatin improved the cell uptake by 3-fold, and its radiosensitizing potential was enhanced by 14-fold. Although Lipoxal(TM) can potentially reduce the adverse effect of oxaliplatin, a synergic effect with radiation was measured only when incubated at a concentration higher than its IC50. Conversely, concomitant treatment with cisplatin did not result in a synergic effect, as in fact a radioprotective effect was measured on the F98 cells. In conclusion, among the five platinum compounds tested, carboplatin and Lipoplatin(TM) showed the best radiosensitizing effect. Lipoplatin(TM) seems the most promising since it led to the best cellular incorporation and has already been reported to be less neurotoxic than other platinum compounds.

  4. Monitoring cisplatin-induced ototoxicity.

    Directory of Open Access Journals (Sweden)

    Ana SÁNCHEZ-MARTÍNEZ

    2016-11-01

    Full Text Available Introduction and objective: The ototoxic damage goes unnoticed to disabling levels, being justified to apply control for its early detection procedures, make it possible to a therapeutic change and if necessary, a speech and auditory rehabilitation. The objective of this study will consist to present Protocol we did at the Hospital Clínico Universitario de Valladolid for the follow-up of the patients treated with cisplatin. Method: Ototoxicity monitoring means serially collect hearing thresholds. It is identified on a visit if hearing has worsened in some ear. The comparison allows to detect the change and indicate if it is significant or not in relation to some criteria. We will also evaluate the occurrence of vestibular damage. As auditory monitoring procedures, we will use high frequency audiometry and acoustic oto-emissions. Results: After giving informed consent and a brief medical history we started with baseline assessment of hearing, prior to treatment, continuing with periodic reviews before each cycle. If any change is detected it is reported to the physician and the patient. To grade the ototoxicity, we apply the Brock and Chang criteria. We maintain post-treatment control. Discussion and conclusion: The incidence of ototoxicity of cisplatin is unknown in our country and it is not possible to predict which patients will experience. The increase in the survival rate for cancer involves improving comorbidity, which in the case of its early ototoxicity supposed to find the best solutions to restore the quality of life of patient’s detection.

  5. Ototoxicity in children receiving cisplatin chemotherapy

    Directory of Open Access Journals (Sweden)

    Hee Jin Jang

    2010-02-01

    Full Text Available Purpose : Cisplatin is highly effective for the treatment of solid tumors in children. However, the clinical use of cisplatin is limited by its ototoxicity. The aim of this study was to evaluate the ototoxicity in children treated with cisplatin. Methods : We performed a single institution retrospective analysis of pediatric oncology patients who received cisplatin therapy between January 2001 and January 2008. Thirty-seven patients with sufficient medical and audiologic data were included in this study. Results : The median age at the time of diagnosis was 10.7 (range 3.8&#8211;16.7 years. There were 16 males and 21 females. The underlying diseases were osteosarcoma (15 cases, medulloblastoma (14 cases, germ cell tumors (7 cases, and hepatoblastoma (1 case. The median individual dose was 100 mg/m2/cycle (56-200. The median cumulative dose was 480 mg/m2 (200-1,490. Sixteen patients (43% received cranial radiotherapy. Of the 37 patients, 17 developed hearing loss, leading to an overall incidence of 46%. Logistic regression showed that age at treatment (P=0.04 and cumulative dose of cisplatin (P=0.005 were the significant risk factors in predicting hearing loss in children treated with cisplatin. In all the patients who had hearing loss, there was neither improvement nor aggravation during the follow-up (3&#8211;68 months. Conclusion : The cumulative dose of cisplatin (&gt;500 mg/m2 and younger age at treatment (&lt;12 years were 2 most important risk factors for ototoxicity in patients treated with cisplatin. Serial audiometric evaluations are needed in the patients with risk factors during and after cisplatin treatment.

  6. Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance.

    Science.gov (United States)

    Song, Wantong; Tang, Zhaohui; Shen, Na; Yu, Haiyang; Jia, Yanjie; Zhang, Dawei; Jiang, Jian; He, Chaoliang; Tian, Huayu; Chen, Xuesi

    2016-06-10

    A poly(l-glutamic acid) graft polyethylene glycol-cisplatin complex (PGA-CisPt) performs well in reducing the toxicity of free cisplatin and greatly enhances the accumulation and retention of cisplatin in solid tumors. However, there is a lack of effective treatment options for cisplatin-resistant tumors. A major reason for this is the dense PEG shell, which ensures that the PGA-CisPt maintains a long retention time in the blood that may result in it bypassing the tumor cells or failing to be endocytosed within the tumor microenvironment. Consequently, the cisplatin from PGA-CisPt is released to the extracellular space in the presence of cisplatin-resistant tumor cells and the resistant problem to free cisplatin still valid. Therefore, we devised a strategy to combat the resistance of cisplatin in the tumor microenvironment using nanoparticles-loaded disulfiram (NPs-DSF) as a modulator. In vitro, cisplatin, in combination with DSF, had a synergistic effect and decreased cell survival rate of cisplatin-resistant A549DDP cells. This effect was also observed when combining PGA-CisPt with NPs-DSF. Similarly, in Balb/C nude mice with A549DDP xenografts, NPs-DSF improved PGA-CisPt effectiveness in inhibiting tumor growth while maintaining low toxicity. Our data demonstrate that DSF reduces intracellular glutathione (GSH) levels, inhibits NFκB activity, and modulates the expression of apoptosis-related proteins Bcl-2 and Bax, thereby improves the effectiveness of cisplatin in resistant cell lines. Here, we provide a promising method for overcoming cisplatin resistance in tumors, while maintaining the in vivo benefits of the PGA-CisPt complex.

  7. Duration of cisplatin excretion in breast milk.

    Science.gov (United States)

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

    2013-11-01

    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 demonstrates minimal exposure to platinum via breast milk, following a single 70-mg intravenous dose of cisplatin.

  8. Neoadjuvant induction dose-dense MVAC for muscle invasive bladder cancer : efficacy and safety compared with classic MVAC and gemcitabine/cisplatin

    NARCIS (Netherlands)

    van de Putte, Elisabeth E Fransen; Mertens, Laura S.; Meijer, Richard P.; van der Heijden, Michiel S.; Bex, Axel; van der Poel, Henk G.; Kerst, J. Martijn; Bergman, Andries M.; Horenblas, Simon; van Rhijn, Bas W G

    2016-01-01

    Purpose: To investigate the efficacy and safety of neoadjuvant induction dose-dense MVAC (dd-MVAC) for muscle invasive bladder cancer (MIBC). Results of the 2-week-per-cycle regimen were compared with classic MVAC (4 weeks per cycle) and gemcitabine/cisplatin (GC, 3 weeks per cycle). Methods: We inc

  9. 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.

  10. Suramin protects from cisplatin-induced acute kidney injury.

    Science.gov (United States)

    Dupre, Tess V; Doll, Mark A; Shah, Parag P; Sharp, Cierra N; Kiefer, Alex; Scherzer, Michael T; Saurabh, Kumar; Saforo, Doug; Siow, Deanna; Casson, Lavona; Arteel, Gavin E; Jenson, Alfred Bennett; Megyesi, Judit; Schnellmann, Rick G; Beverly, Levi J; Siskind, Leah J

    2016-02-01

    Cisplatin, a commonly used cancer chemotherapeutic, has a dose-limiting side effect of nephrotoxicity. Approximately 30% of patients administered cisplatin suffer from kidney injury, and there are limited treatment options for the treatment of cisplatin-induced kidney injury. Suramin, which is Federal Drug Administration-approved for the treatment of trypanosomiasis, improves kidney function after various forms of kidney injury in rodent models. We hypothesized that suramin would attenuate cisplatin-induced kidney injury. Suramin treatment before cisplatin administration reduced cisplatin-induced decreases in kidney function and injury. Furthermore, suramin attenuated cisplatin-induced expression of inflammatory cytokines and chemokines, endoplasmic reticulum stress, and apoptosis in the kidney cortex. Treatment of mice with suramin 24 h after cisplatin also improved kidney function, suggesting that the mechanism of protection is not by inhibition of tubular cisplatin uptake or its metabolism to nephrotoxic species. If suramin is to be used in the context of cancer, then it cannot prevent cisplatin-induced cytotoxicity of cancer cells. Suramin did not alter the dose-response curve of cisplatin in lung adenocarcinoma cells in vitro. In addition, suramin pretreatment of mice harboring lung adenocarcinomas did not alter the initial cytotoxic effects of cisplatin (DNA damage and apoptosis) on tumor cells. These results provide evidence that suramin has potential as a renoprotective agent for the treatment/prevention of cisplatin-induced acute kidney injury and justify future long-term preclinical studies using cotreatment of suramin and cisplatin in mouse models of cancer.

  11. Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma. Final report of a pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Balducci, M.; Diletto, B.; Chiesa, S.; D' Agostino, G.R.; Gambacorta, M.A.; Ferro, M.; Valentini, V. [Catholic University of the Sacred Heart, Department of Radiation Oncology, Rome (Italy); Colosimo, C. [Catholic University of the Sacred Heart, Department of Radiology, Rome (Italy); Maira, G.; Anile, C. [Catholic University of the Sacred Heart, Department of Neurosurgery, Rome (Italy)

    2014-04-15

    Evaluated in this study were the feasibility and the efficacy of concurrent low dose fractionated radiotherapy (LD-FRT) and chemotherapy as palliative treatment for recurrent/progressive glioblastoma multiforme (GBM). Eligible patients had recurrent or progressive GBM, Karnofsky performance status ≥70, prior surgery, and standard radiochemotherapy treatment. Recurrence/progression disease during temozolomide (TMZ) received cisplatin (CDDP; 30 mg/m{sup 2} on days 1, 8, 15), fotemustine (FTM; 40 mg/m{sup 2} on days 2, 9, 16), and concurrent LD-FRT (0.3 Gy twice daily); recurrence/progression after 4 months from the end of adjuvant TMZ were treated by TMZ (150/200 mg/m{sup 2} on days 1-5) concomitant with LD-FRT (0.4 Gy twice daily). Primary endpoints were safety and toxicity. A total of 32 patients were enrolled. Hematologic toxicity G1-2 was observed in 18.7% of patients and G3-4 in 9.4%. One patient (3.1%) had complete response, 3 (9.4%) had partial response, 8 (25%) had stable disease for at least 8 weeks, while 20 patients (62.5%) experienced progressive disease. The clinical benefit was 37.5%. Median progression-free survival (PFS) and overall survival (OS) were 5 and 8 months, respectively. Survival rate at 12 months was of 27.8%. LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted. (orig.)

  12. Evaluation of the toxicity of tirapazamine plus cisplatin in a mouse tumor model; Untersuchungen zur Toxizitaet von Tirapazamine plus Cisplatin in einem Maus-Tumormodell

    Energy Technology Data Exchange (ETDEWEB)

    Adam, M. [Praxis fuer Strahlentherapie, Weilheim (Germany); Ottenjann, S. [Klinik und Poliklinik fuer Strahlentherapie und Radiologische Onkologie, Technische Univ. Muenchen (Germany); Inst. fuer Experimentelle Onkologie und Therapieforschung, Technische Univ. Muenchen (Germany); Kuenzel, G.; Nieder, C.; Molls, M. [Klinik und Poliklinik fuer Strahlentherapie und Radiologische Onkologie, Technische Univ. Muenchen (Germany); Busch, R. [Inst. fuer Medizinische Statistik und Epidemiologie, Technische Univ. Muenchen (Germany); Erhardt, W. [Inst. fuer Experimentelle Onkologie und Therapieforschung, Technische Univ. Muenchen (Germany)

    2006-04-15

    Background and purpose: tirapazamine (TPZ) is an anticancer drug that is selectively activated by the low oxygen environment in solid tumors. Furthermore, TPZ also enhances the tumor cell-killing effect of cisplatin. So far, detailed information on the toxicity of combined treatment is rare. The authors evaluated the toxicity of TPZ in combination with cisplatin in a mouse tumor model. For this purpose, general toxicity was monitored and all inner organs were examined histologically. Material and methods: RIF-1 fibrosarcomas of murine origin growing in the right hindfoot dorsum of C3H mice were used. The animals were treated with 10 x 2 Gy irradiation plus six i.p. injections of 4 mg/kg cisplatin (total dose 24 mg/kg) together with varying doses of TPZ (0-28 mg/kg per injection; total dose 0, 43.2, 86.4, 129.6, 151.2, 172.8 mg/kg). Treatment was applied within 2 weeks (figure 1). Total observation period was up to 35 days. Results: combined treatment with TPZ led to a dose-dependent, significant decrease in motor activity (table 1) and body weight and an increase in mortality (figures 2 and 3, tables 2 and 3). Histological analyses showed areas of necrosis in the heart, liver and kidney and gastric ulcers (table 4). Cisplatin alone produced no severe toxicity. Tumor doubling times were TPZ dose-dependent and comparable with data from the literature (figures 4 and 5, table 3). (orig.)

  13. Effects of SC-560 in Combination with Cisplatin or Taxol on Angiogenesis in Human Ovarian Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Wei Li

    2014-10-01

    Full Text Available This study was designed to evaluate the effect of cyclooxygenase-1 (COX-1 inhibitor, SC-560, combined with cisplatin or taxol, on angiogenesis in human ovarian cancer xenografts. Mice were treated with intraperitoneal (i.p. injections of SC-560 6 mg/kg/day, i.p. injections of cisplatin 3 mg/kg every other day and i.p. injections of taxol 20 mg/kg once a week for 21 days. Vascular endothelial growth factor (VEGF mRNA levels were detected by reverse transcription-polymerase chain reaction (RT-PCR; microvessel density (MVD was determined by immunohistochemistry; and prostaglandin E2 (PGE2 levels were determined using ELISA. Expression levels of VEGF mRNA and MVD in treatment groups were inhibited significantly when compared with the control group (p < 0.05 for all, and SC-560 combined with cisplatin displayed a greater reduction in the expression of VEGF and MVD than SC-560 or cisplatin alone (p < 0.05. SC-560 combined with taxol showed a greater inhibition on VEGF mRNA expression than SC-560 or taxol alone (p < 0.05. The level of PGE2 in treatment groups was significantly reduced when compared with the control group (p < 0.01 for all. These findings may indicate that cisplatin or taxol supplemented by SC-560 in human ovarian cancer xenografts enhances the inhibition effect of cisplatin or taxol alone on angiogenesis.

  14. Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

    Science.gov (United States)

    Kohda, Yuka; Kawai, Yoshiko; Iwamoto, Noriaki; Matsunaga, Yoshiko; Aiga, Hiromi; Awaya, Akira; Gemba, Munekazu

    2005-11-01

    Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

  15. Membrane Transition Temperature Determines Cisplatin Response

    OpenAIRE

    Krishnan Raghunathan; Aarif Ahsan; Dipankar Ray; Mukesh K. Nyati; 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...

  16. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer.

    Science.gov (United States)

    Ross, P; Nicolson, M; Cunningham, D; Valle, J; Seymour, M; Harper, P; Price, T; Anderson, H; Iveson, T; Hickish, T; Lofts, F; Norman, A

    2002-04-15

    We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) (ECF) with the combination of mitomycin, cisplatin, and PVI 5-FU (MCF) in previously untreated patients with advanced esophagogastric cancer. Five hundred eighty patients with adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma were randomized to receive either ECF (epirubicin 50 mg/m(2) every 3 weeks, cisplatin 60 mg/m(2) every 3 weeks and PVI 5-FU 200 mg/m(2)/d) or MCF (mitomycin 7 mg/m(2) every 6 weeks, cisplatin 60 mg/m(2) every 3 weeks, and PVI 5-FU 300 mg/m(2)/d) and analyzed for survival, response, toxicity, and quality of life (QOL). The overall response rate was 42.4% (95% confidence interval [CI], 37% to 48%) with ECF and 44.1% (95% CI, 38% to 50%) with MCF (P =.692). Toxicity was tolerable, and there were only two toxic deaths. ECF resulted in more grade 3/4 neutropenia and grade 2 alopecia, but MCF caused more thrombocytopenia and plantar-palmar erythema. Median survival was 9.4 months with ECF and 8.7 months with MCF (P =.315); at 1 year, 40.2% (95% CI, 34% to 46%) of ECF and 32.7% (95% CI, 27% to 38%) of MCF patients were alive. Median failure-free survival was 7 months with both regimens. Global QOL scores were better with ECF at 3 and 6 months. This study confirms response, survival, and QOL benefits of ECF observed in a previous randomized study. The equivalent efficacy of MCF was demonstrated, but QOL was superior with ECF. ECF remains one of the reference treatments for advanced esophagogastric cancer.

  17. Concomitant administration of zoster and pneumococcal vaccines in adults ≥60 years old.

    Science.gov (United States)

    MacIntyre, C Raina; Egerton, Tony; McCaughey, Malcolm; Parrino, Janie; Campbell, Bernadette V; Su, Shu-Chih; Pagnoni, Marco F; Stek, Jon E; Xu, Jin; Annunziato, Paula W; Chan, Ivan S F; Silber, Jeffrey L

    2010-11-01

    This study evaluated safety & immunogenicity of ZOSTAVAX® (zoster vaccine: ZV) administered concomitantly versus nonconcomitantly with PNEUMOVAX® 23 (pneumococcal vaccine: PPV23). This randomized, double-blind, placebo-controlled study enrolled 473 subjects ≥60 years old in 1:1 ratio to receive ZV & PPV23 concomitantly (Day 1) or nonconcomitantly (PPV23 Day 1, ZV Week 4). Blood samples obtained for pneumococcal polysaccharide (PnPs) antibody (Ab) testing by enzyme-linked immunosorbent assay (ELISA) and varicella-zoster virus (VZV) Ab testing by glycoprotein ELISA. Subjects followed for adverse experiences (AEs) for 28 days postvaccination. Mean baseline VZV geometric mean titers (GMT) in nonconcomitant group were lower than concomitant group. Four weeks postvaccination with ZV, VZV Ab response in concomitant group was not similar to nonconcomitant group; estimated VZV GMT ratio [concomitant/nonconcomitant] was 0.70 (95% CI, 0.61-0.80). VZV Ab response was acceptable in concomitant group; estimated geometric mean foldrise (GMFR) from baseline was 1.9 (95% CI, 1.7-2.1). PnPs serotype-specific Ab responses were similar in both groups. All 6 reported serious AEs were deemed not related to study vaccine. Postvaccination of ZV, incidence of injection-site AEs was similar in both groups; clinical AEs were numerically but not significantly higher in nonconcomitant group. In summary, VZV GMT Ab response induced by ZV administered concomitantly with PPV23 was inferior to that induced nonconcomitantly. These results indicate that, to avoid a potential decrease in ZV immunogenicity, ZV & PPV23 should not be given concomitantly. Concomitant administration did not affect response to PPV23 serotypes tested. When administered concomitantly, ZV & PPV23 vaccines were generally well tolerated.

  18. Resveratrol attenuates cisplatin renal cortical cytotoxicity by modifying oxidative stress.

    Science.gov (United States)

    Valentovic, Monica A; Ball, John G; Brown, J Mike; Terneus, Marcus V; McQuade, Elizabeth; Van Meter, Stephanie; Hedrick, Hayden M; Roy, Amy Allison; Williams, Tierra

    2014-03-01

    Cisplatin, a cancer chemotherapy drug, is nephrotoxic. The aim of this study was to investigate whether resveratrol (RES) reduced cisplatin cytotoxicity and oxidative stress. Rat renal cortical slices were pre-incubated 30min with 0 (VEH, ethanol) or 30μg/ml RES followed by 60, 90 or 120min co-incubation with 0, 75, or 150μg/ml cisplatin. Lactate dehydrogenase (LDH) leakage was unchanged at 60 and 90min by cisplatin. Cisplatin increased (pCisplatin induced oxidative stress prior to LDH leakage as cisplatin depressed glutathione peroxidase and superoxide dismutase (SOD) activity, increased lipid peroxidation, protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins within 60min. RES failed to reverse glutathione (GSH) depression by cisplatin. In order to eliminated an extracellular interaction between RES and cisplatin, additional studies (RINSE studies) allowed a 30min RES uptake into slices, transfer of slices to buffer lacking RES, followed by 120min cisplatin incubation. RES in the RINSE studies prevented LDH leakage by cisplatin indicating that RES protection was not via a physical interaction with cisplatin in the media. These findings indicate that RES diminished cisplatin in vitro renal toxicity and prevented the development of oxidative stress.

  19. Re-irradiation with cetuximab or cisplatin-based chemotherapy for recurrent squamous cell carcinoma of the head and neck

    Energy Technology Data Exchange (ETDEWEB)

    Dornoff, Nicolas; Weiss, Christian; Roedel, Franz [J. W. Goethe University, Department of Radiotherapy and Oncology, Frankfurt a. M. (Germany); Wagenblast, Jens [J. W. Goethe University, Department of Otorhinolaryngology, Frankfurt a. M. (Germany); Ghanaati, Shahram [J. W. Goethe University, Department of Maxillofacial Surgery, Frankfurt a. M. (Germany); Atefeh, Nateghian; Roedel, Claus; Balermpas, Panagiotis [J. W. Goethe University, Department of Radiotherapy and Oncology, Frankfurt a. M. (Germany); German Cancer Research Center (DKFZ), Heidelberg (Germany); German Cancer Consortium (DKTK) partner site: Frankfurt, Frankfurt a. M. (Germany)

    2015-08-15

    Locoregional recurrence remains the main pattern of failure after primary combined modality treatment of squamous cell carcinoma of the head and neck (SCCHN). We compared the efficacy and toxicity of either cisplatin or cetuximab in combination with re-irradiation (ReRT) for recurrent unresectable SCCHN. Various clinicopathological factors were investigated to establish a prognostic score. Between 2007 and 2014, 66 patients with recurrent SCCHN originating in a previously irradiated area received cetuximab (n = 33) or cisplatin-based chemotherapy (n = 33) concomitant with ReRT. Toxicity was evaluated weekly and at every follow-up visit. Physical examination, endoscopy, CT or MRI scans were used to evaluate response and disease control. With a mean follow-up of 18.3 months, the 1-year overall survival (OS) rates for Re-RT with cetuximab and cisplatin-based chemotherapy were 44.4 and 45.5 % (p = 0.352), respectively. At 1 year, local control rates (LCR) were 46.4 and 54.2 % (p = 0.625), freedom from metastases (FFM) rates 73.6 and 81 % (p = 0.842), respectively. Haematological toxicity ≥ grade 3 occurred more often in the cisplatin group (p < 0.001), pain ≥ grade 3 was increased in the cetuximab group (p = 0.034). A physiological haemoglobin level and a longer interval between primary RT and ReRT, proved to be significant prognostic factors for OS (multivariate: p = 0.003, p = 0.002, respectively). Site of the recurrence and gross target volume (GTV) did not show a significant impact on OS in multivariate analysis (p = 0.160, p = 0.167, respectively). A prognostic-score (1-4 points) based on these four variables identified significantly different subgroups: 1-year OS for 0/1/2/3/4 prognostic points: 10, 38, 76, 80 and 100 %, respectively (p < 0.001). Both cetuximab- and cisplatin-based ReRT of SCCHN recurrences are feasible and effective treatment options with comparable results in terms of tumour control and survival. Acute adverse events may differ slightly

  20. Chemoradiation in cervical cancer with cisplatin and high-dose rate brachytherapy combined with external beam radiotherapy. Results of a phase-II study

    Energy Technology Data Exchange (ETDEWEB)

    Strauss, H.G.; Laban, C.; Puschmann, D.; Koelbl, H. [Dept. of Gynecology, Martin-Luther Univ. Halle-Wittenberg (Germany); Kuhnt, T.; Pigorsch, S.; Dunst, J.; Haensgen, G. [Dept. of Radiotherapy, Martin-Luther Univ. Halle-Wittenberg (Germany)

    2002-07-01

    Background: In 1999, five randomized studies demonstrated that chemoradiation with cisplatin and low-dose rate (LDR) brachytherapy has a benefit in locally advanced cervical cancer and for surgically treated patients in high-risk situations. We evaluated the safety and efficacy of concomitant chemoradiation with cisplatin and high-dose rate (HDR) brachytherapy in patients with cervical cancer. Patients and Method: 27 patients were included in our phase-II trial: 13 locally advanced cases (group A) and 14 adjuvant-therapy patients in high-risk situations (group B). A definitive radiotherapy was performed with 25 fractions of external beam therapy (1.8 Gy per fraction/middle shielded after eleven fractions). Brachytherapy was delivered at HDR schedules with 7 Gy in point A per fraction (total dose 35 Gy) in FIGO Stages IIB-IIIB. The total dose of external and brachytherapy was 70 Gy in point A and 52-54 Gy in point B. All patients in stage IVA were treated without brachytherapy. Adjuvant radiotherapy was performed with external beam radiotherapy of the pelvis with 1.8 Gy single-dose up to 50.4 Gy. Brachytherapy was delivered at HDR schedules with two fractions of 5 Gy only in patients with tumor-positive margins or tumor involvement of the upper vagina. The chemotherapeutic treatment schedule provided six courses of cisplatin 40 mg/m{sup 2} weekly recommended in the randomized studies GOG-120 and -123. Results: A total of 18/27 patients (66.7%) completed all six courses of chemotherapy. Discontinuation of radiotherapy due to therapy-related morbidity was not necessary in the whole study group. G3 leukopenia (29.6%) was the only relevant acute toxicity. There were no differences in toxicity between group A and B. Serious late morbidity occurred in 2/27 patients (7.4%). 12/13 patients (92.3%) with IIB-IVA cervical cancer showed a complete response (CR). 13/14 adjuvant cases (92.8%) are free of recurrence (median follow up: 19.1 months). Conclusion: Concomitant

  1. Enhancement of cisplatin sensitivity of cisplatin-resistant human cervical carcinoma cells by bryostatin 1.

    Science.gov (United States)

    Mohanty, Sanghamitra; Huang, Jie; Basu, Alakananda

    2005-09-15

    Bryostatin 1, a unique protein kinase C (PKC) activator, is already in the clinical trials. An understanding of complex regulation of PKC by bryostatin 1 is essential for effective use of bryostatin 1 in the clinic. We have previously shown that the ability of bryostatin 1 to enhance cisplatin sensitivity correlated with its ability to down-regulate PKCdelta in HeLa cells. We have investigated how bryostatin 1 influences PKCdelta regulation in cisplatin-resistant HeLa (HeLa/CP) cells, and if bryostatin 1 could be used to reverse cisplatin resistance. Phorbol 12,13-dibutyrate (PDBu), bryostatin 1, and small interfering RNA were used to manipulate PKC level/activation status. Cell death was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Annexin V dye-binding assay, and analysis of hypodiploid peak in a flow cytometer. Bryostatin 1 elicited a biphasic concentration response on PKCdelta down-regulation and cisplatin-induced cell death in HeLa/CP cells; the maximum effect was achieved with 1 nmol/L bryostatin 1. Down-regulation of PKCalpha increased with increasing concentrations of bryostatin 1. PDBu induced down-regulation of PKCalpha in HeLa and HeLa/CP cells but it had little effect on PKCdelta down-regulation in HeLa/CP cells. However, both PDBu and bryostatin 1 enhanced the sensitivity of HeLa/CP cells to cisplatin. Knockdown of PKCdelta by small interfering RNA inhibited cisplatin-induced apoptosis but knockdown of PKCalpha enhanced cisplatin-induced cell death. These results suggest that although PKCdelta acts as a proapoptotic protein, full-length PKCdelta may inhibit cisplatin-induced cell death. Thus, persistent activation/down-regulation of PKCdelta by bryostatin 1 was associated with cisplatin sensitization. Furthermore, PKCalpha acts as an antiapoptotic protein and down-regulation of PKCalpha by PDBu was associated with cellular sensitization to cisplatin.

  2. Cisplatin enhances the cytotoxicity of fast neutrons in a murine lymphoma cell line

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, B.; Benzina, S.; Ganansia-Leymarie, V. [Hopitaux Universitaires, Lab. de Cancerologie Experimentale et de Radiobiologie, Strasbourg CEDEX (France); Denis, J.M. [Universite Catholique de Louvain (UCL-RBNT), Lab. de Radiobiologie et de Radioprotection, Faculte de Medecine, Bruxelles (Belgium); Bergerat, J.P.; Dufour, P. [Hopitaux Universitaires, Lab. de Cancerologie Experimentale et de Radiobiologie, Strasbourg CEDEX (France); Gueulette, J. [Universite Catholique de Louvain (UCL-RBNT), Lab. de Radiobiologie et de Radioprotection, Faculte de Medecine, Bruxelles (Belgium); Bischoff, P. [Hopitaux Universitaires, Lab. de Cancerologie Experimentale et de Radiobiologie, Strasbourg CEDEX (France)]. E-mail: Pierre.Bischoff@ircad.u-strasbg.fr

    2004-02-01

    The utilization of high linear energy transfer (LET) radiations, such as fast neutrons or carbon ions (hadrontherapy), offers promising perspectives in radiotherapy. While it is well known that by combining radiotherapy and chemotherapy, important therapeutic advantages can be obtained to cure cancer, there have been, so far, very few investigations on the effects of treatments combining an irradiation with high-LET particles and cancer drugs. The present study was therefore undertaken to examine the effects of exposure to 65 MeV fast neutrons combined with cisplatin in a murine T cell lymphoma (RDM4) in vitro. The cells were irradiated at doses ranging from 2 to 8 Gy without or with addition of cisplatin shortly before the irradiation, at concentrations between 0.3 and 12.5 {mu}M. These treatments were applied concomitantly. Proliferation and apoptosis were assessed at different time intervals thereafter. The combination of irradiation with cisplatin was found to be more cytotoxic than either treatment alone. Furthermore, the cytotoxicity induced by this cotreatment resulted not only from apoptosis but also from other forms of cell death. (author)

  3. A phase I study of combination S-1 plus cisplatin chemotherapy with concurrent thoracic radiation for locally advanced non-small cell lung cancer.

    Science.gov (United States)

    Chikamori, Kenichi; Kishino, Daizo; Takigawa, Nagio; Hotta, Katsuyuki; Nogami, Naoyuki; Kamei, Haruhito; Kuyama, Shoichi; Gemba, Kenichi; Takemoto, Mitsuhiro; Kanazawa, Susumu; Ueoka, Hiroshi; Segawa, Yoshihiko; Takata, Saburo; Tabata, Masahiro; Kiura, Katsuyuki; Tanimoto, Mitsune

    2009-07-01

    A combination of S-1, a newly developed oral 5-fluorouracil derivative, and cisplatin is reported to show anti-tumour activity against advanced non-small cell lung cancer (NSCLC). Because S-1 shows synergistic effects with radiation, we conducted a phase I study to evaluate the maximum tolerated doses (MTDs), recommended doses (RDs), and dose-limiting toxicities (DLTs) of cisplatin and S-1 when combined with concurrent thoracic radiation (total dose of 60 Gy with 2 Gy per daily fraction) in patients with locally advanced NSCLC. Chemotherapy consisted of two 4-week cycles of cisplatin administered on days 1 and 8, and S-1 administered on days 1-14. S-1/cisplatin dosages (mg/m(2)/day) were escalated as follows: 60/30, 60/40, 70/40, 80/40 and 80/50. Twenty-two previously untreated patients were enrolled. The MTDs and RDs for S-1/cisplatin were 80/50 and 80/40, respectively. DLTs included febrile neutropaenia, thrombocytopaenia, bacterial pneumonia and delayed second cycle of chemotherapy. No patient experienced radiation pneumonitis>grade 2 and only one patient experienced grade 3 radiation oesophagitis. The overall response rate was 86.4% with a median survival time of 24.4 months. These results indicate that combination cisplatin-S-1 chemotherapy with concurrent thoracic radiation would be a feasible treatment option and a phase II study is currently under way.

  4. Is there a gender-related susceptibility for cisplatin ototoxicity?

    Science.gov (United States)

    Kirkim, Günay; Olgun, Yüksel; Aktas, Safiye; Kiray, Müge; Kolatan, Efsun; Altun, Zekiye; Erçetin, Pınar; Bagriyanik, Alper; Yilmaz, Osman; Ellidokuz, Hülya

    2015-10-01

    Ototoxicity is a well-known side effect of cisplatin. Some genetic and non-genetic risk factors were described for cisplatin ototoxicity. Although there are some studies which point out a sex-related difference for cisplatin nephrotoxicity and neurotoxicity, sex-related differences for cisplatin ototoxicity have not been studied. The aim of this study is to reveal whether there is any gender-related difference for susceptibility to cisplatin ototoxicity in rats. Fourteen male, 14 female Wistar albino rats were divided into four groups; a female control, a male control, a female cisplatin and a male cisplatin group. Distortion Product Otoacoustic Emission and, Auditory Brainstem Response measurements were obtained. For the cisplatin groups 16 mg/kg of cisplatin was applied. On the 4th day audiological examinations were repeated. After killing, cochleae and brainstem tissues were evaluated by light and electron microscopy. The hearing of the female rat cisplatin group was found to have deteriorated more than the hearing of the male rat cisplatin group. Histopathological evaluation revealed more serious damage in the spiral ganglion and brainstem tissues of female rats. Hearing of female rats deteriorated more than the hearing of male rats upon application of cisplatin. This difference in hearing can be attributed to the more severe damage seen in neuronal tissues such as spiral ganglion cells and brainstem neurons.

  5. 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.

  6. 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.

  7. 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.

  8. Continuous-infusion cisplatin and bolus 5-fluorouracil in colorectal carcinoma.

    Science.gov (United States)

    Posner, M R; Belliveau, J F; Weitberg, A B; Sabbath, K; Wiemann, M C; Cummings, F J; Calabresi, P

    1987-10-01

    Twenty-one evaluable patients with metastatic colorectal carcinoma were treated with a combination of continuous-infusion cisplatin (25 mg/m2/day X 3 days) and bolus 5-fluorouracil (400 mg/m2/day X 3 days). Toxicity was minimal. Seven patients (33%) responded. All responses were observed among the 16 previously untreated patients (44%) and lasted a median of 30 weeks. The results indicate the need for phase III trials of this treatment.

  9. A single centre experience with sequential and concomitant chemoradiotherapy in locally advanced stage IV tonsillar cancer

    Directory of Open Access Journals (Sweden)

    Coyle Catherine

    2010-12-01

    Full Text Available Abstract Background Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil. Methods A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone. Results Median age was 55 years (range 34-76 years and 28 (68% patients were male. 35/41 patients (85% received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78% had a clinical response. Concomitant chemotherapy was given to 30/41 (73%. All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15% patients had gastrostomy tubes placed before treatment, and 22 (54% required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85% patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months. Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8% patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively. Conclusion Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer.

  10. Reversibly PEGylated nanocarrier for cisplatin delivery.

    Science.gov (United States)

    Stoyanova, Ekaterina; Mitova, Violeta; Shestakova, Pavletta; Kowalczuk, Agnieszka; Momekov, Georgi; Momekova, Denitsa; Marcinkowski, Andrzej; Koseva, Neli

    2013-03-01

    A star-shaped copolymer bearing a shell of poly(ethylene glycol) (PEG) chains was designed as a carrier of cisplatin. The proposed strategy was based on synthesis of a PEGylating agent and the incorporation of cisplatin as a reversible linker for PEG modification of the star macromolecules. The attachment of PEG chains to the stars and their release under physiological conditions, as well as the changes in particle size and mobility upon drug loading, was evidenced by diffusion ordered NMR spectroscopy (DOSY). The results demonstrated that PEGylation reduced inter-stars cross-linking and increased the stability of the nanocolloidal solution. The formation of PEG shell resulted in higher drug payload and improved drug release profile of the nanoconjugates. The in vitro bioassay in a panel of human tumor cell lines confirmed that the PEGylated conjugates exhibited superior growth inhibitory activity compared to the cisplatin-loaded nonPEGylated carrier.

  11. Concomitant vs. Comparative Advantages: Sufficient vs. Necessary Conditions.

    Science.gov (United States)

    Flaningam, Carl D.

    1981-01-01

    Discusses the concomitant advantages case in academic debate. Examines the distinction between concomitant and comparative advantages and the implications of this distinction for concomitant advantages as a form of argument. (PD)

  12. Phase II study of a 3-day schedule with topotecan and cisplatin in patients with previously untreated small cell lung cancer and extensive disease

    DEFF Research Database (Denmark)

    Sorensen, M.; Lassen, Ulrik Niels; Jensen, Peter Buhl;

    2008-01-01

    and cisplatin are needed. The aim of this phase II study was to establish the response rate and response duration in chemo-naive patients with SCLC receiving a 3-day topotecan and cisplatin schedule. METHODS: Simons optimal two-stage design was used. Patients with previously untreated extensive disease SCLC......, adequate organ functions and performance status less than 3 were eligible. Topotecan (2.0 mg/m, intravenously) was administered on days 1 to 3 with cisplatin (50 mg/m, intravenously) on day 3 every 3 weeks for a total of six cycles. RESULTS: Forty-three patients received 219 cycles of chemotherapy. Median.......3-7.7), respectively. CONCLUSION: Three-day topotecan with cisplatin on day 3 is active and safe in extensive disease SCLC. An ongoing phase III randomized trial compares this combination to standard treatment Udgivelsesdato: 2008/8...

  13. 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.

  14. Low renal toxicity of lipoplatin compared to cisplatin in animals.

    Science.gov (United States)

    Devarajan, Prasad; Tarabishi, Ridwan; Mishra, Jaya; Ma, Qing; Kourvetaris, Andreas; Vougiouka, Maria; Boulikas, Teni

    2004-01-01

    Cisplatin is one of the most widely used and effective chemotherapeutic agents for the treatment of several human malignancies. Although the effectiveness of cisplatin is high, its toxicities justify the demand for improved formulations of this drug. A liposomal formulation of cisplatin, Lipoplatin, was developed in order to reduce the systemic toxicity of cisplatin. Mice and rats injected with cisplatin developed renal insufficiency with clear evidence of tubular damage, but those injected with the same dose of Lipoplatin were almost completely free of kidney injury. The maximum levels of total platinum in rat kidneys after intraperitoneal bolus injection of cisplatin or Lipoplatin at similar doses were similar, but the steady state accumulation of total platinum in the kidney was 5 times higher for cisplatin compared to Lipoplatin. This is proposed as one mechanism to explain the low renal toxicity of Lipoplatin.

  15. Is intratympanic injection of erdosteine protective against cisplatin-induced ototoxicity?

    Science.gov (United States)

    Saliba, Issam; El Fata, Fouad

    2012-04-01

    Cisplatin induces ototoxicity in adult and pediatric population. Our aim was (1) to assess the protective effect of intratympanic injections of erdosteine in the prevention of cisplatin-induced ototoxicity and (2) to investigate inner ear protection using a scanning electron microscope. Ears of 20 Hartley guinea pigs were assigned to four subgroups and received an intratympanic injection of: E1-erdosteine 1.125 mg/cc, NS-normal saline, E2-erdosteine 2.25 mg/cc and E4-erdosteine 4.5 mg/cc. After 45 min, an intraperitoneal cisplatin injection of 3 mg/kg was performed and repeated 8 times, once a week to achieve 24 mg/kg. Auditory brainstem responses were recorded before any injection and after 24 mg/kg of cisplatin for the frequencies 1, 2, 4, 6 and 8 kHz. Cochleas were analyzed under scanning electron microscope. Average hearing loss in the NS subgroup was 29.8 dB which was lower than E1, E2 and E4 subgroups (40, 43.9, and 51.7 dB, respectively). Difference in the mean threshold increase was statistically significant between NS and the three erdosteine subgroups (P  0.05). However, difference was significant between E1 and E4 (P erdosteine showed a diffuse inflammatory reaction and osteitis of the middle ear. Low or high concentration of intratympanic erdosteine does not offer protection against cisplatin-induced ototoxicity as it causes a considerable inflammatory reaction.

  16. Chemoradiation With Concomitant Boosts Followed by Radical Surgery in Locally Advanced Cervical Cancer: Long-term Results of the ROMA-2 Prospective Phase 2 Study

    Energy Technology Data Exchange (ETDEWEB)

    Ferrandina, Gabriella, E-mail: gabriella.ferrandina@libero.it [Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome (Italy); Gambacorta, Antonietta [Division of Radiotherapy, Catholic University of the Sacred Heart, Rome (Italy); Gallotta, Valerio [Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome (Italy); Smaniotto, Daniela [Division of Radiotherapy, Catholic University of the Sacred Heart, Rome (Italy); Fagotti, Anna [Gynecologic Surgery, University of Perugia, Terni (Italy); Tagliaferri, Luca [Division of Radiotherapy, Catholic University of the Sacred Heart, Rome (Italy); Foti, Elvira; Fanfani, Francesco [Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome (Italy); Autorino, Rosa [Division of Radiotherapy, Catholic University of the Sacred Heart, Rome (Italy); Scambia, Giovanni [Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome (Italy); Valentini, Vincenzo [Division of Radiotherapy, Catholic University of the Sacred Heart, Rome (Italy)

    2014-11-15

    Purpose: This prospective, phase 2 study aimed at assessing the efficacy of accelerated fractionation radiation therapy by concomitant boosts (CBs) associated with chemoradiation therapy (CRT) of the whole pelvis, in improving the rate of pathological complete response (pCR) to treatment in patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IB2-IVA locally advanced cervical cancer. Methods and Materials: Neoadjuvant CRT included conformal irradiation of the whole pelvis with a total dose of 39.6 Gy (1.8 cGy/fraction, 22 fractions), plus additional irradiation of primary tumor and parametria with 10.8 Gy administered with CBs (0.9 cGy/fraction, 12 fractions, every other day). Concomitant chemotherapy included cisplatin (20 mg/m{sup 2}, days 1-4 and 26-30 of treatment), and capecitabine (1300 mg/m{sup 2}/daily, orally) during the first 2 and the last 2 weeks of treatment. Radical hysterectomy plus pelvic with or without aortic lymphadenectomy was performed within 6 to 8 weeks from CRT. Toxicity was recorded according to Radiation Therapy Oncology Group toxicity criteria and Chassagne grading system. Based on the Simon design, 103 cases were required, and the regimen would be considered active if >45 pCR were registered (α error = 0.05; β error = 0.1). Results: pCR was documented in 51 cases (50.5%), and the regimen was considered active, according to the planned statistical assumptions. At median follow-up of 36 months (range: 7-85 months), the 3-year local failure rate was 7%, whereas the 3-year disease-free and overall survival rates were 73.0% and 86.1%, respectively. Grade 3 leukopenia and neutropenia were reported in only 1 and 2 cases, respectively. Gastrointestinal toxicity was always grade 1 or 2. Conclusions: Addition of CBs in the accelerated fractionation modality to the whole pelvis chemoradiation followed by radical surgery results in a high rate of pathologically assessed complete response to CRT and a very

  17. Cisplatin-induced anorexia and ghrelin.

    Science.gov (United States)

    Hattori, Tomohisa; Yakabi, Koji; Takeda, Hiroshi

    2013-01-01

    Cisplatin, a formidable anticancer treatment, is used for several varieties of cancer. There are, however, many cases in which treatment must be abandoned due to a decrease in the patient's quality of life from loss of appetite associated with vomiting and nausea. There is a moderate degree of improvement in prevention of cisplatin-induced nausea and vomiting when serotonin (5-HT) 3 receptor antagonists, neurokinin 1 receptor antagonists, and steroids-either alone or in combination-are administered. The mechanism of action for anorexia, which continues during or after treatment, is, however, still unclear. This anorexia is, similar to the onset of vomiting and nausea, caused by the action of large amounts of 5-HT released as a result of cisplatin administration on tissue 5-HT receptors. Among the 5-HT receptors, the activation of 5-HT2b and 5-HT2c receptors, in particular, seems to play a major role in cisplatin-induced anorexia. Following activation of these two receptors, there is reduced gastric and hypothalamic secretion of the appetite-stimulating hormone ghrelin. There is ample evidence of the usefulness of exogenous ghrelin, synthetic ghrelin agonists, and the endogenous ghrelin signal-enhancer rikkunshito, which are expected to play significant roles in the clinical treatment and prevention of anorexia in future.

  18. A Mathematical Model for Cisplatin Cellular Pharmacodynamics

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    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.

  19. Prophylactic etanercept treatment in cisplatin ototoxicity.

    Science.gov (United States)

    Dasli, Sinem; Topdag, Murat; Mutlu, Ahmet; Kara, Ahmet; Ozturk, Murat

    2017-07-20

    The aim of our study was to evaluate the audiological protective effects of etanercept using distortion product otoacoustic emission (DPOAE) in rats with hearing loss due to cisplatin ototoxicity. The study began with 36 healthy female albino rats; 31 rats had good measurements in DPOAE and were included in the study. On day 0, a single dose of etanercept was given by intraperitoneal administration to 15 rats (etanercept group). No medication was given to the control group. After 24 h, 16 mg/kg cisplatin was given to all rats. DPOAE measurements were performed on the 3rd, 7th, and 21st day. After the DPOAE test on the 21st day, the animals were killed by decapitation. Between-group and intra-group comparisons were made using the data of the two groups. A statistically significant difference was observed on the 3rd day at 4921 Hz and higher frequencies, on the 7th day at 6064 Hz and higher frequencies, and on the 21st day at 6494 Hz and higher frequencies (p ototoxicity in the etanercept group and 56% ototoxicity in the control group. A single dose of etanercept 1 day before cisplatin administration decreases cisplatin ototoxicity in the early period. This effect comes to the fore especially over 4500 Hz frequencies at 65 dB and higher.

  20. 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.

  1. Protective Effect of Tempol against Cisplatin-Induced Ototoxicity.

    Science.gov (United States)

    Youn, Cha Kyung; Kim, Jun; Jo, Eu-Ri; Oh, Jeonghyun; Do, Nam Yong; Cho, Sung Il

    2016-11-18

    One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1). Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL) assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose) polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity.

  2. Protective Effect of Tempol against Cisplatin-Induced Ototoxicity

    Directory of Open Access Journals (Sweden)

    Cha Kyung Youn

    2016-11-01

    Full Text Available One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1. Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity.

  3. Cyclophosphamide, doxorubicin, and cisplatin combined in the treatment of advanced sarcomas.

    Science.gov (United States)

    Edmonson, J H; Hahn, R G; Schutt, A J; Bisel, H F; Ingle, J N

    1983-01-01

    Twenty-five patients with evaluable histologically confirmed inoperable metastatic sarcomas were treated once every four weeks with cyclophosphamide, doxorubicin, and cisplatin in doses of 400, 40, and 60 mg/m2, respectively. Cyclophosphamide and doxorubicin were given by rapid intravenous injection followed immediately by cisplatin by slow intravenous infusion (2-6 hr) in 1 liter of 0.45% saline with mannitol added. Leukopenia, alopecia, and vomiting were common side effects and three patients refused further treatment because of vomiting following their initial courses. No drug-related deaths occurred and we removed no one from the study because of toxicity problems. Among the 9 patients who experienced objective tumor regression were 2 of 2 with hemangiosarcoma, 3 of 5 with malignant fibrous histiocytoma, 3 of 5 with osteosarcoma, and 1 of 1 with pleomorphic liposarcoma of bone. Although not therapeutically gratifying, these results appear to be better than any previously observed at our institution.

  4. Understanding the Risk Factors and Long-Term Consequences of Cisplatin-Associated Acute Kidney Injury: An Observational Cohort Study.

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    Zeenat Yousuf Bhat

    Full Text Available Acute kidney injury (AKI is a well-known complication of cisplatin-based chemotherapy; however, its impact on long-term patient survival is unclear. We sought to determine the incidence and risk factors for development of cisplatin-associated AKI and its impact on long-term renal function and patient survival. We identified 233 patients who received 629 cycles of high-dose cisplatin (99±9mg/m2 for treatment of head and neck cancer between 2005 and 2011. These subjects were reviewed for development of AKI. Cisplatin nephrotoxicity (CN was defined as persistent rise in serum creatinine, with a concomitant decline in serum magnesium and potassium, in absence of use of nephrotoxic agents and not reversed with hydration. All patients were hydrated per protocol and none had baseline glomerular filtration rate (GFR via CKD-EPI<60mL/min/1.73m2. The patients were grouped based on development of AKI and were staged for levels of injury, per KDIGO-AKI definition. Renal function was assessed via serum creatinine and estimated glomerular filtration rate (eGFR via CKD-EPI at baseline, 6- and 12-months. Patients with AKI were screened for the absence of nephrotoxic medication use and a temporal decline in serum potassium and magnesium levels. Logistic regression models were constructed to determine risk factors for cisplatin-associated AKI. Twelve-month renal function was compared among groups using ANOVA. Kaplan-Maier curves and Cox proportional hazard models were constructed to study its impact on patient survival. Of 233 patients, 158(68% developed AKI; 77 (49% developed stage I, 55 (35% developed stage II, and 26 (16% developed stage III AKI. Their serum potassium and magnesium levels correlated negatively with level of injury (p<0.05. African American race was a significant risk factor for cisplatin-associated AKI, OR 2.8 (95% CI 1.3 to 6.3 and 2.8 (95% CI 1.2 to 6.7 patients with stage III AKI had the lowest eGFR value at 12 months (p = 0.05 and long

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

    National Research Council Canada - National Science Library

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

    2009-01-01

    .... 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...

  6. Combined intraarterial cisplatin infusion and radiation therapy for invasive bladder cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mizoguchi, Hiroaki; Nomura, Yoshio; Terada, Katsuhiko; Nakagawa, Masayuki; Ogata, Jiro [Oita Medical Univ., Hasama (Japan)

    1995-03-01

    Twenty-three patients with invasive bladder cancer (T2 in 17, T3 in 6) were treated initially with combined intraarterial cisplatin infusion and radiation therapy. Cisplatin (50 mg) was infused into the internal iliac artery through a subcutaneous reservoir twice a week over three weeks while concurrent radiation therapy with 30 Gy, delivered in 15 fractions, was given. In 23 patients, 6 received additional cisplatin infusion and the other 17 had transurethral resection of bladder tumor (TURBT). Two of the patients undergoing total cystectomy exhibited a complete response (CR). Thus overall response rate was 87% (CR in 13 and partial response in 7). CR was achieved in 53% for T2 patients and 67% for T3 patients. CR was slightly higher in patients with non-papillary cancer than those with papillary one. Toxic reaction included a decrease in bladder capacity in 2 patients and severe diarrhea due to methicillin-resistant Staphylococcus aureus colitis in one. The other toxicities, including nausea, vomiting, neurotoxicity and myelosuppression, were tolerable. All except for one are alive. Seven patients had a local recurrence of bladder cancer. One patient developed invasive bladder cancer reaching the prostatic urethra. One other patient had recurrence at the same site as the previous tumor. Five others had superficial bladder cancer and were managed by TURBT. Bladder function was preserved in 65% at a mean follow-up of 29 months. In conclusion, the combined intraarterial cisplatin infusion and radiation therapy is useful for the initial treatment of invasive bladder cancer. (N.K.).

  7. Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma

    OpenAIRE

    Viet, Chi T.; Dongmin Dang; Stacy Achdjian; Yi Ye; Katz, Samuel G.; Schmidt, Brian L.

    2014-01-01

    Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose require...

  8. Anthropophobia: its meaning and concomitant experiences.

    Science.gov (United States)

    Zhang, A Y; Yu, L C; Zhang, J; Tang, D; Draguns, J G

    2001-01-01

    This study investigated the essential feature and concomitant experiences of anthropophobia, a culturally specific phobic disorder in China and Japan. One hundred and fifty subjects, including 50 anthropophobic, 50 neurasthenic and 50 normal subjects, were recruited from hospitals and downtown residential areas in Beijing. Measures of anthropophobic symptoms and DSM-III-R depressive and anxiety symptoms were administered to all subjects. Nonparametric analysis of variance, analysis of variance (ANOVA and MANOVA) and Fisher's exact test were performed to examine group differences on each symptomatic item of the three measures. Results indicate that the core anthropophobic symptoms include a fear of making eye contact with others and a fear of being watched by others, which essentially express fears of others' judgement or opinion of oneself. Anxiety and depression are associated features of anthropophobia. However, these concomitants are experienced more cognitively and less somatically in the case of anthropophobia than neurasthenia.

  9. Cisplatin-induced peptic ulcers, vagotomy, adrenal and calcium modulation.

    Science.gov (United States)

    Aggarwal, S K; San Antonio, J D; Sokhansanj, A; Miller, C

    1994-04-01

    Cytochemical and autoradiographic studies in Wistar rats [Crl:(WI)BR] show that cisplatin treatment (9 mg/kg) inhibits the release of acetylcholine from the axonal endings of the stomach smooth muscle resulting in bloating of the stomach and ulceration. Cisplatin also induces corticosteroid release from the adrenal gland stimulating peptic ulceration. Vagotomy helps ameliorate the effect but not eliminate it. Calcium supplementation restores normal neuromuscular function to gastric smooth muscle, thereby eliminating the gastro-intestinal toxicity due to cisplatin.

  10. Cisplatin-associated anemia: an erythropoietin deficiency syndrome.

    OpenAIRE

    Wood, P A; Hrushesky, W J

    1995-01-01

    Cisplatin-based therapy results in a cumulative anemia that is disproportionate to the effects on other blood cells. The severity of this treatment-induced anemia and the resultant transfusion requirement in cancer patients correlate with cisplatin-induced renal tubular dysfunction. Observed/expected serum erythropoietin (EPO) ratios decline with progressive cisplatin therapy and are proportionate to the degree of renal dysfunction. Recovery from anemia and of observed/expected serum EPO rati...

  11. Salvia Officinalis and Cisplatin Effects on Pentylenetetrazole Induced Seizure Threshold

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    Mir Hadi Khayate-Nouri

    2013-11-01

    Full Text Available Background: Studies have shown that cisplatin have neuropathic effects and Salvia officinalis (SO could have therapeutic effects on nervous system. The aim of this study was to investigate the effects of SO hydroalcoholic extract and cisplatin on pentylenetetrazole (PTZ induced seizure in mice. Materials and methods: This is an experimental interventional study. For this purpose first group received normal saline, second group received SO extract, third group received cisplatin, in the fourth group received SO extract plus cisplatin and the subsequent seizure threshold was determined for each group. Results: The results showed that SO extract significantly (p<0.05 increased and in cisplatin group significantly (p<0.05 decreased seizure threshold. Simultaneous uses of cisplatin and SO extract caused to significantly increased seizure threshold (p<0.05 compared with cisplatin group. Conclusion: Considering different types of ingredients in SO extract which have beneficial effects on nervous system, it might be used to reduce cisplatin induced neuropathic effects. It seems that SO extract could be useful in cisplatin-induced seizure but further investigations are needed.

  12. Cisplatin Ototoxicity Blocks Sensory Regeneration in the Avian Inner Ear

    Science.gov (United States)

    Slattery, Eric L.; Warchol, Mark E.

    2010-01-01

    Cisplatin is a chemotherapeutic agent that is widely-used in the treatment of solid tumors. Ototoxicity is a common side effect of cisplatin therapy, and often leads to permanent hearing loss. The sensory organs of the avian ear are able to regenerate hair cells after aminoglycoside ototoxicity. This regenerative response is mediated by supporting cells, which serve as precursors to replacement hair cells. Given the antimitotic properties of cisplatin, we examined whether the avian ear was also capable of regeneration after cisplatin ototoxicity. Using cell and organ cultures of the chick cochlea and utricle, we found that cisplatin treatment caused apoptosis of both auditory and vestibular hair cells. Hair cell death in the cochlea occurred in a unique pattern, progressing from the low frequency (distal) region toward the high frequency (proximal) region. We also found that cisplatin caused a dose-dependent reduction in the proliferation of cultured supporting cells as well as increased apoptosis in those cells. As a result, we observed no recovery of hair cells after ototoxic injury caused by cisplatin. Finally, we explored the potential for nonmitotic hair cell recovery via activation of Notch pathway signaling. Treatment with the γ-secretase inhibitor DAPT failed to promote the direct transdifferentiation of supporting cells into hair cells in cisplatin-treated utricles. Taken together, our data show that cisplatin treatment causes maintained changes to inner ear supporting cells and severely impairs the ability of the avian ear to regenerate either via proliferation or by direct transdifferentiation. PMID:20203207

  13. Role of autophagy in cisplatin-induced ototoxicity.

    Science.gov (United States)

    Youn, Cha Kyung; Kim, Jun; Park, Jun-Hee; Do, Nam Yong; Cho, Sung Il

    2015-11-01

    Hearing loss is a major side effect of cisplatin chemotherapy. Although cell death in cisplatin-induced ototoxicity is primarily caused by apoptosis, the exact mechanism behind the ototoxic effects of cisplatin is not fully understood. Autophagy is generally known as a pro-survival mechanism that protects cells under starvation or stress conditions. However, recent research has reported that autophagy plays a functional role in cell death also. This study aimed to investigate the role of autophagy in cisplatin-induced ototoxicity in an auditory cell line. Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 48 h, and cell viability was tested using MTT assays. To evaluate whether autophagy serves to cell death after cisplatin exposure, western blotting and immunofluorescence staining for LC3-II were performed. Markers of two autophagy-related pathways, mTOR and class III PI3K, were also investigated. The formation of the autophagic protein LC3-II in response to 30 μM cisplatin increased with time. The early upregulation of autophagy exerted cytoprotective activity via the class III PI3K pathway. But later increase in autophagy induced cell death by suppressing the mTOR pathway. Our results prove that autophagy could induce cell death during cisplatin-induced ototoxicity, and modulating the autophagic pathway might be another strategy against cisplatin-induced ototoxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Effects of cisplatin on potassium currents in CT26 cells

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    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.

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

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    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.

  16. Cisplatin cytotoxicity is dependent on mitochondrial respiration in Saccharomyces cerevisiae

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    Santhipriya Inapurapu

    2017-01-01

    Full Text Available Objective(s: To understand the role of mitochondrial respiration in cisplatin sensitivity, we have employed wild-type and mitochondrial DNA depleted Rho0 yeast cells. Materials and Methods: Wild type and Rho0 yeast cultured in fermentable and non-fermentable sugar containing media, were studied for their sensitivity against cisplatin by monitoring growth curves, oxygen consumption, pH changes in cytosol/mitochondrial compartments, reactive oxygen species production and respiratory control ratio. Results: Wild-type yeast grown on glycerol exhibited heightened sensitivity to cisplatin than yeast grown on glucose. Cisplatin (100 μM, although significantly reduced the growth of wild- type cells, only slightly altered the growth rate of Rho0 cells. Cisplatin treatment decreased both pHcyt and pHmit to a similar extent without affecting the pH difference. Cisplatin dose-dependently increased the oxidative stress in wild-type, but not in respiration-deficient Rho0 strain. Cisplatin decreased the respiratory control ratio. Conclusion: These results suggest that cisplatin toxicity is influenced by the respiratory capacity of the cells and the intracellular oxidative burden. Although cisplatin per se slightly decreased the respiration of yeast cells grown in glucose, it did not disturb the mitochondrial chemiosmotic gradient.

  17. Respiratory tract infections and concomitant pericoronitis of the wisdom teeth.

    Science.gov (United States)

    Meurman, J H; Rajasuo, A; Murtomaa, H; Savolainen, S

    1995-04-01

    To discover if there is an association between respiratory tract infections and pericoronitis of erupting third molars in young adults. Data from male military conscripts' medical records were collected over five years and the incidence of respiratory tract infection before and after acute pericoronitis (191 cases) and before and after standard (722 cases) and operative (741) extractions compared with that in controls (n = 703) who had no infections in the third molar regions. 14,500 male military conscripts aged 20. Garrisons in Valkeala and Kouvola, Finland. The incidence of respiratory tract infection was significantly higher during the two weeks before acute pericoronitis was diagnosed compared with that in controls. The highest incidence was observed in the three days before pericoronitis (odds ratio 6.8; 95% confidence interval 3.0 to 15.0). The incidence was also increased in the first week after pericoronitis (odds ratio 3.7; 1.6 to 8.4) and three days before (odds ratio 2.6; 0.9 to 7.5) and during the first week after extraction of third molars (odds ratio 2.6; 1.3 to 5.3). Respiratory tract infection may precipitate and occur concomitantly with acute pericoronitis. Third molar surgery for pericoronitis, on the other hand, may trigger respiratory tract infection.

  18. A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin.

    Science.gov (United States)

    Veal, G J; Griffin, M J; Price, E; Parry, A; Dick, G S; Little, M A; Yule, S M; Morland, B; Estlin, E J; Hale, J P; Pearson, A D; Welbank, H; Boddy, A V

    2001-04-20

    Pre-clinical studies indicate that cisplatin encapsulated in STEALTH((R))liposomes (SPI-77) retains anti-tumour activity, but has a much reduced toxicity, compared to native cisplatin. A phase I study was conducted to determine the toxicity and pharmacokinetics of SPI-77 administered to children with advanced cancer not amenable to other treatment. Paediatric patients were treated at doses ranging from 40 to 320 mg m(-2)by intravenous infusion every 4 weeks. Blood samples taken during, and up to 3 weeks after, administration and plasma and ultrafiltrate were prepared immediately. Urine was collected, when possible, for 3 days after administration. SPI-77 administration was well tolerated with the major toxicity being an infusion reaction which responded to modification of the initial infusion rate of SPI-77. Limited haematological toxicity and no nephrotoxicity were observed. No responses to treatment were seen during the course of this phase I study. Measurement of total plasma platinum showed that cisplatin was retained in the circulation with a half life of up to 134 h, with maximum plasma concentrations approximately 100-fold higher than those reported following comparable doses of cisplatin. Comparison of plasma and whole blood indicated that cisplatin was retained in the liposomes and there was no free platinum measurable in the ultrafiltrate. Urine recovery was less than 4% of the dose administered over 72 h. Results from this phase I study indicate that high doses of liposomal cisplatin can safely be given to patients, but further studies are required to address the issue of reformulation of liposomally bound cisplatin.

  19. Long-term aerobic exercise protects against cisplatin-induced nephrotoxicity by modulating the expression of IL-6 and HO-1.

    Directory of Open Access Journals (Sweden)

    Mariana Yasue Saito Miyagi

    Full Text Available Nephrotoxicity is substantial side effect for 30% of patients undergoing cancer therapy with cisplatin and may force them to change or even abandon the treatment. Studies regarding aerobic exercise have shown its efficacy for the treatment of many types of diseases and its capacity to reduce tumors. However, little is known about the impact of physical exercise on cisplatin-induced acute kidney injury (AKI. In the present study, our aim was to investigate the role of physical exercise in AKI induced by cisplatin. We submitted C57Bl6 male mice to seven weeks of chronic exercise on a training treadmill and treated them with single i.p. injection of cisplatin (20 mg/kg in the last week. Exercise efficacy was confirmed by an increased capillary-to-fiber ratio in the gastrocnemius muscle of exercised groups (EX and CIS-EX. The group submitted to exercise before cisplatin administration (CIS-EX exhibited less weight loss and decreased serum urea levels compared to the cisplatin group (CIS. Exercise also showed a protective role against cisplatin-induced cell death in the kidney. The CIS-EX group showed a lower inflammatory response, with less TNF and IL-10 expression in the kidney and serum. In the same group, we observed an increase of IL-6 and HO-1 expression in the kidney. Taken together, our results indicate that chronic aerobic exercise is able to attenuate AKI by inducing IL-6 and HO-1 production, which results in lower inflammatory and apoptotic profiles in the kidney.

  20. Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer

    OpenAIRE

    Stathopoulos, G. P.; Antoniou, D.; Dimitroulis, J.; STATHOPOULOS, J.; Marosis, K.; Michalopoulou, P.

    2011-01-01

    Purpose Liposomal cisplatin was developed to reduce the systemic toxicity of cisplatin, particularly the nephrotoxicity, and it has been used in combination with other agents in pancreatic and head and neck cancers and non-small-cell lung cancer (NSCLC). Our objective was to compare the effectiveness of lipoplatin combined with paclitaxel versus cisplatin with paclitaxel in advanced non-squamous NSCLC. Methods During 2007–2010, 202 patients with non-squamous NSCLC (stage IIIB and IV) were rec...

  1. Chemotherapy with cisplatin and vinorelbine for elderly patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC

    Directory of Open Access Journals (Sweden)

    Nikaedo Sueli M

    2004-09-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusion Age does not preclude assessment on the role of cisplatin-vinorelbine CT for elderly NSCLC patients with good performance status and adequate bodily functions.

  2. Accelerated high-dose radiotherapy alone or combined with either concomitant or sequential chemotherapy; treatments of choice in patients with Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Pieters Bradley R

    2007-07-01

    Full Text Available Abstract Background Results of high-dose chemo-radiotherapy (CRT, using the treatment schedules of EORTC study 08972/22973 or radiotherapy (RT alone were analyzed among all patients (pts with Non Small Cell Lung Cancer (NSCLC treated with curative intent in our department from 1995–2004. Material Included are 131 pts with medically inoperable or with irresectable NSCLC (TNM stage I:15 pts, IIB:15 pts, IIIA:57 pts, IIIB:43 pts, X:1 pt. Treatment Group I: Concomitant CRT: 66 Gy/2.75 Gy/24 fractions (fx/33 days combined with daily administration of cisplatin 6 mg/m2: 56 pts (standard. Group II: Sequential CRT: two courses of a 21-day schedule of chemotherapy (gemcitabin 1250 mg/m2 d1, cisplatin 75 mg/m2 d2 followed by 66 Gy/2.75 Gy/24 fx/33 days without daily cisplatin: 26 pts. Group III: RT: 66 Gy/2.75 Gy/24 fx/33 days or 60 Gy/3 Gy/20 fx/26 days: 49 pts. Results The 1, 2, and 5 year actuarial overall survival (OS were 46%, 24%, and 15%, respectively. At multivariate analysis the only factor with a significantly positive influence on OS was treatment with chemo-radiation (P = 0.024 (1-, 2-, and 5-yr OS 56%, 30% and 22% respectively. The incidence of local recurrence was 36%, the incidence of distant metastases 46%. Late complications grade 3 were seen in 21 pts and grade 4 in 4 patients. One patient had a lethal complication (oesophageal. For 32 patients insufficient data were available to assess late complications. Conclusion In this study we were able to reproduce the results of EORTC trial 08972/22973 in a non-selected patient population outside of the setting of a randomised trial. Radiotherapy (66 Gy/24 fx/33 days combined with either concomitant daily low dose cisplatin or with two neo-adjuvant courses of gemcitabin and cisplatin are effective treatments for patients with locally advanced Non-Small Cell Lung Cancer. The concomitant schedule is also suitable for elderly people with co-morbidity.

  3. 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.

  4. Detouring of cisplatin to access mitochondrial genome for overcoming resistance.

    Science.gov (United States)

    Marrache, Sean; Pathak, Rakesh K; Dhar, Shanta

    2014-07-22

    Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a strain-promoted alkyne-azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle (NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria of neuroblastoma cells resulting in ∼17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatin-based therapy.

  5. Comparison between nedaplatin and cisplatin plus docetaxel combined with intensity-modulated radiotherapy for locoregionally advanced nasopharyngeal carcinoma: a multicenter randomized phase II clinical trial

    Science.gov (United States)

    Tang, Chunyuan; Wu, Fang; Wang, Rensheng; Lu, Heming; Li, Guisheng; Liu, Meilian; Zhu, Haisheng; Zhu, Jinxian; Zhang, Yong; Hu, Kai

    2016-01-01

    Nasopharyngeal carcinoma (NPC) is highly incident in southern China. Metastasis is the major cause of death in NPC patients. Concurrent chemoradiotherapy (CCRT) has been accepted as standard in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). However, induction chemotherapy (IC) also has benefits in this disease, especially in the patients with certain high-risk factors such as bulky and/or extensive nodal disease. It has been presented that adding IC to CCRT might be a reasonable approach and need more work to confirm. The optimal chemotherapeutic regimen combined with radiotherapy has not been determined so far. It is important to explore high effective and low toxic chemotherapy for the patients. In the multicenter prospective study, 223 patients with locoregionally advanced untreated NPC were randomized into experimental group and control group. The patients received two cycles of induction chemotherapy (IC) with docetaxel (DOC) plus nedaplatin (NDP) in experimental group every 3 weeks, followed by IMRT concurrent with weekly NDP for six cycles, and NDP was replaced by cisplatin (CDDP) in control group. More patients in experimental group could receive full courses of IC and concurrent chemoradiotherapy (CCRT) (P=0.013). There was no significant difference between the two groups in the percentage of reduction of GTVnx and GTVnd after IC (P=0.207 and P=0.107) and CR rate three months after completion of chemoradiotherapy (P=0.565 and P=0.738). With a mean follow-up of 35.1 months, no statistically significant difference in the 3-year OS, LRFS, RRFS, DMFS, and PFS was found. During IC, more patients suffered vomiting in control group (P=0.001). During CCRT, grade 3/4 neutropenia/thrombocytopenia were more common in experimental group (P=0.028 and P=0.035); whereas, severe anemia and vomiting were more common in control group (P=0.0001 and P=0.023). In conclusions, patients with locoregionally advanced NPC showed good

  6. Primary Pure Squamous Cell Carcinoma of the Breast Might Be Sensitive to Cisplatin-Based Chemotherapy

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    Swei H. Tsung

    2012-10-01

    Full Text Available Pure squamous cell carcinoma of the breast (PSCCB is a rare condition. Surgery is usually the initial treatment. In some cases, complete excision of the tumor may be enough, while in other cases a mastectomy is required. In the literature, studies reported that PSCCB is an extremely aggressive disease associated with frequent locoregional and distant relapses and resultant death. Better therapy is therefore needed to improve patients’ outcome. A literature review revealed that several patients with locoregional and distant metastasis were successfully treated using cisplatin-based regimens. I encountered a case of a patient with PSCCB who received neoadjuvant therapy using cytoxan, epirubicin, and fluorouracil without any response. Therefore, she underwent a mastectomy with lymph node dissection. Local recurrence occurred 3 weeks after surgery. She was started on taxotere and cisplatin. Four months after therapy, the recurrent tumors completely regressed. At this point, there is only circumstantial evidence that cisplatin-based regimens could be a promising option for the treatment of PSCCB. Clinical trials including large series of PSCCB are needed to increase our knowledge.

  7. A CONSANGUINEOUS MATING COUPLE AND THEIR CONCOMITANT ESOTROPIA TWINS

    Institute of Scientific and Technical Information of China (English)

    1991-01-01

    A first cousin marriage couple and their 8-year-old identical twin daughters with concomitant strabismus are described.This family would indicate an autosomal recessive inheritance in concomitant strabismus.

  8. Phase I trial of 18F-Fludeoxyglucose based radiation dose painting with concomitant cisplatin in head and neck cancer

    DEFF Research Database (Denmark)

    Rasmussen, Jacob H; Håkansson, Katrin; Vogelius, Ivan R

    2016-01-01

    : Median follow up time from the end of treatment was 18months (range 7-21months). All 15 patients completed treatment without interruptions and no incidents of early grade 4+ toxicity were observed. Four patients had ulceration at the evaluation two months after treatment, two have subsequently healed...

  9. Split-course chemoradiotherapy with S-1, a novel oral fluorouracil, and cisplatin for distant metastases of oesophageal cancer stage IVb

    Directory of Open Access Journals (Sweden)

    Iwase H

    2017-01-01

    Full Text Available Objectives: To evaluate the efficacy and safety of split-course chemoradiotherapy with S-1, a novel oral fluorouracil, together with cisplatin in patients with distant oesophageal cancer stage IVb metastasis. Methods: Forty-one patients with distant oesophageal cancer metastasis and performance status 0 or 1 received split-course chemoradiotherapy with S-1 and cisplatin. All 41 patients were reviewed retrospectively. Chemoradiotherapy comprised two courses of 30-Gy radiotherapy over three weeks plus daily oral S-1 (70mg/m2/day for two weeks and a 24 h cisplatin infusion (70mg/m2 on Day 8, with a two week interval between the two courses. Results: The most frequent adverse events (AEs were grade 3 and 4 neutropenia (29.2%, thrombocytopenia (9.8%, and anaemia (7.3%. Non-haematological AEs were generally mild. AEs in the initial course of chemoradiotherapy remitted during the second interval week. Overall, the complete response rate was 22.0% and endoscopic complete response rate for primary lesion was 65.9%. Thirty-one patients (75.6% became asymptomatic and regained normal swallowing function. The overall median survival time was 12 months. Conclusion: This retrospective investigation showed that split-course chemoradiotherapy with S-1 and cisplatin had an encouraging safety profile together with good efficacy. Potentially, this regimen may become a standard for distant metastasis of oesophageal cancer stage IVb.

  10. Paclitaxel, ifosfamide and cisplatin with granulocyte colony-stimulating factor or recombinant human interleukin 3 and granulocyte colony-stimulating factor in ovarian cancer : A feasibility study

    NARCIS (Netherlands)

    Veldhuis, GJ; Willemse, PHB; Beijnen, JH; Piersma, H; vanderGraaf, WTA; deVries, EGE; Boonstra, J.

    1997-01-01

    The tolerability and efficacy of four courses of paclitaxel and ifosfamide plus cisplatin every 3 weeks was evaluated in patients with residual or refractory ovarian cancer. Additionally, supportive haematological effects of recombinant human interleukin 3 (rhIL-3) and recombinant human granulocyte

  11. Characterization of sterically stabilized cisplatin liposomes by nuclear magnetic resonance.

    Science.gov (United States)

    Peleg-Shulman, T; Gibson, D; Cohen, R; Abra, R; Barenholz, Y

    2001-02-09

    Extensive scientific efforts are directed towards finding new and improved platinum anticancer agents. A promising approach is the encapsulation of cisplatin in sterically stabilized, long circulating, PEGylated 100 nm liposomes. This liposomal cisplatin (STEALTH cisplatin, formerly known as SPI-77) shows excellent stability in plasma and has a longer circulation time, greater efficacy and lower toxicity than much free cisplatin. However, so far, the physicochemical characterization of STEALTH cisplatin has been limited to size distribution, drug-to-lipid ratio and stability. Information on the physical state of the drug in the liposome aqueous phases and the drug's interaction with the liposome membrane has been lacking. This study was aimed at filling this gap. We report a multinuclear NMR study in which several techniques have been used to assess the physical nature of cisplatin in liposomal formulations and if and to what extent the drug affects the liposome phospholipids. Since NMR detects only the soluble cisplatin in the liposomes and not the insoluble drug, combining NMR and atomic absorption data enables one to determine how much of the encapsulated drug is soluble in the intraliposomal aqueous phase. Our results indicate that almost all of the cisplatin remains intact during the loading process, and that the entire liposomal drug is present in a soluble form in the internal aqueous phase of the liposomes.

  12. Is Glutathione the Major Cellular Target of Cisplatin?

    DEFF Research Database (Denmark)

    Kasherman, Yonit; Stürup, Stefan; gibson, dan

    2009-01-01

    Cisplatin is an anticancer drug whose efficacy is limited because tumors develop resistance to the drug. Resistant cells often have elevated levels of cellular glutathione (GSH), believed to be the major cellular target of cisplatin that inactivates the drug by binding to it irreversibly, forming...

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    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...

  14. 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.

  15. Oxytocin as a protective agent in cisplatin-induced ototoxicity.

    Science.gov (United States)

    Bekmez Bilmez, Zekiye Eda; Aydin, Sedat; Şanli, Arif; Altintoprak, Niyazi; Demir, Mehmet Gökhan; Atalay Erdoğan, Banu; Kösemihal, Ebru

    2016-04-01

    Cisplatin is a potent chemotherapeutic drug with serious side effects such as ototoxicity which is characterized by irreversible, bilateral, progressive sensorineural hearing loss. Oxytocin, which is a well-known hormone secreting during pregnancy, has antioxidant and antiinflammatory effect. Our study aims to test and compare the effect of intratympanic (IT) and intraperitoneal (IP) oxytocin on cisplatin ototoxicity with DPOAE. A total of 24 Wistar albino rats were randomly divided into four groups: Group 1 received 0.1-0.3 ml IT saline + IP saline solutions for 4 days (n = 6), Group 2 received cumulative dose of 20 mg/kg IP cisplatin divided into two equal doses in first and second days of experiment + 0.1-0.3 ml IT saline for 4 days, Group 3 received same dose of cisplatin as Group 2 + 0.1-0.3 ml IT oxytocin for 4 days, and Group 4 received same dose of cisplatin as Groups 2 and 3 + IP oxytocin with dose of 1 mg/kg. DPOAE was performed prior to procedure and at the end of the experiment on day 5. Group 2 showed severe ototoxic effect of cisplatin according to DPOAE result (p ototoxicity. We suggest oxytocin in cisplatin ototoxicity, especially via IT route even with high-dose cisplatin.

  16. [Treatment of non accomodated concomitant strabismus].

    Science.gov (United States)

    Kikolashvili, M Sh; Shengeliia, D G; Tsomaia, L V

    2011-02-01

    The aim of the study was comparative evaluation of surgical treatment and complex pre and postoperative pleoptic, orthoptic, diploptic treatment of non accommodated concomitant strabismus and identification of the optimum age for surgical treatment of strabismus. The 75 patients (from 2 to 10 years old) with manifested concomitant convergent strabismus were divided into two groups: patients operated at the age from 2 to 4 years old; patients operated at the age of 4-10 years). The 75 of patients operated at the age from 2 to 4 years old, which underwent orthoptic-diploptic treatment pre- and postoperatively got binocular vision showed the full recovery in only 40% of cases of the same age-group undergone the surgical treatment in combination with the direct occlusion. Binocular vision was achieved in 68% of patients operated at the age of 4-10 years with complex treatment, and in 25% in patients of the same age group with surgical treatment plus occlusion. The findings showed the efficacy of complex treatment as well as pre and postoperative pleoptic-orthoptic-diploptic treatment of strabismus and direct occlusion. Thus, the results of this study suggest that the delay of surgical treatment limits the ability to obtain optimal results.

  17. Concomitant pseudopolymorphs of 10-deacetyl baccatin III.

    Science.gov (United States)

    Tatini, Lakshmi Kumar; Rao, N Someswara; Khan, Muzaffar; Peraka, Krishna Sumanth; Reddy, K V S R Krishna

    2013-06-01

    Three new solvates [mono-dimethyl sulfoxide (mono-DMSO), mono-dimethyl acetamide (mono-DMA) and mono-dimethyl formamide (mono-DMF)] of 10-Deacetyl baccatin III, were generated by slow evaporation in DMSO, DMF, and DMSO/DMA (1:1) solvent systems respectively. Two concomitant forms mono-DMSO(a new form) and di-DMSO (a known form) were obtained in the DMSO solvent system. Yet two other concomitant forms mono-DMA (a new form) and di-DMSO (a known form) were obtained in DMSO/DMA (1:1) solvent system. A fourth solvate mono-DMF (a new form) was crystallized in unimolar ratio using DMF as a solvent. These solvates were characterized using powder X-ray diffraction, differential scanning calorimeter, thermogravimetric analysis (TGA), and spectroscopic [(13)C solid-state nuclear magnetic spectroscopy, solution (1)H NMR, and Fourier transform infrared] techniques. The interactions between host and guest molecules were elucitated by single-crystal X-ray diffraction data. In all the cases, guest molecules are connected to the host molecules by O-H∙∙∙O hydrogen bonds. A remarkable difference in the desolvation onset temperatures of di- and mono-DMSO solvates was observed which was also featured by a corresponding weight loss during TGA analysis.

  18. Continuous dose-intense temozolomide and cisplatin in recurrent glioblastoma patients.

    Science.gov (United States)

    Wang, Yu; Kong, Xiangyi; Guo, Yi; Wang, Renzhi; Ma, Wenbin

    2017-03-01

    In glioblastoma multiforme (GBM), both temozolomide (TMZ) and cisplatin are very active at various toxic levels. Previous studies demonstrated that cisplatin with the standard regimen of TMZ is active in patients suffering from recurrent GBM, generating a moderate level of toxicity. Also, continuous dose-intense TMZ is a helpful therapy for patients with recurrent GBM. We have conducted a research to evaluate the security and effectiveness of cisplatin with constant dose-intense TMZ for reduplicative GBM. The time to progression (TTP) and progression-free survival (PFS) at 6 months (PFS-6) was the major end point. Toxicity, overall survival, and response are the secondary end points. GBM patients who suffered from progression or relapse after surgery, radiotherapy, and chemotherapy were qualified. Cisplatin 40, 30, and 30 mg were given on days 1, 2, and 3 before the corresponding TMZ doses, respectively. Without interruption, TMZ was given at a dose of 50 mg/m on everyday basis (dose-intense) until development or progression of unacceptable side effects. A cycle was defined as 28 days. Response Assessment in Neuro-Oncology criteria were utilized to evaluate the response. Twenty-seven patients in total (median Karnofsky performance status-80, ranging from 60 to 100; average age-56 years, ranging from 24 to 78 years) were accrued in the research. PFS-12 was 11.1% (95% confidence interval [CI], -0.7% to 22.9%), and PFS-6 was 37% (95% CI, 18.8%-55.2%). Twenty-three weeks was the median TTP (95% CI, 17-29 weeks). In the 27 evaluative patients, 6 partial responses were observed with an overall response rate of 22.2% (95% CI, 6.5%-37.9%), while no complete response was obtained. Toxicity was mostly of grades 1 to 2 amongst 116 therapy cycles. Hematological and gastroenterological toxicities were the major limiting side effect found in the research. One patient has received leukopenia World Health Organization grade 4 at cycle 5 during her treatment. Eight percent of

  19. Mechanism of hyperthermic potentiation of cisplatin action in cisplatin-sensitive and -resistant tumour cells

    NARCIS (Netherlands)

    Hettinga, JVE; Lemstra, W; Meijer, C; Dam, WA; Uges, DRA; Konings, AWT; DeVries, EGE; Kampinga, HH

    1997-01-01

    In this study, the mechanism(s) by which heat increases cis-diamminedichloroplatinum (cisplatin, cDDP) sensitivity in cDDP-sensitive and -resistant cell lines of murine as well as human origin were investigated. Heating cells at 43 degrees C during cDDP exposure was found to increase drug accumulati

  20. Comparing two lower-dose cisplatin programs for radio-chemotherapy of locally advanced head-and-neck cancers.

    Science.gov (United States)

    Rades, Dirk; Seidl, Daniel; Janssen, Stefan; Strojan, Primoz; Karner, Katarina; Bajrovic, Amira; Hakim, Samer G; Wollenberg, Barbara; Schild, Steven E

    2017-02-01

    Radio-chemotherapy is a common treatment for locally advanced squamous cell head-and-neck cancers (LA-SCCHN). Cisplatin (100 mg/m(2)) every 3 weeks is very common but associated with considerable toxicity. Therefore, cisplatin programs with lower daily doses were introduced. There is a lack of studies comparing lower-dose programs. In this study, 85 patients receiving radio-chemotherapy with 20 mg/m(2) cisplatin on 5 days every 4 weeks (group A) were retrospectively compared to 85 patients receiving radio-chemotherapy with 30-40 mg/m(2) cisplatin weekly (group B). Groups were matched for nine factors including age, gender, performance score, tumor site, T-/N-category, surgery, hemoglobin before radio-chemotherapy, and radiation technique. One- and 3-year loco-regional control rates were 83 and 69 % in group A versus 74 and 63 % in group B (p = 0.12). One- and 3-year survival rates were 93 % and 73 % in group A versus 91 and 49 % in group B (p = 0.011). On multivariate analysis, survival was significantly better for group A (HR 1.17; p = 0.002). In groups A and B, 12 and 28 % of patients, respectively, did not receive a cumulative cisplatin dose ≥180 mg/m(2) (p = 0.016). Toxicity rates were not significantly different. On subgroup analyses, group A patients had better loco-regional control (p = 0.040) and survival (p = 0.005) than group B patients after definitive radio-chemotherapy. In patients receiving adjuvant radio-chemotherapy, outcomes were not significantly different. Thus, 20 mg/m(2) cisplatin on 5 days every 4 weeks resulted in better loco-regional control and survival in patients receiving definitive radio-chemotherapy and may be preferable for these patients. Confirmation of these results in a randomized trial is warranted.

  1. Molecular mechanisms of cisplatin resistance in cervical cancer

    Directory of Open Access Journals (Sweden)

    Zhu H

    2016-06-01

    Full Text Available 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 disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer. Keywords: cisplatin, epithelial–mesenchymal transition, microRNA, molecular mechanism, resistance

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

    NARCIS (Netherlands)

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

    2016-01-01

    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,

  3. 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

  4. Decitabine rescues cisplatin resistance in head and neck squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Chi T Viet

    Full Text Available Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.

  5. Efficacy of safranal to cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Karafakıoğlu, Yasemin Sunucu; Bozkurt, Mehmet Fatih; Hazman, Ömer; Fıdan, A Fatih

    2017-03-20

    The aim of the present study was to investigate the effects of safranal on cisplatin-induced nephrotoxicity and oxidative stress in rats. Adult male Sprague-Dawley rats were randomly divided into five groups. The control group received physiological saline; animals in Group 2 received only safranal and in Group 3 received only cisplatin; 5 days of safranal treatment was performed following administration of cisplatin for the animals in Group 4; 5 days of safranal pretreatment was applied to the animals in Group 5 before administration of cisplatin. Cisplatin (7 mg/kg) was intraperitoneally injected as a single dose and safranal (200 mg/kg) was administered by gavage. Biochemical and histopathological methods were utilized for evaluation of the nephrotoxicity. The concentrations of creatinine and urea in plasma and levels of malondialdehyde (MDA) and glutathione (GSH) as well as total antioxidant status (TAS) and total oxidant status (TOS) were determined in kidney tissue. Administration of cisplatin to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. MDA and TOS levels of rats that received cisplatin alone were not significantly different compared with those of the control group, but GSH and TAS levels in the only cisplatin-administered group were significantly decreased. Safranal administration produced amelioration in biochemical indices of nephrotoxicity in both plasma and kidney tissues when compared with the only cisplatin-administered group, pretreatment with safranal being more effective. As a result, safranal treatment might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat.

  6. Quantitation of cis-diamminedichloroplatinum II (cisplatin)-DNA-intrastrand adducts in testicular and ovarian cancer patients receiving cisplatin chemotherapy.

    Science.gov (United States)

    Reed, E; Yuspa, S H; Zwelling, L A; Ozols, R F; Poirier, M C

    1986-02-01

    The antitumor activity of cis-diamminedichloroplatinum II (cisplatin) is believed to be related to its covalent interaction with DNA where a major DNA binding product is an intrastrand N7-bidentate adduct on adjacent deoxyguanosines. A novel immunoassay was used to quantitate this adduct in buffy coat DNA from testicular and ovarian cancer patients undergoing cisplatin therapy. 44 out of 120 samples taken from 45 cisplatin patients had detectable cisplatin-DNA adducts. No adducts were detected in 18 samples of DNA taken from normal controls, patients on other chemotherapy, or patients before treatment. The quantity of measurable adducts increased as a function of cumulative dose of cisplatin. This was observed both during repeated daily infusion of the drug and over long-term, repeated 21-28 d cycles of administration. These results suggested that adduct removal is slow even though the tissue has a relatively rapid turnover. Patients receiving cisplatin for the first time on 56-d cycles, and those given high doses of cisplatin as a "salvage" regimen, did not accumulate adducts as rapidly as patients on first time chemotherapy on 21- or 28-d cycles. Disease response data, evaluated for 33 cisplatin-treated patients, showed a positive correlation between the formation of DNA adducts and response to drug therapy. However, more data will be required to confirm this relationship. These data show that specific immunological probes can readily be applied to quantitate DNA adducts in patients undergoing cancer chemotherapy.

  7. A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin

    OpenAIRE

    Veal, G J; Griffin, M. J.; Price, E.; Parry, A; Dick, G S; Little, M. A; Yule, S. M.; Morland, B.; Estlin, E J; Hale, J P; Pearson, A D J; Welbank, H; Boddy, A V

    2001-01-01

    Pre-clinical studies indicate that cisplatin encapsulated in STEALTH®liposomes (SPI-77) retains anti-tumour activity, but has a much reduced toxicity, compared to native cisplatin. A phase I study was conducted to determine the toxicity and pharmacokinetics of SPI-77 administered to children with advanced cancer not amenable to other treatment. Paediatric patients were treated at doses ranging from 40 to 320 mg m−2by intravenous infusion every 4 weeks. Blood samples taken during, and up to 3 ...

  8. RH-ENDOSTATIN PLUS GEMCITABINE/NAVELBINE AND CISPLATIN AS FIRST-LINE TREATMENT PROTOCOL FOR NON-SMALL CELL LUNG CANCER PATIENTS:A SINGLE CENTRE STUDY

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    Objective To assess the efficacy of Rh-endostatin plus the combination of gemcitabine/navelbine and cisplatin in patients with non-small cell lung cancer (NSCLC).Methods NSCLC patients,not receiving chemotherapy,were divided into two groups.Then they were given the combination of gemcitabine/navelbine and cisplatin with or without Rh-endostatin at 2-week intervals for 4 treatment cycles.Results Forty patients were enrolled and all of them were assessable for response and toxicity.None had complete response ...

  9. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial

    DEFF Research Database (Denmark)

    Stein, A.; Arnold, D.; Bridgewater, J.;

    2015-01-01

    selected the combination of gemcitabine and cisplatin for 24 weeks as investigational treatment. Based on adjuvant trials in pancreatic cancer with comparable postoperative recovery time, inclusion of patients within a maximum interval of 16 weeks between surgery and start of chemotherapy was stipulated...

  10. Results of the phase II EORTC 22971 trial evaluating combined accelerated external radiation and chemotherapy with 5FU and cisplatin in patients with muscle invasive transitional cell carcinoma of the bladder

    Energy Technology Data Exchange (ETDEWEB)

    Poortmans, Philip M. (Dept. of Radiation Oncology, Dr. Bernard Verbeeten Inst., Tilburg (NL)); Van Der Hulst, Marleen; Richaud, Pierre (Dept. of Radiation Oncology, Inst. Bergonieacute, Bordeaux (France)); Collette, Laurence; Pierart, Marianne (Statistics Dept., EORTC Data Center, Brussels (Belgium)); Ho Goey, S. (Dept. of Medical Oncology, TweeSteden Hospital, Tilburg (NL)); Bolla, Michel (Dept. of Radiation Oncology, CHU, Grenoble (France))

    2008-06-15

    Introduction. We prospectively evaluated concomitant radiotherapy and chemotherapy for advanced bladder cancer in a phase II EORTC trial to test whether it could be further studied as a potential treatment of bladder cancer. Patients and methods. Patients up to 75 years of age with invasive transitional-cell carcinoma of the bladder up to 5 cm, stage pT2 to pT3b, N0M0, without residual macroscopical tumour after transurethral excision were eligible. Radiotherapy consisted of 2 fractions of 1.2 Gy daily up to 60 Gy delivered in a period of 5 weeks. During the first and the last week, cisplatin 20 mg/m2/day and 5 FU 375 mg/m2/day were given concomitantly. Results. The study was interrupted early due to poor recruitment. Nine patients of the originally 43 planned were treated. Mean age was 63 years. Five patients had tumour stage pT2, 1 stage pT3a and 3 stage pT3b. All patients completed radiotherapy and chemotherapy as scheduled. Only one grade 3 and no grade 4 toxicity was seen. All patients were evaluated 3 months after treatment: eight patients had no detectable tumour and one had para-aortic lymph nodes. During further follow-up, a second patient got lymph node metastases and two patients developed distant metastases (lung in the patient with enlarged lymph nodes at the first evaluation and abdominal in one other). Those three patients died at respectively 19, 14, and 18 months after registration. Late toxicity was limited and often temporary. After 26 to 57 months of follow-up, no local recurrences were seen. Six patients remained alive without disease. Discussion. Despite the small cohort, this combination of concomitant chemotherapy and accelerated hyperfractionated radiotherapy for invasive bladder cancer seemed to be well tolerated and to result in satisfactory local control with limited early and late toxicity. It could therefore be considered for study in further clinical trials

  11. Cisplatin treatment of C6 rat glioma in vivo did not influence copy number alterations and growth pattern of tumor-derived resistant cells

    Directory of Open Access Journals (Sweden)

    Stepanenko A. A.

    2015-06-01

    Full Text Available Aim. To investigate whether the cisplatin treatment of C6 rat glioma in vivo impacts the copy number alterations (CNAs, proliferation and colony formation efficiency (CFE of tumor-derived cisplatin-resistant cells. Methods. The glioma modeling was performed by means of intracerebral stereotactic implantation of rat glioma C6 cells into the striatum region of rats. The rats received 20 % dimethyl sulfoxide DMSO (C6R1 or cisplatin (C6R4CIS and C6R5CIS injected intraperitoneally (5 mg/kg three times per week. After 10 injections, gliomas were resected and the cells were cultured for in vitro analysis. CNAs were analyzed by array comparative genome hybridization, proliferation by direct cell counting in hemocytometer, CFE by soft agar assay. Results. No significant changes in the CNAs and CFE of cisplatin-treated rat glioma C6R4CIS and C6R5CIS cell lines were observed compared to the vehicle-treated control C6R1 cells. However, C6R5CIS but not C6R4CIS had a reduced proliferation. Interestingly, both cisplatin- and vehicle-treated brain-grown cells had a reduced proliferation and CFE in comparison to the parental C6 cells. Conclusions. Despite numerous reports on the destabilizing effects of cisplatin on genome and phenotype, the cisplatin treatment of C6 cells in vivo did not affect genome stability, CFE, and had an inconsistent effect on the proliferation in vitro. The rat brain microenvironment may potentially impact the growth characteristics of rat glioma cells.

  12. Randomised comparison of cisplatin with cyclophosphamide/cisplatin and with cyclophosphamide/doxorubicin/cisplatin in advanced ovarian cancer. Gruppo Interegionale Cooperativo Oncologico Ginecologia.

    Science.gov (United States)

    1987-08-15

    565 patients with stage III-IV epithelial ovarian cancer were randomly assigned to receive cisplatin (P), cyclophosphamide and cisplatin (CP), or cyclophosphamide, doxorubicin, and cisplatin (CAP). Data on 531 patients were analysed. Treatment with CAP resulted in a significantly higher overall (complete and partial) response rate (66 vs 56 vs 49% for CAP, CP, and P, respectively), but the rate of complete surgical response for the three treatment arms was similar (26, 21, and 20%). Size of residual tumour after first surgery and Karnofsky index were the best predictors of complete remission. Survival and disease-free survival were not significantly different in the three arms, although progression-free survival was significantly longer after CAP. However, tumour size, cell type, and Karnofsky index, but not therapy, were independent predictors for survival. Haematological toxicity was highest with CAP. The addition of cyclophosphamide or doxorubicin and cyclophosphamide to cisplatin does not substantially increase the number of potentially curable, advanced ovarian cancer patients.

  13. [Atrial fibrillation concomitant with valvular heart disease].

    Science.gov (United States)

    Ishii, Yosuke

    2013-01-01

    Patients with valvular heart disease frequently have atrial fibrillation(AF) due to elevated pressure and dilatation of the left and right atria and pulmonary veins. Guidelines for valvular heart disease and AF recommend that surgical treatment for the valvular heart disease should be performed concomitantly with AF surgery. The Full-Maze procedure has evolved into the gold standard of treatment for medically refractory AF. In addition to the pulmonary vein isolation, the right and left atrial incisions of the Full-Maze procedure are designed to block potential macroreentrant pathways. According to the mechanisms of AF with valvular heart disease, the Full-Maze procedure is more effective for the patients than the pulmonary vein isolation alone.

  14. [Emphysematous gastritis with concomitant portal venous air].

    Science.gov (United States)

    Jeong, Min Yeong; Kim, Jin Il; Kim, Jae Young; Kim, Hyun Ho; Jo, Ik Hyun; Seo, Jae Hyun; Kim, Il Kyu; Cheung, Dae Young

    2015-02-01

    Emphysematous gastritis is a rare form of gastritis caused by infection of the stomach wall by gas forming bacteria. It is a very rare condition that carries a high mortality rate. Portal venous gas shadow represents elevation of intestinal luminal pressure which manifests as emphysematous gastritis or gastric emphysema. Literature reviews show that the mortality rate is especially high when portal venous gas shadow is present on CT scan. Until recently, the treatment of emphysematous gastritis has been immediate surgical intervention. However, there is a recent trend of avoiding surgery because of the frequent occurrence of post-operative complications such as anastomosis leakage. In addition, aggressive surgical treatment has failed to show significant improvement in prognosis. Recently, the authors experienced a case of emphysematous gastritis accompanied by portal venous gas which was treated successfully by conservative treatment without immediate surgical intervention. Herein, we present a case of emphysematous gastritis with concomitant portal venous air along with literature review.

  15. Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate

    DEFF Research Database (Denmark)

    Sørensen, Belinda Halling; Thorsteinsdottir, Unnur Arna; Lambert, Ian Henry

    2014-01-01

    Cisplatin resistance is a major challenge in the treatment of cancer and develops through reduced drug accumulation and an increased ability to avoid drug-induced cell damage, cell shrinkage, and hence initiation of apoptosis. Uptake and release of the semiessential amino acid taurine contribute...... to cell volume homeostasis, and taurine has been reported to have antiapoptotic effects. Here we find that volume-sensitive taurine release in cisplatin-sensitive [wild-type (WT)] human ovarian cancer A2780 cells is reduced in the presence of the phospholipase A2 inhibitor bromenol lactone, the 5......-induced cell death in RES A2780 cells correlates with an increased accumulation of taurine, due to an increased taurine uptake and a concomitant impairment of the volume-sensitive taurine release pathway, as well an inability to reduce cell volume after osmotic cell swelling. Downregulation of volume...

  16. 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.

  17. 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 ...

  18. 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 ...

  19. New Therapeutic Concept of NAD Redox Balance for Cisplatin Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Gi-Su Oh

    2016-01-01

    Full Text Available Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects such as ototoxicity, nephrotoxicity, and peripheral neuropathy. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses are closely associated with cisplatin-induced nephrotoxicity; however, the precise mechanism remains unclear. The cofactor nicotinamide adenine dinucleotide (NAD+ has emerged as a key regulator of cellular energy metabolism and homeostasis. Recent studies have demonstrated associations between disturbance in intracellular NAD+ levels and clinical progression of various diseases through the production of reactive oxygen species and inflammation. Furthermore, we demonstrated that reduction of the intracellular NAD+/NADH ratio is critically involved in cisplatin-induced kidney damage through inflammation and oxidative stress and that increase of the cellular NAD+/NADH ratio suppresses cisplatin-induced kidney damage by modulation of potential damage mediators such as oxidative stress and inflammatory responses. In this review, we describe the role of NAD+ metabolism in cisplatin-induced nephrotoxicity and discuss a potential strategy for the prevention or treatment of cisplatin-induced adverse effects with a particular focus on NAD+-dependent cellular pathways.

  20. Targeted amelioration of cisplatin-induced ototoxicity in guinea pigs.

    Science.gov (United States)

    Mohan, Shaulnie; Smyth, Brendan J; Namin, Arya; Phillips, Grady; Gratton, Michael Anne

    2014-11-01

    This pilot study compared otoprotection provided by trans-tympanic formulations and systemic intraperitoneal administration of L-N-acetylcysteine from cisplatin-induced cochlear oxidative stress. Protection was assessed by measures of hearing loss and cochlear glutathione levels. All groups received an equivalent single dose of L-N-acetylcysteine followed by cisplatin. Cisplatin was administered subcutaneously for 3 days (5.5 mg/kg/day). Two hours prior to day 1 cisplatin, L-N-acetylcysteine was administered either intraperitoneally (250 mg/kg), trans-tympanic as 2% L-N-acetylcysteine in gel, or trans-tympanic as L-N-acetylcysteine-loaded nanocapsules in gel. Hearing was assessed prior to and 3 days after cisplatin followed by microdissection of cochlear tissue. The levels of reduced (GSH) and oxidized (GSSG) glutathione in homogenized tissue supernatants were determined via luminometry. Intraperitoneal L-N-acetylcysteine administration preceding cisplatin resulted in less hearing loss and a higher GSH/GSSG ratio than either trans-tympanic formulation. This suggests that for equivalent doses of L-N-acetylcysteine, systemic rather than targeted cochlear delivery provides increased otoprotection from cisplatin ototoxicity.

  1. Dunnione ameliorates cisplatin ototoxicity through modulation of NAD(+) metabolism.

    Science.gov (United States)

    Kim, Hyung-Jin; Pandit, Arpana; Oh, Gi-Su; Shen, AiHua; Lee, Su-Bin; Khadka, Dipendra; Lee, SeungHoon; Shim, Hyeok; Yang, Sei-Hoon; Cho, Eun-Young; Kwak, Tae Hwan; Choe, Seong-Kyu; Park, Raekil; So, Hong-Seob

    2016-03-01

    Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that cisplatin-induced ototoxicity is related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of energy metabolism and cellular homeostasis. Here, we demonstrate that the levels and activities of sirtuin-1 (SIRT1) are suppressed by the reduction of intracellular NAD(+) levels in cisplatin-mediated ototoxicity. We provide evidence that the decreases in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) polymerase-1 (PARP-1) activation and microRNA-34a levels through cisplatin-mediated p53 activation aggravate the associated ototoxicity. Furthermore, we show that the induction of cellular NAD(+) levels using dunnione, which targets intracellular NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Protective role of misoprostol against cisplatin-induced ototoxicity.

    Science.gov (United States)

    Doğan, Murat; Polat, Halil; Yaşar, Mehmet; Kaya, Altan; Bayram, Ali; Şenel, Fatma; Özcan, İbrahim

    2016-11-01

    Cis-diammineedichloroplatinum (cisplatin) is a chemotherapeutic agent that is widely used in the treatment of many cancers. Nephrotoxicity, ototoxicity and neurotoxicity are dose-limiting adverse effects for cisplatin. The cellular and molecular mechanisms underlying cisplatin-induced ototoxicity aren't fully understood. It has been proposed that cisplatin primarily cause damage at the cochlea, outer hair cells in particular, leading to excessive production of free oxygen radicals in the organ of Corti, stria vascularis, spiral ligament, and spiral ganglionic cells. The cytotoxicity is associated with the generation of reactive oxygen species (ROS); thus, there is an increasing interest on antioxidants with an effort to discover the established protection against cisplatin-induced ototoxicity over time. Misoprostol (MP) has gained considerable interest as a reactive oxygen species scavenger in recent years. To best of our knowledge, there is no study about protective effect of MP, a prostaglandin E1 (PGE1) analogue, on cisplatin-induced ototoxicity. In our study, we show that protective effects of misoprostol on cisplatin-induced ototoxcity on rats.

  3. Calpain mediated cisplatin-induced ototoxicity in mice

    Science.gov (United States)

    Chang, Liang; Wang, Aimei

    2013-01-01

    Ototoxic drug-induced apoptosis of inner ear cells has been shown to be associated with calpain expression. Cisplatin has severe ototoxicity, and can induce cochlear cell apoptosis. This study assumed that cisplatin activated calpain expression in apoptotic cochlear cells. A mouse model of cisplatin-induced ototoxicity was established by intraperitoneal injection with cisplatin (2.5, 3.5, 4.5, 5.5 mg/kg). Immunofluorescence staining, image analysis and western blotting were used to detect the expression of calpain 1 and calpain 2 in the mouse cochlea. At the same time, the auditory brainstem response was measured to observe the change in hearing. Results revealed that after intraperitoneal injection with cisplatin for 5 days, the auditory brainstem response threshold shifts increased in mice. Calpain 1 and calpain 2 expression significantly increased in outer hair cells, the spiral ganglion and stria vascularis. Calpain 2 protein expression markedly increased with an increased dose of cisplatin. Results suggested that calpain 1 and calpain 2 mediated cisplatin-induced ototoxicity in BALB/c mice. During this process, calpain 2 plays a leading role. PMID:25206508

  4. Cisplatin ototoxicity involves cytokines and STAT6 signaling network

    Institute of Scientific and Technical Information of China (English)

    Hyung-Jin Kim; Jeong-Dug Sul; Channy Park; Sang-Young Chung; Sung-Kyun Moon; David J Lim; Hong-Seob So; Raekil Park; Gi-Su Oh; Jeong-Han Lee; Ah-Ra Lyu; Hye-Min Ji; Sang-Heon Lee; Jeho Song; Sung-Joo Park; Yong-Ouk You

    2011-01-01

    We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type,WT) and STAT4-/-,but not in STAT6-/- mice. Moreover,the expression levels of the protein and mRNA of proinflammatory cytokines,including TNF-α,IL-1β,and IL-6,were markedly increased in the serum and cochlea of WT and STAT4+,but not STAT6-/- mice. Organotypic culture revealed that the shape of stereocilia bundles and arrays of sensory hair cell layers in the organ of Corti from STAT6-/- mice were intact after treatment with cisplatin,whereas those from WT and STAT4-/- mice were highly distorted and disarrayed after the treatment. Cisplatin induced the phosphorylation of STAT6 in HEI-OC1 auditory cells,and the knockdown of STAT6 by STAT6-specific siRNA significantly protected HEI-OC1 auditory cells from cisplatin-induced cell death and inhibited pro-inflammatory cytokine production. We further demonstrated that IL-4 and IL-13 induced by cisplatin modulated the phosphorylation of STAT6 by binding with IL-4 receptor alpha and IL-13Rα1. These findings suggest that STAT6 signaling plays a pivotal role in cisplatin-mediated pro-inflammatory cytokine production and ototoxicity.

  5. Cisplatin ototoxicity involves cytokines and STAT6 signaling network.

    Science.gov (United States)

    Kim, Hyung-Jin; Oh, Gi-Su; Lee, Jeong-Han; Lyu, Ah-Ra; Ji, Hye-Min; Lee, Sang-Heon; Song, Jeho; Park, Sung-Joo; You, Yong-Ouk; Sul, Jeong-Dug; Park, Channy; Chung, Sang-Young; Moon, Sung-Kyun; Lim, David J; So, Hong-Seob; Park, Raekil

    2011-06-01

    We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type, WT) and STAT4(-/-), but not in STAT6(-/-) mice. Moreover, the expression levels of the protein and mRNA of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, were markedly increased in the serum and cochlea of WT and STAT4(-/-), but not STAT6(-/-) mice. Organotypic culture revealed that the shape of stereocilia bundles and arrays of sensory hair cell layers in the organ of Corti from STAT6(-/-) mice were intact after treatment with cisplatin, whereas those from WT and STAT4(-/-) mice were highly distorted and disarrayed after the treatment. Cisplatin induced the phosphorylation of STAT6 in HEI-OC1 auditory cells, and the knockdown of STAT6 by STAT6-specific siRNA significantly protected HEI-OC1 auditory cells from cisplatin-induced cell death and inhibited pro-inflammatory cytokine production. We further demonstrated that IL-4 and IL-13 induced by cisplatin modulated the phosphorylation of STAT6 by binding with IL-4 receptor alpha and IL-13Rα1. These findings suggest that STAT6 signaling plays a pivotal role in cisplatin-mediated pro-inflammatory cytokine production and ototoxicity.

  6. Pathophysiology of Cisplatin-Induced Acute Kidney Injury

    Directory of Open Access Journals (Sweden)

    Abdullah Ozkok

    2014-01-01

    Full Text Available Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI. The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-α or IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality.

  7. 10-DHGD ameliorates cisplatin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Elseweidy, Mohamed M; Zaghloul, Mohamed S; Younis, Nahla N

    2016-10-01

    Organs subjected to chronic injuries may develop tissue fibrosis. Several factors contribute to the combat injurious stimuli to repair, heal and alleviate any disturbance. Secretion of chemokines, migration of inflammatory cells to the affected site and activation of fibroblast for production of extracellular matrix (ECM) are examples. Recently, few studies have delt with 10-dehydrogingerdione (10-DHGD), one of the active constituent of ginger extracts that has been published. This constituent proved to be potent antioxidant, anti-inflammatory, cholesterol ester transfer protein (CETP) inhibitor, indeed, a hypolipemic agent. It has been selected in the present study as a natural anti-inflammatory agent to combat inflammation, nephrotoxicity and renal fibrosis-induced by cisplatin. Renal fibrosis state demonstrated a significant increase in creatinine, urea, nuclear factor kappa (NF-kB), insulin like growth factor I (IGF-I), fibroblast growth factor-23 (FGF-23) along with a significant decrease of hepatocytes growth factor (HGF), renal glutathione (GSH) and in confirm to histopathological examination of kidney tissue. Administration of 10-DHGD orally daily for 4 weeks resulted in a significant improvement of both the biomarkers studied in addition to the histopathological profile of the renal tissues.

  8. A phase II study of STEALTH cisplatin (SPI-77) in patients with advanced non-small cell lung cancer.

    Science.gov (United States)

    Kim, E S; Lu, C; Khuri, F R; Tonda, M; Glisson, B S; Liu, D; Jung, M; Hong, W K; Herbst, R S

    2001-12-01

    Cisplatin-based chemotherapy improves survival in appropriately selected patients with stage IV non-small cell lung cancer (NSCLC). However, cisplatin-based regimens have well-known dose-related toxicities, particularly renal insufficiency and neurotoxicity. On the basis of prior preclinical and phase I studies, we initiated a phase II study of SPI-77 (STEALTH) Liposomal Cisplatin) in patients with stage IIIB and IV NSCLC who failed previous treatment with platinum. Disease in all subjects had progressed during therapy, failed to respond, or progressed within 3 months after discontinuing the platinum-based chemotherapy. Between January and June 1999, 13 patients were enrolled at our institution. Patient characteristics included: seven women, six men; median age, 61 years; median Karnofsky performance status, 80%; median number of prior chemotherapy regimens, two (range, 1-3). All patients had adequate hepatic and renal function. SPI-77 was administered at a dose of 260 mg/m(2) IV every 3 weeks. A median of two cycles (range 1-6) were given; the total number of cycles was 35. Among the 12 patients evaluable for response, two had (17%) stable disease and ten (83%) had progressive disease. The median survival was 24.3 weeks, and the median follow-up was 43.9 weeks. Toxicity could be evaluated in all subjects. Moderate anemia (46% of cycles, or=grade 3) with minimal granulocytopenia and thrombocytopenia (26% of cycles grade 1; 0% of cycles, >or=grade 2) were the most notable manifestations of myelosuppression. Grade 3 nonhematological toxicities included dyspnea (8%), fatigue (8%), and pain (8%). There were no grade 4 toxicities. These data suggest that this liposomal cisplatin formulation does not have appreciable activity in this population of patients with NSCLC who had received prior platinum-based chemotherapy. The lack of encouraging results from SPI-77 use in other phase I and II studies resulted in early closure of this trial by the manufacturer.

  9. 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

  10. Cisplatin Analogs Confer Protection against Cyanide Poisoning.

    Science.gov (United States)

    Nath, Anjali K; Shi, Xu; Harrison, Devin L; Morningstar, Jordan E; Mahon, Sari; Chan, Adriano; Sips, Patrick; Lee, Jangwoen; MacRae, Calum A; Boss, Gerry R; Brenner, Matthew; Gerszten, Robert E; Peterson, Randall T

    2017-05-18

    Cisplatin holds an illustrious position in the history of chemistry most notably for its role in the virtual cure of testicular cancer. Here we describe a role for this small molecule in cyanide detoxification in vivo. Cyanide kills organisms as diverse as insects, fish, and humans within seconds to hours. Current antidotes exhibit limited efficacy and are not amenable to mass distribution requiring the development of new classes of antidotes. The binding affinity of the cyanide anion for the positively charged metal platinum is known to create an extremely stable complex in vitro. We therefore screened a panel of diverse cisplatin analogs and identified compounds that conferred protection from cyanide poisoning in zebrafish, mice, and rabbits. Cumulatively, this discovery pipeline begins to establish the characteristics of platinum ligands that influence their solubility, toxicity, and efficacy, and provides proof of concept that platinum-based complexes are effective antidotes for cyanide poisoning. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Cisplatin promotes mesenchymal-like characteristics in osteosarcoma through Snail.

    Science.gov (United States)

    Fang, Shuo; Yu, Ling; Mei, Hongjun; Yang, Jian; Gao, Tian; Cheng, Anyuan; Guo, Weichun; Xia, Kezhou; Liu, Gaiwei

    2016-12-01

    More than 30% of patients with osteosarcoma succumb to pulmonary metastases. Epithelial-mesenchymal transition (EMT) is a biological process by which tumor cells gain an increased capacity for invasiveness and metastasis. A previous study confirmed the phenomenon of EMT in osteosarcoma, a mesenchymal-derived tumor. However, whether chemotherapy affects EMT remains to be elucidated. In the present study, the osteosarcoma cells were exposed to a sublethal dose of cisplatin, and any surviving cells were assumed to be more resistant to cisplatin. In addition, these cells exhibited a more mesenchymal phenotype. Immunofluorescence analysis revealed that the cisplatin treated cells had an increased long/short axis ratio and increased expression of N-cadherin compared with control cells. A panel of EMT-associated genes was subsequently assessed by quantitative PCR and western blot analysis, and they were observed to be significantly upregulated in the cisplatin treated cells. The in vitro wound healing and Transwell assay indicated that the cisplatin treated cells were more prone to migrate and invade. An in vivo assay showed that the cisplatin-treated xenograft had increased expression of EMT-associated genes, and exhibited increased pulmonary lesions compared with the control, which indicated an elevated capacity to metastasize. The expression of Snail was knocked down by specific small interfering RNA, and it was observed that Snail inhibition promoted cisplatin sensitivity, and cisplatin-induced EMT was significantly blocked. Taken together, the results of the present study supported that idea that Snail participates in cisplatin-induced EMT in osteosarcoma cells, and targeting EMT-transcription factors may offer promise for the therapeutics of osteosarcoma.

  12. Effect of vinorelbine, ifosfamide, and cisplatin combination chemotherapy in advanced non-small-cell lung cancer.

    Science.gov (United States)

    Ahn, J B; Ko, W K; Lee, J G; Shim, K Y; Jeung, H C; Park, J O; Yoo, N C; Kim, B S; Kim, S K; Kim, S K; Kim, J H

    2000-12-01

    Cisplatin-based chemotherapy is being tried in the treatment of nonoperable cases of non-small-cell lung cancer (NSCLC). However, the prognosis is unfavorable and to improve survival, clinical studies using various combinations of a variety of drugs as well as experimental material are in progress. We compared the efficacy and toxicities of combination chemotherapy using different doses of vinorelbine and ifosfamide with a constant dose of cisplatin in this study. Patients diagnosed with inoperable stage III or IV NSCLC between June 1997 and December 1998 were included. Cisplatin was administered at a constant dose of 80 mg/m2 on day 5, whereas vinorelbine on days 1 and 5 and ifosfamide on day 5 were administered in one of two different doses. In arm A, vinorelbine 25 mg/m2 and ifosfamide 3.0 g/m2 were administered. In arm B, vinorelbine 20 mg/m2 and ifosfamide 2.5 g/m2 were administered. Also, we reviewed for phase II and III studies that test 1) cisplatin, 2) vinorelbine monotherapy, and 3) vinorelbine/cisplatin/ifosfamide combination chemotherapy for stage IIIb-IV non-SCLC. Summation dose intensity (SDI) was calculated in each published and current study. Twenty patients in arm A and 35 patients in arm B were available for evaluation. There was no difference in patient activity, pathologic diagnosis, and differentiation or stage between the two arms. The median number of cycles was four in both arms. The response rate was 50% in arm A and 30% in arm B. The median survival times for arm A and B were 40 and 42 weeks, respectively, whereas the SDI was 1.94 and 1.7, respectively. More than grade III leukopenia was observed in 28.9% in arm A, which is more frequent than the 17.2% in arm B. There was a significant correlation between the SDIs and response rates and median survival (r2 = 0.629, p = 0.001; r2 = 0.453, p = 0.001, respectively). Although the follow-up period is relatively short, the survival time was similar in both arms. Because a high response rate may

  13. Neoadjuvant Paclitaxel Poliglumex (PPX), Cisplatin, and Radiation (RT) for Esophageal Cancer

    Science.gov (United States)

    Ng, T.; Fontaine, J.; Dipetrillo, T.; Suntharalingam, M.; Horiba, N.; Oldenburg, N.; Oconnor, B.; Perez, K.; Birnbaum, A.; Battafarano, R.; Burrows, W.; Safran, H.

    2010-01-01

    Background: Paclitaxel poliglumex (PPX) is a drug conjugate that links paclitaxel to poly-L-glutamic acid thereby increasing its radiation enhancement factor to 4.0–8.0 compared to 1.5–2.0 for paclitaxel. In previous phase I studies, The Brown University Oncology Group evaluated PPX with concurrent radiation and PPX/cisplatin/RT. A phase II study was subsequently performed to evaluate the pathologic response rate of neoadjuvant PPX, cisplatin, and radiation for patients with esophageal cancer. Methods: Eligible patients had pathologically confirmed adenocarcinoma or squamous cell carcinoma of the esophagus or GE junction with no evidence of distant metastasis. Patients received weekly PPX 50 mg/m2 and cisplatin 25 mg/m2 for 6 weeks with concurrent 50.4 Gy of radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. Results: The study has completed accrual of 40 patients, 37 with adenocarcinoma and 3 with squamous cell cancer. The median age is 62 years. Toxicity data are available for the first 35 patients. Four of 35 patients experienced grade 4 non-hematologic toxicities, which included electrolyte abnormalities, glucose intolerance, hypersensitivity reaction, and thromboembolus. Eleven of 35 patients had grade 3 non-hematologic toxicities including electrolyte abnormalities (n=5), nausea (n=3), dysphagia (n=2), fatigue (n=2), glucose intolerance (n=2), and hypersensitivity reaction (n=1). Grade 3 anorexia was reported in only 1 patient who subsequently was given TPN. No patients required a feeding tube. There were no grade 4 hematologic toxicities; grade 3 hematologic toxicities included neutropenia (n=2) and anemia (n=1). Of the first 28 patients undergoing surgery, all with adenocarcinoma, 7 of 28 (25%) have had a pathologic complete response. Conclusion: PPX, cisplatin and concurrent radiation is a well tolerated, easily administered regimen for esophageal cancer with a very low incidence of significant

  14. Induction chemotherapy with paclitaxel and cisplatin followed by radiotherapy for larynx organ preservation in advanced laryngeal and hypopharyngeal cancer offers moderate late toxicity outcome (DeLOS-I-trial).

    Science.gov (United States)

    Dietz, Andreas; Rudat, Volker; Dreyhaupt, Jens; Pritsch, Maria; Hoppe, Florian; Hagen, Rudolph; Pfreundner, Leo; Schröder, Ursula; Eckel, Hans; Hess, Markus; Schröder, Michael; Schneider, Petra; Jens, Bünzel; Zenner, Hans P; Werner, Jochen A; Engenhardt-Cabillic, Rita; Vanselow, Bernhard; Plinkert, Peter; Niewald, Marcus; Kuhnt, Thomas; Budach, Wilfried; Flentje, Michael

    2009-08-01

    A prospective multicenter phase-II trial (12 centers) was performed by the German larynx organ preservation group (DeLOS) to evaluate the effect of induction chemotherapy (ICHT) with paclitaxel/cisplatin (TP), followed by accelerated-hyperfractionated (concomitant boost) radiotherapy (RT) in responders. The trial was focused on larynx preservation, tumor control, survival, salvage surgery and late toxicity in patients with advanced larynx/hypopharynx carcinoma eligible for total laryngectomy (LE). Seventy-one patients (40 larynx, 87.5% St. III, IV; 31 hypopharynx, 93.4% St. III, IV) were enrolled into the study and treated with ICHT (200 mg/m(2) paclitaxel, 100 mg/m(2) cisplatin; day 1, 22) according to the DeLOS protocol. Patients with complete or partial tumor response proceeded to RT (69.9 Gy in 5.5 weeks). Non-responders received a LE followed by postoperative RT (56-70 Gy in 5.5-7 weeks). The response rate to ICHT for larynx cancer was 69.6% (7.1% complete, 62.5% partial response) and for hypopharyngeal cancer was 84.3% (6.9% complete, 77.4% partial response). Overall survival after 36 months was 60.3% (95% CI, 48.4-72.2%), after 42 months was 56.5% (95% CI, 44.2-68.8%). Laryngectomy-free survival was as follows: after 36 months, 43.0% (95% CI, 30.9-55.0%); after 42 months, 41.3% (95% CI, 29.3-53.3%). Both parameters did not show different outcomes after distinguishing larynx from hypopharynx. LE was indicated in 15 non-responders after ICHT. Five of the 15 non-responders refused the laryngectomy. Two of the five received RT instead and had no evidence of disease 42 months after RT. Late toxicity (dysphagia III, IV LENT SOMA score in laryngectomy-free survivors: after 6 months, 1.8%; 12 months, 11.4%; 18 months, 14.5%; 24 months, 8.1%; 36 months, 16%) and salvage surgery (4 pharyngocutaneous fistulas in 27 operations) were tolerable. In a large portion of patients eligible for LE, the larynx could be preserved with satisfying functional outcome. Good

  15. Golden Week, Golden Effect

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ The Golden Week Holiday System was established in 1999. Bv adding legal holidays and the time off from the previous and following weekends, China made three Golden Weeks (7-day holidays), for the Spring Festival, May Labor Day and National Day in October.Since it was introduced eight years ago,the Golden Weeks have added considerably to China's economic development.The significant role they have played in promoting economic development and changing the Chinese people's concept of consumption and way of living has been witnessed by everyone.

  16. 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.

  17. Clinical effects of adalimumab treatment with concomitant azathioprine in Japanese Crohn’s disease patients

    Science.gov (United States)

    Ishida, Kumi; Inoue, Takuya; Fujiwara, Kaori; Sakanaka, Taisuke; Narabayashi, Ken; Nouda, Sadaharu; Okada, Toshihiko; Kakimoto, Kazuki; Kuramoto, Takanori; Kawakami, Ken; Abe, Yosuke; Takeuchi, Toshihisa; Murano, Mitsuyuki; Tokioka, Satoshi; Umegaki, Eiji; Higuchi, Kazuhide

    2013-01-01

    AIM: To assess adalimumab’s efficacy with concomitant azathioprine (AZA) for induction and maintenance of clinical remission in Japanese Crohn’s disease (CD) patients. METHODS: This retrospective, observational, single-center study enrolled 28 consecutive CD patients treated with adalimumab (ADA). Mean age and mean disease duration were 38.1 ± 11.8 years and 11.8 ± 10.1 years, respectively. The baseline mean Crohn’s disease activity index (CDAI) and C-reactive protein were 177.8 ± 82.0 and 0.70 ± 0.83 mg/dL, respectively. Twelve of these patients also received a concomitant stable dose of AZA. ADA was subcutaneously administered: 160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week. Clinical response and remission rates were assessed via CDAI and C-reactive protein for 24 wk. RESULTS: The mean CDAI at weeks 2, 4, 8, and 24 was 124.4, 120.2, 123.6, and 135.1, respectively. The CDAI was significantly decreased at weeks 2 and 4 with ADA and was significantly suppressed at 24 wk with ADA/AZA. Overall clinical remission rates at weeks 4 and 24 were 66.7% and 63.2%, respectively. Although no statistically significant difference in C-reactive protein was demonstrated, ADA with AZA resulted in a greater statistically significant improvement in CDAI at 24 wk, compared to ADA alone. CONCLUSION: Scheduled ADA with concomitant AZA may be more effective for clinical remission achievement at 24 wk in Japanese Crohn’s disease patients. PMID:23674875

  18. Paclitaxel plus cisplatin vs. 5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer

    OpenAIRE

    Liu, Ying; Ren, Zhonghai; Yuan, Long; Xu, Shuning; Yao, Zhihua; Qiao, Lei; Li, Ke

    2016-01-01

    Paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin treatments are effective strategies for patients with advanced esophageal squamous cell carcinoma. This study was to evaluate the safety and efficacy of paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin as first-line chemotherapy for patients with advanced esophageal squamous cell carcinoma. A total of 398 patients with advanced esophageal squamous cell carcinoma who received chemotherapy were included and divided into 2 gr...

  19. Concomitant overdosing of other drugs in patients with paracetamol poisoning

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2002-01-01

    AIMS: Paracetamol is frequently involved in intended self-poisoning, and concomitant overdosing of other drugs is commonly reported. The purpose of the study was to investigate further concomitant drug overdose in patients with paracetamol poisoning and to evaluate its effects on the outcome...... of the paracetamol intoxication. METHODS: Six hundred and seventy-one consecutive patients admitted with paracetamol poisoning were studied and concomitant drug intake was recorded. The relative risk of hepatic encephalopathy, death or liver transplantation, hepatic dysfunction, liver cell damage, and renal...... favourable outcome was observed in patients with concomitant NSAID overdose. CONCLUSIONS: Concomitant overdosing of benzodiazepines or analgesics is frequent in patients admitted with paracetamol poisoning. Concomitant benzodiazepine or acetylsalicylic acid overdose was associated with more severe toxicity...

  20. Concomitant overdosing of other drugs in patients with paracetamol poisoning

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2002-01-01

    ), acetylsalicylic acid (33 cases), and NSAID (32 cases) predominated. Concomitant benzodiazepine overdose was an independent risk factor in the development of hepatic encephalopathy (odds ratio [OR] 1.91; CI 1.00, 3.65) and renal dysfunction (OR 1.81; CI 1.00, 3.22). Concomitant overdosing of opioid analgesics...... was a protective factor in the development of hepatic encephalopathy (OR 0.26; CI 0.07, 0.96). Concomitant acetylsalicylic acid overdose was a risk factor in the development of hepatic encephalopathy (OR 4.87; CI 1.52, 15.7) and death or liver transplantation (OR 6.04; CI 1.69, 21.6). A tendency towards a more...... favourable outcome was observed in patients with concomitant NSAID overdose. CONCLUSIONS: Concomitant overdosing of benzodiazepines or analgesics is frequent in patients admitted with paracetamol poisoning. Concomitant benzodiazepine or acetylsalicylic acid overdose was associated with more severe toxicity...

  1. Concomitant Suppurative Parotitis and Condylar Osteomyelitis.

    Science.gov (United States)

    Vorrasi, John; Zinberg, Geoffrey

    2017-03-01

    Parotitis is a common occurrence in the immunocompromised, dehydrated, and malnourished patient as a result of dysfunctional ductal and parotid cells. Inflammation can be acute or chronic based on clinical history, and it can be suppurative based on the presence of micro or macro abscess formation within the substance of the gland. This report presents a case of concomitant condylar osteomyelitis and chronic suppurative parotitis in the setting of previous methicillin-susceptible Staphylococcus aureus foot infection. Ultimately, resection of osteomyelitis, drainage of parotid infection, and intravenous antibiotic therapy led to full resolution of the infection and symptoms. The final pathology of osteomyelitis of the temporomandibular joint and methicillin-resistant S aureus infection is an unusual consequence of chronic parotitis. The patient was restored with a total joint replacement approximately 3 months after resection with no recurrence of infection after 24 months. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  2. Endometrial Adenocarcinoma with Concomitant Left Atrial Myxoma

    Directory of Open Access Journals (Sweden)

    Lisa N. Abaid

    2009-08-01

    Full Text Available Background: Atrial myxomas are the most common primary heart tumors and predominantly considered to be benign lesions. Case Study: We report a case involving a 77-year-old woman who presented with a pelvic mass. She was found to have a primary endometrial cancer and primary lung cancer with concomitant metastatic adrenal gland and mesenteric lesions. Her prior medical history also included an untreated 4.0 × 2.0-cm left atrial myxoma which was identified on CT scan during the workup of her pelvic mass. Results: A clinical decision was made to proceed with surgery for the pelvic mass with a subsequent recommendation for left atrial mass resection. Currently, the patient is scheduled to begin chemotherapy for primary lung cancer. Conclusion: The reported incidence of uterine cancer and a concurrent atrial myxoma is very rare. Consequently, the manner and timing in which treatment should be provided is imprecise. In the present case, the risk for cardiac complications was high, but given the presence of a partial bowel obstruction and the need to diagnose the primary site of her metastatic malignancy, the decision was made to proceed with exploratory abdominal surgery.

  3. Cisplatin-DNA adduct formation in patients treated with cisplatin-based chemoradiation: lack of correlation between normal tissues and primary tumor.

    NARCIS (Netherlands)

    Hoebers, F.J.; Pluim, D.; Hart, A.A.M.; Verheij, M.; Balm, A.J.M.; Fons, G.; Rasch, C.R.; Schellens, J.H.M.; Stalpers, L.J.A.; Bartelink, H.; Begg, A.C.

    2008-01-01

    PURPOSE: In this study, the formation of cisplatin-DNA adducts after concurrent cisplatin-radiation and the relationship between adduct-formation in primary tumor tissue and normal tissue were investigated. METHODS: Three intravenous cisplatin-regimens, given concurrently with radiation, were studie

  4. Cisplatin-DNA adduct formation in patients treated with cisplatin-based chemoradiation: lack of correlation between normal tissues and primary tumor

    NARCIS (Netherlands)

    Hoebers, F.J.P.; Pluim, D.; Hart, A.A.M.; Verheij, M.; Balm, A.J.M.; Fons, G.; Rasch, C.R.N.; Schellens, J.H.M.; Stalpers, L.J.A.; Bartelink, H.; Begg, A.C.

    2007-01-01

    Purpose: In this study, the formation of cisplatin-DNA adducts after concurrent cisplatin-radiation and the relationship between adduct-formation in primary tumor tissue and normal tissue were investigated. Methods: Three intravenous cisplatin-regimens, given concurrently with radiation, were stu

  5. Antitumor activity of Herceptin in combination with STEALTH liposomal cisplatin or nonliposomal cisplatin in a HER2 positive human breast cancer model.

    Science.gov (United States)

    Colbern, G T; Hiller, A J; Musterer, R S; Working, P K; Henderson, I C

    1999-10-01

    Single agent antitumor activity of Herceptin, a humanized monoclonal antibody directed against HER2, has been demonstrated in numerous preclinical and clinical studies. Additionally, combination therapy with Herceptin and chemotherapy (CRx) has demonstrated additive antitumor activity in both preclinical models and early clinical trials. STEALTH (pegylated) liposomal (PL) cisplatin, also known as SPI-077, is currently in clinical trials for a variety of solid tumors. The three studies reported here discuss the antitumor activity of the combination of Herceptin and nonliposomal cisplatin or PL-cisplatin in two xenograft tumor models, initiated from the cell lines, BT474 and MDA453, that overexpress the oncogene, HER2. Herceptin alone had significant antitumor activity in all three experiments (p cisplatin and PL-cisplatin were both effective antitumor agents but, at tolerable dose levels, PL-cisplatin was superior to nonliposomal cisplatin (p cisplatin or PL-cisplatin, was most significant at moderate doses of H (0.5 mg/kg, p cisplatin with Herceptin had statistically similar antitumor activity to that of nonliposomal cisplatin with Herceptin in all experiments. We conclude that combination therapy with PL-cisplatin and Herceptin results in significant antitumor activity with the potential for reducing toxicity in metastatic breast cancer patients.

  6. Oral vinorelbine plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of advanced non-squamous non-small-cell lung cancer: cost minimization analysis in 12 European countries.

    Science.gov (United States)

    Grossi, Francesco; Bennouna, Jaafar; Havel, Libor; Hochmair, Maximillian; Almodovar, Teresa

    2016-09-01

    A combination of vinorelbine and cisplatin is a standard treatment in non-small-cell lung cancer; oral vinorelbine is registered in 45 countries. Pemetrexed and cisplatin are recommended in front-line chemotherapy of non-squamous non-small-cell lung cancer (NS-NSCLC). The objective of this study was to conduct a cost minimization analysis from the perspective of the national health service (NHS) in each of 12 European countries, based on a randomized phase II study in NS-NSCLC (NAVoTRIAL01), with 100 oral vinorelbine plus cisplatin patients (arm A) and 51 pemetrexed plus cisplatin patients (arm B). Country-specific costs and DRG codes considered included those relating to anticancer drugs, administration settings (out-patient/in-patient/at home), serious adverse events (defined as involving hospitalization and considered due to anticancer drugs) and concomitant medications. Relevant costs were calculated based on country-specific reimbursement procedures and official tariffs. Cost and savings per patient. Using the NHS perspective, savings per patient treated with oral vinorelbine ranged from €1317 (Denmark) to €35,001 (Germany). Expressed as percentages, savings per patient treated with oral vinorelbine compared with pemetrexed ranged between 5% (France) and 83% (Czech Republic). Pooled average costs for each treatment arm across the 12 countries resulted in cost savings for payers of €12,871, favoring oral vinorelbine plus cisplatin. Given the reported efficacy with both regimens, this pan-European economic analysis provides compelling evidence supporting oral vinorelbine use over pemetrexed for the treatment of NS-NSCLC. Oral vinorelbine provides similar efficacy and an easily manageable safety profile at lower overall cost per patient treated, combined with an easier/more convenient mode of administration. Sensitivity analysis across varied scenarios demonstrated the robustness of the results. The principle weakness of our study was its reliance upon a

  7. [Concomitant radiochemotherapy in cancer of the cervix uteri: modifications of the standards].

    Science.gov (United States)

    Haie-Meder, C; Lhommé, C; de Crevoisier, R; Morice, P; Resbeut, M

    2000-11-01

    For a long time, combined external irradiation and brachytherapy has been considered as the standard treatment in patients with advanced cervical cancers. Recently, five clinical randomized trials assessing the role of cis-platin-based chemotherapy delivered concomitantly to radiotherapy have been conducted in the United States. Another clinical randomized trial assessing the role of epirubicin was conducted by the Queen Mary Hospital in Hong Kong. With more than 2,000 enrolled patients, these studies showed converging results with an overall and disease-free survival improvement in the arms combining cis-platin and epirubicin-based chemotherapy and irradiation. These combinations led to a significant decrease in loco-regional evolution or recurrence rates, or even in pulmonary metastases rates. The relative risk of recurrences was decreased by 50%. The relative risk of death was decreased by 40%. The differences, however, were less significant in patients with advanced stages III or IVA. Hematological and digestive acute toxicity was significantly higher in the radiochemotherapy groups, but long-term complications were comparable. The results of these randomized trials have led to a modification in the standard of treatment in these poor prognosis cervix cancers. Five of the randomized trials evidenced the superiority of cis-platin-based chemotherapy, but the optimal chemotherapeutic regimens remain to be defined.

  8. Comparative analysis of cisplatin-induced nephrotoxicity in head and neck cancer and carcinoma cervix during concurrent chemoradiotherapy

    Directory of Open Access Journals (Sweden)

    Puneet Kumar Bagri

    2014-01-01

    Full Text Available Background: Cisplatin is widely used as radio sensitizer in head and neck cancer (HNC and carcinoma cervix (CaCx. This study aims to see comparative nephrotoxicity of cisplatin in HNC and in CaCx without obstructive uropathy treated by concurrent chemoradiotherapy (CCRT. Materials and Methods: Fifty patients of HNC and 50 patients of CaCx stage II/III without obstructive uropathy were included in this study. Cisplatin 50 mg intravenous weekly was given before EBRT with adequate hydration and premedication in both groups. Before chemotherapy; blood urea, serum creatinine, and glomerular filtration rate (GFR were measured. GFR was measured using 99m Tc diethylene triamine pentacaetic acid (DTPA renogram study. Results: At the end of 4 th week, blood urea level 41-45 mg% was in 40 and 4% in HNC and CaCx, respectively (P = 0.018. At the end of 3 rd and 4 th week, blood urea level >45 mg% was 10 and 6% in HNC cases, respectively. At the end of 4 th week, serum creatinine level 1.1-1.5 mg% was 50 and 8% in HNC and CaCx, respectively (P = 0.047. Serum creatinine level >1.5 mg% was 6, 8, and 22% in HNC at the end of 2 nd , 3 rd , and 4 th week, respectively. GFR <80 ml/min at the end of 4 th week was 14% in HNC and only 2% in CaCx. GFR <100ml/min was significant at the end of 4 th week (P = 0.04. Univariate analysis showed significant relation between reduced oral fluid intake and reduced GFR (P < 0.001. Conclusion: In HNC, during concurrent chemoradiation, as the 3 rd -4 th week is reached, oral mucosal reactions increase and affect oral intake which further add to the cisplatin-induced nephrotoxicity. In CaCx without obstructive uropathy, renal function impairment is less severe as oral intake of water and liquid is not much impaired.

  9. Polysilsesquioxane Nanoparticles for Triggered Release of Cisplatin and Effective Cancer Chemoradiotherapy

    Science.gov (United States)

    Rocca, Joseph Della; Werner, Michael E.; Kramer, Stephanie A.; Huxford-Phillips, Rachel C.; Sukumar, Rohit; Cummings, Natalie D.; Vivero-Escoto, Juan L.; Wang, Andrew Z.; Lin, Wenbin

    2014-01-01

    Chemoradiotherapy is a well-established treatment paradigm in oncology. There has been strong interest in identifying strategies to further improve its therapeutic index. An innovative strategy is to utilize nanoparticle (NP)chemotherapeutics in chemoradiation. Since the most commonly utilized chemotherapeutic with radiotherapy is cisplatin, the development of a NP cisplatin for chemoradiotherapy has the highest potential impact on this treatment. Here, we report the development of a NP comprised of polysilsesquioxane (PSQ) polymer crosslinked by a cisplatin prodrug (Cisplatin-PSQ) and its utilization in chemoradiotherapy using non-small cell lung cancer as a disease model. Cisplatin-PSQ NP has an exceptionally high loading of cisplatin. Cisplatin-PSQ NPs were evaluated in chemoradiotherapy in vitro and in vivo. They demonstrated significantly higher therapeutic efficacy when compared to cisplatin. These results suggest that the Cisplatin-PSQ NP holds potential for clinical translation in chemoradiotherapy. PMID:25038495

  10. 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.

  11. Central retinal vein occlusion concomitant with dengue fever.

    Science.gov (United States)

    Velaitham, Punithamalar; Vijayasingham, Nandini

    2016-01-01

    Dengue virus infection is on the rise and there is increasing number of ocular complications that are being reported. Most common ocular complications are macular edema, macular hemorrhages, and foveolitis. There are case reports on branch retinal vessel occlusions. Most of the ocular complications are attributed to the bleeding tendency and transudative process in dengue viral infection. This is a case report of ischemic central retinal vein occlusion (CRVO) concomitant with dengue fever. A 41 year old Malay female was admitted to medical ward and diagnosed to have "dengue fever with warning signs". On the day of admission she noted sudden onset of right eye blurring of vision. She presented to our clinic 1 week later. Ocular examination revealed right eye visual acuity of <20/1000 and ischaemic CRVO with macular edema. She had no other risk factors to develop retinal vein occlusion. She progressively developed proliferative retinopathy and received multiple laser therapy. There was no anterior segment neovascularization. However, her vision improved to only 20/400 despite of resolution of macular edema and new vessels elsewhere. Dengue virus infection is known to cause thrombocytopenia which can result in hemorrhagic events. It can also cause procoagulant state which can result in thrombotic events secondary to immune reaction. Awareness among treating physicians of such ocular complication which can result in significant morbidity for patient is necessary.

  12. Concomitant physeal fractures of the distal femur and proximal tibia

    Energy Technology Data Exchange (ETDEWEB)

    Sferopoulos, N.K. [Aristotle University of Thessaloniki, Department of Pediatric Orthopaedics, Thessaloniki (Greece)

    2005-07-01

    Concomitant physeal fractures of the distal femur and proximal tibia are very rare in children and adolescents. They are included in the classification of the ''floating knee'' injuries. Two cases with this combined injury are reported. They were closed injuries and in both patients the fracture of the proximal tibial epiphyseal plate was nondisplaced. In the first, a six-year-old girl, an early diagnosis was made radiographically. The intra-articular femoral fracture was operatively reduced and fixed. No growth abnormality was encountered 12 years later. The second patient, a 16-year-old boy, was conservatively treated for a displaced fracture-separation of the distal femoral epiphysis. Four weeks later there was physeal widening on both sides of the knee which indicated an associated fracture of the proximal tibial epiphyseal plate. One year after injury there was a varus deformity of the knee that was treated with a corrective osteotomy. Ten years later there is normal alignment of the leg. (orig.)

  13. Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?

    Directory of Open Access Journals (Sweden)

    Juan Pablo Cayún Pellizaris

    2014-11-01

    Full Text Available In recent times, several investigations have been seeking an explanation for the great variability in both outcome and toxicity in cisplatin-based therapy through pharmacogenetic studies. These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular and esophageal cancer. In this review, we seek to update the reader in this area of investigation, focusing primarily on DNA reparation enzymes and cisplatin metabolism through Glutathione S-Transferases (GST genes. Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes where cisplatin is the cornerstone of these treatments. Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinic utility.

  14. An integrated view of cisplatin-induced nephrotoxicity and ototoxicity.

    Science.gov (United States)

    Karasawa, Takatoshi; Steyger, Peter S

    2015-09-17

    Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. Bio-inspired cisplatin nanocarriers for osteosarcoma treatment

    National Research Council Canada - National Science Library

    Zhou, Haidong; Wang, Gangxiang; Lu, Yiyun; Pan, Zhijun

    2016-01-01

    In this study, cisplatin ( cis -diaminedichloroplatinum, CDDP) nanocarriers with phosphorylcholine surface tailoring were developed to enhance the anti-tumor potential of CDDP for the treatment of osteosarcoma. Poly...

  16. Amelioration of cisplatin-induced nephrotoxicity by statins

    Directory of Open Access Journals (Sweden)

    Rajesh A Maheshwari

    2013-01-01

    Conclusions: This finding suggests that simvastatin and rosuvastatin may have a protective effect against cisplatin-induced kidney damage via amelioration of lipid peroxidation as well as due to improvement of renal function, and lipid-lowering effects.

  17. Phase II trial of adjuvant pelvic radiation “sandwiched” between ifosfamide or ifosfamide plus cisplatin in women with uterine carcinosarcoma✰,✰✰,★

    Science.gov (United States)

    Einstein, Mark H.; Klobocista, Merieme; Hou, June Y.; Lee, Stephen; Mutyala, Subhakar; Mehta, Keyur; Reimers, Laura L.; Kuo, Dennis Y.-S.; Huang, Gloria S.; Goldberg, Gary L.

    2013-01-01

    Objective Uterine carcinosarcoma (CS) is a rare uterine tumor with an extremely poor prognosis. In the adjuvant setting, efficacy has been shown with radiotherapy (RT), systemic chemotherapy, or both. This is the first report describing the efficacy and toxicity of adjuvant ifosfamide or ifosfamide plus cisplatin “sandwiched” with RT in patients with surgically staged and completely resected uterine carcinosarcoma. Methods Women with surgically staged CS with no gross residual disease were initially administered ifosfamide (1.2 g/m2/day × 5 days) with cisplatin (20 mg/m2/day × 5 days) every 3 weeks for 3 cycles followed by pelvic external beam RT and brachytherapy followed by 3 additional cycles of ifosfamide (1.0 g/m2/day) with cisplatin (20 mg/m2/day × 5 days) every 3 weeks. Similar to the GOG trial in recurrent CS (Sutton et al, 2000), the addition of cisplatin added toxicity without additional efficacy, so mid-study, the cisplatin was eliminated from the regimen. Toxicities were recorded and disease-free survival (DFS) was calculated with Kaplan-Meier statistical methods. Results In total, 12 patients received ifosfamide and cisplatin and 15 patients received ifosfamide alone, both ‘sandwiched’ with RT. The median follow up was 35.9 months (range 6–88). The 2 year DFS was similar in both the ifosfamide/cisplatin and ifosfamide groups (log-rank p = 0.16), so they were combined for analysis. 19 patients (70%) completed the protocol. As expected, stage 1 patients had a better 2-year DFS (18.75 ± 1.12 months; log-rank p = 0.008 when compared to stages 2, 3, 4). Also, in stages 2, 3 and 4 patients, the DFS was 15.81 ± 1.73 months. Grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 18%, 4% and 4% of cycles, respectively. Conclusions Ifosfamide “sandwiched” with RT appears to be an efficacious regimen for surgically staged CS patients with no residual disease, even in patients with advanced stage. The addition of cisplatin to the regimen

  18. Pericardiocentesis with cisplatin for malignant pericardial effusion and tamponade

    Institute of Scientific and Technical Information of China (English)

    Takatsugu; Oida; Kenji; Mimatsu; Hiso; Kano; Atsushi; Kawasaki; Youichi; Kuboi; Nobutada; Fukino; Sadao; Amano

    2010-01-01

    AIM:To evaluate the role and outcome of pericardiocentesis with intrapericardial cisplatin instillation for malignant pericardial effusion resulting from esophageal cancer. METHODS:We retrospectively studied 7 patients who underwent pericardiocentesis with intrapericardial cisplatin instillation for malignant pericardial effusion resulting from esophageal cancer.After pericardiocentesis,we performed catheterization of the pericardial space under ultrasonogram guidance.Malignant etiology of the pericardial f...

  19. The protective effect of theophyline in cisplatin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Seyed Seifollah Beladi Mousavi

    2014-01-01

    Full Text Available Cisplatin is a potent and a major anti-neoplastic drug in the treatment of a broad spectrum of malignancies. However, its clinical use is limited by renal tubular dysfunction that occurs in a significant percent of patients. The aim of the present study was to evaluate the possible protective effect of theophyline in the prevention of cisplatin-induced nephrotoxicity. The trial design was prospective, randomized, double-blinded and placebo controlled. Chemotherapeutic patients who received cisplatin at a dosage of at least 50 mg/m 2 alone or in combination with other chemotherapy agent(s were included in the study. There were a total of 76 patients who were randomly divided into two groups. In group 1 (n = 38, placebo was advised; in group 2 (n = 38, patients received 4 mg/kg aminophyline as an intravenous loading dose, followed by theophyline in a dose of 200 mg three times daily orally for four consecutive days. The placebo group had 22 males and 16 females and the theophyline group had 26 males and 12 females. The mean age was 51 ± 17.6 years and the mean dose of cisplatin was 86.71 ± 43.18 mg. The prevalence of cisplatin nephrotoxicity in groups 1 and 2 was 7.9 and 5.3%, respectively, and the difference was not significant (P = 1. In addition, there was no significant association of cisplatin nephrotoxicity with age (P = 0.1, gender (P = 0.64 and mean dose of cisplatin (P = 0.8. These results indicate that prophy-lactic application of aminophyline and theophyline does not have a protective effect against cisplatin nephrotoxicity.

  20. Cisplatin and platinum drugs at the molecular level. (Review).

    Science.gov (United States)

    Boulikas, Teni; Vougiouka, Maria

    2003-01-01

    Over twenty years of intensive work toward improvement of cisplatin, and with hundreds of platinum drugs tested, has resulted in the introduction of the widely used carboplatin and of oxaliplatin used only for a very narrow spectrum of cancers. A number of interesting platinum compounds including the orally administered platinum drug JM216, nedaplatin, the sterically hindered platinum(II) complex ZD0473, the trinuclear platinum complex BBR3464, and the liposomal forms Lipoplatin and SPI-77 are under clinical evaluation. This review summarizes the molecular mechanisms of platinum compounds for DNA damage, DNA repair and induction of apoptosis via activation or modulation of signaling pathways and explores the basis of platinum resistance. Cisplatin, carboplatin, oxaliplatin and most other platinum compounds induce damage to tumors via induction of apoptosis; this is mediated by activation of signal transduction leading to the death receptor mechanisms as well as mitochondrial pathways. Apoptosis is responsible for the characteristic nephrotoxicity, ototoxicity and most other toxicities of the drugs. The major limitation in the clinical applications of cisplatin has been the development of cisplatin resistance by tumors. Mechanisms explaining cisplatin resistance include the reduction in cisplatin accumulation inside cancer cells because of barriers across the cell membrane, the faster repair of cisplatin adducts, the modulation of apoptotic pathways in various cells, the upregulation in transcription factors, the loss of p53 and other protein functions and a higher concentration of glutathione and metallothioneins in some type of tumors. A number of experimental strategies to overcome cisplatin resistance are at the preclinical or clinical level such as introduction of the bax gene, inhibition of the JNK pathway, introduction of a functional p53 gene, treatment of tumors with aldose reductase inhibitors and others. Particularly important are combinations of platinum

  1. 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.

  2. Phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate in dogs with naturally occurring malignant tumors.

    Science.gov (United States)

    Cai, Shuang; Zhang, Ti; Forrest, W C; Yang, Qiuhong; Groer, Chad; Mohr, Eva; Aires, Daniel J; Axiak-Bechtel, Sandra M; Flesner, Brian K; Henry, Carolyn J; Selting, Kimberly A; Tate, Deborah; Swarz, Jeffrey A; Bryan, Jeffrey N; Forrest, M Laird

    2016-09-01

    OBJECTIVE To conduct a phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate (HA-Pt) in dogs with naturally occurring malignant tumors. ANIMALS 18 healthy rats, 9 healthy mice, and 16 dogs with cancer. PROCEDURES HA-Pt was prepared and tested by inductively coupled plasma mass spectrometry; DNA-platinum adduct formation and antiproliferation effects of cisplatin and HA-Pt were compared in vitro. Effects of cisplatin (IV) and HA-Pt (SC) in rodents were tested by clinicopathologic assays. In the clinical trial, dogs with cancer received 1 to 4 injections of HA-Pt (10 to 30 mg/m(2), intratumoral or peritumoral, q 3 wk). Blood samples were collected for pharmacokinetic analysis; CBC, serum BUN and creatinine concentration measurement, and urinalysis were conducted before and 1 week after each treatment. Some dogs underwent hepatic enzyme testing. Tumors were measured before the first treatment and 3 weeks after each treatment to assess response. RESULTS No adverse drug effects were detected in pretrial assessments in rodents. Seven of 16 dogs completed the study; 3 had complete tumor responses, 3 had stable disease, and 1 had progressive disease. Three of 7 dogs with oral and nasal squamous cell carcinoma (SCC) that completed the study had complete responses. Myelosuppression and cardiotoxicosis were identified in 6 and 2 dogs, respectively; none had nephrotoxicosis. Four of 5 dogs with hepatic enzymes assessed had increased ALT activities, attributed to diaquated cisplatin products in the HA-Pt. Pharmacokinetic data fit a 3-compartment model. CONCLUSIONS AND CLINICAL RELEVANCE HA-Pt treatment resulted in positive tumor responses in some dogs, primarily those with SCC. The adverse effect rate was high. IMPACT FOR HUMAN MEDICINE Oral SCC in dogs has characteristics similar to human head and neck SCC; these results could be useful in developing human treatments.

  3. Phase I study of vandetanib with radiation therapy with or without cisplatin in locally advanced head and neck squamous cell carcinoma

    Science.gov (United States)

    Papadimitrakopoulou, VA; Frank, SJ; Cohen, EW; Hirsch, FR; Myers, JN; Heymach, JV; Lin, H; Tran, HT; Chen, CR; Jimeno, A; Nedzi, L; Vasselli, JR; Lowe, ES; Raben, D

    2014-01-01

    Background Vandetanib, added to cisplatin and radiation (RT) overcomes chemo RT and EGFR inhibitor resistance in head and neck squamous cell carcinoma (HNSCC) lines and models. Methods Patients with previously untreated HNSCC received vandetanib daily for 14 days (starting dose 100 mg) then vandetanib +RT (2.2 Gy/day, 5 days/week) for 6 weeks (regimen 1) or vandetanib +RT (2 Gy/day, 5 days/week) + cisplatin (30 mg/m2 weekly) for 7 weeks (regimen 2). Primary objective was the maximum tolerated dose (MTD) of vandetanib with RT +/− cisplatin. Results Of 33 treated patients, 30 completed therapy (regimen 1, n=12; regimen 2, n=18). MTD in regimen 2 was 100 mg [3 dose limiting toxicities (DLT) at 200 mg], while regimen 1 was stopped due to poor recruitment (one DLT at 200 mg). Most common grade ≥3 AEs were dysphagia (30%), stomatitis (33%) and mucosal inflammation (27%). Five patients discontinued vandetanib due to AEs. Conclusions Vandetanib with chemo RT was feasible. PMID:25352401

  4. 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. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Rapamycin alleviates cisplatin-induced ototoxicity in vivo.

    Science.gov (United States)

    Fang, Bin; Xiao, Hongjun

    2014-06-13

    Cisplatin-induced ototoxicity affects a high percentage of new cancer patients worldwide. The detailed mechanism of cisplatin-induced ototoxicity is not completely understood. We investigated whether rapamycin could protect rats from cisplatin-induced ototoxicity. Forty-eight male Wistar rats were randomly divided into six groups. Three groups were intraperitoneally (IP) infused with cisplatin at a dose of 16 mg/kg and immediately injected with either dimethylsulfoxide (DMSO), rapamycin, or chloroquine (CQ). The remaining three groups were treated with rapamycin, CQ, or saline alone. The auditory brainstem response (ABR) test was performed to detect the rats' hearing status. Serum was isolated to measure the level of the oxidative marker malondialdehyde (MDA), the basilar membrane was prepared to count the outer hair cell loss, and soft tissue samples extracted from the cochleae were lysed to analyze the microtubule-associated protein light chain 3 (LC3) and Beclin-1. The rapamycin treatment significantly attenuated cisplatin-induced hearing loss, decreased oxidative stress, and alleviated the hair cell damage that was associated with the upregulation of the LC3-II/GAPDH ratio and increased Beclin-1 expression. Our results demonstrated that rapamycin has an otoprotective effect; it attenuates cisplatin-induced ototoxicity, probably by attenuating oxidative damage and inducing autophagy. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Calpain mediated cisplatin-induced ototoxicity in mice*

    Institute of Scientific and Technical Information of China (English)

    Liang Chang; Aimei Wang

    2013-01-01

    Ototoxic drug-induced apoptosis of inner ear cel s has been shown to be associated with calpain expression. Cisplatin has severe ototoxicity, and can induce cochlear cel apoptosis. This study assumed that cisplatin activated calpain expression in apoptotic cochlear cel s. A mouse model of cisplatin-induced ototoxicity was established by intraperitoneal injection with cisplatin (2.5, 3.5, 4.5, 5.5 mg/kg). Immunofluorescence staining, image analysis and western blotting were used to detect the expression of calpain 1 and calpain 2 in the mouse cochlea. At the same time, the auditory brainstem response was measured to observe the change in hearing. Results revealed that after intraperitoneal injection with cisplatin for 5 days, the auditory brainstem response threshold shifts increased in mice. Calpain 1 and calpain 2 expression significantly increased in outer hair cel s, the spiral ganglion and stria vascularis. Calpain 2 protein expression markedly increased with an in-creased dose of cisplatin. Results suggested that calpain 1 and calpain 2 mediated cispla-tin-induced ototoxicity in BALB/c mice. During this process, calpain 2 plays a leading role.

  7. Phun Week: Understanding Physiology

    Science.gov (United States)

    Limson, Mel; Matyas, Marsha Lakes

    2009-01-01

    Topics such as sports, exercise, health, and nutrition can make the science of physiology relevant and engaging for students. In addition, many lessons on these topics, such as those on the cardiovascular, respiratory, and digestive systems, align with national and state life science education standards. Physiology Understanding Week (PhUn…

  8. A Week for Space

    Science.gov (United States)

    Comstock, Diane

    2008-01-01

    Space Week focuses on concepts that enable students to make concrete observations in the early grades (K-2) and move to concepts that help students develop their internet research and writing skills in middle and upper grades (Grades 3-5), and culminates with the development of science investigation design skills (Grade 6). To help launch your…

  9. 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.

  10. Ellagic acid prevents cisplatin-induced oxidative stress in liver and heart tissue of rats.

    Science.gov (United States)

    Yüce, Abdurrauf; Ateşşahin, Ahmet; Ceribaşi, Ali Osman; Aksakal, Mesut

    2007-11-01

    Cisplatin is one of the most active cytotoxic agents in the treatment of cancer. High doses of cisplatin have also been known to produce hepatotoxicity, and several studies suggest that supplemental antioxidants can reduce cisplatin-induced hepatotoxicity. The present study was designed to determine the effects on the liver and heart oxidant/antioxidant system and the possible protective effects of ellagic acid on liver and heart toxicity induced by cisplatin. The control group received 0.9% saline; animals in the ellagic acid group received only ellagic acid (10 mg/kg); animals in the cisplatin group received only cisplatin (7 mg/kg); animals in cisplatin + ellagic acid group received ellagic acid for 10 days after cisplatin. The rats were killed at the end of the treatment period. Malondialdehyde (MDA) and glutathione (GSH) levels, glutathione-peroxidase (GSH-Px) and catalase (CAT) activities were determined in liver and heart tissue. While administration of cisplatin increased the MDA levels in liver and heart tissues, it decreased the GSH, GSH-Px and CAT in these samples when compared to the control group. The administration of ellagic acid to cisplatin-treated rats decreased the MDA levels, and increased GSH, GSH-Px and CAT in these samples. Cisplatin caused marked damages in the histopathological status of liver and heart tissues. These damages were ameliorated by ellagic acid administration. In conclusion, ellagic acid may be used in combination with cisplatin in chemotherapy to improve cisplatin-induced oxidative stress parameters.

  11. Protective effect of resveratrol against cisplatin-induced ototoxicity in HEI-OC1 auditory cells.

    Science.gov (United States)

    Lee, Se Hee; Kim, Hyung Sub; An, Yun Suk; Chang, Jiwon; Choi, June; Im, Gi Jung

    2015-01-01

    Cisplatin is an effective chemotherapeutic drug, but it generates reactive oxygen species (ROS) that induce severe adverse effects such as ototoxicity. Resveratrol reportedly prevents oxidative stress-induced cell death. Thus, we hypothesized that the anti-oxidative effect of resveratrol could protect against cisplatin-induced ototoxicity. The present study examined the protective effect of resveratrol against cisplatin-induced ototoxicity in HEI-OC1 auditory cells. HEI-OC1 cells were pretreated with resveratrol at 1μM for 24h and then exposed to 15μM cisplatin for 48h. Resulting cytotoxicity was measured by the MTT method, and intracellular ROS was measured using flow cytometry. Protective effect of resveratrol was compared with other anti-oxidants. Pretreatment with resveratrol 1μM protected HEI-OC1 auditory cells against cisplatin-induced cytotoxicity and significantly reduced a cisplatin-induced increase in ROS. Resveratrol provided significant protection against 15μM cisplatin applied for 48h (50.8% cell viability in the cisplatin group vs. 57.6% in the cisplatin-plus-resveratrol group), and there was a 9% decrease in cisplatin-induced ROS associated with resveratrol. This is the study investigating the protective effects of resveratrol against cisplatin-induced ototoxicity in an auditory cell line. Resveratrol significantly reduced a cisplatin-induced increase in ROS and thereby inhibited cisplatin-induced cytotoxicity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. Hematopoietic stem cells derived from human umbilical cord ameliorate cisplatin-induced acute renal failure in rats.

    Science.gov (United States)

    Shalaby, Rokaya H; Rashed, Laila A; Ismaail, Alaa E; Madkour, Naglaa K; Elwakeel, Sherien H

    2014-01-01

    Injury to a target organ can be sensed by bone marrow stem cells that migrate to the site of damage, undergo differentiation, and promote structural and functional repair. This remarkable stem cell capacity prompted an investigation of the potential of mesenchymal and hematopoietic stem cells to cure acute renal failure. On the basis of the recent demonstration that hematopoietic stem cells (HSCs) can differentiate into renal cells, the current study tested the hypothesis that HSCs can contribute to the regeneration of renal tubular epithelial cells after renal injury. HSCs from human umbilical cord blood which isolated and purified by magnetic activated cell sorting were transplanted intraperitoneal into acute renal failure (ARF) rats which was established by a single dose of cisplatin 5 mg/kg for five days. The Study was carried on 48 male white albino rats, of average weight 120-150 gm. The animals were divided into 4 groups, Group one Served as control and received normal saline throughout the experiments. Group two (model control) received a single dose of cisplatin. Group three and four male-albino rats with induced ARF received interapritoneally (HSCs) at two week and four week respectively. Injection of a single dose of cisplatin resulted in a significant increase in serum creatinine and urea levels, histo-pathological examination of kidney tissue from cisplatin showed severe nephrotoxicity in which 50-75% of glomeruli and renal tubules exhibited massive degenerative change. Four weeks after HSC transplantation, Serum creatinine and urea nitrogen decreased 3.5 times and 2.1 times as well as HGF, IGF-1, VEGF and P53 using quantitative real-time PCR increased 4.3 times, 3.2, 2.4 and 4.2 times compared to ARF groups, respectively. The proliferation of cell nuclear antigen (PCNA)-positive cells (500.083±35.167) was higher than that in the cisplatin groups (58.612±15.743). In addition, the transplanted umbilical cord hematopoietic stem cells UC-HSCs could

  13. Pemirolast reduces cisplatin-induced kaolin intake in rats.

    Science.gov (United States)

    Tatsushima, Yoko; Egashira, Nobuaki; Matsushita, Naohiro; Kurobe, Kentaro; Kawashiri, Takehiro; Yano, Takahisa; Oishi, Ryozo

    2011-07-01

    Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK(1) receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT(3) receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK(1) receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. The role of peroxiredoxin I in cisplatin-induced ototoxicity.

    Science.gov (United States)

    Le, Quang; Tabuchi, Keiji; Warabi, Eiji; Hara, Akira

    2017-04-01

    Peroxiredoxin (Prx) is a new family of antioxidative proteins. Prx I is ubiquitously expressed in various tissues and is important in the defense of tissues from increases in reactive oxygen species (ROS). The present study was designed to examine the expression of Prx subtypes in the mouse cochlea and to show the possible involvement of Prx I in protecting the cochlea against cisplatin ototoxicity. Postnatal-day-3-to-5 wildtype mice and Prx I-deficient mice were used. Prx expression in the cochlea was assessed by real-time PCR assay. Prx I protein expression was examined by immunofluorescence staining. Cochlear explants were exposed to 2, 5, and 10-μM cisplatin for 48h, and the cochlear hair cell losses of the wildtype and Prx I-deficient mice were compared. In addition, the histologic features of the cochlear lateral wall were examined after cisplatin incubation. mRNAs of all Prx subtypes were expressed in the mouse cochlea. Prx I was one of the abundant subtypes and was upregulated after 48-h exposure to 5-μM cisplatin. Immunofluorescence staining showed the ubiquitous expression of Prx I in the cochlea. No difference in cochlear hair cell loss induced by cisplatin was found between the wildtype mice and the Prx I-deficient mice. However, spiral ligament fibrocytes of Prx I-deficient mice were significantly sensitive to cisplatin at 20-μM or lower. Prx I is important for protection of at least the spiral ligament fibrocytes of the cochlear lateral wall in cisplatin ototoxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Monitoring of Tumor Response to Cisplatin Using Optical Spectroscopy

    Science.gov (United States)

    Spliethoff, Jarich W.; Evers, Daniel J.; Jaspers, Janneke E.; Hendriks, Benno H.W.; Rottenberg, Sven; Ruers, Theo J.M.

    2014-01-01

    INTRODUCTION: Anatomic imaging alone is often inadequate for tuning systemic treatment for individual tumor response. Optically based techniques could potentially contribute to fast and objective response monitoring in personalized cancer therapy. In the present study, we evaluated the feasibility of dual-modality diffuse reflectance spectroscopy–autofluorescence spectroscopy (DRS-AFS) to monitor the effects of systemic treatment in a mouse model for hereditary breast cancer. METHODS: Brca1−/−; p53−/− mammary tumors were grown in 36 mice, half of which were treated with a single dose of cisplatin. Changes in the tumor physiology and morphology were measured for a period of 1 week using dual-modality DRS-AFS. Liver and muscle tissues were also measured to distinguish tumor-specific alterations from systemic changes. Model-based analyses were used to derive different optical parameters like the scattering and absorption coefficients, as well as sources of intrinsic fluorescence. Histopathologic analysis was performed for cross-validation with trends in optically based parameters. RESULTS: Treated tumors showed a significant decrease in Mie-scattering slope and Mie-to-total scattering fraction and an increase in both fat volume fraction and tissue oxygenation after 2 days of follow-up. Additionally, significant tumor-specific changes in the fluorescence spectra were seen. These longitudinal trends were consistent with changes observed in the histopathologic analysis, such as vital tumor content and formation of fibrosis. CONCLUSIONS: This study demonstrates that dual-modality DRS-AFS provides quantitative functional information that corresponds well with the degree of pathologic response. DRS-AFS, in conjunction with other imaging modalities, could be used to optimize systemic cancer treatment on the basis of early individual tumor response. PMID:24726234

  16. Ceramide-1-phosphate protection of cochlear hair cells against cisplatin ototoxicity

    Directory of Open Access Journals (Sweden)

    Quang Le

    2016-01-01

    Conclusion: The present findings confirmed the protective effects of C1P in the cisplatin ototoxicity. The balance between ceramide and C1P may play a critical role in the determination of hair cell fate in cisplatin ototoxicity.

  17. 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.

  18. Discovery – Cisplatin and The Treatment of Testicular and Other Cancers

    Science.gov (United States)

    Prior to the discovery of cisplatin in 1965, men with testicular cancer had few medical options. Now, thanks to NCI research, cisplatin and similar chemotherapy drugs are known for curing testicular and other forms of cancer.

  19. The effects of nabumetone, a cyclooxygenase-2 inhibitor, on cisplatin-induced 5-hydroxytryptamine release from the isolated rat ileum.

    Science.gov (United States)

    Kudo, C; Minami, M; Hirafuji, M; Endo, T; Hamaue, N; Akita, K; Murakami, T; Kawaguchi, H

    2001-01-01

    In order to elucidate 5-HT release influenced by PGE2 in the background of the anticancer drug-induced emesis, the effect of nabumetone, a COX-2 inhibitor, on the release of 5-HT from the isolated rat ileum was investigated. PGE2 produced a concentration-dependent increase (10(-9) to 10 M) and decrease (10(-8) to 10(-6) M) in 5-HT release. Arachidonic acid also demonstrated a similar bell-shaped 5-HT release. The arachidonic acid-induced 5-HT release at 3 x 10(-6) M (313.04 +/- 25.90%) was significantly inhibited by the concomitant perfusion with BRL10720 (10(-6) M) (161.98 +/- 19.4%, pnabumetone, or indomethacin (3 x 10(-7) M)(190.01 +/- 16.19%, pnabumetone or BRL10720, but was not affected by the 3-day administration of dexamethasone. After 72 hours, however, the in vivo 3-days administration of nabumetone, BRL10720 or dexamethasone had no effect on the increase in ileal 5-HT levels induced by cisplatin. The use of COX-2 inhibitors to ameliorate delayed emesis induced by cisplatin-based anticancer chemotherapy has been proposed. On the other hand, there is a possibility that dexamethasone works through a mechanism other than 5-HT release in delayed emesis.

  20. Beneficial Effects of Hesperidin against Cisplatin-Induced Nephrotoxicity and Oxidative Stress in Rats

    OpenAIRE

    Wafaa R Mohamed; Arafa, El-Shaimaa A.; Basim A. Shehata; Gamal A. El Sherbiny; Abdel Nasser A.M. Elgendy

    2015-01-01

    Cisplatin has been frequently used for treatment of wide variety of tumors. The use of cisplatin is associated with severe cytotoxicity such as nephrotoxicity, hepatotoxicity and spermiotoxicity which radically limits its clinical use. The present study aimed to investigate the possible protective effects of multiple doses of hesperidin against cisplatin-induced nephrotoxicity induced by single i.p injection of cisplatin (7.5 mg/kg). Hesperidin was given to rats at two different doses (100 an...

  1. Antitumor activity and biodistribution of cisplatin nanocapsules in nude mice bearing human ovarian carcinoma xenografts

    OpenAIRE

    Staffhorst, R.W.H.M.; Born, K.; Erkelens, C.A.M.; Hamelers, I.H.L.; Peters, G J; Boven, E.; de Kroon, A.I.P.M.

    2008-01-01

    Cisplatin nanocapsules represent a novel lipid formulation of the anticancer drug cis-diamminedichloridoplatinum(II) (cisplatin), characterized by an unprecedented cisplatin-tolipid molar ratio, and exhibiting strongly increased in-vitro cytotoxicity compared with the free drug. In this study, antitumor efficacy and biodistribution of PEGylated cisplatin nanocapsules were compared with those of the free drug in a mouse tumor model. Nude mice bearing human ovarian carcinoma OVCAR-3 xenografts ...

  2. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress

    OpenAIRE

    Amel M. Soliman; Shreen Desouky; Mohamed Marzouk; Sayed, Amany A.

    2016-01-01

    Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE) on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3...

  3. Treatment of newly diagnosed glioblastoma multiforme with carmustine, cisplatin and etoposide followed by radiotherapy. A phase II study

    DEFF Research Database (Denmark)

    Lassen, U; Kristjansen, P E; Wagner, A;

    1999-01-01

    A meta-analysis and several studies of patients with grade III and IV gliomas have indicated that the addition of nitrosurea based chemotherapy to surgery and radiation may improve survival. We performed a phase II study of pre-irradiative chemotherapy with BCNU, cisplatin and etoposide. This imp......A meta-analysis and several studies of patients with grade III and IV gliomas have indicated that the addition of nitrosurea based chemotherapy to surgery and radiation may improve survival. We performed a phase II study of pre-irradiative chemotherapy with BCNU, cisplatin and etoposide....... This implies a short total treatment duration and a reliable response evaluation. The treatment schedule was three cycles of BCNU 200 mg/m2 i.v. on day 1, cisplatin 20 mg/m2 i.v. on day 1-5 and etoposide (VP-16) 100 mg/m2 i.v. on day 1-5, given every five weeks and followed by localized radiation, 60 Gy in 30...

  4. Extended Field Intensity Modulated Radiation Therapy With Concomitant Boost for Lymph Node–Positive Cervical Cancer: Analysis of Regional Control and Recurrence Patterns in the Positron Emission Tomography/Computed Tomography Era

    Energy Technology Data Exchange (ETDEWEB)

    Vargo, John A.; Kim, Hayeon; Choi, Serah [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Sukumvanich, Paniti; Olawaiye, Alexander B.; Kelley, Joseph L.; Edwards, Robert P.; Comerci, John T. [Department of Gynecologic Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Beriwal, Sushil, E-mail: beriwals@upmc.edu [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States)

    2014-12-01

    Purpose: Positron emission tomography/computed tomography (PET/CT) is commonly used for nodal staging in locally advanced cervical cancer; however the false negative rate for para-aortic disease are 20% to 25% in PET-positive pelvic nodal disease. Unless surgically staged, pelvis-only treatment may undertreat para-aortic disease. We have treated patients with PET-positive nodes with extended field intensity modulated radiation therapy (IMRT) to address the para-aortic region prophylactically with concomitant boost to involved nodes. The purpose of this study was to assess regional control rates and recurrence patterns. Methods and Materials: Sixty-one patients with cervical cancer (stage IBI-IVA) diagnosed from 2003 to 2012 with PET-avid pelvic nodes treated with extended field IMRT (45 Gy in 25 fractions with concomitant boost to involved nodes to a median of 55 Gy in 25 fractions) with concurrent cisplatin and brachytherapy were retrospectively analyzed. The nodal location was pelvis-only in 41 patients (67%) and pelvis + para-aortic in 20 patients (33%). There were a total of 179 nodes, with a median number of positive nodes of 2 (range, 1-16 nodes) per patient and a median nodal size of 1.8 cm (range, 0.7-4.5 cm). Response was assessed by PET/CT at 12 to 16 weeks. Results: Complete clinical and imaging response at the first follow-up visit was seen in 77% of patients. At a mean follow-up time of 29 months (range, 3-116 months), 8 patients experienced recurrence. The sites of persistent/recurrent disease were as follows: cervix 10 (16.3%), regional nodes 3 (4.9%), and distant 14 (23%). The rate of para-aortic failure in patients with pelvic-only nodes was 2.5%. There were no significant differences in recurrence patterns by the number/location of nodes, largest node size, or maximum node standardized uptake value. The rate of late grade 3+ adverse events was 4%. Conclusions: Extended field IMRT was well tolerated and resulted in low regional recurrence

  5. Chemoradiotherapy with or without consolidation chemotherapy using cisplatin and 5-fluorouracil in anal squamous cell carcinoma: long-term results in 31 patients

    Directory of Open Access Journals (Sweden)

    Roh Jae

    2008-01-01

    Full Text Available Abstract Background The objectives of this study were to evaluate long-term results of concurrent chemoradiotherapy (CRT with 5-fluorouracil and cisplatin and the potential benefit of consolidation chemotherapy in patients with anal squamous cell carcinoma (ASCC. Methods Between January 1995 and February 2006, 31 patients with ASCC were treated with CRT. Radiotherapy was administered at 45 Gy over 5 weeks, followed by a boost of 9 Gy to complete or partial responders. Chemotherapy consisted of 5-fluorouracil (750 or 1,000 mg/m2 daily on days 1 to 5 and days 29 to 33; and, cisplatin (75 or 100 mg/m2 on day 2 and day 30. Twelve patients had T3–4 disease, whereas 18 patients presented with lymphadenopathy. Twenty-one (67.7% received consolidation chemotherapy with the same doses of 5-fluorouracil and cisplatin, repeated every 4 weeks for maximum 4 cycles. Results Nineteen patients (90.5% completed all four courses of consolidation chemotherapy. After CRT, 28 patients showed complete responses, while 3 showed partial responses. After a median follow-up period of 72 months, the 5-year overall, disease-free, and colostomy-free survival rates were 84.7%, 82.9% and 96.6%, demonstrating that CRT with 5-fluorouracil and cisplatin yields a good outcome in terms of survival and sphincter preservation. No differences in 5-year OS and DFS rates between patients treated with CRT alone and CRT with consolidation chemotherapy was observed. Conclusion our study shows that CRT with 5-FU and cisplatin, with or without consolidation chemotherapy, was well tolerated and proved highly encouraging in terms of long-term survival and the preservation of anal function in ASCC. Further trials with a larger patient population are warranted in order to evaluate the potential role of consolidation chemotherapy.

  6. Intra-arterial cisplatin and concurrent radiation for invasive bladder cancer

    Energy Technology Data Exchange (ETDEWEB)

    Miyanaga, Naoto; Ohtani, Mikinobu; Noguchi, Ryosuke (Tsukuba Univ., Ibaraki (Japan). Inst. of Clinical Medicine) (and others)

    1991-10-01

    Fifteen patients with invasive bladder cancer were treated with selective intra-arterial cisplatin and external beam radiotherapy (30.6 Gy over 3 weeks) prior to a planned cystectomy. Cisplatin, in total 200 mg, was administered via bilateral internal iliac artery infusion during the course of radiotherapy. Seven patients were evaluated for local response. Partial response (PR) was revealed in 4, and minor response (MR) in 3. Ten patients received total cystectomy, and pathological effects by the criteria adipted by Japanese Urological Association and The Japanese Society of Pathology, were as follows: Ef.3 in 1 case, Ef.2 in 6. Ef.1b in 1 and Ef.1a in 2. Down staging was observed in 8 patients from the clinical to the pathological stage. Thirteen patients are alive for 21 months. Two patients have died (1 lung infarction, 1 pancreatic cancer). Though nausea and sciatica-like pain were observed in some cases, there were no severe systemic side effects such as bone marrow suppression and renal toxicity. From these results it is concluded that this therapeutic modality could be effective in the preoperative work-up of candidates for total cystectomy, and also that it could be useful in the treatment of patients in whom total cystectomy is contraindicated. (author).

  7. Preoperative docetaxel/cisplatin/5-fluorouracil chemotherapy in patients with locally advanced gastro-esophageal adenocarcinoma.

    Science.gov (United States)

    Bayraktar, Ulas Darda; Bayraktar, Soley; Hosein, Peter; Chen, Emerson; Koniaris, Leonidas G; Rocha-Lima, Caio Max S; Montero, Alberto J

    2012-09-01

    Perioperative chemotherapy plus surgery improves survival compared to surgery alone in GE junctional (GEJ) and gastric adenocarcinomas. The docetaxel/cisplatin/5-fluorouracil (DCF) combination is superior to CF in patients with metastatic gastric cancer. We retrospectively evaluated the safety and efficacy of preoperative DCF chemotherapy in patients with locally advanced gastric and GEJ cancer. Twenty-one gastric and 10 gastroesophageal junctional (GEJ) cancer patients received 2-3 cycles of preoperative docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, 5-FU 750 mg/m(2) (continuous infusion) on days 1-5 every 3 weeks. Clinical response was evaluated by comparing pre- and postchemotherapy CT scans. Overall survival (OS) and progression-free survival (PFS) were calculated from the initiation of chemotherapy. None of the patients achieved complete clinical remission while 11 (35%) patients achieved partial clinical remission. Ten patients with GEJ cancer (100%) and 13 with gastric cancer (62%) underwent curative surgery (P = 0.023). Seventeen (55%) patients experienced grade 3-4 chemotherapy-related adverse events. The most common adverse events were anemia, nausea/vomiting, diarrhea, and febrile neutropenia. At a median follow-up of 17.0 months, median OS and PFS were 26.1 months (95% CI: 22.7-29.5) and 18.8 months (95% CI: 9.9-27.7), respectively. The DCF regimen is active in patients with gastric and GEJ adenocarcinoma in the preoperative setting.

  8. Soft Robotics Week

    CERN Document Server

    Rossiter, Jonathan; Iida, Fumiya; Cianchetti, Matteo; Margheri, Laura

    2017-01-01

    This book offers a comprehensive, timely snapshot of current research, technologies and applications of soft robotics. The different chapters, written by international experts across multiple fields of soft robotics, cover innovative systems and technologies for soft robot legged locomotion, soft robot manipulation, underwater soft robotics, biomimetic soft robotic platforms, plant-inspired soft robots, flying soft robots, soft robotics in surgery, as well as methods for their modeling and control. Based on the results of the second edition of the Soft Robotics Week, held on April 25 – 30, 2016, in Livorno, Italy, the book reports on the major research lines and novel technologies presented and discussed during the event.

  9. CERN safety week

    CERN Multimedia

    DG Unit

    2009-01-01

    Following an increase in the number of accidents in 2008, the Safety Commission is organising a CERN safety week from 8 to 12 June for riders of bicycles, scooters and motorbikes. We invite you to take part in the programme, which will be held in the Main Building (Bldg. 500) and will consist of an exhibition, organised events and hands-on activities, including demonstrations of emergency braking, a driving simulator, simulation of what it feels like to drive under the influence of alcohol, demonstrations by the Fire Brigade, video projections, etc. There will also be a number of prizes to be won. Please sign up via your DSO.

  10. CERN safety week

    CERN Multimedia

    DG Unit

    2009-01-01

    Following an increase in the number of accidents in 2008, the Safety Commission is organising a CERN safety week from 8 to 12 June for riders of bicycles, scooters and motorbikes. We invite you to take part in the programme, which will be held in the Main Building (Bldg. 500) and will consist of an exhibition, organised events and hands-on activities, including demonstrations of emergency braking, a driving simulator, simulation of what it feels like to drive under the influence of alcohol, demonstrations by the Fire Brigade, video projections, etc. There will also be a number of prizes to be won. Please sign up via your DSO.

  11. Phase III randomized trial comparing moderate-dose cisplatin to combined cisplatin and carboplatin in addition to mitomycin and ifosfamide in patients with stage IV non-small-cell lung cancer

    Science.gov (United States)

    Sculier, J-P; Lafitte, J-J; Paesmans, M; Thiriaux, J; Alexopoulos, C G; Baumöhl, J; Schmerber, J; Koumakis, G; Florin, M C; Zacharias, C; Berghmans, T; Mommen, P; Ninane, V; Klastersky, J

    2000-01-01

    A phase III randomized trial was conducted in patients with metastatic NSCLC, to determine if, in association with mitomycin (6 mg m–2) and ifosfamide (3 g m–2), the combination of moderate dosages of cisplatin (60 mg m–2) and carboplatin (200 mg m–2) – CarboMIP regimen – improved survival in comparison with cisplatin (50 mg m–2) alone – MIP regimen. A total of 305 patients with no prior chemotherapy were randomized, including 297 patients assessable for survival (147 in the MIP arm and 150 in the CarboMIP arm) and 268 patients assessable for response to chemotherapy. All but eight (with malignant pleural effusion) had stage IV disease. There was a 27% (95% CI, 19–34) objective response (OR) rate to MIP (25% of the eligible patients) and a 33% (95% CI, 24–41) OR rate to CarboMIP (29% of the eligible patients). This difference was not statistically significant (P = 0.34). Duration of response was not significantly different between both arms. There was also no difference (P = 0.67) in survival: median survival times were 28 weeks (95% Cl, 24–32) for MIP and 32 weeks (95% Cl, 26–35) for CarboMIP, with respectively 1-year survival rates of 24% and 23% and 2-year survival rates of 5% and 2%. The main toxicities consisted in emesis, alopecia, leucopenia and thrombocytopenia, that were, except alopecia, significantly more severe in the CarboMIP arm. Our trial failed to demonstrate a significant improvement in response or survival when patients with metastatic NSCLC were treated, in addition to ifosfamide and mitomycin, by combination of moderate dosages of cisplatin and carboplatin instead of moderate dosage of cisplatin alone. The results support the use of a moderate dose (50 mg m–2) of cisplatin in combination with ifosfamide and mitomycin for the chemotherapy of this disease. © 2000 Cancer Research Campaign PMID:11027424

  12. Antitumor activity and biodistribution of cisplatin nanocapsules in nude mice bearing human ovarian carcinoma xenografts

    NARCIS (Netherlands)

    Staffhorst, R.W.H.M.; van der Born, K.; Erkelens, C.A.M.; Hamelers, I.H.L.; Peters, G.J.; Boven, E.; de Kroon, A.I.P.M.

    2008-01-01

    Cisplatin nanocapsules represent a novel lipid formulation of the anticancer drug cis-diamminedichloridoplatinum(II) (cisplatin), characterized by an unprecedented cisplatin-tolipid molar ratio, and exhibiting strongly increased in-vitro cytotoxicity compared with the free drug. In this study, antit

  13. [Experimental study of protective effect of solcoseryl on cisplatin nephrotoxicity].

    Science.gov (United States)

    Satoh, H; Mori, Y

    1992-01-01

    Cis-diamminedichloroplatinum (II) (cisplatin) is known to possess nephrotoxicity. Recently, it is said that the nephrotoxicity closely correlated with active oxygen. In the present study, an attempt was made to examine, whether or not solcoseryl, antioxidant like scavenger, decreases the nephrotoxicity. Three groups of Sprague-dawley rats were injected cisplatin (3mg/kg) only (C group), cisplatin and 2 times solcoseryl (8mg/kg), (CS2 group), and cisplatin and 5 times solcoseryl (CS5 group). BUN levels in C and CS2 groups were elevated compared to CS5 group. In the light microscopy, 62.5% to 100% in C and CS2 groups revealed massive necrosis in straight part of the proximal tubules, while the damage in CS5 group was only 25%. In the electron microscopy, these findings were similar to the light microscopic observations. Solcoseryl is known to have several antioxidative effects such as inhibition of superoxide producing and hyperperoxidation. It is suggested that these effects of solcoseryl might decrease the nephrotoxicity. Solcoseryl seems to be a useful drug for reducing nephrotoxicity and also it is a safe drug. Therefore, solcoseryl can be used for the prevention of cisplatin nephrotoxicity.

  14. Cisplatin-Associated Ototoxicity: A Review for the Health Professional.

    Science.gov (United States)

    Paken, Jessica; Govender, Cyril D; Pillay, Mershen; Sewram, Vikash

    2016-01-01

    Cisplatin is an effective drug used in the treatment of many cancers, yet its ototoxic potential places cancer patients, exposed to this drug, at risk of hearing loss, thus negatively impacting further on a patient's quality of life. It is paramount for health care practitioners managing such patients to be aware of cisplatin's ototoxic properties and the clinical signs to identify patients at risk of developing hearing loss. English peer-reviewed articles from January 1975 to July 2015 were assessed from PubMed, Science Direct, and Ebscohost. Seventy-nine articles and two books were identified for this review, using MeSH terms and keywords such as "ototoxicity", "cisplatin", "hearing loss", and "ototoxicity monitoring". This review provides an up-to-date overview of cisplatin-associated ototoxicity, namely, its clinical features, incidence rates, and molecular and cellular mechanisms and risk factors, to health care practitioners managing the patient with cancer, and highlights the need for a team-based approach to complement an audiological monitoring programme to mitigate any further loss in the quality of life of affected patients, as there is currently no otoprotective agent recommended routinely for the prevention of cisplatin-associated ototoxicity. It also sets the platform for effective dialogue towards policy formulation and strengthening of health systems in developing countries.

  15. Structural changes of linear DNA molecules induced by cisplatin

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zhiguo, E-mail: cn.zguoliu@yahoo.com [State Engineering Laboratory of Bio-Resource Eco-Utilization, Harbin 150040 (China); Engineering Research Center of Forest Bio-preparation, Ministry of Education, Northeast Forestry University, Harbin 150040 (China); Key Laboratory of Forest Plant Ecology of Ministry of Education, Northeast Forestry University, Harbin 150040 (China); Liu, Ruisi; Zhou, Zhen; Zu, Yuangang; Xu, Fengjie [State Engineering Laboratory of Bio-Resource Eco-Utilization, Harbin 150040 (China); Engineering Research Center of Forest Bio-preparation, Ministry of Education, Northeast Forestry University, Harbin 150040 (China); Key Laboratory of Forest Plant Ecology of Ministry of Education, Northeast Forestry University, Harbin 150040 (China)

    2015-02-20

    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.

  16. Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations

    Directory of Open Access Journals (Sweden)

    Natalia Zisman

    2011-01-01

    Full Text Available The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (Tm ranged from 42–55°C. The high Tm formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest Tm formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10 with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle.

  17. Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations.

    Science.gov (United States)

    Zisman, Natalia; Dos Santos, Nancy; Johnstone, Sharon; Tsang, Alan; Bermudes, David; Mayer, Lawrence; Tardi, Paul

    2011-01-01

    The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (T(m)) ranged from 42-55°C. The high T(m) formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest T(m) formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle.

  18. Clinical analysis of preoperative induction chemotherapy with gemcitabine combined with cisplatin for locally advanced non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    Qianping Li; Jianjun Wang; Jun Zhang; Chengyi Lin

    2012-01-01

    Objective: The purpose of this study was to assess the curative effect and adverse reaction of preoperative induction chemotherapy with gemcitabine combined with cisplatin for locally advanced non-small cell lung cancer (NSCLC). Methods: This prospective randomized controlled trial included 115 patients with locally advanced NSCLC were randomly divided into experimental and control groups and were treated from January 2007 to January 2010. The experimental group of 63 cases was treated with two cycles of induction chemotherapy before operation, radical surgery had been performed about three weeks after completion of chemotherapy, followed by received two cycles of chemotherapy. And the control group (52 cases) was treated at first with radical surgery, then treated with four cycles of chemotherapy. Two groups of the cases received routine thoracic radiotherapy with a total dose of 45 Gy. One cycle of gemcitabine combined with cisplatin regimen in-cluded gemcitabine 1000 mg/m2 on day 1 and day 8 and cisplatin 25 mg/m2 on day 1, day 2 and day 3 by intravenous infusion, with 21 days as one cycle. The tumor recurrence was evaluated by chest CT and abdominal B-ultrasound. Efficacy and toxicity results were compared by two groups. Results: All patients were followed up for three months to two years. The surgical stage of the experimental group reduced, two-years disease-free survival and postoperative recovery in the experimental group were better than in the control group, the difference was statistical significant. Toxicity and side effect after chemotherapy were mainly bone marrow suppression and gastrointestinal reactions, other complications included thrombocytopenia, leuko-penia, anemia, liver and kidney dysfunction were no significant difference in two groups. Conclusion: Preoperative induction chemotherapy with gemcitabine combined with cisplatin for locally advanced lung cancer can reduce the surgical staging and extend the postoperative disease-free survival.

  19. 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.

  20. a week in space

    Science.gov (United States)

    collette, christian

    2016-04-01

    COLLETTE Christian Institut Saint Laurent Liège Belgium. I am a science teacher at a technical high school. Generally, my students don't come from a privileged social background and are not particularly motivated for studies. For 10 years, I organize, for one of my sections, a spatial (and special) school year that ends in a spatial week. Throughout this year, with the help of my colleagues, I will introduce into all themes a lot of concepts relating to space. French, history, geography, English, mathematics, technical courses, sciences, and even gymnastics will be training actors in space culture. In spring, I will accompany my class in the Euro Space Center (Redu- Belgium) where we will live one week 24 hours on "like astronauts" One third of the time is dedicated to astronaut training (moonwalk, remote manipulator system, mission simulation, weightless wall, building rockets, satellites, etc.), One third to more intellectual activities on space (lectures, research, discovery of the outside run) the last one third of time in outside visits (museums, site of ESA-Redu) or in movies about space (October sky, Apollo 13, etc.) During this year, the profits, so educational as human, are considerable!

  1. ATLAS overview week highlights

    CERN Multimedia

    D. Froidevaux

    2005-01-01

    A warm and early October afternoon saw the beginning of the 2005 ATLAS overview week, which took place Rue de La Montagne Sainte-Geneviève in the heart of the Quartier Latin in Paris. All visitors had been warned many times by the ATLAS management and the organisers that the premises would be the subject of strict security clearance because of the "plan Vigipirate", which remains at some level of alert in all public buildings across France. The public building in question is now part of the Ministère de La Recherche, but used to host one of the so-called French "Grandes Ecoles", called l'Ecole Polytechnique (in France there is only one Ecole Polytechnique, whereas there are two in Switzerland) until the end of the seventies, a little while after it opened its doors also to women. In fact, the setting chosen for this ATLAS overview week by our hosts from LPNHE Paris has turned out to be ideal and the security was never an ordeal. For those seeing Paris for the first time, there we...

  2. Neoadjuvant cisplatin plus temozolomide versus standard treatment in patients with unresectable glioblastoma or anaplastic astrocytoma: a differential effect of MGMT methylation.

    Science.gov (United States)

    Capdevila, Laia; Cros, Sara; Ramirez, Jose-Luis; Sanz, Carolina; Carrato, Cristina; Romeo, Margarita; Etxaniz, Olatz; Hostalot, Cristina; Massuet, Ana; Cuadra, Jose Luis; Villà, Salvador; Balañà, Carmen

    2014-03-01

    Patients with unresectable glioblastoma or anaplastic astrocytoma have a dismal prognosis. The role of neoadjuvant chemotherapy prior to irradiation in these patients has been studied primarily in non-randomized studies. We have compared the effect of neoadjuvant chemotherapy plus radiotherapy versus concomitant radiotherapy plus temozolomide in a retrospective analysis of two consecutive series of patients in whom surgery consisted of biopsy only. From 2003 to 2005, 23 patients received two cycles of temozolomide plus cisplatin followed by radiotherapy (Cohort 1), and from 2006 to 2010, 23 additional patients received concomitant radiotherapy and temozolomide followed by adjuvant temozolomide (Cohort 2). In Cohort 1, 91.3 % of patients received all planned chemotherapy cycles. Progression-free and overall survival were 3.3 and 8.5 months, respectively. In Cohort 2, progression-free and overall survival were 5.1 and 11.2 months, respectively. No differences between the two groups were observed in rate of completion of radiotherapy, progression-free or overall survival. MGMT methylation was assessed in 91.3 % of patients. In Cohort 1, patients without MGMT methylation showed a trend towards shorter progression-free survival (P = 0.09), while in Cohort 2, patients without MGMT methylation had longer progression-free survival (P = 0.04). In the overall patient population, neoadjuvant temozolomide plus cisplatin had neither a positive nor negative influence on outcome. However, our findings indicate that patients with methylated MGMT may derive greater benefit from neoadjuvant temozolomide than those with unmethylated MGMT.

  3. Protective Role of Aerobic Exercise Against Cisplatin-Induced Nephrotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Zeynali

    2015-09-01

    Full Text Available Background Cisplatin (CP is a chemotherapy drug and nephrotoxicity is considered as its major side effect. Aerobic exercise is well known as an approach to reduce the side effects of many drugs. Objectives This study was designed to determine the protective role of aerobic exercise against CP-induced nephrotoxicity. Materials and Methods Thirty male Wistar rats were randomly divided into four groups. Group I had aerobic exercise on a treadmill one hour per day and five days per week for eight weeks. Then, the exercise protocol was continued for another week, but during this week, the animals also received CP (2.5 mg/kg/day; ip. Group II underwent the same protocol as group I without exercise in the last week during the CP therapy. Groups III and IV were assigned as positive and negative control groups, and were treated with CP and saline without exercise, respectively. Finally, the animals were sacrificed for the biochemical measurement and tissue histopathology investigation. Results CP alone without exercise increased serum levels of blood urea nitrogen (BUN, creatinine (Cr, and malondialdehyde (MDA; and kidney nitrite level, while treadmill exercise in group I significantly ameliorated these parameters (P < 0.05. Kidney and serum levels of MDA and nitrite did not alter significantly. Also, the severity of kidney tissue damage decreased significantly in groups I and II (P < 0.05. Conclusions Aerobic exercise may reduce CP-induced nephrotoxicity with a favorable effect on renal function by increasing activation of antioxidant system.

  4. Congenital Cases of Concomitant Harlequin and Horner Syndromes.

    Science.gov (United States)

    Miquel, Juliette; Piyaraly, Saguiraly; Dupuy, Alain; Cochat, Pierre; Phan, Alice

    2017-03-01

    We report three pediatric cases of concomitant congenital Horner and Harlequin syndromes. This association suggests a lesion at the superior cervical ganglion or just inferior. Often, no underlying lesion is documented.

  5. Potential of the Akt inhibitor LY294005 to antagonize the efficacy of Cisplatin against HCT116 tumor cells in a DNA mismatch repair-dependent manner.

    Science.gov (United States)

    Fedier, Andre; Erdmann, Ruediger; Boulikas, Teni; Fink, Daniel

    2006-11-01

    Human colorectal adenocarcinoma sublines either deficient (HCT116+ch2) or proficient (HCT116+ch3) in the function of MLH1, one of five proteins crucial to DNA mismatch repair (MMR), were used to investigate whether the Akt-specific inhibitor LY294005 could not only increase the efficacy of platinum drugs in HCT116 cells in general but also increase the efficacy of the cisplatinum compounds Cisplatin and Lipoplatin specifically in MLH1-deficient, Cisplatin- and Lipoplatin-resistant HCT116 cells. We report that, under the conditions it increased the efficacy of Docetaxel and did not affect that of 6-thioguanine, LY294005 decreased the sensitivity of both sublines to Cisplatin, Lipoplatin, Oxaliplatin, and Lipoxal. Notably, the LY294005-imposed decrease was significantly higher in the MLH1-proficient than in the MLH1-deficient subline with Cisplatin and Lipoplatin, whereas it was nearly the same in both sublines with Oxaliplatin and Lipoxal. These LY294005-imposed changes in drug sensitivity, i.e. increase with Docetaxel and decreases with platinum compounds, were not associated with the concomitant abrogation in the levels of phospho-Aktser473. Analogous changes in drug sensitivity were also observed with the PI3-kinase inhibitor LY294002, but these changes were associated with complete abrogation of phospho-Aktser473. These observations suggest a possible relationship between MMR-mediated cisplatinum DNA damage signaling and the Akt signaling pathway, e.g. a common target for both pathways. A possibly novel property of Akt in aggravating drug sensitivity may also be proposed.

  6. Saxagliptin efficacy and safety in patients with type 2 diabetes receiving concomitant statin therapy.

    Science.gov (United States)

    Bryzinski, Brian; Allen, Elsie; Cook, William; Hirshberg, Boaz

    2014-01-01

    To examine whether concomitant statin therapy affects glycemic control with saxagliptin 2.5 and 5mg/d in patients with type 2 diabetes mellitus (T2DM). Efficacy and safety were analyzed post hoc for pooled data from 9 saxagliptin randomized, placebo-controlled trials with a primary 24-week treatment period (4 monotherapy, 2 add-on to metformin, 1 each add-on to a sulfonylurea, thiazolidinedione, or insulin±metformin). Safety was also assessed in an 11-study, 24-week pool and an extended 20-study pool, which included 9 additional 4- to 52-week randomized studies. Comparisons were performed for patient groups defined by baseline statin use. Saxagliptin produced greater mean reductions in glycated hemoglobin than placebo, with no interaction between treatment and baseline statin use (P=0.47). In patients receiving saxagliptin 2.5 and 5mg and placebo, the proportion of patients with ≥1 adverse event (AE) was 78.1%, 64.0%, and 63.2%, respectively, in patients with any statin use and 70.6%, 57.9%, and 55.0% in patients with no statin use. Serious AEs, deaths, and symptomatic confirmed hypoglycemia (fingerstick glucose ≤50mg/dL) were few and similar, irrespective of baseline statin use. Saxagliptin improves glycemic control and is generally well tolerated in patients with T2DM, irrespective of concomitant statin therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Concomitant hypo-hyperdontia: Report of two cases

    Directory of Open Access Journals (Sweden)

    Amita Sharma

    2012-01-01

    Full Text Available Concomitant hypo-hyperdontia is a rare condition of coexisting missing teeth and supernumerary teeth in the same subject. Its etiology is still not exactly known. Permanent dentition is usually affected. Presented here are two uncommon cases of bimaxillary concomitant hypo-hyperdontia during the mixed dentition period. Early diagnosis of the condition and multidisciplinary approach for management of such cases is recommended.

  8. Concomitant pseudomembranous colitis in colonic resection for acute diverticulitis.

    Science.gov (United States)

    Byrns, Simon; Canterbury, Laura A

    2015-06-01

    Diverticulitis and Clostridium difficile infection (CDI) are common conditions in the surgical population. However, they are usually 2 distinct clinical entities. Here, we report the case of acute diverticulitis with concomitant pseudomembranous colitis, presumably due to CDI. The clinical course as well as gross and microscopic pathology findings are discussed. A literature search revealed a single previous report of these findings concomitant in a surgical specimen. A brief discussion of the pathophysiology of CDI and acute diverticulitis is included.

  9. Radiation-induced cisplatin resistance in two human cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Eichholtz-Wirth, H.; Stotzer, O. [GSF-Institute of Radiobiology and Cytometry, Neuherberg (Germany); Marx, K. [Medical Clin. III, University, Munich (Germany)

    1997-03-01

    Cisplatin resistance has been induced in human HT-29 and HeLa cells after low-dose fractionated {gamma}-irradiation. The drug resistance is modest and does not confer cross-resistance to irradiation. Alterations that were recently shown to correlate with radiation-induced cisplatin resistance in murine cells are not involved in the resistant HeLa-C3 cells. Scavengers, such as GSH or metallothioneins are unchanged and there is no alteration of the cGMP transduction pathway. Preliminary results in HeLa-C3 cells indicate that resistance is associated with differences of the apoptotic pathway, with enhancement of the p53 suppressor protein after cisplatin treatment but unchanged bcl-2 protein expression. (authors)

  10. The Effect of Dexpanthenol on Ototoxicity Induced by Cisplatin.

    Science.gov (United States)

    Toplu, Yuksel; Sapmaz, Emrah; Parlakpinar, Hakan; Kelles, Mehmet; Kalcioglu, M Tayyar; Tanbek, Kevser; Kizilay, Ahmet

    2016-03-01

    This study was aimed to investigate the protective effects of dexpanthenol (Dxp) on against cisplatin-induced ototoxicity. To examine this effect, distortion product otoacoustic emissions (DPOAEs) measurements and serum levels of oxidative and antioxidant status (including malondialdehyde, superoxide dismutase, catalase, glutathione, glutathione peroxidase, total oxidant status, total antioxidant status, and oxidative stress index) were evaluated. Thirty-two adult female Wistar albino rats were randomly divided into 4 equal groups; control (K), cisplatin (C), cisplatin plus Dxp (CD), and Dxp (D). In all groups DPOAEs measurements, between 996 and 10,078 Hz as DPOAEs and input/output functions, were performed on days 0, 1th, 5th, and 12th. Prior to death, the last DPOAEs measurements and blood samples were taken. In the C group, statistically significant differences were detected at all frequencies between 0 and 5 days and 0 and 12 days measurements (Pototoxicity.

  11. Epoetin alfa ja namaluva nefrotoksicnosta inducirana so cisplatin kaj staorci

    Directory of Open Access Journals (Sweden)

    Dimce Zafirov

    2006-06-01

    Full Text Available Klinickata efikasnost na cisplatin kako antitumorski lek e nesomnena, no dozno-limitiracki faktor za negova upotreba pretstavuva izrazitata nefrotoksicnost. Najnovite istrazuvawa pokazuvaat deka epoetin alfa moze da ima znacajna uloga ne samo vo terapiski celi za korekcija na razni vidovi na anemii, tuku istiot moze da bide efikasen i kako nevroprotektiv, hepatoprotektiv, kardioprotektiv i osobeno znacajno kako nefroprotektiv kaj nefrotoksicnost inducirana od preparati na baza na platina. Glavna cel na ovaa studija bese da se utvrdi efektot na epoetin alfa vo prevencijata na nefrotoksicnost eksperimentalno inducirana so dolgotrajna administracija na cisplatin vo doza od 2 mg/kg/t.t./nedela vo tek na 8 nedeli, kaj Wistar staorci. Dobienite rezultati od ovaa studija pokazuvaat deka epoetin alfa signifikantno gi ublazuva funkcionalnite bubrezni poremetuvawa inducirani so dolgotrajna administracija na cisplatin, ja podobruva opstata sostojba i go namaluva mortalitetot kaj ispituvanite zivotni.

  12. Cisplatin-induced cardiotoxicity: Mechanisms and cardioprotective strategies.

    Science.gov (United States)

    El-Awady, El-Sayed E; Moustafa, Yasser M; Abo-Elmatty, Dina M; Radwan, Asmaa

    2011-01-10

    Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of cisplatin as an anti-tumoral drug. Our study was conducted to evaluate the protective potential of acetyl-l-carnitine, DL-α-lipoic acid and silymarin against cisplatin-induced myocardial injury. Eighty male albino rats were divided into eight groups. The first four groups were treated with normal saline, acetyl-l-carnitine (500mg/kg, i.p.), DL-α-lipoic acid (100mg/kg, p.o.) and silymarin (100mg/kg, p.o.) respectively, for 10 successive days. The remaining groups were treated with the same doses of normal saline, acetyl-l-carnitine, DL-α-lipoic acid and silymarin, respectively, for 5 successive days before and after a single dose of cisplatin (10mg/kg, i.p.). Serum activities of lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB) and plasma cardiac troponin I (cTnI) concentration were estimated. Malondialdehyde (MDA), reduced glutathione (GSH) contents, superoxide dismutase activity (SOD) and protein content in cardiac tissues were measured. Moreover, integrity of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) was also examined. Cisplatin-treated rats experienced a significant elevation of serum activities of LDH, CK, CK-MB and cTnI plasma concentration. These effects were accompanied by a significant increase in MDA level. On the other hand, a significant decrease in GSH content, SOD activity and total protein content was observed. In addition, both mtDNA and nDNA were heavily damaged. However, acetyl-l-carnitine, DL-α-lipoic acid and silymarin significantly attenuated the cisplatin-evoked disturbances in the above-mentioned parameters. In conclusion, the former drugs were proven to be potential candidates to ameliorate cisplatin-induced cardiotoxicity.

  13. 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...

  14. Presumed Isotretinoin-Induced, Concomitant Autoimmune Thyroid Disease and Ocular Myasthenia Gravis: A Case Report

    Directory of Open Access Journals (Sweden)

    Huseyin Gursoy

    2012-11-01

    Full Text Available Introduction: There are many adverse effects that have been described for isotretinoin. To the best of our knowledge, this is the first report of a possible association of oral isotretinoin intake with autoimmune thyroiditis and ocular myasthenia gravis (OMG. Case Presentation: A 19-year-old Caucasian male, who had used oral isotretinoin for severe acne disease for the previous six months, was referred to our clinic. He had a three-week history of diplopia and variable bilateral ptosis. Physical examination showed moderate periorbital edema and limitations of up- and down-gaze in the left eye. Laboratory findings and thyroid ultrasound were consistent with autoimmune thyroiditis. Antithyroid therapy did not relieve the clinical symptoms. Concomitant OMG was suspected. Variable ptosis and a positive response to oral prednisolone of 40 mg/day and pyridostigmine of 360 mg/day supported the diagnosis of concomitant autoimmune thyroiditis and OMG. Conclusion: Autoimmune disorders may be triggered by oral isotretinoin treatment. Clinicians prescribing isotretinoin should be aware of the possible association between isotretinoin intake and concomitant autoimmune thyroiditis and OMG.

  15. 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...... significant amount within 24 h incubation. The accumulation and cytotoxicity of HSA-Pt was compared to 10 µmol L¿¹ cisplatin for which a larger accumulation and cytotoxicity were observed in EATC compared to Lettré. The experiment was performed with cell medium exchange every fourth hour as HSA...

  16. Preclinical antitumor activity of ethyldeshydroxysparsomycin in combination with cisplatin.

    Science.gov (United States)

    Hofs, H P; Wagener, D J; De Valk-Bakker, V; Van Rennes, H; De Vos, D; Doesburg, W H; Ottenheijm, H C; De Grip, W J

    1995-01-01

    The efficacy of cisplatin (CDDP) in combination with the protein synthesis inhibitor ethyldeshydroxysparsomycin (EDSM) has been tested in two tumor models at various schedules. Mice with L1210 leukemia or B16 melanoma were treated with CDDP alone or in combination with EDSM. Against L1210 leukemia, which is sensitive to CDDP, combinations elicited increases in life-span for all treatment schedules compared to those achieved with the corresponding dose of CDDP. Moreover, the combination of EDSM with this platinum compound yielded a cure rate > 80%, compared to cisplatin efficacy is only seen when the tumor is sensitive to CDDP.

  17. Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3.

    Science.gov (United States)

    St Germain, Carly; Niknejad, Nima; Ma, Laurie; Garbuio, Kyla; Hai, Tsonwin; Dimitroulakos, Jim

    2010-07-01

    The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.

  18. Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy.

    Science.gov (United States)

    Bobylev, Ilja; Joshi, Abhijeet R; Barham, Mohammed; Neiss, Wolfram F; Lehmann, Helmar C

    2017-01-21

    Sensory neuropathy is a relevant side effect of the antineoplastic agent cisplatin. Mitochondrial damage is assumed to play a critical role in cisplatin-induced peripheral neuropathy, but the pathomechanisms underlying cisplatin-induced mitotoxicity and neurodegeneration are incompletely understood. In an animal model of cisplatin-induced neuropathy, we determined in detail the extent and spatial distribution of mitochondrial damage during cisplatin treatment. Changes in the total number of axonal mitochondria during cisplatin treatment were assessed in intercostal nerves from transgenic mice that express cyan fluorescent protein. Further, we explored the impact of cisplatin on the expression of nuclear encoded molecules of mitochondrial fusion and fission, including mitofusin-2 (MFN2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (DRP1). Cisplatin treatment resulted in a loss of total mitochondrial mass in axons and in an abnormal mitochondrial morphology including atypical enlargement, increased vacuolization, and loss of cristae. These changes were observed in distal and proximal nerve segments and were more prominent in axons than in Schwann cells. Transcripts of fusion and fission proteins were reduced in distal nerve segments. Significant reduced expression levels of the fusion protein MFN2 was detected in nerves of cisplatin-exposed animals. In summary, we provide for the first time an evidence that cisplatin alters mitochondrial dynamics in peripheral nerves. Loss of MFN2, previously implicated in the pathogenesis of other neurodegenerative diseases, also contributes to the pathogenesis in cisplatin-induced neuropathy.

  19. Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia.

    Science.gov (United States)

    Yakabi, Koji; Sadakane, Chiharu; Noguchi, Masamichi; Ohno, Shino; Ro, Shoki; Chinen, Katsuya; Aoyama, Toru; Sakurada, Tomoya; Takabayashi, Hideaki; Hattori, Tomohisa

    2010-08-01

    Although chemotherapy with cisplatin is a widely used and effective cancer treatment, the undesirable gastrointestinal side effects associated with it, such as nausea, vomiting, and anorexia, markedly decrease patients' quality of life. To elucidate the mechanism underlying chemotherapy-induced anorexia, focusing on the hypothalamic ghrelin secretion-anorexia association, we measured hypothalamic ghrelin secretion in fasted and cisplatin-treated rats. Hypothalamic ghrelin secretion changes after vagotomy or administration of cisplatin. Cisplatin + rikkunshito, a serotonin 2C receptor antagonist or serotonin 3 receptor antagonist, was investigated. The effects of intracerebroventricular (icv) administration of ghrelin or the serotonin 2C receptor antagonist SB242084 on food intake were also evaluated in cisplatin-treated rats. Hypothalamic ghrelin secretion significantly increased in 24-h-fasted rats compared to freely fed rats and was markedly reduced 24 and 48 h after cisplatin treatment in cisplatin-treated rats compared to saline-treated rats, although their plasma ghrelin levels were comparable. In cisplatin-treated rats, icv ghrelin administration reversed the decrease in food intake, vagotomy partially restored hypothalamic ghrelin secretion, and hypothalamic serotonin 2C receptor mRNA expression increased significantly. Administration of rikkunshito (an endogenous ghrelin enhancer) or a serotonin 2C receptor antagonist reversed the decrease in hypothalamic ghrelin secretion and food intake 24 h after cisplatin treatment. Cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. Cerebral serotonin 2C receptor activation partially induces decrease in hypothalamic ghrelin secretion, and rikkunshito suppresses cisplatin-induced anorexia by enhancing this secretion.

  20. Baicalein and its underlying mechanism as a protector against liver injury induced by cisplatin in mice

    Directory of Open Access Journals (Sweden)

    Chengwei Niu

    2017-01-01

    Full Text Available Cisplatin is widely used for the treatment of a variety of cancers but with a high incidence of hepatotoxicity. Baicalein is originally isolated from the root of Scutellaria baicalensis Georgi with broad bioactivities. The present study aims to investigate the protective effect of baicalein against cisplatin-induced acute liver injury and the underlying mechanism of this protective effect. Administration of cisplatin (40 mg/kg for 24 h increased the serum alanine and aspartate aminotransferases and alkaline phosphatase levels, while baicalein could reverse all those changes induced by cisplatin. Liver histological analysis further evidenced the protection of baicalein against cisplatin-induced liver injury. Baicalein counteracted the increased liver malondialdehyde (amount induced by cisplatin, while baicalein could further increase the cisplatin-induced elevation of the amount of reduced glutathione in the liver. Further results showed that baicalein reversed the cisplatin-induced decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S transferase and glutathione reductase. On the other hand, baicalein alleviated the increase in the serum levels of tumour necrosis factor alpha and interleukin 6 induced by cisplatin. Taken together, our results demonstrate that baicalein can inhibit cisplatin-induced hepatic oxidative stress and inflammation, which contributes greatly to the amelioration of cisplatin-induced liver injury.

  1. Protective agent, erdosteine, against cisplatin-induced hepatic oxidant injury in rats.

    Science.gov (United States)

    Koc, Ahmet; Duru, Mehmet; Ciralik, Harun; Akcan, Ramazan; Sogut, Sadik

    2005-10-01

    Cisplatin, one of the most active cytotoxic agents against cancer, has several toxicities. Hepatotoxicity is one of them occurred during high doses treatment. The aim of this study was to determine the effects of erdosteine against cisplatin-induced liver injury through tissue oxidant/antioxidant parameters and light microscopic evaluation. The rats were randomly divided into three groups: control (n=5), cisplatin (10 mg/kg, n=6) and cisplatin+erdosteine (50 mg/kg/day oral erdosteine, n=8) groups. The rats were sacrificed at the 5th day of cisplatin treatment. The liver tissues were examined with light microscopy and oxidant/antioxidant biochemical parameters. The malondialdehyde (MDA) and nitric oxide (NO) levels were increased in the cisplatin group in comparison with the control and cisplatin+erdosteine groups (perdosteine groups. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were higher in cisplatin+erdosteine group than cisplatin group (perdosteine group, a decrease in cytoplasmic changes with the hepatocytes and sinusoidal dilatations around cells of central vein were noticed in as compared to cisplatin group. In the light of microscopic and biochemical results, it was concluded that cisplatin-induced liver damage in high dose and erdosteine prevented this toxic side effect by the way of its antioxidant and radical scavenging effects.

  2. Inhibition of cisplatin-resistance by RNA interference targeting metallothionein using reducible oligo-peptoplex.

    Science.gov (United States)

    Lee, Jong-Hwan; Chae, Ji-Won; Kim, Jang Kyoung; Kim, Hyung Jin; Chung, Jee Young; Kim, Yong-Hee

    2015-10-10

    Effective intracellular level of a platinum anti-cancer drug, cisplatin, following repeated injections can be decreased either by the active efflux via ATP pump or by interactions with glutathione and metallothionein. Cisplatin in cytoplasm preferably binds to cysteine-rich proteins such as glutathione and metallothionein (MT). Detoxification of cisplatin by intracellular thiol-containing proteins has been considered to be major hurdles to overcome. The short hairpin RNA targeting MT (shMT) was tested to down-regulate MT and recover cisplatin resistance. A reducible polymer, poly(oligo-d-arginine) (rPOA), formed stable complex with shMT and demonstrated superior transfection efficiency. Efficient transfection of shMT/rPOA oligo-peptoplexes was found to significantly inhibit MT over-expression, resulting in 45% decrease of cell viability compared to the cisplatin alone group. This decrease was mediated by the synergistic effect of shMT/rPOA oligo-peptoplex and cisplatin. Co-administration of shMT/rPOA oligo-peptoplex and cisplatin in in vivo tumor model showed noticeable tumor-suppressing effect by inducing reversal of cisplatin resistance following effective intracellular delivery of shMT by rPOA. Combination therapy through co-administration of shMT/rPOA oligo-peptoplex and cisplatin was found to effectively reverse cisplatin resistance by RNA interference and consequently improve anti-cancer activity of cisplatin.

  3. A memorable week

    CERN Document Server

    2012-01-01

    This has been a memorable week for CERN, starting with the award of a Special Fundamental Physics Prize and ending with the handover of the CERN Council Presidency from Michel Spiro to Agnieszka Zalewska. In between, the LHC team demonstrated its expertise with a successful pilot run with 25 nanosecond bunch spacing, a new application for Associate Membership was received, and we had good news on the budget.   The award of the Fundamental Physics Prize, and the manner in which it was divided between ATLAS, CMS and the LHC, is fitting recognition of the efforts of the thousands of people who have contributed over many years to the success of our flagship scientific endeavour. In making the award, the Milner Foundation aims to raise the profile of fundamental physics and its value to society. The Fundamental Physics Prize comes hot on the heels of the European Physical Society’s first Edison Volta Prize, which Sergio Bertolucci, Steve Myers and I were honoured to accept on behalf of t...

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

    DEFF Research Database (Denmark)

    Kutwin, Marta; Sawosz, Ewa; Jaworski, Sławomir;

    2014-01-01

    of 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......Side effects and resistance of cancer cells to cisplatin are major drawbacks to its application, and recently, the possibility of replacing cisplatin with nanocompounds has been considered. Most chemotherapeutic agents are administered intravenously, and comparisons between the interactions......,6 μg/ml), when incubated with chicken embryo RBC, were detrimental to cell structure and induced haemolysis. The level of haemolytic injury was increased after cisplatin and NP-Pt treatments compared to the control group. Treatment with cisplatin caused structural damage to cell membranes...

  5. 紫杉醇联合顺铂治疗复发性宫颈癌的临床观察%Clinical study of paclitaxel plus cisplatin in the treatment of recurrent cervical cancer

    Institute of Scientific and Technical Information of China (English)

    Yingqiu Song; Guiling Li; Fang Zhu; Fangzheng Zhou; Sheng Zhang; Jing Wang; Zhongyuan Ying

    2007-01-01

    Objective:To observe the efficacy and toxicities of paclitaxel plus cisplatin in the treatment of recurrent cervical cancer.Methods:Twenty-three patients with a diagnosis of recurrent cervical cancer were eligible.Three-weekly chemotherapy reqimen consisted of paclitaxel 135-150 mg/m2 infusion for 3 h on day 1.cisplatin 25 mg/m2 infusion on day 1 to 3.All patients received at least two cycles treatment.Results:The response rates was 47.8%,including CR 2 cases(8.7%),PR9 cases(39.1%).The major toxicity included neutropenia,nausea vomiting,arthralgia,myalgia and alopecia.Conclusion:Paclitaxel combined with cisplatin is an effective therapy with acceptable adverse reactions for recurrent cervical cancer.

  6. Effects of ozone (O3) therapy on cisplatin-induced ototoxicity in rats.

    Science.gov (United States)

    Koçak, Hasan Emre; Taşkın, Ümit; Aydın, Salih; Oktay, Mehmet Faruk; Altınay, Serdar; Çelik, Duygu Sultan; Yücebaş, Kadir; Altaş, Bengül

    2016-12-01

    The aim of this study is to investigate the effect of rectal ozone and intratympanic ozone therapy on cisplatin-induced ototoxicity in rats. Eighteen female Wistar albino rats were included in our study. External auditory canal and tympanic membrane examinations were normal in all rats. The rats were randomly divided into three groups. Initially, all the rats were tested with distortion product otoacoustic emissions (DPOAE), and emissions were measured normally. All rats were injected with 5-mg/kg/day cisplatin for 3 days intraperitoneally. Ototoxicy had developed in all rats, as confirmed with DPOAE after 1 week. Rectal and intratympanic ozone therapy group was Group 1. No treatment was administered for the rats in Group 2 as the control group. The rats in Group 3 were treated with rectal ozone. All the rats were tested with DPOAE under general anesthesia, and all were sacrificed for pathological examination 1 week after ozone administration. Their cochleas were removed. The outer hair cell damage and stria vascularis damage were examined. In the statistical analysis conducted, a statistically significant difference between Group 1 and Group 2 was observed in all frequencies according to the DPOAE test. In addition, between Group 2 and Group 3, a statistically significant difference was observed in the DPOAE test. However, a statistically significant difference was not observed between Group 1 and Group 3 according to the DPOAE test. According to histopathological scoring, the outer hair cell damage score was statistically significantly high in Group 2 compared with Group 1. In addition, the outer hair cell damage score was also statistically significantly high in Group 2 compared with Group 3. Outer hair cell damage scores were low in Group 1 and Group 3, but there was no statistically significant difference between these groups. There was no statistically significant difference between the groups in terms of stria vascularis damage score examinations

  7. 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

  8. 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.

  9. Synergistic Inhibition of Lactobacillus Rhamnosus and Cisplatin on the Multiplication of Tumoral Cells in BALB/c Mice with Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ghaderi Pakdel

    2011-12-01

    Full Text Available Introduction: The probiotic strains of Lactic Acid Bacillus (LAB not only affect gastrointestinal tract microflora and stimulate local immune system of this tract but also modify and stimulate systemic immunity by influence on lymph nodes and spleen. Several studies have shown the anti-tumor effect of these kinds of bacteria. This study was designed to assess the probiotic effects of lactobacillus rhamnosus on cisplatin efficacy among Balb/c mice with breast cancer. Methods: L. rhamnosus strain was inoculated in MRS agar and cultivated for 24 h at 37 °C. Female BalbC mice (n=20 with invasive ductal carcinoma transplantation were divided into four groups: Control, L. rhamnosus, cisplatin and cisplatin plus L. rhamnosus. Cisplatin (5 mg/kg, i.p. was injected twice a week. Lr was administered daily by gastric intubation (3×10 8 CFU/day. The tumor size was measured every 3 days and mice were sacrificed 24 h after the last injection and tumor tissue was removed for more tests. Results: The results showed that oral administration of L. rhamnosus decreased the growth rate of tumor (p<0.05. One reason for antineoplastic effect of lactobacilli is immune system enhancement. The results of delayed-type hypersensitivity show the stimulation of immune system and inhibition of tumor growth by this mechanism. In pathologic assessments probiotic administration increased the antineoplastic effect of cisplatin. Conclusion: According to the findings of this study it can be expected that human studies also show the satisfactory effect of lactobacillus administration besides common therapeutic methods for cancer treatment.

  10. First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia.

    Science.gov (United States)

    Brandes, Alba A; Basso, Umberto; Reni, Michele; Vastola, Francesca; Tosoni, Alicia; Cavallo, Giovanna; Scopece, Luciano; Ferreri, Andres J; Panucci, Maria G; Monfardini, Silvio; Ermani, Mario

    2004-05-01

    Cisplatin and temozolomide (TMZ) are active in glioblastoma multiforme (GBM), with different profiles of toxicity. A bid regimen of TMZ achieves a strong inhibition of O(6)-alkylguanine DNA-alkyl transferase (AGAT), and cisplatin reduces AGAT activity in vitro, suggesting a possible synergic interaction. The primary end point of the present multicenter phase II study was progression-free survival (PFS) at 6 months (PFS-6); secondary end points included response, toxicity, and overall survival. Chemotherapy-naive patients with GBM who experienced disease recurrence or progression after surgery and standard radiotherapy were eligible. Chemotherapy cycles consisted of cisplatin 75 mg/m(2) on day 1, TMZ 130 mg/m(2) bolus followed by nine doses of 70 mg/m(2) every 12 hours (total of 5 days) from day 2 every 4 weeks. In the absence of hematologic toxicity, TMZ was escalated to 1,000 mg/m(2) in 5 days. A total of 50 patients (median age, 53.4 years; range, 27 to 70 years; median Karnofsky performance status, 80; range, 60 to 100) were accrued in the study. PFS-6 was 34% (95% CI, 23% to 50%), and PFS-12 was 4% (95% CI, 0.3% to 16%). Median PFS was 18.4 weeks (95% CI, 13 to 25.9 weeks). Among 49 assessable patients, one complete response and nine partial responses were obtained, with an overall response rate of 20.4% (95% CI, 7.7% to 33%). Among 203 treatment cycles delivered, the most common grade 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (6%). The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.

  11. A 12-Week Cycling Training Regimen Improves Gait and Executive Functions Concomitantly in People with Parkinson’s Disease

    Science.gov (United States)

    Nadeau, Alexandra; Lungu, Ovidiu; Duchesne, Catherine; Robillard, Marie-Ève; Bore, Arnaud; Bobeuf, Florian; Plamondon, Réjean; Lafontaine, Anne-Louise; Gheysen, Freja; Bherer, Louis; Doyon, Julien

    2017-01-01

    Background: There is increasing evidence that executive functions and attention are associated with gait and balance, and that this link is especially prominent in older individuals or those who are afflicted by neurodegenerative diseases that affect cognition and/or motor functions. People with Parkinson’s disease (PD) often present gait disturbances, which can be reduced when PD patients engage in different types of physical exercise (PE), such as walking on a treadmill. Similarly, PE has also been found to improve executive functions in this population. Yet, no exercise intervention investigated simultaneously gait and non-motor symptoms (executive functions, motor learning) in PD patients. Objective: To assess the impact of aerobic exercise training (AET) using a stationary bicycle on a set of gait parameters (walking speed, cadence, step length, step width, single and double support time, as well as variability of step length, step width and double support time) and executive functions (cognitive inhibition and flexibility) in sedentary PD patients and healthy controls. Methods: Two groups, 19 PD patients (Hoehn and Yahr ≤2) and 20 healthy adults, matched on age and sedentary level, followed a 3-month stationary bicycle AET regimen. Results: Aerobic capacity, as well as performance of motor learning and on cognitive inhibition, increased significantly in both groups after the training regimen, but only PD patients improved their walking speed and cadence (all p training-related improvements in aerobic capacity correlated positively with improvements in walking speed (r = 0.461, p training and they could be due to indirect action mechanisms (i.e., improvement of cardiovascular capacity). These results are also relevant for the development of targeted AET interventions to improve functional autonomy in PD patients. PMID:28127282

  12. Efficacy and Toxicity of Pemetrexed or Gemcitabine Combined with Cisplatin in the Treatment of Patients with Advanced Non-small Cell Lung Cancer

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    Xingsheng HU

    2012-10-01

    Full Text Available Background and objective Due to the various inter-individual differences in the biological characteristics of tumor cells, as well as issues on the efficacy, adverse reactions, and defects of existing drugs, we compared the clinical efficacy and toxicity of pemetrexed and gemcitabine combined with cisplatin for the treatment of previously untreated advanced non-small cell lung cancer (NSCLC. Methods 251 patients were randomly divided into pemetrexed combined with cisplatin group (PP group with 127 cases and gemcitabine combined with cisplatin group (GP group with 124 cases. PP group received pemetrexed 500 mg/m2 iv infusion d1 and cisplatin 75 mg/m2 iv infusion d1, whereas GP group received gemcitabine 1,000 mg/m2 iv infusion d1,8 and cisplatin 75 mg/m2 iv infusion d1. The treatment cycle was once every three weeks. In addition, folic acid, vitamin B12, and dexamethasone were administered in both groups. Results The total clinical effective rates in PP group and GP group were 25.20% and 17.74%, respectively. The total efficiencies of non-squamous cell carcinoma were 27.62% and 16.00%. The tumor progression duration in these two groups was 6.5 and 5.6 months, respectively. The median survival time in the two groups was 16.9 and 17.0 months, respectively, with 59.62% and 65.87% survival rates of 1 year and 27.28% and 27.93% survival rates of 2 years, respectively. The total efficacy of non-squamous cell carcinoma in the PP group was significantly higher than that in GP group. The results were statistically significant. However, there were no significant differences in total response rates, tumor progression duration, and median survival rates of 1 and 2 years. The rate of adverse reactions, including white blood cell reduction, lower platelet count, lower hemoglobin, and hair loss in the PP group was significantly lower than that in the GP group. The results were statistically significant. Conclusion The clinical efficacy of pemetrexed and

  13. Development and characterization of magnetic iron oxide nanoparticles with a cisplatin-bearing polymer coating for targeted drug delivery.

    Science.gov (United States)

    Unterweger, Harald; Tietze, Rainer; Janko, Christina; Zaloga, Jan; Lyer, Stefan; Dürr, Stephan; Taccardi, Nicola; Goudouri, Ourania-Menti; Hoppe, Alexander; Eberbeck, Dietmar; Schubert, Dirk W; Boccaccini, Aldo R; Alexiou, Christoph

    2014-01-01

    A highly selective and efficient cancer therapy can be achieved using magnetically directed superparamagnetic iron oxide nanoparticles (SPIONs) bearing a sufficient amount of the therapeutic agent. In this project, SPIONs with a dextran and cisplatin-bearing hyaluronic acid coating were successfully synthesized as a novel cisplatin drug delivery system. Transmission electron microscopy images as well as X-ray diffraction analysis showed that the individual magnetite particles were around 4.5 nm in size and monocrystalline. The small crystallite sizes led to the superparamagnetic behavior of the particles, which was exemplified in their magnetization curves, acquired using superconducting quantum interference device measurements. Hyaluronic acid was bound to the initially dextran-coated SPIONs by esterification. The resulting amide bond linkage was verified using Fourier transform infrared spectroscopy. The additional polymer layer increased the vehicle size from 22 nm to 56 nm, with a hyaluronic acid to dextran to magnetite weight ratio of 51:29:20. A maximum payload of 330 μg cisplatin/mL nanoparticle suspension was achieved, thus the particle size was further increased to around 77 nm with a zeta potential of -45 mV. No signs of particle precipitation were observed over a period of at least 8 weeks. Analysis of drug-release kinetics using the dialysis tube method revealed that these were driven by inverse ligand substitution and diffusion through the polymer shell as well as enzymatic degradation of hyaluronic acid. The biological activity of the particles was investigated in a nonadherent Jurkat cell line using flow cytometry. Further, cell viability and proliferation was examined in an adherent PC-3 cell line using xCELLigence analysis. Both tests demonstrated that particles without cisplatin were biocompatible with these cells, whereas particles with the drug induced apoptosis in a dose-dependent manner, with secondary necrosis after prolonged incubation. In

  14. Membrane Transporters as Mediators of Cisplatin Effects and Side Effects

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    Giuliano Ciarimboli

    2012-01-01

    Full Text Available Transporters are important mediators of specific cellular uptake and thus, not only for effects, but also for side effects, metabolism, and excretion of many drugs such as cisplatin. Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, oto-, and peripheral neurotoxicity. For this reason, other platinum derivatives, such as carboplatin and oxaliplatin, with less toxicity but still with antitumoral action have been developed. Several transporters, which are expressed on the cell membranes, have been associated with cisplatin transport across the plasma membrane and across the cell: the copper transporter 1 (Ctr1, the copper transporter 2 (Ctr2, the P-type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter 2 (OCT2, and the multidrug extrusion transporter 1 (MATE1. Some of these transporters are also able to accept other platinum derivatives as substrate. Since membrane transporters display a specific tissue distribution, they can be important molecules that mediate the entry of platinum derivatives in target and also nontarget cells possibly mediating specific effects and side effects of the chemotherapeutic drug. This paper summarizes the literature on toxicities of cisplatin compared to that of carboplatin and oxaliplatin and the interaction of these platinum derivatives with membrane transporters.

  15. Auditory Brainstem Responses in Children Treated with Cisplatin

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    Mohammad Kamali

    2012-03-01

    Full Text Available Background and Aim: In view of improvement in therapeutic outcome of cancer treatment in children resulting in increased survival rates and the importance of hearing in speech and language development, this research project was intended to assess the effects of cisplatin group on hearing ability in children aged 6 months to 12 years.Methods: In this cross-sectional study, hearing of 10 children on cisplatin group medication for cancer who met the inclusion criteria was examined by recording auditory brainstem responses (ABR using the three stimulants of click and 4 and 8 kHz tone bursts. All children were examined twice: before drug administration and within 72 hours after receiving the last dose. Then the results were compared with each other.Results: There was a significant difference between hearing thresholds before and after drug administration (p<0.05. Right and left ear threshold comparison revealed no significant difference.Conclusion: Ototoxic effects of cisplatin group were confirmed in this study. Insignificant difference observed in comparing right and left ear hearing thresholds could be due to small sample size. auditory brainstem responses test especially with frequency specificity proved to be a useful method in assessing cisplatin ototoxicity.

  16. 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.

  17. Cisplatin-Associated Ototoxicity: A Review for the Health Professional

    Science.gov (United States)

    Paken, Jessica; Govender, Cyril D.; Pillay, Mershen

    2016-01-01

    Cisplatin is an effective drug used in the treatment of many cancers, yet its ototoxic potential places cancer patients, exposed to this drug, at risk of hearing loss, thus negatively impacting further on a patient's quality of life. It is paramount for health care practitioners managing such patients to be aware of cisplatin's ototoxic properties and the clinical signs to identify patients at risk of developing hearing loss. English peer-reviewed articles from January 1975 to July 2015 were assessed from PubMed, Science Direct, and Ebscohost. Seventy-nine articles and two books were identified for this review, using MeSH terms and keywords such as “ototoxicity”, “cisplatin”, “hearing loss”, and “ototoxicity monitoring”. This review provides an up-to-date overview of cisplatin-associated ototoxicity, namely, its clinical features, incidence rates, and molecular and cellular mechanisms and risk factors, to health care practitioners managing the patient with cancer, and highlights the need for a team-based approach to complement an audiological monitoring programme to mitigate any further loss in the quality of life of affected patients, as there is currently no otoprotective agent recommended routinely for the prevention of cisplatin-associated ototoxicity. It also sets the platform for effective dialogue towards policy formulation and strengthening of health systems in developing countries. PMID:28115933

  18. A Unique Cause of Proteinuria in Pregnancy: Class II Lupus Nephritis with Concomitant Minimal Change Disease

    Science.gov (United States)

    Kunjal, Ryan; Adam-Eldien, Rabie; Makary, Raafat; Jo-Hoy, Francois; Heilig, Charles W.

    2016-01-01

    We report the case of a 22-year-old African American female who presented to another facility for routine follow-up in the 34th week of pregnancy with lower extremity swelling and nephrotic-range proteinuria. Although she was normotensive, it was initially thought that she had preeclampsia. She was monitored carefully and delivery was induced at 37 weeks of gestation. She was transferred to our hospital, where she was diagnosed with systemic lupus erythematosus (SLE) based on clinical and laboratory criteria. Renal biopsy revealed a surprising finding of minimal change disease (MCD) concomitant with class II lupus nephritis (LN). She was managed with pulses and then tapering doses of steroid therapy with dramatic resolution of the nephrotic syndrome. This case demonstrates not only the rare de novo occurrence of SLE in pregnancy, but the unique finding of MCD coexisting with class II LN. We propose that altered T cell activity may be the link between these seemingly distinct entities.

  19. Comparative Study of Gemcitabine Plus Cisplatin and Gemcitabine Plus Fluorouracil in the Treatment of Advanced Pancreatic Cancer

    Institute of Scientific and Technical Information of China (English)

    YongqionShu; LiankeLiu; LinxiangLiu; PuwenHuang; KoihuoLu; YongmeiYin

    2004-01-01

    OBJECTIVE To compare the efficacy and toxicity of gemcitabine plus cisplatin and gemcitabine plus fluorouracil in the treatment of advanced pancreatic cancer. METHODS Sixty patients with advanced pancreatic cancer were randomly divided into a GP group (gemcitabine + cisplatin, 30 cases) and a GF group (gemcitabine + fluorouracil, 30 cases). All patients were treated with gemcitabine at a dose of 1,000mg/m2 (diluted in 100ml saline solution over 30 min) once a week for 3 consecutive weeks. The GP Group was followed by 40mg cisplatin via intravenous drip on days 15,16,17. Group GF was followed by 500mg/m2 5-Fu (diluted in 5% glucose-saline (GS) 500ml, intravenously, over 6 hr) every day for five subsequent days.RESULTS In the GP group, eight cases (32.0%) were PR and MR, the median survival time was 8.7 months, the Clinical Beneficial Rate (CBR) was 57.7%, and the CA19-9 decreased by over 50% in 13 vases (48.1%). In the GF group, 11 cases (45.8%) were PR and MR, the survival time was 10.1 months, the CBR was 82.1%, and CA19-9 decreased by over 50% in 15 cases(53.6%). There was a significant difference in the CBR between the two groups (P<0.05). The main toxicities in both groups were leucopenia and thrombocytopenia with no significant difference. CONCLUSIONS The treatment given to either the GP or GF group is a feasible and well-tolerated chemotherapy regimen for treating advanced pancreatic cancer with improved therapeutic efficacy and few side effects. The median survival period is long and the CBR is high, especially with the GF regimen.

  20. Adjuvant treatment with concomitant radiotherapy and chemotherapy in high-risk endometrial cancer: a clinical experience.

    Science.gov (United States)

    De Marzi, Patrizia; Frigerio, Luigi; Cipriani, Sonia; Parazzini, Fabio; Busci, Luisa; Carlini, Laura; Viganò, Riccardo; Mangili, Giorgia

    2010-03-01

    The concurrent use of radiotherapy (RT) and chemotherapy (CT) as adjuvant treatment after surgery in high-risk endometrial cancer has been generally considered cautiously. Recently some of us have reported preliminary data on the efficacy and tolerability of concomitant CT and RT. In this paper, we update our experience. A total of 47 patients aged >18 years and endometrial endometrioid carcinomas entered the study. Inclusion criteria were stages IC G3, IIB, IIIA (patients with positive washing without other unfavourable prognostic factors were omitted), IIIB and IIIC. The radiation plan consisted of a total dose of 50.4 Gy, given in five fractions per week (1.8 Gy: daily dose) for 6 weeks. Paclitaxel (P) at a dose of 60 mg/m(2) was infused intravenously in 250 mL of normal saline for 1 h once weekly during RT for 5 weeks. Three further cycles of Paclitaxel, at a dose of 80 mg/m(2), have been given weekly at the end of RT. There was no life-threatening toxicity. The overall 5-year relapse-free survival was 81.8% (95% CI, 65.2-90.9). The 5-year percent overall disease-specific survival was 88.4% (95% CI, 71.1-95.6). These results, based on a larger series, support our previous data: Paclitaxel plus RT may represent an effective and well-tolerated treatment in high-risk endometrial cancer patients.

  1. Pt(IV) complexes as prodrugs for cisplatin.

    Science.gov (United States)

    Shi, Yi; Liu, Shu-An; Kerwood, Deborah J; Goodisman, Jerry; Dabrowiak, James C

    2012-02-01

    The antitumor effects of platinum(IV) complexes, considered prodrugs for cisplatin, are believed to be due to biological reduction of Pt(IV) to Pt(II), with the reduction products binding to DNA and other cellular targets. In this work we used pBR322 DNA to capture the products of reduction of oxoplatin, c,t,c-[PtCl(2)(OH)(2)(NH(3))(2)], 3, and a carboxylate-modified analog, c,t,c-[PtCl(2)(OH)(O(2)CCH(2)CH(2)CO(2)H)(NH(3))(2)], 4, by ascorbic acid (AsA) or glutathione (GSH). Since carbonate plays a significant role in the speciation of platinum complexes in solution, we also investigated the effects of carbonate on the reduction/DNA-binding process. In pH 7.4 buffer in the absence of carbonate, both 3 and 4 are reduced by AsA to cisplatin (confirmed using ((195))Pt NMR), which binds to and unwinds closed circular DNA in a manner consistent with the formation of the well-known 1, 2 intrastrand DNA crosslink. However, when GSH is used as the reducing agent for 3 and 4, ((195))Pt NMR shows that cisplatin is not produced in the reaction medium. Although the Pt(II) products bind to closed circular DNA, their effect on the mobility of Form I DNA is different from that produced by cisplatin. When physiological carbonate is present in the reduction medium, ((13))C NMR shows that Pt(II) carbonato complexes form which block or impede platinum binding to DNA. The results of the study vis-à-vis the ability of the Pt(IV) complexes to act as prodrugs for cisplatin are discussed. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. [Combined physiotherapy of patients with dorsopathies and concomitant osteoarthrosis].

    Science.gov (United States)

    Miriutova, N F; Zaĭtsev, A A; Popova, A V; Mikhaĭlova, E V

    2011-01-01

    The combined treatment of patients presenting with dorsopathies and concomitant osteoarthrosis using magnetic stimulation, ultrasonic and peloidotherapy was shown to promote the recovery of the locomotor function of the vertebral column and the affected limb joints, alleviate pain sensation, and exert anti-inflammatory effect. Moreover, it contributed to the improvement of the overall orthopedic situation in the region. The inclusion of vibrotraction in the combined treatment of patients presenting with dorsopathies and concomitant osteoarthrosis resulted in a marked decrease of the severity of static and dynamic disturbances of the spine, increase in the activity of spinal muscles, extension of the range of locomotor movements, and improvement of working ability of the patients.

  3. Concomitant Rotavirus and Salmonella Infections in Children with Acute Diarrhea

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    Wen-Tzong Lan

    2009-02-01

    Conclusion: Concomitant rotavirus and Salmonella infections accounted for 3.7% of cases in this study. Patients in group C (30.0% had a significantly higher incidence of hypokalemia than group R (7.3% or S (8.8%. Group C consisted of 33 cases of the 895 reviewed cases (3.7%. In a child with rotavirus gastroenteritis, concomitant infection with Salmonella should be considered if the child has sustained a high fever (≥ 39°C for over 4 days and a green stool with mucus and blood.

  4. Is glutathione the major cellular target of cisplatin? A study of the interactions of cisplatin with cancer cell extracts.

    Science.gov (United States)

    Kasherman, Yonit; Sturup, Stefan; Gibson, Dan

    2009-07-23

    Cisplatin is an anticancer drug whose efficacy is limited because tumors develop resistance to the drug. Resistant cells often have elevated levels of cellular glutathione (GSH), believed to be the major cellular target of cisplatin that inactivates the drug by binding to it irreversibly, forming [Pt(SG)(2)] adducts. We show by [(1)H,(15)N] HSQC that the half-life of (15)N labeled cisplatin in whole cell extracts is approximately 75 min, but no Pt-GSH adducts were observed. When the low molecular mass fraction (cisplatin, binding to GSH was observed probably due to removal of high molecular mass platinophiles. Two-thirds of the Pt adducts formed in whole cell extracts, had a molecular mass >3 kDa. [Pt(SG)(2)] cannot account for more than 20% of the Pt adducts. The concentration of reduced thiols in the high molecular mass fraction of the extracts is six times higher than in the low molecular mass fraction.

  5. EGCG Enhances Cisplatin Sensitivity by Regulating Expression of the Copper and Cisplatin Influx Transporter CTR1 in Ovary Cancer.

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    Xuemin Wang

    Full Text Available Cisplatin is one of the first-line platinum-based chemotherapeutic agents for treatment of many types of cancer, including ovary cancer. CTR1 (copper transporter 1, a transmembrane solute carrier transporter, has previously been shown to increase the cellular uptake and sensitivity of cisplatin. It is hypothesized that increased CTR1 expression would enhance the sensitivity of cancer cells to cisplatin (cDDP. The present study demonstrates for the first time that (--epigallocatechin-3-gallate (EGCG, a major polyphenol from green tea, can enhance CTR1 mRNA and protein expression in ovarian cancer cells and xenograft mice. EGCG inhibits the rapid degradation of CTR1 induced by cDDP. The combination of EGCG and cDDP increases the accumulation of cDDP and DNA-Pt adducts, and subsequently enhances the sensitivity of ovarian cancer SKOV3 and OVCAR3 cells to the chemotherapeutic agent. In the OVCAR3 ovarian cancer xenograft nude mice model, the combination of the lower concentration of cDDP and EGCG strongly repressed the tumor growth and exhibited protective effect on the nephrotoxicity induced by cisplatin. Overall, these findings uncover a novel chemotherapy mechanism of EGCG as an adjuvant for the treatment of ovarian cancer.

  6. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance.

    Science.gov (United States)

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia

    2017-03-06

    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance.

  7. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance

    Science.gov (United States)

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia

    2017-01-01

    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance. PMID:28262781

  8. Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS

    Science.gov (United States)

    Crone, Barbara; Aschner, Michael; Schwerdtle, Tanja; Karst, Uwe; Bornhorst, Julia

    2015-01-01

    Cis-diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 µm. In addition, a dose- and time-dependent Cisplatin uptake was corroborated quantitatively by a total reflection X-ray fluorescence spectroscopy (TXRF) method, and the elemental mapping indicated that Cisplatin is located in the intestine and in the head of the worms. Better understanding of the distribution of Cisplatin in this well-established model organism will be instrumental in deciphering Cisplatin toxicity and pharmacokinetics. Since the cytostatic effect of Cisplatin is based on binding the DNA by forming intra- and interstrand crosslinks, the response of poly(ADP-ribose)metabolism enzyme 1 (pme-1) deletion mutants to Cisplatin was also examined. Loss of pme-1, which is the C. elegans ortholog of human poly(ADP-ribose) polymerase 1 (PARP-1) led to disturbed DNA damage response. With respect to survival and brood size, pme-1 deletion mutants were more sensitive to Cisplatin as compared to wildtype worms, while Cisplatin uptake was indistinguishable. PMID:25996669

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

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    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.

  10. Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells.

    Science.gov (United States)

    Sun, Xilong; Wei, Qiang; Cheng, Jie; Bian, Yanzhu; Tian, Congna; Hu, Yujing; Li, Huijie

    2017-07-01

    Osteosarcoma is the most common primary malignant bone tumor. Although cisplatin is the primary chemotherapy used in osteosarcoma treatment, the cisplatin resistance remains a big challenge for improving overall survival. The store-operated calcium (Ca(2+)) entry (SOCE) and its major mediator Stim1 have been shown to be implicated in a number of pathological processes typical for cancer. In this study, we showed that Stim1 expression was significantly increased in chemo-resistant osteosarcoma tissues compared with chemo-sensitivity tissues. Patients with Sitm1 expression exhibited poorer overall survival than Stim1-negative patients. Moreover, un-regulation of Stim1 expression and SOCE were also observed in cisplatin-resistant MG63/CDDP cells compared with their parental cells. Cisplatin treatment obviously reduced Stim1 expression and SOCE in cisplatin-sensitivity MG63 cells, but had no effects on MG63/CDDP cells. In addition, cisplatin resulted in a more pronounced increase of endoplasmic reticulum (ER) stress in MG63 cells than in their resistant variants, which was evidenced by the activation of molecular markers of ER stress, GRP78, CHOP and ATF4. Knockdown of Stim1 using siRNA remarkably enhanced cisplatin-induced apoptosis and ER stress in MG63/CDDP cells, thereby sensitizing cancer cells to cisplatin. On the other hand, overexpression of Stim1 markedly reversed apoptosis and ER stress following cisplatin treatment. Taken together, these results demonstrate that Stim1 as well as Ca(2+) entry contributes cisplatin resistance via inhibition of ER stress-mediated apoptosis, and provide important clues to the mechanisms involved in cisplatin resistance for osteosarcoma treatment. Stim1 represents as a target of cisplatin and blockade of Stim1-mediated Ca(2+) entry may be a useful strategy to improve the efficacy of cisplatin to treat osteosarcoma.

  11. 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.

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

    Science.gov (United States)

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

    2009-03-17

    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 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-gamma 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.

  13. Ursolic acid sensitizes cisplatin-resistant HepG2/DDP cells to cisplatin via inhibiting Nrf2/ARE pathway

    Directory of Open Access Journals (Sweden)

    Wu S

    2016-10-01

    Full Text Available Shouhai Wu,1,2 Tianpeng Zhang,1 Jingsheng Du3 1School of Life Sciences, Sun Yat-sen University, 2Center for Regenerative and Translational Medicine, 3Department of Pharmacy, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China Background: Combinations of adjuvant sensitizers with anticancer drugs is a promising new strategy to reverse chemoresistance. Ursolic acid (UA is one of the natural pentacyclic triterpene compounds known to have many pharmacological characteristics such as anti-inflammatory and anticancer properties. This study investigates whether UA can sensitize hepatocellular carcinoma cells to cisplatin.Materials and methods: Cells were transfected with nuclear factor erythroid-2-related factor 2 (Nrf2 small interfering RNA and Nrf2 complementary DNA by using Lipofectin 2000. The cytotoxicity of cells was investigated by Cell Counting Kit 8 assay. Cell apoptosis, cell cycle, reactive oxygen species, and mitochondrial membrane potential were detected by flow cytometry fluorescence-activated cell sorting. The protein level of Nrf2, NAD(PH quinone oxidoreductase 1 (NQO1, glutathione S-transferase (GST, and heme oxygenase-1 (HO-1 was detected by Western blot analysis.Results: The results showed that the reverse index was 2.9- and 9.69-fold by UA of 1.125 µg/mL and 2.25 µg/mL, respectively, for cisplatin to HepG2/DDP cells. UA–cisplatin combination induced cell apoptosis and reactive oxygen species, blocked the cell cycle in G0/G1 phase, and reduced the mitochondrial membrane potential. Mechanistically, UA–cisplatin dramatically decreased the expression of Nrf2 and its downstream genes. The sensibilization of UA–cisplatin combination was diminished in Nrf2 small interfering RNA-transfected HepG2/DDP cells, as well as in Nrf2 complementary DNA-transfected HepG2/DDP cells.Conclusion: The results confirmed the sensibilization of UA on HepG2/DDP cells to

  14. Accelerated hyperfractionated radiation, concurrent paclitaxel/cisplatin chemotherapy and surgery for stage III non-small cell lung cancer.

    Science.gov (United States)

    Adelstein, David J; Rice, Thomas W; Rybicki, Lisa A; Greskovich, John F; Ciezki, Jay P; Carroll, Marjorie A; DeCamp, Malcolm M

    2002-05-01

    The low surgical cure rate in patients with stage III non-small cell lung cancer has prompted an exploration of multimodality treatment strategies. Mature results are presented from a phase II trial of accelerated hyperfractionated radiation therapy, concurrent paclitaxel/cisplatin chemotherapy and surgery for these patients. Between 1994 and 1997, 45 patients with surgically demonstrated stage III non-small cell lung cancer underwent induction treatment with a 96 h continuous cisplatin infusion (20 mg/m(2) per day) and a 24 h infusion of paclitaxel (175 mg/m(2)) given concurrently with accelerated hyperfractionated radiation therapy (1.5 Gy twice daily) to a total dose of 30 Gy. Induction was completed in ten treatment (12 total) days. Surgical resection was scheduled 4 weeks later with a second identical course of chemoradiotherapy given 4-6 weeks post-operatively, to a total radiation dose of 60-63 Gy. Thirty-five patients had stage III(A) disease and ten had stage III(B) disease (eight with N(3) tumors). Induction toxicity included nausea in 89%, dysphagia in 89%, and neutropenia tolerable despite significant myelosuppression. Locoregional control is excellent and survival is better than historical expectations. Patients downstaged to mediastinal node negativity have a prognosis similar to those with de novo stage I(B) and II disease. Distant metastases are the major cause of treatment failure.

  15. 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.; Maase, Hans von der; Sengeløv, Lisa

    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...

  16. 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 ...

  17. Oxytocin improves follicular reserve in a cisplatin-induced gonadotoxicity model in rats.

    Science.gov (United States)

    Erbaş, Oytun; Akman, Levent; Yavaşoğlu, Altuğ; Terek, Mustafa Cosan; Akman, Tülay; Taskiran, Dilek

    2014-01-01

    Cisplatin (CP), an antitumor agent, has been shown to cause ovarian injury and dysfunction in both animal and human studies. The present study was conducted to investigate the protective effect of oxytocin (OT) on CP-induced ovarian toxicity in rats. Twenty-one adult female rats were included in the study. Fourteen rats were administered intraperitoneally CP (2 mg/kg/day) twice a week for 5 weeks. Control group (n = 7) did not receive any treatment. Following treatment, CP-received rats were randomly divided into two groups and treated with either saline (1 mL/kg/day, n = 7) or OT (160 μg/kg/day, n = 7) for 5 weeks. Then, ovarian toxicity and effects of OT were evaluated by histomorphological and biochemical analysis. Our findings revealed a significant reduction in the number of follicles at each grade in saline-treated group. AMH level was significantly lower in saline group compared to control (P CP toxicity in ovaries and increased AMH levels compared to saline group (P CP-treated rats (P CP-induced ovarian damage and improve follicular reserve by preventing oxidative damage.

  18. Development and validation of a cisplatin dose-ototoxicity model.

    Science.gov (United States)

    Dille, Marilyn F; Wilmington, Debra; McMillan, Garnett P; Helt, Wendy; Fausti, Stephen A; Konrad-Martin, Dawn

    2012-01-01

    Cisplatin is effective in the treatment of several cancers but is a known ototoxin resulting in shifts to hearing sensitivity in up to 50-60% of patients. Cisplatin-induced hearing shifts tend to occur first within an octave of a patient's high frequency hearing limit, termed the sensitive range for ototoxicity (SRO), and progress to lower frequencies. While it is currently not possible to know which patients will experience ototoxicity without testing their hearing directly, monitoring the SRO provides an early indication of damage. A tool to help forecast susceptibility to ototoxic-induced changes in the SRO in advance of each chemotherapy treatment visit may prove useful for ototoxicity monitoring efforts, patient counseling, and therapeutic planning. This project was designed to (1) establish pretreatment risk curves that quantify the probability that a new patient will suffer hearing loss within the SRO during treatment with cisplatin and (2) evaluate the accuracy of these predictions in an independent sample of Veterans receiving cisplatin for the treatment of cancer. Two study samples were used. The Developmental sample contained 23 subjects while the Validation sample consisted of 12 subjects. Risk curve predictions for SRO threshold shifts following cisplatin exposure were developed using a Developmental sample comprised of data from a total of 155 treatment visits obtained in 45 ears of 23 Veterans. Pure-tone thresholds were obtained within each subject's SRO at each treatment visit and compared with baseline measures. The risk of incurring an SRO shift was statistically modeled as a function of factors related to chemotherapy treatment (cisplatin dose, radiation treatment, doublet medication) and patient status (age, pre-exposure hearing, cancer location and stage). The model was reduced so that only statistically significant variables were included. Receiver-operating characteristic (ROC) curve analyses were then used to determine the accuracy of the

  19. B-1 cells and concomitant immunity in Ehrlich tumour progression.

    Science.gov (United States)

    Azevedo, M C; Palos, M C; Osugui, L; Laurindo, M F; Masutani, D; Nonogaki, S; Bachi, A L L; Melo, F H M; Mariano, M

    2014-05-01

    Concomitant immunity is a phenomenon in which a tumour-bearing host is resistant to the growth of an implanted secondary tumour. Metastases are considered to be secondary tumours that develop spontaneously during primary tumour growth, suggesting the involvement of concomitant immunity in controlling the rise of metastases. It has been demonstrated that B-1 cells, a subset of B-lymphocytes found predominantly in pleural and peritoneal cavities, not only increase the metastatic development of murine melanoma B16F10, but also are capable of differentiating into mononuclear phagocytes, modulating inflammatory responses in wound healing, in oral tolerance and in Paracoccidiose brasiliensis infections. Here, we studied B-1 cells' participation in concomitant immunity during Ehrlich tumour progression. Our results show that B-1 cells obtained from BALB/c mice previously injected with Ehrlich tumour in the footpad were able to protect BALB/c and BALB/Xid mice against Ehrlich tumour challenge. In addition, it was demonstrated that BALB/Xid show faster tumour growth and have lost concomitant immunity, and that this state can be partially restored by reconstituting these animals with B-1 cells. However, further researches are required to establish the mechanism involving B-1 cells in Ehrlich tumour growth. Copyright © 2014 Elsevier GmbH. All rights reserved.

  20. Concomitant sublay mesh repair of umbilical hernia and abdominoplasty

    OpenAIRE

    2012-01-01

    Concomitant mesh repair of large umbilical hernias and abdominoplasty pose a serious risk of devascularizing the umbilical stalk. A technique of placing mesh in a sublay manner, deep to the fascial defect, for an umbilical herniorrhaphy to avoid damage to the deep umbilical perforators during an abdominoplasty is described.

  1. Bacterial populations concomitant with Sclerotium rolfsii sclerotia in ...

    African Journals Online (AJOL)

    SARAH

    2015-09-30

    Sep 30, 2015 ... Objective: The bacterial communities concomitant with sclerotia of Sclerotium rolfsii, the causal agent of soybean stem ..... avoid overestimating the variable impact, the multiple coefficient of ..... resembles an anaerobic freshwater habitat, where the .... factor analysis of petroleum contaminated soil from the ...

  2. Schistosomiasis and hepatopulmonary syndrome: the role of concomitant liver cirrhosis

    Directory of Open Access Journals (Sweden)

    Liana Gonçalves-Macedo

    Full Text Available BACKGROUND Hepatopulmonary syndrome (HPS is defined as an oxygenation defect induced by intrapulmonary vasodilation in patients with liver disease or portal hypertension. It is investigated in patients with liver cirrhosis and less frequently in those with portal hypertension without liver cirrhosis, as may occur in hepatosplenic schistosomiasis (HSS. OBJECTIVES To investigate the prevalence of HPS in patients with HSS, and to determine whether the occurrence of HPS is influenced by concomitant cirrhosis. METHODS We evaluated patients with HSS with or without concomitant liver cirrhosis. All patients underwent laboratory testing, ultrasound, endoscopy, contrast echocardiography, and arterial blood gas analysis. FINDINGS Of the 121 patients with HSS, 64 were also diagnosed with liver cirrhosis. HPS was diagnosed in 42 patients (35% and was more frequent among patients with concomitant liver cirrhosis than in those without cirrhosis (42% vs. 26%, but the difference was not significant (p = 0.069. HPS was more common in those with spider naevi, Child-Pugh classes B or C and high model for end stage liver disease (MELD scores (p < 0.05 each. MAIN CONCLUSIONS The prevalence of HPS was 35% in this study. The occurrence of liver cirrhosis concomitantly with HSS may have influenced the frequency of patients presenting with HPS.

  3. Concomitant crystallization for in situ encapsulation of organic materials

    NARCIS (Netherlands)

    Reus, M.A.; Hoetmer, G.; Heijden, A.E.D.M. van der; Horst, J.H. ter

    2014-01-01

    Concomitant crystallization leads to process intensification through the synergistic combination of the partial processes of particle formation and encapsulation within a single process step. Both cooling and electrospray crystallization in multi-component solutions were used to create (sub-)micron

  4. Black esophagus with concomitant candidiasis developed after diabetic ketoacidosis

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Black esophagus is a very rare disease and its pathogenesis has been unclear. Black esophagus developed concomitantly with candidiasis after diabetic ketoacidosis has not been reported yet. We report a case who developed esophageal stricture after the treatment of black esophagus and thus balloon dilatation was performed several times but failed, hence, surgical treatment was performed.

  5. Management of pelvic fractures with concomitant urologic injuries.

    Science.gov (United States)

    Taffet, R

    1997-07-01

    Controversy exists regarding the management of pelvic fractures with concomitant injuries to the lower urologic tract. This can be seen in both the urologic and orthopedic literature as it pertains to the ideal form of treatment for either problem and the timing of surgical intervention, if it is needed. This article reviews the anatomy, mechanism of injury, diagnostic approach, and treatment.

  6. Concomitant crystallization for in situ encapsulation of organic materials

    NARCIS (Netherlands)

    Reus, M.A.; Hoetmer, G.; Heijden, A.E.D.M. van der; Horst, J.H. ter

    2014-01-01

    Concomitant crystallization leads to process intensification through the synergistic combination of the partial processes of particle formation and encapsulation within a single process step. Both cooling and electrospray crystallization in multi-component solutions were used to create (sub-)micron

  7. Immune status in patients with psoriasis and concomitant Malassezia infection

    Directory of Open Access Journals (Sweden)

    K. O. Veretelnyk

    2017-06-01

    Full Text Available Objective: to improve the efficacy of integrated assessment of immunity different links in patients with psoriasis and concomitant Malassezia skin infection. Materials and Methods. The results of this study are based on the data of comprehensive examination and monitoring of 80 patients with psoriasis, 60 of whom are suffered from both diseases - psoriasis and Malassezia skin infection (the main group and 20 patients are suffered only from psoriasis without fungal infection (the comparison group. Research methods – the function of neutrophils, lymphocytic reactions, the level of immunoglobulins A, M, G and cytokines IL-1β, IL-4, TNF-α. Results. 60 patients with psoriasis and concomitant Malassezia infection (the main group in contrast to the patients without fungal infection (comparison group showed immunodeficiency, which manifested by increase in the number of CD22+ and decrease in the ratio CD4+/CD8+. Depressed T-cell immunity was characterized by the dissociation of CD3+ and CD4+, CD8+ levels, and particularly CD16+. The increase in IgG was found in the main group of patients and in the control group. The increase in IgM was identified only in patients with psoriasis and concomitant Malassezia infection. These patients had normal levels of IgA, which indicated an adverse effect of concomitant fungal infection on humoral immunity. Patients with psoriasis and concomitant Malassezia infection compared with patients, who suffered only from psoriasis without mycosis, had inhibition of the phagocytes protective capabilities. The most significant increase in levels of IL-1β, IL-4, TNF-α in the serum of patients with psoriasis was determined in the presence of concomitant Malassezia infection, which directly correlated with PASI and DLQI indices (namely with clinical manifestations of psoriasis and its course. Conclusions. Taking into account the different links of immunity violations in patients with psoriasis and concomitant Malassezia

  8. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin in the treatment of secondary hemophagocytic lymphohistiocytosis with classical Hodgkin lymphoma: a case report and review of the literature.

    Science.gov (United States)

    Hu, Steve; Bansal, Pranshu; Lynch, David; Rojas Hernandez, Cristhiam Mauricio; Dayao, Zoneddy

    2016-12-20

    Hemophagocytic lymphohistiocytosis is becoming an increasingly recognized disorder in adults. Classical Hodgkin lymphoma is a relatively uncommon etiology of hemophagocytic lymphohistiocytosis and may complicate treatment options. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin are discussed here as a treatment regimen. A 66-year-old Hispanic man previously in good health presented with a 1-month history of recurrent fevers, chills, and night sweats and a 3-week history of new onset jaundice. A bone marrow biopsy revealed a normocellular bone marrow with increased histiocytes with areas of hemophagocytic activity. He met five out of eight criteria for hemophagocytic lymphohistiocytosis diagnosis including fevers, pancytopenia, hemophagocytosis, ferritin of 23,292 ng/mL (>500 ng/mL), and soluble-CD25 of 15,330 pg/mL (>1033 pg/mL). A right cervical lymph node biopsy revealed CD15, CD30, MUM-1, and Epstein-Barr virus-encoded small ribonucleic acid-positive cells with morphologic findings of classical Hodgkin lymphoma, lymphocyte-rich subtype. He completed 2 weeks of hemophagocytic lymphohistiocytosis-directed therapy with etoposide and dexamethasone, but then was switched to rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin due to minimal improvement in his pancytopenia and hepatic impairment. He completed one full cycle of rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin with notable improvement in serial hepatic function panels and had an undetectable Epstein-Barr virus viral load. However, he eventually died due to complications of Enterococcus faecalis bacteremia and colonic microperforation in the setting of persistent pancytopenia. This case discusses the challenges facing treatment of adult malignancy-associated hemophagocytic lymphohistiocytosis. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin may be a viable option for patients with secondary

  9. 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...

  10. THE EFFECTS OF HSP27 ON THE CYTOTOXICITY OF RAT EMBRYO FIBROBLAST INDUCED BY CISPLATIN

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To investigate the protective effects of heat shock protein 2700(Hsp27)on cis- platin inducing cytotoxicity in a temperature mutant SV40 large T antigen transformed rat embryo fibroblast (P1-Hsp27). Methods The cytotoxical effects of cisplatin on the proliferation status of P1-Hsp27 cells in the presence or absence of Hsp27 were measured by MTT assay. Results Cisplatin possessed dose-dependent cyto- toxicity on P1-Hsp27 cells. 48h after treatment, about 50% cells were dead in those cells exposed to 200μmol cisplatin. However, no obvious protective effects of Hsp27 on cisplatin induced cytotoxicity could be observed (P>0.05),except in those cells exposed to 500μmol cisplatin 12h after treatment. Conclusion Hsp27 has no obvious protective effects on cisplatin inducing cytotoxicity.

  11. Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Sahu, Bidya Dhar; Rentam, Kiran Kumar Reddy; Putcha, Uday Kumar; Kuncha, Madhusudana; Vegi, Ganga Modi Naidu; Sistla, Ramakrishna

    2011-12-01

    Nephrotoxicity is one of the serious dose limiting side effects of cisplatin when used in the treatment of various malignant conditions. Accumulating evidence suggests that oxidative stress caused by free radicals and apoptosis of renal cells contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Present study was aimed to explore the effect of carnosic acid, a potent antioxidant, against cisplatin induced oxidative stress and nephrotoxicity in rats. A single dose of cisplatin (7.5mg/kg) caused marked renal damage, characterized by a significant (PGSH (reduced glutathione) levels and lowered tissue nitrite, SOD (superoxide dismutase), CAT (catalase), GSH-Px (glutathione peroxidase), GR (glutathione reductase) and GST (glutathione S-transferase) levels compared to normal control. Carnosic acid treatment significantly (PGSH-Px, GR and GST compared to cisplatin control. The present study demonstrates that carnosic acid has a protective effect on cisplatin induced experimental nephrotoxicity and is attributed to its potent antioxidant and antiapoptotic properties.

  12. Comparison of the protective effects of intratympanic dexamethasone and methylprednisolone against cisplatin-induced ototoxicity.

    Science.gov (United States)

    Özel, H E; Özdoğan, F; Gürgen, S G; Esen, E; Genç, S; Selçuk, A

    2016-03-01

    This study aimed to compare the efficacies of intratympanic dexamethasone and methylprednisolone in preventing in cisplatin-induced ototoxicity in rats. Experimental groups of rats (n = 8 each) received intratympanic isotonic saline, intraperitoneal cisplatin and intratympanic isotonic saline, intraperitoneal cisplatin and intratympanic dexamethasone, or intraperitoneal cisplatin and intratympanic methylprednisolone. Distortion product otoacoustic emission thresholds were compared on days 0 and 10 in all rats, and correlations between drug effects and changes in cochlear histology were evaluated. Distortion product otoacoustic emission thresholds were comparable in groups III and IV (p > 0.05). Significant protection against cisplatin-induced ototoxicity was seen in groups III and IV compared with group II (p ototoxicity. Dexamethasone (and possibly methylprednisolone) may be clinically useful as an intratympanic chemopreventive agent to treat cisplatin ototoxicity. Future clinical studies should investigate the use of dexamethasone for this purpose in adult patients.

  13. Electrohydrodynamic encapsulation of cisplatin in poly (lactic-co-glycolic acid) nanoparticles for controlled drug delivery.

    Science.gov (United States)

    Parhizkar, Maryam; Reardon, Philip J T; Knowles, Jonathan C; Browning, Richard J; Stride, Eleanor; Barbara, Pedley R; Harker, Anthony H; Edirisinghe, Mohan

    2016-10-01

    Targeted delivery of potent, toxic chemotherapy drugs, such as cisplatin, is a significant area of research in cancer treatment. In this study, cisplatin was successfully encapsulated with high efficiency (>70%) in poly (lactic-co-glycolic acid) polymeric nanoparticles by using electrohydrodynamic atomization (EHDA) where applied voltage and solution flow rate as well as the concentration of cisplatin and polymer were varied to control the size of the particles. Thus, nanoparticles were produced with three different drug:polymer ratios (2.5, 5 and 10wt% cisplatin). It was shown that smaller nanoparticles were produced with 10wt% cisplatin. Furthermore, these demonstrated the best sustained release (smallest burst release). By fitting the experimental data with various kinetic models it was concluded that the release is dependent upon the particle morphology and the drug concentration. Thus, these particles have significant potential for cisplatin delivery with controlled dosage and release period that are crucial chemotherapy parameters.

  14. Disparity in actions of rosiglitazone against cisplatin-induced nephrotoxicity in female Sprague-Dawley rats.

    Science.gov (United States)

    Kumar, Parveen; Prashanth, Krishna Shastrula; Gaikwad, Anil Bhanudas; Vij, Mohit; Barua, Chandana C; Bezbaruah, Babul

    2013-11-01

    Cisplatin is one of the most common chemotherapeutic drugs used against various solid, tumours. Despite of its therapeutic benefits, its use in clinical practice is often limited because of dose, related toxicity. The nephrotoxic potential of cisplatin has been ascribed to its accumulation in the, renal tubular cells generating reactive oxygen species (ROS), activation of Bax, increased secretion of, TNFα and activation of certain inflammatory mediators like cytokines. The present investigation was, undertaken with an objective to study the effect of rosiglitazone against cisplatin induced, nephrotoxicity. Pretreatment of rosiglitazone prevents cisplatin induced nephrotoxicity which was, clearly evident from the renal biochemical parameters like reduced BUN, creatinine and TNFα levels, and increased albumin levels, which was also supported by histopathological studies of the kidneys. In contrast, posttreatment of rosiglitazone was not able to protect the renal damage in cisplatin induced, renal toxicity. These results showed the variation of pre & posttreatment effects of rosiglitazone, against the cisplatin induced nephrotoxicity.

  15. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway

    Science.gov (United States)

    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-sung

    2016-01-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy-induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292] PMID:26728272

  16. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway.

    Science.gov (United States)

    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-Sung

    2016-05-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy- induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292].

  17. Preventive Effect of Dihydromyricetin against Cisplatin-Induced Nephrotoxicity In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Fei Wu

    2016-01-01

    Full Text Available Nephrotoxicity is a frequent severe side effect of cisplatin chemotherapy, limiting its clinical use despite being one of the most potent chemotherapy drugs. Dihydromyricetin is a highly abundant compound purified from the leaves of Ampelopsis grossedentata. Previous studies have demonstrated the anti-inflammatory and antioxidative effects of Dihydromyricetin both in vitro and in vivo, but little is known about the effects of Dihydromyricetin on cisplatin-induced nephrotoxicity and its underlying mechanisms. In the present study, we investigated its potential renoprotective effect and found that Dihydromyricetin ameliorated the renal functional impairment and structural damage caused by cisplatin. Moreover, Dihydromyricetin markedly attenuated cisplatin-induced oxidative stress, as well as protecting against cisplatin-induced inflammation and apoptotic cell death in mouse kidney tissues. These results collectively highlight the potential of DMY as a rational renoprotective agent against cisplatin.

  18. Relationship between cisplatin or nedaplatin-induced nephrotoxicity and renal accumulation.

    Science.gov (United States)

    Kawai, Yoshiko; Taniuchi, Saburo; Okahara, Shigeki; Nakamura, Masuhisa; Gemba, Munekazu

    2005-08-01

    Nedaplatin is known to exhibit antitumor activity similar to that of cisplatin. However, concerning side effects, nedaplatin causes renal toxicity less frequently than cisplatin. In this study, we compared the incidence of renal toxicity between cisplatin and nedaplatin by investigating the difference in kidney tissue accumulation. Kidney tissue accumulation of cisplatin administered at 3.75 mg/kg was similar to that of nedaplatin administered at 24 mg/kg. At these doses, the plasma creatinine level and urinary excretion of glucose and N-acetyl-beta-D-glucosaminidase (NAG) similarly increased. There was a correlation between kidney accumulation of cisplatin and nedaplatin and the increases in plasma creatinine level and urinary excretion of NAG. Therefore, our results suggest that nedaplatin less frequently causes renal toxicity in comparison to cisplatin due to lower kidney accumulation.

  19. Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

    Science.gov (United States)

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-04-01

    Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

  20. Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study

    OpenAIRE

    Royer, B.; Kalbacher, E; Onteniente, S; Jullien, V; Montange, D; Piedoux, S; Thiery-Vuillemin, A; Delroeux, D; Pili-Floury, S.; Guardiola, E; Combe, M.; Muret, P.; Nerich, V; Heyd, B; Chauffert, B

    2011-01-01

    Background: Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis. Methods: Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n=26) or without (n=29) epinephrine were analysed using NONMEM. Results: Epinephrine halves...

  1. The mechanism of mesna in protection from cisplatin-induced ovarian damage in female rats

    OpenAIRE

    Li, Xiaohuan; Yang, Shu; Lv,Xiangyang; Sun, Haimei; Weng, Jing; Liang, Yuanjing; Zhou, Deshan

    2013-01-01

    Objective Cisplatin is a widely used chemotherapeutic agent in the treatment of cancers in clinic; but it often induces adverse effects on ovarian functions such as reduced fertility and premature menopause. Mesna could attenuate the cisplatin-induced ovarian damages; however, the underlying mechanism is still unknown. This study aimed to figure out the underlying mechanism of the protection of mesna for ovaries against cisplatin therapy in cancers. Methods We performed female adult Sprague-D...

  2. Electrohydrodynamic encapsulation of cisplatin in poly (lactic-co-glycolic acid) nanoparticles for controlled drug delivery.

    OpenAIRE

    Parhizkar, M.; Reardon, PJT; Knowles, JC; Browning, RJ; Stride, E.; Pedley, RB; Harker, AH; Edirisinghe, M.

    2016-01-01

    Targeted delivery of potent, toxic chemotherapy drugs, such as cisplatin, is a significant area of research in cancer treatment. In this study, cisplatin was successfully encapsulated with high efficiency (>70%) in Poly (lactic-co-glycolic acid) polymeric nanoparticles by using electrohydrodynamic atomization (EHDA) where applied voltage and solution flow rate as well as the concentration of cisplatin and polymer were varied to control the size of the p...

  3. Identifizierung von chemischen Modulatoren der Cisplatin-induzierten Apoptose in Lungenkrebszellen

    OpenAIRE

    2015-01-01

    Ziel dieser Doktorarbeit war ein tieferes Verständnis der Cisplatin-induzierten Apoptose. Hierfür wurde der Ablauf Cisplatin-induzierter Apoptose in A549 Zellen charakterisiert. Es konnten u.a. durch den Einsatz des Mikroskopie-basierten Chemikalienscreens neben schon bekannten Signalwegen / Schlüsselproteinen der Apoptose neue Regulatoren identifiziert werden. Speziell die verstärkende oder hemmende Wirkung vieler Medikamente auf die Cisplatin-induzierte Apoptose bedarf weiterer Forschung.

  4. MutS homologue hMSH5: role in cisplatin-induced DNA damage response

    OpenAIRE

    Tompkins Joshua D; Wu Xiling; Her Chengtao

    2012-01-01

    Abstract Background Cisplatin (cis-diamminedichloroplatinum (II), CDDP) and its analogues constitute an important class of anticancer drugs in the treatment of various malignancies; however, its effectiveness is frequently affected by mutations in genes involved in the repair and signaling of cisplatin-induced DNA damage. These observations necessitate a need for a better understanding of the molecular events governing cellular sensitivity to cisplatin. Results Here, we show that hMSH5 mediat...

  5. Gap Junction Enhancer Potentiates Cytotoxicity of Cisplatin in Breast Cancer Cells

    OpenAIRE

    Ding, Ying; Nguyen, Thu Annelise

    2012-01-01

    Cisplatin is one of the most widely used anti-cancer drugs due to its ability to damage DNA and induce apoptosis. However, increasing reports of side effects and drug resistance indicate the limitation of cisplatin in cancer therapeutics. Recent studies showed that inhibition of gap junctions diminishes the cytotoxic effect and contributes to drug resistance. Therefore, identification of molecules that counteract gap junctional inhibition without decreasing the anti-cancer effect of cisplatin...

  6. Antiemetic role of thalidomide in a rat model of cisplatin-induced emesis.

    Science.gov (United States)

    Han, Zheng-xiang; Xu, Jie; Wang, Hong-mei; Ma, Jan; Sun, Xuan; Du, Xiu-ping

    2014-09-01

    The efficacy of thalidomide to attenuate cisplatin-induced emesis was evaluated in a rat model. Four groups were utilized: control group (peritoneal injection and gastric lavage with normal saline), cisplatin group (peritoneal injection of cisplatin at 10 mg/kg and gastric lavage with normal saline), thalidomide group (cisplatin as above and gastric lavage with thalidomide at 10 mg/kg), and granisetron group (positive control for antiemetic effects; cisplatin given as above and gastric lavage done with granisetron at 0.5 mg/kg). The cisplatin-induced kaolin consumption (pica behavior) was used as a model of emesis in patients. The animals' kaolin and food intakes were measured. Further, medulla and gastric tissues were obtained 5 and 33 h after peritoneal injections to quantify the levels of Substance P and Neurokinin-1 receptor (NK-1R). The cisplatin-induced kaolin consumption was significantly (p thalidomide 72 h after the injection. The levels of Substance P in the medulla and gastric tissue were increased 5 h after the injection in both cisplatin and thalidomide groups, however, returned faster to normal levels in the thalidomide group (p thalidomide, and granisetron group were significantly increased at both 5 and 33 h (p thalidomide attenuates animal equivalent of cisplatin-induced emesis, and this beneficial effect is associated with decreased levels of Substance P levels in the medulla and gastric tissue.

  7. Increased procoagulant activity of red blood cells in the presence of cisplatin

    Institute of Scientific and Technical Information of China (English)

    L(U) Cheng-fang; YU Hong-juan; HOU Jin-xiao; ZHOU Jin

    2008-01-01

    Background Cisplatin based chemotherapy is a well recognized risk factor for coagulation disordrs and thrombosis.The pathophysiological mechanisms by which cisplatin promote thrombosis are not well understood.Methods Red blood cells (RBCs) were separated from peripheral blood of patients with breast cancer (n=10) and healthy adults (n=6) and treated with cisplatin. Coagulation time of RBCs was assessed by one step recalcification time and the productions of thrombin, intrinsic and extrinsic factor Xa were measured in the presence or absence of various concentrations of lactadherin. Exposed phosphatidylserine was stained with lactadherin and observed by confocal microscopy and flow cytometry.Results Neither fresh RBCs nor RBCs treated without cisplatin had potent procoagulant activity. Cisplatin treatment increased procoagulant activity of RBCs in a cell number- and concentration-dependent manner. Exposed phosphatidylserine was stained with lactadherin and after cisplatin treatment, strong fluorescence was revealed by confocal microscopy. Lactadherin bound RBCs from patients with breast cancer increased from (1.9±0.5)% on control RBCs to (68.0±3.5)% on RBCs treated with 10 pmol/L cisplatin for 24 hours.Conclusions Cisplatin treatment increases procoagulant activity of RBCs, which have a strong association with exposure of phosphatidylserine. The increased procoagulant activity may contribute to the pathogenesis of thrombophilia during cisplatin based chemotherapy in breast cancer patients.

  8. Fabrication and Cytotoxicity of Fucoidan-Cisplatin Nanoparticles for Macrophage and Tumor Cells

    Directory of Open Access Journals (Sweden)

    Pai-An Hwang

    2017-03-01

    Full Text Available Fucoidan, an anionic, sulfated polysaccharide from brown seaweed, is known to exhibit antitumor and immunomodulatory functions. To develop an immune protection and chemotherapeutic agent, fucoidan-cisplatin nanoparticles (FCNPs were designed. FCNPs were prepared by mixing cisplatin with fucoidan solution or fucoidan with cisplatin solution, followed by dialysis to remove trace elements. The nanoparticles, comprising 10 mg of fucoidan and 2 mg of cisplatin, which exhibited the highest cisplatin content and loading efficiency during the production process, were named as Fu100Cis20. The cisplatin content, cisplatin loading efficiency, nanoparticle size, and zeta potential of Fu100Cis20 were 18.9% ± 2.7%, 93.3% ± 7.8%, 181.2 ± 21.0 nm, and −67.4 ± 2.3 mV, respectively. Immune protection assay revealed that Fu100Cis20-treated RAW264.7 cells were protected from the cytotoxicity of cisplatin. Furthermore, antitumor assay indicated that Fu100Cis20-treated HCT-8 cells showed stronger cytotoxicity than those treated with cisplatin alone. These results suggested that fucoidan-based nanoparticles exhibited suitable particle size and high drug encapsulation, and that Fu100Cis20 has potential application in both immunotherapy and chemotherapy.

  9. ROLE OF MISMATCH REPAIR PROTEINS IN THE PROCESSING OF CISPLATIN INTERSTRAND CROSS-LINKS

    Science.gov (United States)

    Sawant, Akshada; Kothandapani, Anbarasi; Zhitkovich, Anatoly; Sobol, Robert W.; Patrick, Steve M.

    2015-01-01

    Mismatch repair (MMR) deficiency gives rise to cisplatin resistance and can lead to poor prognosis in cancers. Various models have been proposed to explain this low level of resistance caused due to loss of MMR proteins. We have shown that MMR proteins are required to maintain cisplatin interstrand cross-links (ICLs) on the DNA leading to increased cellular sensitivity. In our previous studies, we have shown that BER processing of the cisplatin ICLs is mutagenic. Polymerase β (Polβ) can generate mismatches which leads to the activation and the recruitment of mismatch repair proteins. In this paper, we distinguished between the requirement of different downstream MMR proteins for maintaining cisplatin sensitivity. We show that the MutSα (MSH2-MSH6) heterocomplex is required to maintain cisplatin sensitivity, whereas the Mutsβ complex has no effect. These results can be correlated with the increased repair of cisplatin ICLs and ICL induced DNA double strand breaks (DSBs) in the resistant cells. Moreover, we show that MLH1 proficient cells displayed a cisplatin sensitive phenotype when compared with the MLH1 deficient cells and the ATPase activity of MLH1 is essential to mediate this effect. Based on these results, we propose that MutSα as well as the downstream MMR pathway proteins are essential to maintain a cisplatin sensitive phenotype as a consequence of processing Polβ induced mismatches at sites flanking cisplatin ICLs. PMID:26519826

  10. Structural and biochemical changes in mitochondria after cisplatin treatment of Dalton's lymphoma-bearing mice.

    Science.gov (United States)

    Prasad, Surya Bali; Rosangkima, Gabriel; Kharbangar, Arpaia

    2010-01-01

    Cisplatin treatment of tumor-bearing mice and analysis of ultrastructural features of mitochondria in the kidney and Dalton's lymphoma cells showed the appearance of more roundish mitochondria with thickened membranes. It also caused the reduction in the number and irregularity in the shape of cristae and formation of vacuoles in the mitochondria. After cisplatin treatment, decreased level of protein, succinate dehydrogenase activity, and increased level of lipid peroxidation were noted in Dalton's lymphoma tumor cells and kidney. Cisplatin-mediated decrease in SDH activity, GSH level and an increase in LPO in the mitochondria of kidney could play an important role to produce nephrotoxicity. However, in DL cells, decrease in cellular GSH could be noteworthy than mt-GSH, along with decrease in SDH activity and increase in LPO in the cisplatin-mediated anticancer activity. These changes could play an important role to produce both the cisplatin-mediated effects i.e. anticancer activity and nephrotoxicity. Cisplatin-induced biochemical and ultrastructural changes in mitochondria after cisplatin treatment should be an important factor in the development of biochemical injury in mitochondria and affecting the overall metabolism in the cells. The findings from the present studies indicate multilevel effect of cisplatin in the cells and do support the earlier view that mitochondria could be a critical target in cisplatin-mediated anticancer activity and toxicity in the hosts.

  11. Identification of cisplatin-binding proteins using agarose conjugates of platinum compounds.

    Directory of Open Access Journals (Sweden)

    Takatoshi Karasawa

    Full Text Available 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 primarily due to drug-protein interactions, instead of drug-DNA binding. To identify proteins that bind to cisplatin, we synthesized two different platinum-agarose conjugates, one with two amino groups and another with two chlorides attached to platinum that are available for protein binding, and conducted pull-down assays using cochlear and kidney cells. Mass spectrometric analysis on protein bands after gel electrophoresis and Coomassie blue staining identified several proteins, including myosin IIA, glucose-regulated protein 94 (GRP94, heat shock protein 90 (HSP90, calreticulin, valosin containing protein (VCP, and ribosomal protein L5, as cisplatin-binding proteins. Future studies on the interaction of these proteins with cisplatin will elucidate whether these drug-protein interactions are involved in ototoxicity and nephrotoxicity, or contribute to tumor sensitivity or resistance to cisplatin treatment.

  12. Effect of metformin against cisplatin induced acute renal injury in rats: a biochemical and histoarchitectural evaluation.

    Science.gov (United States)

    Sahu, Bidya Dhar; Kuncha, Madhusudana; Putcha, Uday Kumar; Sistla, Ramakrishna

    2013-09-01

    Although cisplatin has been a mainstay for cancer therapy, its use is limited mainly because of nephrotoxicity. Accumulating literature suggest the antioxidant and cytoprotective effect of metformin, a first line antidiabetic drug. With this background, we investigated the effect of metformin on the cisplatin induced nephrotoxicity in rats. A single injection of cisplatin (7.5 mg/kg, i.p.) caused marked renal damage, characterized by a significant increase in blood urea nitrogen (BUN), serum creatinine (Cr) and abnormal histo-architecture of kidney. These were accompanied by significant elevation of malondialdehyde (MDA), total reactive oxygen species (tROS) and caspase-3 levels and decreased antioxidant levels. Metformin treatment significantly attenuated the increase in malondialdehyde and tROS generation and restores the decrease in both enzymatic and non-enzymatic antioxidants. However metformin treatment did not prevent the cisplatin induced renal injury as there was no significant difference of renal function parameters (BUN and Cr), kidney histopathology as well as caspase-3 activity between cisplatin per se and metformin plus cisplatin treated rats. Histopathology studies revealed that similar glomerular and tubular pathological architecture in both cisplatin per se and cisplatin plus metformin group. In conclusion, the present study demonstrated that metformin is not an adjuvant drug to treat nephrotoxicity associated with cisplatin therapy.

  13. The renoprotective activity of hesperetin in cisplatin induced nephrotoxicity in rats: Molecular and biochemical evidence.

    Science.gov (United States)

    Kumar, Mukesh; Dahiya, Vicky; Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Lahkar, Mangala

    2017-03-14

    Nephrotoxicity remain a major life-threatening complication in cancer patients on cisplatin chemotherapy. In this study, we investigated the protective effect and possible cellular mechanism of the hesperetin, a naturally-occurring bioflavonoid against cisplatin-induced renal injury in rats. Hesperetin was administered at a dose of 50mg/kg and 100mg/kg orally for 10days and cisplatin (7.5mg/kg, ip) was administered on the 5th day of experiment. Cisplatin induced nephrotoxicity was evidenced by alteration in the level of markers such as blood urea nitrogen, creatinine, serum albumin and severe histopathological changes in kidney. Cisplatin administration also resulted in significant increase in the tissue oxidative stress and inflammatory cytokines. The level of antioxidants enzymes were decreased significantly in the cisplatin administered rats. Hesperetin treatment (50mg/kg and 100mg/kg) normalized the renal function by attenuation of the cisplatin-induced oxidative stress, lipid peroxidation, and inflammatory cytokines and histopathological alterations. On the basis of these experimental findings our present study postulate that co-administration of hesperetin with cisplatin chemotherapy may be promising preventive approach to limit the major mortal side effect of cisplatin.

  14. 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.

  15. The Mechanism of Cisplatin-induced Apoptosis in HeLa Cells

    Institute of Scientific and Technical Information of China (English)

    Youqing Liu; Hui Xing; Xiaobing Han; Xiaoyan Shi; Fengqi Liang; Gang Chen; Ding Ma

    2005-01-01

    OBJECTIVE To study the mechanism of apoptosis induced by cisplatin in vitro in HeLa cells cervical cancer cell line.METHODS The inhibitory effect of cisplatin on HeLa cell growth was analyzed by the MTT assay. Cell apoptosis was measured with flow cytometry and Hoechst 33258 staining following cisplatin treatment. The effect of cisplatin on transcription of HPV E6 was analyzed by RT-PCR and protein expression of E6, P53, p21, Bax and Bcl-2 was studied by Western blots.RESULTS Cisplatin inhibited cellular proliferation in a time and dosedependant manner. The sub-G1 peak by flow cytometry showed a higher apoptotic rate in the experimental group compared to the controls and Hoechst 33258 staining indicated that apoptosis was induced by cisplatin. Results of RT-PCR demonstrated that cisplatin decreased transcription of E6. Western Blots showed that cisplatin decreased protein expression of E6 and increased protein expression of P53, p21 and Bax but had no effect on protein expression of Bcl-2.CONCLUSION Cisplatin induces apoptosis and death of HeLa cells through the suppression of HPV E6 and restoration of p53 function.

  16. Autophagic flux promotes cisplatin resistance in human ovarian carcinoma cells through ATP-mediated lysosomal function.

    Science.gov (United States)

    Ma, Liwei; Xu, Ye; Su, Jing; Yu, Huimei; Kang, Jinsong; Li, Hongyan; Li, Xiaoning; Xie, Qi; Yu, Chunyan; Sun, Liankun; Li, Yang

    2015-11-01

    Lysosomes are involved in promoting resistance of cancer cells to chemotherapeutic agents. However, the mechanisms underlying lysosomal influence of cisplatin resistance in ovarian cancer remain incompletely understood. We report that, compared with cisplatin-sensitive SKOV3 cells, autophagy increases in cisplatin-resistant SKOV3/DDP cells treated with cisplatin. Inhibition of early-stage autophagy enhanced cisplatin-mediated cytotoxicity in SKOV3/DDP cells, but autophagy inhibition at a later stage by disturbing autophagosome-lysosome fusion is more effective. Notably, SKOV3/DDP cells contained more lysosomes than cisplatin-sensitive SKOV3 cells. Abundant lysosomes and lysosomal cathepsin D activity were required for continued autolysosomal degradation and maintenance of autophagic flux in SKOV3/DDP cells. Furthermore, SKOV3/DDP cells contain abundant lysosomal ATP required for lysosomal function, and inhibition of lysosomal ATP accumulation impaired lysosomal function and blocked autophagic flux. Therefore, our findings suggest that lysosomes at least partially contribute to cisplatin resistance in ovarian cancer cells through their role in cisplatin-induced autophagic processes, and provide insight into the mechanism of cisplatin resistance in tumors.

  17. 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.

  18. The hepatoprotective potential of Spirulina and vitamin C supplemention in cisplatin toxicity.

    Science.gov (United States)

    Bhattacharyya, Shalmoli; Mehta, Pooja

    2012-02-01

    Spirulina platensis is a microalgae with potent dietary phyto-antioxidant, anti-inflammatory and anti-carcinogenic properties. We investigated the mechanism of cisplatin induced hepatotoxicity and whether this natural antioxidant provided protection against cisplatin hepatotoxicity. The study was carried out in a mice model where the animals were segregated into different groups according to their treatments, e.g. control group with no treatment, cisplatin treated, cisplatin + Spirulina treated, cisplatin + vitamin C treated and cisplatin + Spirulina + vitamin C treated. The liver marker enzymes were found to be elevated following cisplatin treatment, signifying hepatotoxicity. The supplementation of Spirulina and vitamin C could effectively bring down the levels of these enzymes. Light microscopy also showed that cisplatin treatment induced liver injury and that histopathological abnormalities were prevented by Spirulina and vitamin C supplementation. This protective effect was further substantiated by the estimation of antioxidant levels and extent of lipid peroxidation in the Spirulina, vitamin C and Spirulina + vitamin C supplemented groups as compared to cisplatin alone.

  19. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Amel M. Soliman

    2016-05-01

    Full Text Available Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3 mg/kg body weight, and a group that received both cisplatin and OMEE (500 mg/kg body weight for 14 days. Cisplatin induced a significant increase in creatinine, urea, uric acid, blood urea nitrogen, malondialdehyde, and nitric oxide levels. However, glutathione, superoxide dismutase, and catalase levels were significantly diminished. Conversely, OMEE significantly modulated the renal and oxidative markers negatively impacted by cisplatin. OMEE significantly reduced the effects of cisplatin-induced changes in renal and oxidative markers, possibly through its free radical scavenging activity. Thus, OMEE may be combined with cisplatin to alleviate nephrotoxicity in cancer chemotherapy.

  20. Gap Junction Enhancer Potentiates Cytotoxicity of Cisplatin in Breast Cancer Cells.

    Science.gov (United States)

    Ding, Ying; Nguyen, Thu Annelise

    2012-11-01

    Cisplatin is one of the most widely used anti-cancer drugs due to its ability to damage DNA and induce apoptosis. However, increasing reports of side effects and drug resistance indicate the limitation of cisplatin in cancer therapeutics. Recent studies showed that inhibition of gap junctions diminishes the cytotoxic effect and contributes to drug resistance. Therefore, identification of molecules that counteract gap junctional inhibition without decreasing the anti-cancer effect of cisplatin could be used in combinational treatment, potentiating cisplatin efficacy and preventing resistance. This study investigates the effects of combinational treatment of cisplatin and PQ1, a gap junction enhancer, in T47D breast cancer cells. Our results showed that combinational treatment of PQ1 and cisplatin increased gap junctional intercellular communication (GJIC) as well as expressions of connexins (Cx26, Cx32 and Cx43), and subsequently decreased cell viability. Ki67, a proliferation marker, was decreased by 75% with combinational treatment. Expressions of pro-apoptotic factors (cleaved caspase-3/-8/-9 and bax) were increased by the combinational treatment with PQ1 and cisplatin; whereas, the pro-survival factor, bcl-2, was decreased by the combinational treatment. Our study demonstrates for the first time that the combinational treatment with gap junction enhancers can counteract cisplatin induced inhibition of gap junctional intercellular communication and reduction of connexin expression, thereby increasing the efficacy of cisplatin in cancer cells.

  1. Effect of Camel's Milk on Cisplatin-Induced Nephrotoxicity in Swiss Albino Mice

    Directory of Open Access Journals (Sweden)

    Mohamed M.E. Afifi

    2010-01-01

    Full Text Available Problem statement: Nephrotoxicity is a major complication and a dose limiting factor for cisplatin therapy. Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species. Camel's milk has good nutritive value, antigenotoxic and anticytotoxic effects. The aim of the present study was to assess the protective effect of camel's milk against Cisplatin-induced renal oxidative stress in mice. Approach: Forty mal Swiss albino mice were randomly divided into four groups (n = 10. Group I, control group. Group II was received cisplatin (12 mg kg-1 for 5 alternate days. Group III was received camel's milk (33 mL kg-1 for consecutive 30 days. Group IV was received camel's milk (33 mL kg-1 for consecutive 30 days before administration of Cisplatin. Results: Cisplatin-induced oxidative stress was indicated by increased level of tissue Malondialdehyde (MDA, serum creatinine and urea, decreased the concentration of reduced Glutathione (GSH, Vitamin C (Vit. C and Vitamin E (Vit. E and decreased both activities and gene expression of Superoxid Dismutase (SOD, Catalase (CAT, Glutathione Raductase (GR and Glutathione Peroxidase (GPx. Camel's milk reduced these biochemical changes and counteracted the deleterious effects of cisplatin Conclusion: The present study demonstrated the renoprotective potential of camel's milk against cisplatin-induced oxidative stress and renal dysfunction in mice. Hence, camel's milk has a potential to be used as therapeutic adjuvant in cisplatin nephrotoxicity.

  2. Genotoxicity and cytotoxicity of cisplatin treatment combined with anaesthetics on EAT cells in vivo.

    Science.gov (United States)

    Brozovic, Gordana; Orsolic, Nada; Knezevic, Fabijan; Horvat Knezevic, Anica; Benkovic, Vesna; Sakic, Katarina; Hrgovic, Zlatko; Bendelja, Kreso; Fassbender, Walter J

    2009-06-01

    In this study, DNA damage in tumour cells, as well as irreversible cell damage leading to apoptosis induced in vivo by the combined application of cisplatin and inhalation anaesthetics, was investigated. The genotoxicity of anaesthetics on Ehrlich ascites tumour (EAT) cells of mice, alone or in combined application with cisplatin, was estimated by using the alkaline comet assay. The percentage of EAT cell apoptosis was quantified by flow cytometry. Groups of EAT-bearing mice were (i) treated intraperitoneally with cisplatin, (ii) exposed to repeated anaesthesia with inhalation anaesthetic, and (iii) subjected to combined treatment of exposure to anaesthetics after cisplatin for 3 days. Sevoflurane, halothane and isoflurane caused strong genotoxic effects on tumour cells in vivo. The tested anaesthetics alone showed no direct effect on programmed cell death although sevoflurane and especially halothane decreased the number of living EAT cells in peritoneal cavity lavage. Repeated anaesthesia with isoflurane had stimulatory effects on EAT cell proliferation and inhibited tumour cell apoptosis (6.11%), compared to the control group (10.26%). Cisplatin caused massive apoptosis of EAT cells (41.14%) and decreased the number of living EAT cells in the peritoneal cavity. Combined cisplatin and isoflurane treatment additionally increased EAT cell apoptosis to 51.32%. Combined treatment of mice with cisplatin and all anaesthetics increased the number of living tumour cells in the peritoneal cavity compared to cisplatin treatment of mice alone. These results suggest that the inhalation of anaesthetics may protect tumour cells from the cisplatin-induced genotoxic and cytotoxic effects.

  3. Knockdown of NAPA using short-hairpin RNA sensitizes cancer cells to cisplatin: implications to overcome chemoresistance.

    Science.gov (United States)

    Wu, Zchong-Zcho; Chao, Chuck C-K

    2010-09-15

    Cisplatin is a widely used anti-cancer drug which targets DNA in replicating cells. In the present study, we found that NAPA--a protein found in the endoplasmic reticulum (ER) and implicated in protein trafficking--protects cells against cisplatin. Accordingly, knockdown of NAPA using lentivirus-encoded shRNA (shNAPA) induced ER stress similar to cisplatin treatment in HEK293 cells. A low dose of cisplatin also elicited a mild ER stress response associated with the accumulation of the protective proteins BiP and NAPA. Remarkably, knockdown of NAPA induced apoptosis and enhanced cisplatin-induced cytotoxicity/apoptosis, thereby sensitizing cancer cells to cisplatin. On the other hand, overexpression of NAPA increased resistance to cisplatin by reducing cisplatin-induced ER stress and apoptosis. The modulatory effects of shNAPA required the tumor suppressor p53 since the effects of NAPA knockdown were reduced by the p53 inhibitor PFT-alpha and in H1299 cells which are p53-null. A partial reversal of cisplatin resistance was also observed in cisplatin-resistant HeLa cells following knockdown of NAPA. Our results also indicated that calpain is required for ER-mediated apoptosis. Importantly, combined cisplatin/shNAPA treatment suppressed tumor growth in vivo in xenograph experiments performed in nude mice. Taken together, these observations suggest that NAPA represents a target of cisplatin, and that knockdown of NAPA may improve cisplatin-based cancer therapy.

  4. Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation

    Science.gov (United States)

    Estrela, Gabriel R.; Wasinski, Frederick; Batista, Rogério O.; Hiyane, Meire I.; Felizardo, Raphael J. F.; Cunha, Flavia; de Almeida, Danilo C.; Malheiros, Denise M. A. C.; Câmara, Niels O. S.; Barros, Carlos C.; Bader, Michael; Araujo, Ronaldo C.

    2017-01-01

    The antineoplastic drug cisplatin promotes renal injury, which limits its use. Protocols that reduce renal cisplatin toxicity will allow higher doses to be used in cisplatin treatment. Here, we compare physical exercise and caloric restriction (CR) as protocols to reduce cisplatin renal injury in mice. Male C57BL/6 were divided into four groups: Control, cisplatin, exercise + cisplatin, and 30% CR + cisplatin. Animals were injected with a single dose of cisplatin (20 mg/kg i.p.) and sacrificed 96 h after injection. Quantitative real time PCR, histological analyses, immunohistochemistry, and biochemical measurements were performed to investigate renal injury, necrosis, apoptosis, and inflammatory mechanisms. Both protocols protected against cisplatin renal injury, but CR was more effective in reducing uraemia and renal necrosis. The CR + Cisplatin group exhibited reduced serum IL-1β and TNF-α levels. No differences were noted in the renal mRNA expression of cytokines. Both interventions reduced apoptosis, but only the CR + Cisplatin group decreased TNFR2 protein expression. PPAR-α was activated in mice after CR. An antagonist of PPAR-α blocked the protective effect of CR. Both interventions attenuated the nephrotoxicity caused by cisplatin injection, but CR + Cisplatin showed a better response by modulating TNFR2. Moreover, part of the CR benefit depends on PPAR-α activation. PMID:28303105

  5. Structural dynamics of cisplatin binding to histidine in a protein

    Directory of Open Access Journals (Sweden)

    Simon W. M. Tanley

    2014-05-01

    Full Text Available The platinum anti-cancer agents cisplatin and carboplatin bind to the histidine 15 residue in the model protein hen egg white lysozyme. By using temperatures either side of the protein glass transition state (∼180 K, several platinum binding modes are seen and show that not all these platinum modes are stable. In particular, the mean square displacement vibration amplitudes of the cisplatin and of the histidine to which it is bound are analysed in detail. As well as the multiple platinum peaks, the electron density for the His-15 side chain is weak to absent at 150 K and 200 K, which points to the imidazole ring of the His side chain sampling multiple positions. Most interestingly, the His-15 imidazole becomes more ordered at room temperature.

  6. Structural dynamics of cisplatin binding to histidine in a protein

    Science.gov (United States)

    Tanley, Simon W. M.; Helliwell, John R.

    2014-01-01

    The platinum anti-cancer agents cisplatin and carboplatin bind to the histidine 15 residue in the model protein hen egg white lysozyme. By using temperatures either side of the protein glass transition state (∼180 K), several platinum binding modes are seen and show that not all these platinum modes are stable. In particular, the mean square displacement vibration amplitudes of the cisplatin and of the histidine to which it is bound are analysed in detail. As well as the multiple platinum peaks, the electron density for the His-15 side chain is weak to absent at 150 K and 200 K, which points to the imidazole ring of the His side chain sampling multiple positions. Most interestingly, the His-15 imidazole becomes more ordered at room temperature. PMID:26798779

  7. Cisplatin, vindesine, and bleomycin (DVB) combination chemotherapy for esophageal carcinoma.

    Science.gov (United States)

    Kelsen, D P; Bains, M; Chapman, R; Golbey, R

    1981-01-01

    Forty-six patients with epidermoid carcinoma of the esophagus have been treated with a three-drug combination of cisplatin, vindesine, and bleomycin. Of the 40 patients currently evaluable for response, 21 have had partial remissions (52%). At least four of these responses were almost complete, with only microscopic disease found on endoscopy or review of the resected specimen. Toxic effects have, in general, been manageable. The major toxic effects included nausea and vomiting, nephrotoxicity, and myelosuppression. There were two drug-related deaths: one due to renal failure and one due to sepsis. The three-drug combination appears to be substantially more effective than either the two-drug combination of cisplatin and bleomycin or vindesine alone. Effects on survival cannot yet be evaluated.

  8. Elective caesarean section at 38 weeks versus 39 weeks

    DEFF Research Database (Denmark)

    Glavind, Julie; Kindberg, S F; Uldbjerg, N;

    2013-01-01

    To investigate whether elective caesarean section before 39 completed weeks of gestation increases the risk of adverse neonatal or maternal outcomes.......To investigate whether elective caesarean section before 39 completed weeks of gestation increases the risk of adverse neonatal or maternal outcomes....

  9. Tropisetron attenuates cisplatin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Zirak, Mohammad Reza; Rahimian, Reza; Ghazi-Khansari, Mahmoud; Abbasi, Ata; Razmi, Ali; Mehr, Shahram Ejtemaei; Mousavizadeh, Kazem; Dehpour, Ahmad Reza

    2014-09-05

    Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated by α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.

  10. Friend or foe? Effect of oral resveratrol on cisplatin ototoxicity.

    Science.gov (United States)

    Olgun, Yüksel; Kırkım, Günay; Kolatan, Efsun; Kıray, Müge; Bagrıyanık, Alper; Olgun, Aybüke; Kızmazoglu, Deniz Cakır; Ellıdokuz, Hülya; Serbetcıoglu, Bulent; Altun, Zekiye; Aktas, Safiye; Yılmaz, Osman; Günerı, Enis Alpin

    2014-03-01

    Our objectives were to study effects of orally administered resveratrol (RV) against cisplatin (CDDP) ototoxicity in different doses and to investigate ultrastructural changes in the cochlea and brainstem. In vivo study using an animal model. Thirty-two male Wistar albino rats were divided into six groups. Baseline distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) measurements were made. In groups I, II, and III, only saline, RV, and CDDP were given, respectively. Group IV, V, and VI animals were administered 10 mg/kg/day, 1 mg/kg/day, and 0.1 mg/kg/day of RV for 10 days, respectively, before 16 mg/kg CDDP injections were administered on day 11. All animals were sacrificed after repeated DPOAEs and ABR measurements were made on day 14. Cochleas of animals were investigated with transmission electron microscopy. Apoptosis were investigated with caspase-3 activity and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in the brainstem. In groups IV and V, DPOAEs and ABR findings revealed that oral administration of RV 10 mg/kg/day and 1 mg/kg/day doses before CDDP injection enhanced ototoxicity. In group VI, electomicroscopy revealed better ultrastructural findings than in the cisplatin group; however, these changes were not reflected in the audiological findings accordingly. Our results implied that there were noticeable differences between different oral RV doses used for cisplatin ototoxicity. Especially in higher doses, RV was observed to enhance cisplatin ototoxicity. © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

  11. WBDOC Weekly Workload Status Report

    Data.gov (United States)

    Social Security Administration — Weekly reports of workloads processed in the Wilkes Barre Data Operation Center. Reports on quantities of work received, processed, pending and average processing...

  12. Red ginseng ameliorates acute cisplatin-induced nephropathy.

    Science.gov (United States)

    Kim, Young-Jung; Lee, Mee-Young; Son, Hwa-Young; Park, Bae-Keun; Ryu, Si-Yun; Jung, Ju-Young

    2014-06-01

    Korean red ginseng is one of the traditional herbal medicines most widely used in China, Korea, and Japan. To determine whether Korean red ginseng extract can mitigate acute renal nephropathy, we examined its renoprotective effects in a model of cisplatin-induced acute renal failure in Sprague Dawley rats. Korean red ginseng was administered to rats by oral gavage once a day at doses of 100, 300, or 500 mg/kg for 28 days. On day 23, the animals received an intraperitoneal injection of cisplatin (5 mg/kg) to induce acute renal failure. Body weight gain, urine volume, blood urea nitrogen and creatinine concentrations, and expression of p53 were measured. Terminal deoxynucleotidyl transferase dUTP nick end-labeling was used to analyze apoptosis. Kidney tissues from the control and experimental groups were analyzed by immunohistochemistry for inflammatory cytokines and histopathological examination. To identify the mechanism responsible for the renoprotective effects of Korean red ginseng, we measured malondialdehyde concentration as an end product of lipid peroxidation and the activities of the antioxidants superoxide dismutase and glutathione. Korean red ginseng significantly decreased the levels of indicators of renal dysfunction, inflammatory cytokine expression, apoptosis, and malondialdehyde content in the kidney and also significantly attenuated the histopathological changes associated with acute renal failure. These findings suggest that Korean red ginseng has renoprotective effects against cisplatin-induced acute renal failure by reducing oxidative stress and inflammation. Georg Thieme Verlag KG Stuttgart · New York.

  13. Cisplatin-Associated Ototoxicity: A Review for the Health Professional

    Directory of Open Access Journals (Sweden)

    Jessica Paken

    2016-01-01

    Full Text Available Cisplatin is an effective drug used in the treatment of many cancers, yet its ototoxic potential places cancer patients, exposed to this drug, at risk of hearing loss, thus negatively impacting further on a patient’s quality of life. It is paramount for health care practitioners managing such patients to be aware of cisplatin’s ototoxic properties and the clinical signs to identify patients at risk of developing hearing loss. English peer-reviewed articles from January 1975 to July 2015 were assessed from PubMed, Science Direct, and Ebscohost. Seventy-nine articles and two books were identified for this review, using MeSH terms and keywords such as “ototoxicity”, “cisplatin”, “hearing loss”, and “ototoxicity monitoring”. This review provides an up-to-date overview of cisplatin-associated ototoxicity, namely, its clinical features, incidence rates, and molecular and cellular mechanisms and risk factors, to health care practitioners managing the patient with cancer, and highlights the need for a team-based approach to complement an audiological monitoring programme to mitigate any further loss in the quality of life of affected patients, as there is currently no otoprotective agent recommended routinely for the prevention of cisplatin-associated ototoxicity. It also sets the platform for effective dialogue towards policy formulation and strengthening of health systems in developing countries.

  14. Cisplatin encapsulated nanoparticle as a therapeutic agent for anticancer treatment

    Science.gov (United States)

    Eka Putra, Gusti Ngurah Putu; Huang, Leaf; Hsu, Yih-Chih

    2016-03-01

    The knowledge of manipulating size of biomaterials encapsulated drug into nano-scale particles has been researched and developed in treating cancer. Cancer is the second worldwide cause of death, therefore it is critical to treat cancers challenging with therapeutic modality of various mechanisms. Our preliminary investigation has studied cisplatin encapsulated into lipid-based nanoparticle and examined the therapeutic effect on xenografted animal model. We used mice with tumor volume ranging from 195 to 214 mm3 and then few mice were grouped into three groups including: control (PBS), lipid platinum chloride (LPC) nanoparticles and CDDP (cis-diamminedichloroplatinum(II) at dose of 3mg cisplatin /kg body weight. The effect of the treatment was observed for 12 days post-injection. It showed that LPC NPs demonstrated a better therapeutic effect compared to CDDP at same 3mg cisplatin/kg drug dose of tumor size reduction, 96.6% and 11.1% respectively. In addition, mouse body weight loss of LPC, CDDP and PBS treated group are 12.1%, 24.3% and 1.4%. It means that by compared to CDDP group, LPC group demonstrated less side effect as not much reduction of body weight have found. Our findings have shown to be a potential modality to further investigate as a feasible cancer therapy modality.

  15. Clinical overview on Lipoplatin: a successful liposomal formulation of cisplatin.

    Science.gov (United States)

    Boulikas, Teni

    2009-08-01

    Nanoparticle formulations for packaging existing drugs have been used to treat cancer. Lipoplatin is a liposomal cisplatin encapsulated into liposome nanoparticles of an average diameter of 110 nm. Lipoplatin has substantially reduced the renal toxicity, peripheral neuropathy, ototoxicity, myelotoxicity as well as nausea/vomiting and asthenia of cisplatin in Phase I, II and III clinical studies with enhanced or similar efficacy to cisplatin. During clinical development, 10- to 200-fold higher accumulation of Lipoplatin in solid tumors compared to adjacent normal tissue was found in patients. Targeting of tumor vasculature by Lipoplatin in animals suggested its antiangiogenesis potential and Lipoplatin was proposed to act like a double-sword: as chemotherapy and an antiangiogenesis drug. Lipoplatin has finished successfully one Phase III non-inferiority clinical study as first-line against NSCLC in its combination with paclitaxel showing statistically significant reduction in nephrotoxicity; two more Phase III studies are in progress, one in NSCLC with gemcitabine also showing noninferiority with reduced toxicity and another in squamous cell carcinoma of the head and neck with 5-fluorouracil. A registrational Phase II/III study against pancreatic cancer is in progress under the orphan drug status granted to Lipoplatin by the European Medicines Agency. Phase II studies are continuing in advanced breast cancer with vinorelbine and gastrointestinal cancers with radiotherapy and 5-fluorouracil. The highlights of the clinical development of Lipoplatin are reviewed.

  16. 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.

  17. Biochemical changes associated with ascorbic acid–cisplatin combination therapeutic efficacy and protective effect on cisplatin-induced toxicity in tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    Amenla Longchar

    2015-01-01

    Full Text Available Cisplatin is one of the well-established anticancer drugs being used against a wide spectrum of cancers. However, full therapeutic efficacy of the drug is limited due to development of various toxicities in the host. This study examines the comparative therapeutic effectiveness and toxicities of cisplatin alone and in combination of dietary ascorbic acid (AA in ascites Dalton's lymphoma-bearing mice. The findings show that the combination treatment of mice with ascorbic acid plus cisplatin has much better therapeutic efficacy against murine ascites Dalton's lymphoma (DL in comparison to cisplatin alone and this may involve a decrease in reduced glutathione (GSH, catalase activity and increased lipid peroxidation (LPO in Dalton's lymphoma tumor cells. At the same time, combination treatment indicates a protective role of ascorbic acid against cisplatin-induced tissue toxicities (side effects in the hosts. Cisplatin-induced histopathological changes in liver, kidney and testes were decreased after combination treatment. The analysis of renal function test (RFT, liver function test (LFT and sperm abnormalities also suggest an improvement in these parameters after combination treatment. Therefore, it may be concluded that the increased GSH level, catalase activity and decreased LPO in the tissues, i.e., liver, kidney and testes after combination treatment may be involved in its protective ability against cisplatin-induced tissue toxicities in the host.

  18. A Case of Concomitant Perforated Acute Cholecystitis and Pancreatitis

    Directory of Open Access Journals (Sweden)

    Marlon Perera

    2013-01-01

    Full Text Available Introduction. Concomitant cholecystitis and gallstone pancreatitis is an infrequent clinical encounter, reported sparsely in the literature. Concurrent acute cholecystitis and pancreatitis complicated by gall bladder perforation has not been reported before. Presentation of Case. We report a 39-year-old female presenting with concomitant cholecystitis and acute pancreatitis, complicated by gallbladder perforation. Discussion. There is much controversy surrounding the timing of cholecystectomy following gallstone pancreatitis, with the recent literature suggesting that “early” operation is safe. In the current case, gallbladder perforation altered the “routine” management of gallstone pancreatitis and posed as a management dilemma. Conclusion. Clinical judgement dictated timing of operative management and ultimately cholecystectomy was performed safely.

  19. A Clinical Report of Nonsyndromic Concomitant Hypo-Hyperdontia

    Directory of Open Access Journals (Sweden)

    Siddarth Gupta

    2013-01-01

    Full Text Available Although hypodontia and supernumerary teeth are often considered as mutually exclusive conditions, this case report presents an unusual case of hypodontia and a supernumerary tooth occurring simultaneously. An adolescent male was referred to the local hospital department regarding upper arch crowding. Plain film radiographs confirmed the congenital absence of both lower lateral incisors in addition to an unerupted conical supernumerary tooth in the maxillary midline. This condition has been called hypo-hyperdontia and in this paper, we discuss the clinical findings and treatment planning considerations in relation to the limited number of previously reported cases. The case report raises awareness of concomitant hypo-hyperdontia and serves to highlight that concomitant anomalies should be excluded when hypodontia or supernumerary teeth are diagnosed.

  20. 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

  1. Effect of tunicamycin on cisplatin induced apoptosis of HeLa cells

    Directory of Open Access Journals (Sweden)

    Ye XU

    2013-04-01

    Full Text Available Objective  To investigate the effect of endoplasmic reticulum stress (ER stress in cisplatin-induced apoptosis of human cervical cancer HeLa cells. Methods  HeLa cells were used as the study object which were divided into four groups: TUNI (5mg/L group, cisplatin (6mg/L group, TUNI(5mg/L+cisplatin(6mg/L group, and negative control group (no drug treatment. MTT assay was employed to examine the growth status of the cells. Hoechst staining was used to observe the morphological change in the nucleus. Immunoblotting was used to detect the activation of apoptotic proteins, caspase-3 and caspase-4. Indirect immunofluorescence was used to assess the expression of the protein disulfide isomerase (PDI and phosphorylated histone H2AX (γ-H2AX. Results  MTT assay showed that the growth inhibition rates were 2.65%±2.71%, 19.60%±4.34%, 44.69%±7.07% and 0% in TUNI group, cisplatin group, TUNI+cisplatin group and control group, respectively (P<0.05. Cisplatin showed a significant inhibitory effect on the growth of HeLa cells, and TUNI enhanced the effect of cisplatin. Statistical significance was found between TUNI+cisplatin group and cisplatin group (P<0.05. Hoechst staining showed that the fluorescence of the nucleus in control group was weak and well-distributed. At 12h after treatment, the nuclei in some HeLa cells in cisplatin group and TUNI+cisplatin group diminished in size, thus showing dense hyperfluorescence, and some of them were broken. The proportion of karyorrhexis cells in TUNI+cisplatin group (44.5%±5.1% was significantly higher than that in cisplatin group (22.7%±3.9%, P<0.05. Immunoblotting showed the expressions of activated caspase-3 and caspase-4 were up-regulated obviously in cisplatin group. Compared to cisplatin group, the expressions of those proteins significantly increased in TUNI+cisplatin group (P<0.05. Indirect immunofluorescence staining showed no PDI expression and weak fluorescence was found in control group. PDI

  2. Central retinal vein occlusion concomitant with dengue fever

    OpenAIRE

    Velaitham, Punithamalar; Vijayasingham, Nandini

    2016-01-01

    Background Dengue virus infection is on the rise and there is increasing number of ocular complications that are being reported. Most common ocular complications are macular edema, macular hemorrhages, and foveolitis. There are case reports on branch retinal vessel occlusions. Most of the ocular complications are attributed to the bleeding tendency and transudative process in dengue viral infection. This is a case report of ischemic central retinal vein occlusion (CRVO) concomitant with dengu...

  3. Central retinal vein occlusion concomitant with dengue fever

    OpenAIRE

    Velaitham, Punithamalar; Vijayasingham, Nandini

    2016-01-01

    Background Dengue virus infection is on the rise and there is increasing number of ocular complications that are being reported. Most common ocular complications are macular edema, macular hemorrhages, and foveolitis. There are case reports on branch retinal vessel occlusions. Most of the ocular complications are attributed to the bleeding tendency and transudative process in dengue viral infection. This is a case report of ischemic central retinal vein occlusion (CRVO) concomitant with dengu...

  4. Local anesthesia selection algorithm in patients with concomitant somatic diseases.

    Science.gov (United States)

    Anisimova, E N; Sokhov, S T; Letunova, N Yu; Orekhova, I V; Gromovik, M V; Erilin, E A; Ryazantsev, N A

    2016-01-01

    The paper presents basic principles of local anesthesia selection in patients with concomitant somatic diseases. These principles are history taking; analysis of drugs interaction with local anesthetic and sedation agents; determination of the functional status of the patient; patient anxiety correction; dental care with monitoring of hemodynamics parameters. It was found that adhering to this algorithm promotes prevention of urgent conditions in patients in outpatient dentistry.

  5. Concomitant hypodontia and hyperdontia: A report of two cases.

    Science.gov (United States)

    Tewari, Nitesh; Pandey, Ramesh Kumar; Singh, Subash

    2017-01-01

    "Concomitant hypodontia and hyperdontia" is a very rare dental anomaly of number, having a prevalence rate of 0.002%-3.1%. It describes the simultaneous presence of hypodontia or missing teeth and supernumerary teeth in the same individual. It represents the opposite forces of nature acting simultaneously. Two rare cases of this anomaly involving different jaws and a classification based on the literature review have been presented here.

  6. Combined niclosamide with cisplatin inhibits epithelial-mesenchymal transition and tumor growth in cisplatin-resistant triple-negative breast cancer.

    Science.gov (United States)

    Liu, Junjun; Chen, Xiaosong; Ward, Toby; Pegram, Mark; Shen, Kunwei

    2016-07-01

    Women with triple-negative breast cancer have worse prognosis compared to other breast cancer subtypes. Acquired drug resistance remains to be an important reason influencing triple-negative breast cancer treatment efficacy. A prevailing theory postulates that the cancer resistance and recurrence results from a subpopulation of tumor cells with stemness program, which are often insensitive to cytotoxic drugs such as cisplatin. Recent studies suggested that niclosamide, an anti-helminthic drug, has potential therapeutic activities against breast cancer stem cells, which prompts us to determine its roles on eliminating cisplatin-resistant cancer cells. Hence, we established a stable cisplatin-resistant MDA-MB-231 cell line (231-CR) through continuously exposure to increasing concentrations of cisplatin (5-20 μmol/l). Interestingly, 231-CR exhibited properties associated to epithelial-mesenchymal transition with enhanced invasion, preserved proliferation, increased mammosphere formation, and reduced apoptosis compared to naive MDA-MB-231 sensitive cells (231-CS). Importantly, niclosamide or combination with cisplatin inhibited both 231-CS and 231-CR cell proliferation in vitro. In addition, niclosamide reversed the EMT phenotype of 231-CR by downregulation of snail and vimentin. Mechanistically, niclosamide treatment in combination with or without cisplatin significantly inhibited Akt, ERK, and Src signaling pathways. In vivo study showed that niclosamide or combination with cisplatin could repress the growth of xenografts originated from either 231-CS or 231-CR cells, with prominent suppression of Ki67 expression. These findings suggested that niclosamide might serve as a novel therapeutic strategy, either alone or in combination with cisplatin, for triple-negative breast cancer treatment, especially those resistant to cisplatin.

  7. Can pure accelerated radiotherapy given as six fractions weekly be an option in locally advanced carcinoma cervix: Results of a prospective randomized phase III trial

    Directory of Open Access Journals (Sweden)

    Mukesh Sharma

    2016-01-01

    Conclusions: Accelerated radiotherapy given as six fractions per week is an effective alternative to concomitant chemoradiation in locally advanced carcinoma cervix and has shown lesser toxicities in our study.

  8. Golden Week: A Holiday Revolution

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ As one of the most important and far-reaching focal points in people's lives, the Golden-Week holiday, is much more than a year 21-day vacation. How did the Golden Week take shape over the past few years, gradually attracting people's attention, and having an increasingly important impact in China each year?

  9. Selenium Protects Retinal Cells from Cisplatin-Induced Alterations in Carbohydrate Residues

    Science.gov (United States)

    Akşit, Dilek; Yazıcı, Alper; Akşit, Hasan; Sarı, Esin S.; Yay, Arzu; Yıldız, Onur; Kılıç, Adil; Ermiş, Sıtkı S.; Seyrek, Kamil

    2016-01-01

    Background: Investigate alterations in the expression and localization of carbohydrate units in rat retinal cells exposed to cisplatin toxicity. Aims: The aim of the study was to evaluate putative protective effects of selenium on retinal cells subjected to cisplatin. Study Design: Animal experiment. Methods: Eighteen healthy Wistar rats were divided into three equal groups: 1. Control, 2. Cisplatin and 3. Cisplatin+selenium groups. After anesthesia, the right eye of each rat was enucleated. Results: Histochemically, retinal cells of control groups reacted with α-2,3-bound sialic acid-specific Maackia amurensis lectin (MAA) strongly, while cisplatin reduced the staining intensity for MAA. However, selenium administration alleviated the reducing effect of cisplatin on the binding sites for MAA in retinal cells. The staining intensity for N-acetylgalactosamine (GalNAc residues) specific Griffonia simplicifolia-1 (GSL–1) was relatively slight in control animals and cisplatin reduced this slight staining for GSL-1 further. Selenium administration mitigated the reducing effect of cisplatin on the binding sites for GSL-1. A diffuse staining for N-acetylglucosamine (GlcNAc) specific wheat germ agglutinin (WGA) was observed throughout the retina of the control animals. In particular, cells localized in the inner plexiform and photoreceptor layers are reacted strongly with WGA. Compared to the control animals, binding sites for WGA in the retina of rats given cisplatin were remarkably decreased. However, the retinal cells of rats given selenium reacted strongly with WGA. Conclusion: Cisplatin reduces α-2,3-bound sialic acid, GlcNAc and GalNAc residues in certain retinal cells. However, selenium alleviates the reducing effect of cisplatin on carbohydrate residues in retinal cells. PMID:27606141

  10. Intraperitoneal curcumin and vitamin E combination for the treatment of cisplatin-induced ototoxicity in rats.

    Science.gov (United States)

    Soyalıç, Harun; Gevrek, Fikret; Koç, Sema; Avcu, Mustafa; Metin, Mehmet; Aladağ, İbrahim

    2016-10-01

    Cisplatin ototoxicity is characterized by irreversible, progressive, bilateral sensorineural hearing loss at high frequencies, accompanied by tinnitus. The aim of this study is to demonstrate the protective action of curcumin alone or in combination with vitamin E against cisplatin-induced ototoxicity in animal models. The study included 42 rats. Experimental animals were randomized into 6 groups. In the first group, intra-peritoneal cisplatin was administered alone. In the second group, intra-peritoneal cisplatin and curcumin were administered together. In the third group, intra-peritoneal cisplatin and vitamin E were administered together. In the fourth group, intra-peritoneal cisplatin was administered together with curcumin in combination with vitamin E. In the fifth group, intra-peritoneal curcumin was administered alone. The sixth group was sacrificed directly without administration of any drugs. A distortion product otoacoustic emission (DPOAE) test was applied to both ears of all experimental animals. Curcumin was administered 1 h before cisplatin treatment continued for three successive days. Vitamin E was administered only as a single dose 30 min prior to cisplatin. All animals were sacrificed following DPOAE testing on the 5th day of cisplatin administration. Histopathological findings included a TUNEL (TdT-mediated deoxyuridine triphosphate nick end-labeling) assay, and the percentage of apoptotic cells was calculated. DPOAE values and the percentage of apoptotic cells were compared before and after treatment and between experimental groups. In Group 1, DPOAE values were significantly decreased at all frequencies (3000 Hz, 4000 Hz and 6000 Hz; P  0.05). Apoptotic index values were lower in all treatment groups compared to the cisplatin group, however the difference was only statistically significant in group 3 (p = 0.009). In rats, cisplatin ototoxicity can be prevented with curcumin or curcumin-vitamin E combination. Copyright © 2016 Elsevier

  11. DFT study of the molecular and crystal structure and vibrational analysis of cisplatin

    Science.gov (United States)

    Georgieva, I.; Trendafilova, N.; Dodoff, N.; Kovacheva, D.

    2017-04-01

    DFT and periodic-DFT (PAW-PBE method, code VASP) calculations have been performed to study the structural and vibrational characteristics of cis-diamminedichloroplatinum(II) (cisplatin) at molecular and outside molecular level. To estimate the effect of the intermolecular interactions in crystal on the structural and vibrational properties of cisplatin, three theoretical models are considered in the present study: monomer (isolated molecule), hydrogen bonded dimer and periodic solid state structures. The work focused on the role of the theoretical models for correct modeling and prediction of geometrical and vibrational parameters of cisplatin. It has been found that the elaborate three-dimensional intermolecular hydrogen bonding network in the crystalline cisplatin significantly influences the structural and vibrational pattern of cisplatin and therefore the isolated cisplatin molecule is not the correct computational model regardless of the theoretical level used. To account for the whole intermolecular hydrogen bonding network in direction of both a and c axis and for more reliable calculations of structural and vibrational parameters periodic DFT calculations were carried out in the full crystalline periodic environment with the known lattice parameters for each cisplatin polymorph phase. The model calculations performed both at molecular level and for the periodic structures of alpha and beta cisplatin polymorph forms revealed the decisive role of the extended theoretical model for reliable prediction of the structural and vibrational characteristics of cisplatin. The powder diffraction pattern and the calculated IR and Raman spectra predicted beta polymorph form of our cisplatin sample freshly synthesized for the purposes of the present study using the Dhara's method. The various rotamers realized in the polymorph forms of cisplatin were explained by the low population of the large number of rotamers in solution as well as with the high rotamer

  12. Novel synthetic protective compound, KR-22335, against cisplatin-induced auditory cell death.

    Science.gov (United States)

    Shin, Yoo Seob; Song, Suk Jin; Kang, Sungun; Hwang, Hye Sook; Jung, Young-Sik; Kim, Chul-Ho

    2014-02-01

    Cisplatin [cis-diammine-dichloroplatinum (II)] is a widely used chemotherapeutic agent, and one of its most severe side effects is ototoxicity. In the course of developing a new protective agent against cisplatin-induced ototoxicity, we have been interested in a novel synthetic compound, 3-Amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR-22335). We evaluated the effectiveness of KR-22335 as an otoprotective agent against cisplatin-induced toxicity. The otoprotective effect of KR-22335 against cisplatin was tested in vitro in cochlear organs of Corti-derived cell lines, HEI-OC1, and in vivo in a zebrafish (Danio rerio) model. Cisplatin-induced apoptosis, cell cycle arrest and an increase in intracellular reactive oxygen species (ROS) generation were demonstrated in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced apoptosis and mitochondrial injury in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced activation of JNK, p-38, caspase-3 and PARP in HEI-OC1 cells. Scanning and transmission electron micrographs showed that KR-22335 prevented cisplatin-induced destruction of kinocilium and stereocilia in zebrafish neuromasts. Tissue TUNEL of neuromasts in zebrafish demonstrated that KR-22335 blocked cisplatin-induced TUNEL positive hair cells in neuromasts. The results of this study suggest that KR-22335 may prevent ototoxicity caused by the administration of cisplatin through the inhibition of mitochondrial dysfunction and suppression of ROS generation. KR-22335 may be considered as a potential candidate for protective agents against cisplatin-induced ototoxicity.

  13. 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

  14. 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

  15. Prediction of treatment outcome by cisplatin-DNA adduct formation in patients with stage III/IV head and neck squamous cell carcinoma, treated by concurrent cisplatin-radiation (RADPLAT).

    NARCIS (Netherlands)

    Hoebers, F.J.; Pluim, D.; Verheij, M.; Balm, A.J.M.; Bartelink, H.; Schellens, J.H.M.; Begg, A.C.

    2006-01-01

    The purpose of our study was to test the predictive value of cisplatin-DNA adduct levels in head and neck squamous cell carcinoma (HNSCC) patients treated with cisplatin-radiation. Patients with advanced-stage HNSCC were treated within a randomized trial, investigating the optimal route of cisplatin

  16. Treatment of Advanced or Recurrent Cervical Cancer with Cisplatin or Cisplatin Containing Regimens: A Cost Effective Analysis

    Directory of Open Access Journals (Sweden)

    John P. Geisler, Jayanth Swathirajan, Katherine L. Wood, Kelly J. Manahan

    2012-01-01

    Full Text Available Background: Trials have demonstrated improvements in survival with adding paclitaxel (P or topotecan (T to cisplatin (C for the treatment of advanced cervical cancer. We sought to evaluate the cost effectiveness of these regimens.Methods: A decision model was developed based on Gynecologic Oncology Group (GOG protocols 169 and 179. Arm 1 is 6 cycles of cisplatin. Arm 2 is 6 cycles of CP while arm 3 is 6 cycles of CT. Parameters include overall survival (OS, cost and complications. Sensitivity analyses were performed.Results: The incremental cost-effectiveness ratio (ICER for C versus CP is $13,654/quality-adjusted life-year (QALY gained. For CT compared to C, the ICER is $152,327/QALY. When compared simultaneously, CT is dominated. At a willingness to pay (WTP threshold of $50,000/QALY, C is the preferred option but CP is acceptable. Sensitivity analyses suggest that CT would become the preferred option if it was to improve OS to 24 months (compared to 9.4 months.Conclusions: In this model, CP is an acceptable alternative to cisplatin for the treatment of these patients with an increase in cost of only $13,654/QALY. The addition of topotecan did not increase survival enough to justify the increased cost.

  17. Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

    OpenAIRE

    Kachadourian, Remy; LEITNER, VHEATHER M.; Day, Brian J.

    2007-01-01

    Adjuvant therapies that enhance the anti-tumor effects of cisplatin are actively being pursued. Growing evidence supports the involvement of mitochondrial dysfunction in the anti-cancer effect of cis-diammineplatinum(II) dichloride (cisplatin, CDDP). We examined the potential of using selective flavonoids that are effective in depleting tumor cells of glu-tathione (GSH) to potentiate cisplatin-mediated cytotoxicity in human lung adenocarcinoma (A549) cells. We found that cisplatin (40 μM, 48-...

  18. A Retrospective Study of the Efficacy and Toxicity of Irinotecan in Combination with Nedaplatin versus Irinotecan in Combination with Cisplatin as Salvage
Treatment in Refractory or Relapsed Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Shufei YU

    2013-09-01

    Full Text Available Background and objective At present no standard second-line combination has been established for recurrent small cell lung cancer (SCLC. Therefore we evaluate the efficacy and safety of irinotecan in combination with nedaplatin/cisplatin against refractory or relapsed small cell lung cancer. Methods In this retrospective study, we analyzed the data of 1,140 patients who diagnosed small cell lung cancer at our hospital from April 2009 to April 2012. Of all the patients, 34 patients were treated with irinotecan and nedaplatin (irinotecan 60 mg/m2 on days 1, 8 nedaplatin 85 mg/m2 day 1, every 3 weeks , and 20 patients were treated with irinotecan and cisplatin (irinotecan 60 mg/m2 on days 1, 8 cisplatin 75 mg/m2 day 1, every 3 weeks as the second-line treatment. Prognostic factors of overall survival (OS were estimated by Kaplan-Meier and Cox's Regression-proportional hazards model. Results Of all the 54 eligible patients, median progression free survival (PFS was 4.9 months, and median OS was 13.3 months. Median PFS was 5.4 months for irinotecan plus nedaplatin (IN and 4.9 months for irinotecan plus cisplatin (IC, respectively (P=0.465. Median OS was 14.3 months and 13.3 months, respectively (P=0.704. In multivariate analysis, ECOG PS, number of metastases and cycles of chemotherapy were independent prognostic factors. The toxicities were mild, while toxicity profile was slightly different for each of the arms: hematologic toxicity was higher in IN group, and diarrhea was higher in IC group. Conclusion Irinotecan plus platinum is effective and tolerable for refractory and relapsed small cell lung cancer. Irinotecan plus nedaplatin is non-inferior to irinotecan plus cisplatin in terms of efficacy and safety.

  19. VINDESINE WITH CYCLOPHOSPHAMIDE-EPIRUBICIN-CISPLATIN IN THE TREATMENT LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER

    Institute of Scientific and Technical Information of China (English)

    HU Yan-ping; KE Yu-hua; FU Xiao-yu

    1999-01-01

    Objective: To evaluate the addition of vindesine to a cyclophosphamide-epirubicin-cisplatin (CAP) regimen for treating the patients with locally advanced non-small cell lung cancer (NSCLC). Methods: From May 1994to August 1998, 59 previously untreated patients with stage Ⅲa and Ⅲb non-small cell lung cancer were enrolled into this trial. Patients characteristics were the following: the median age was 52 years; the median performance status was 1; there were 19 stage Ⅲa and 40 stage Ⅲb; there were 47 adenocarcinoma, 10squamous cell carcinoma and 2 large cell carcinoma. All patients were treated with vindesine (2 mg/m2, on day 1and day 8), cyclophosphamide (0.6/m2, on day 1),epirubicin (40 mg/m2, on day 1) and cisplatin (60 mg/m2,on day 1) every 3 or 4 weeks. Results: Four achieved a complete response (6.8%), 29 achieved a partial response (49.2%), 15 had stable disease, and 10 had progressive disease. A clinical improvement was in 45 of 59 patients (76.3%). The most frequent major toxic effects were myelosuppression, nausea and vomiting.Conclusion: The vindesine with CAP regimen was active combination chemotherapy in patients with locally advanced NSCLC accompanied by the limited side effects.

  20. Electrospray ionization mass spectrometry for the hydrolysis complexes of cisplatin : Implications for the hydrolysis process of platinum complexes

    NARCIS (Netherlands)

    Xie, Feifan; Colin, Pieter; Van Bocxlaer, Jan

    Non-enzyme-dependent hydrolysis of the drug cisplatin is important for its mode of action and toxicity. However, up until today, the hydrolysis process of cisplatin is still not completely understood. In the present study, the hydrolysis of cisplatin in an aqueous solution was systematically

  1. Intracellular GSH Alterations and Its Relationship to Level of Resistance following Exposure to Cisplatin in Cancer Cells.

    Science.gov (United States)

    Jamali, Bardia; Nakhjavani, Maryam; Hosseinzadeh, Leila; Amidi, Salimeh; Nikounezhad, Nastaran; H Shirazi, Farshad

    2015-01-01

    One of the major complications in cancer chemotherapy with cisplatin as one of the important medicines in treatment regimens of different cancers is the development of resistance. One of the most described cellular defense mechanisms involved in resistance is glutathione (GSH), thus in this study, the effects of cisplatin on the total intracellular GSH level (GSHi) in some sensitive and resistant variants of human cell lines (hepatocarcinoma HepG2, skin A375, cisplatin sensitive glioblastoma U373MG and cisplatin resistant glioblastoma U373MGCP, cisplatin sensitive ovary A2780S and cisplatin resistant A2780CP cells) were studied. MTT assay was performed to measure cytotoxicity of cisplatin (33.3 µM for 1 hour). Following cisplatin exposure, GSHi (per million cells) was evaluated using a photometrical assay up to 90 minutes. Our results indicate that there are significant differences between GSHi content of A2780CP and U373MGCP cells compared to other cell lines. Moreover, IC50 of cisplatin in different cells seems to have a relation with mean of GSH level in 90 minutes (GSH (mean)90). As a conclusion, it seems that resistance to cisplatin in different cell lines is more related with the diverse patterns of GSHi variations following cisplatin exposure than its original level, and/or its cellular increase or decrease. It is also suggested that GSH (mean)90 may be used as a factor for the prediction of cellular resistance to cisplatin.

  2. ROLE OF ERK1/2 KINASE IN CISPLATIN-INDUCED APOPTOSIS IN HUMAN OVARIAN CARCINOMA CELLS

    Institute of Scientific and Technical Information of China (English)

    Shu-qin Wei; Li-hua Sui; Jian-hua Zheng; Guang-mei Zhang; Yan-Lin Kao

    2004-01-01

    Objective To investigate the role of extracellular regulated kinase (ERK1/2) pathway in cisplatin-induced apoptosis in human ovarian carcinoma cells.Methods Cisplatin-induced apoptosis were stained with DAPI and was assessed microscopically in human epithelial adenocarcinoma ovarian cell line SKOV3 cells. ERK activation was determined by Western blotting using an anti-phosphoERK antibody to detect ERK activity. The effect of PD98059 on ERK activity induced by cisplatin was detected by MTT assay.Results Marked apoptosis of SKOV3 cells resulted from 48 hours treatment with 20 μg/mL cisplatin. Strong activation of ERK was led to by 15 μg/mL cisplatin. Dose response and time course of cisplatin induced apoptosis in SKOV3 cells.Cisplatin-induced ERK activation occurred at 12 hours and increased to highest induction at 24 hours by Western blotting.The effect of PD 98059 on ERK activity induced by cisplatin at the concentration of 100 μmol/L PD 98059. Statistically significant decreased in cell survival were observed with 100 μmol/L PD 98059 at 15 and 20 μg/mL cisplatin (P< 0.05).Conclusions Cisplatin activates the ERK signaling pathway in ovarian cancer cell line SKOV3. Inhibition of ERK activity enhances sensitivity to cisplatin cytotoxity in ovarian cancer cell line SKOV3. Evaluation of ERK activity could be useful in predicting which ovarian cancer will response most favorably to cisplatin therapy.

  3. Electrospray ionization mass spectrometry for the hydrolysis complexes of cisplatin : implications for the hydrolysis process of platinum complexes

    NARCIS (Netherlands)

    Xie, Feifan; Colin, Pieter; Van Bocxlaer, Jan

    2017-01-01

    Non-enzyme dependent hydrolysis of the drug cisplatin is important for its mode of action and toxicity. However, up until today, the hydrolysis process of cisplatin is still not completely understood. In the present study, the hydrolysis of cisplatin in an aqueous solution was systematically investi

  4. 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

    2015-07-21

    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 apo