Stability Studies of Certain Chemotherapeutic Agents Following Gamma Irradiation and Silver Nanoparticles Conjugation

International Nuclear Information System (INIS)

El-Sayyad, Gh.E.S.M.

2014-01-01

The Chemical stability of drug is of great importance since it becomes less effective as it undergoes degradation in case of applied of gamma irradiation process. The application of gamma irradiation for different chemotherapeutic agents Such as (ofloxacin, sodium ampicillin, sodium cefotaxime, gentamycin and amoxicillin) and studying the effect of applied doses on chemical structure and biological activity of the irradiated antibiotics compared to unirradiated ones was studied by ultraviolet-Visible spectrophotometer (UV-Visible), Fourier transform infrared spectroscopy measurements (FTIR spectra) and high performance liquid chromatography (HPLC) in addition to microbiological assay were run before and after irradiation to probe any change after irradiation. The results showed that all of the irradiated compounds remain stable and radio resistant; retaining their structure and activity unchanged up to 25 KGy. The radiation-induced AgNPs synthesis is a simple, clean which involves radiolysis of aqueous solution that provides an efficient method to reduce metal ions. Also, in this study, Bacillus megaterium was found to be an effective biological tool for the extracellular biosynthesis of stable AgNPs which are highly stable and this method has advantages over other methods as the organism used here is safe. This study would therefore lead to an easy procedure for producing silver nanoparticles with the added advantage of bio safety. The Synthesized AgNPs exhibit remarkable antimicrobial activity against both Gram-positive and Gram negative bacterial strains regardless of their drug-resistant mechanisms. The bactericidal activity have proved that AgNPs kill bacteria at such low concentrations (units of ppm), which Stability Studies of Certain Chemotherapeutic Agents Following Gamma Irradiation and Silver Nanoparticles Conjugation. do not reveal acute toxic effects on human cell, in addition to overcoming resistance, and lowering cost when compared to conventional

Current Research and Development of Chemotherapeutic Agents for Melanoma

Directory of Open Access Journals (Sweden)

Kyaw Minn Hsan

2010-04-01

Full Text Available Cutaneous malignant melanoma is the most lethal form of skin cancer and an increasingly common disease worldwide. It remains one of the most treatment-refractory malignancies. The current treatment options for patients with metastatic melanoma are limited and in most cases non-curative. This review focuses on conventional chemotherapeutic drugs for melanoma treatment, by a single or combinational agent approach, but also summarizes some potential novel phytoagents discovered from dietary vegetables or traditional herbal medicines as alternative options or future medicine for melanoma prevention. We explore the mode of actions of these natural phytoagents against metastatic melanoma.

The clinical application of ultrasonography-guided percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent for the treatment of hilar lymphatic metastasis

International Nuclear Information System (INIS)

Zhao Guangsheng; Zhang Yuewei; Yang Xiaohong; Li Chuang; Zhao Mu; Wang Wenqing; Wang Ruoyu

2010-01-01

Objective: To discuss the technique and the clinical effect of ultrasonography-guided percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent for the treatment of hepatic hilar lymphatic metastasis. Methods: Under ultrasonographic guidance,percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent, so-called chemo-ablation, into the diseased lymph nodes was performed in thirteen patients with hepatic hilar lymphatic metastasis. The therapeutic results were evaluated based on the post-operative imaging examinations as well as the alleviation of the clinical symptoms. Results: Percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent into the diseased lymph nodes was successfully carried out in all thirteen patients. After the procedure,the patients were followed up for a mean period of 13.5 months. The therapeutic effectiveness was 100%, while the regression rate of the lesions was 76.9%. No operation-related complications occurred. Conclusion: Percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent into the diseased lymph nodes under ultrasonographic guidance is an effective and safe treatment for hepatic hilar lymphatic metastasis with reliable effectiveness. (authors)

PET studies of potential chemotherapeutic agents: Pt. 10

International Nuclear Information System (INIS)

Conway, T.; Diksic, M.; McGill Univ., Montreal, PQ

1991-01-01

Carbon-11-labeled HECNU [1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea] a potential chemotherapeutic agent, has been prepared by the nitrosation of the corresponding carbon-11-labeled urea, HECU, [1-(2-chloroethyl)-3-(2-hydroxyethyl) urea]. The isomeric byproduct of nitrosation, 1-(2-chloroethyl)-3-nitroso-3-(2-hydroxyethyl) urea can be efficiently removed by preparative scale HPLC on a Partisil column. ( 11 C)-HECU was prepared by reacting ethanolamine with ( 11 C)-2-chloroethyl-isocyanate which was itself prepared by reacting ( 11 C)-phosgene with 2-chloroethylamine hydrochloride suspended in dioxane at 60-65 o C. This synthesis yielded ( 11 C)-HECNU with an average radiochemical purity of 98% in an average radiochemical yield of 18% relative to the radioactivity measured at the end of the 11 C-phosgene introduction. (author)

Activation of the human immune system by chemotherapeutic or targeted agents combined with the oncolytic parvovirus H-1

International Nuclear Information System (INIS)

Moehler, Markus; Sieben, Maike; Roth, Susanne; Springsguth, Franziska; Leuchs, Barbara; Zeidler, Maja; Dinsart, Christiane; Rommelaere, Jean; Galle, Peter R

2011-01-01

Parvovirus H-1 (H-1PV) infects and lyses human tumor cells including melanoma, hepatoma, gastric, colorectal, cervix and pancreatic cancers. We assessed whether the beneficial effects of chemotherapeutic agents or targeted agents could be combined with the oncolytic and immunostimmulatory properties of H-1PV. Using human ex vivo models we evaluated the biological and immunological effects of H-1PV-induced tumor cell lysis alone or in combination with chemotherapeutic or targeted agents in human melanoma cells +/- characterized human cytotoxic T-cells (CTL) and HLA-A2-restricted dendritic cells (DC). H-1PV-infected MZ7-Mel cells showed a clear reduction in cell viability of >50%, which appeared to occur primarily through apoptosis. This correlated with viral NS1 expression levels and was enhanced by combination with chemotherapeutic agents or sunitinib. Tumor cell preparations were phagocytosed by DC whose maturation was measured according to the treatment administered. Immature DC incubated with H-1PV-induced MZ7-Mel lysates significantly increased DC maturation compared with non-infected or necrotic MZ7-Mel cells. Tumor necrosis factor-α and interleukin-6 release was clearly increased by DC incubated with H-1PV-induced SK29-Mel tumor cell lysates (TCL) and was also high with DC-CTL co-cultures incubated with H-1PV-induced TCL. Similarly, DC co-cultures with TCL incubated with H-1PV combined with cytotoxic agents or sunitinib enhanced DC maturation to a greater extent than cytotoxic agents or sunitinib alone. Again, these combinations increased pro-inflammatory responses in DC-CTL co-cultures compared with chemotherapy or sunitinib alone. In our human models, chemotherapeutic or targeted agents did not only interfere with the pronounced immunomodulatory properties of H-1PV, but also reinforced drug-induced tumor cell killing. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a pronounced DC maturation, better cytokine

Measuring the Acoustic Release of a Chemotherapeutic Agent from Folate-Targeted Polymeric Micelles.

Science.gov (United States)

Abusara, Ayah; Abdel-Hafez, Mamoun; Husseini, Ghaleb

2018-08-01

In this paper, we compare the use of Bayesian filters for the estimation of release and re-encapsulation rates of a chemotherapeutic agent (namely Doxorubicin) from nanocarriers in an acoustically activated drug release system. The study is implemented using an advanced kinetic model that takes into account cavitation events causing the antineoplastic agent's release from polymeric micelles upon exposure to ultrasound. This model is an improvement over the previous representations of acoustic release that used simple zero-, first- and second-order release and re-encapsulation kinetics to study acoustically triggered drug release from polymeric micelles. The new model incorporates drug release and micellar reassembly events caused by cavitation allowing for the controlled release of chemotherapeutics specially and temporally. Different Bayesian estimators are tested for this purpose including Kalman filters (KF), Extended Kalman filters (EKF), Particle filters (PF), and multi-model KF and EKF. Simulated and experimental results are used to verify the performance of the above-mentioned estimators. The proposed methods demonstrate the utility and high-accuracy of using estimation methods in modeling this drug delivery technique. The results show that, in both cases (linear and non-linear dynamics), the modeling errors are expensive but can be minimized using a multi-model approach. In addition, particle filters are more flexible filters that perform reasonably well compared to the other two filters. The study improved the accuracy of the kinetic models used to capture acoustically activated drug release from polymeric micelles, which may in turn help in designing hardware and software capable of precisely controlling the delivered amount of chemotherapeutics to cancerous tissue.

Using a device for continuous infusion of a chemotherapeutic agent in the perception of the oncologic patient

Directory of Open Access Journals (Sweden)

Julianna de Freitas Siqueira

2014-01-01

Full Text Available This is a qualitative study whose aim was to describe the perception of an oncologic patient regarding the use of a device for continuous infusion of a chemotherapeutic agent. It was carried out with eight patients, through a semi-structured interview with this guiding question: “How do you feel about using a device for continuous infusion of a chemotherapeutic agent?”. Three categories emerged: avoiding hospitalization; unveiling the unknown; and performing activities. The patient highlights the benefit of going home and the possibility of performing activities, despite the anxiety regarding the presence of the device and the new experience in her/his daily life. The results were important to direct the guidelines related to the positive and negative aspects of this technology.

Polymeric Micelles with Ionic Cores Containing Biodegradable Crosslinks for Delivery of Chemotherapeutic Agents

OpenAIRE

Kim, Jong Oh; Sahay, Gaurav; Kabanov, Alexander V.; Bronich, Tatiana K.

2010-01-01

Novel functional polymeric nanocarriers with ionic cores containing biodegradable cross-links were developed for delivery of chemotherapeutic agents. Block ionomer complexes (BIC) of poly(ethylene oxide)-b-poly(methacylic acid) (PEO-b-PMA) and divalent metal cations (Ca2+) were utilized as templates. Disulfide bonds were introduced into the ionic cores by using cystamine as a biodegradable cross-linker. The resulting cross-linked micelles with disulfide bonds represented soft, hydrogel-like n...

Lung Damage due to Chemotherapeutic Agents

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Serdar Kalemci

2014-12-01

Full Text Available Chemotherapeutic drug-induced pulmonary toxicity not only emerges in cumulative doses, but also can be observed even at low dosages. Combined administration of many drugs, concurrent radiotherapy applications, opportunistic infections, lymphangitic tumor extension and pleural metastases complicate the disease diagnosis.

The chemotherapeutic agent paclitaxel selectively impairs learning while sparing source memory and spatial memory.

Science.gov (United States)

Smith, Alexandra E; Slivicki, Richard A; Hohmann, Andrea G; Crystal, Jonathon D

2017-03-01

Chemotherapeutic agents are widely used to treat patients with systemic cancer. The efficacy of these therapies is undermined by their adverse side-effect profiles such as cognitive deficits that have a negative impact on the quality of life of cancer survivors. Cognitive side effects occur across a variety of domains, including memory, executive function, and processing speed. Such impairments are exacerbated under cognitive challenges and a subgroup of patients experience long-term impairments. Episodic memory in rats can be examined using a source memory task. In the current study, rats received paclitaxel, a taxane-derived chemotherapeutic agent, and learning and memory functioning was examined using the source memory task. Treatment with paclitaxel did not impair spatial and episodic memory, and paclitaxel treated rats were not more susceptible to cognitive challenges. Under conditions in which memory was not impaired, paclitaxel treatment impaired learning of new rules, documenting a decreased sensitivity to changes in experimental contingencies. These findings provide new information on the nature of cancer chemotherapy-induced cognitive impairments, particularly regarding the incongruent vulnerability of episodic memory and new learning following treatment with paclitaxel. Copyright © 2016 Elsevier B.V. All rights reserved.

Anti-cancer effects of newly developed chemotherapeutic agent, glycoconjugated palladium (II) complex, against cisplatin-resistant gastric cancer cells

International Nuclear Information System (INIS)

Tanaka, Mamoru; Kamiya, Takeshi; Joh, Takashi; Kataoka, Hiromi; Yano, Shigenobu; Ohi, Hiromi; Kawamoto, Keisuke; Shibahara, Takashi; Mizoshita, Tsutomu; Mori, Yoshinori; Tanida, Satoshi

2013-01-01

Cisplatin (CDDP) is the most frequently used chemotherapeutic agent for various types of advanced cancer, including gastric cancer. However, almost all cancer cells acquire resistance against CDDP, and this phenomenon adversely affects prognosis. Thus, new chemotherapeutic agents that can overcome the CDDP-resistant cancer cells will improve the survival of advanced cancer patients. We synthesized new glycoconjugated platinum (II) and palladium (II) complexes, [PtCl 2 (L)] and [PdCl 2 (L)]. CDDP-resistant gastric cancer cell lines were established by continuous exposure to CDDP, and gene expression in the CDDP-resistant gastric cancer cells was analyzed. The cytotoxicity and apoptosis induced by [PtCl 2 (L)] and [PdCl 2 (L)] in CDDP-sensitive and CDDP-resistant gastric cancer cells were evaluated. DNA double-strand breaks by drugs were assessed by evaluating phosphorylated histone H2AX. Xenograft tumor mouse models were established and antitumor effects were also examined in vivo. CDDP-resistant gastric cancer cells exhibit ABCB1 and CDKN2A gene up-regulation, as compared with CDDP-sensitive gastric cancer cells. In the analyses of CDDP-resistant gastric cancer cells, [PdCl 2 (L)] overcame cross-resistance to CDDP in vitro and in vivo. [PdCl 2 (L)] induced DNA double-strand breaks. These results indicate that [PdCl 2 (L)] is a potent chemotherapeutic agent for CDDP-resistant gastric cancer and may have clinical applications

In vitro sensitivity of Trichomonas vaginalis and Candida albicans to chemotherapeutic agents.

Science.gov (United States)

Lövgren, T; Salmela, I

1978-06-01

Strains of fresh clinical isolates of Trichomonas vaginalis and Candida albicans have been tested in vitro for their sensitivity to eight drugs used in the therapy of monilial and trichomonal vaginitis. Three of the chemotherapeutic agents, chlorchinaldol, clotrimazole and broxyquinoline were effective against both organisms. Tinidazole and metronidazole were active against T. vaginalis. The strains of C. albicans were also sensitive to trichomycin, natamycin and nystatin. Tinidazole was the most effective trichomonacide, clotrimazole and chlorchinaldol were most effective against C. albicans, while chlorchinaldol had the best in vitro effect against both organisms. The ranges of the MICs are compared to values previously reported.

Utilization of a selective tumour artery catheterization technique for the intra-arterial delivery of chemotherapeutic agents and radiopharmaceuticals in a combined chemotherapy-radiotherapy clinical research programme

International Nuclear Information System (INIS)

Wiley, A.L. Jr.; Wirtanen, G.W.; Holden, J.E.; Polcyn, R.E.

1977-01-01

Combined intra-arterial chemotherapeutic agents (principally actinomycin-D) and radiation therapy has been utilized in the treatment of 35 patients with massive unresectable malignancies. The goals may be separated into three distinct categories. An attempt has been made to convert unresectable malignancies to surgical resectability, to provide a definitive therapy for massive tumours in patients who either refuse surgery or are not surgery candidates, and to provide palliation. Twelve of 15 initially unresectable tumours treated with actinomycin-D became surgically resectable (no resection was attempted in the other four because they either developed metastasis during therapy or did not complete the therapy), 4 of 6 massive tumours treated definitively have remained locally controlled from 18 to 108 months, and 7 of 9 patients treated palliatively were significantly benefited by the therapy. Impressive responses were also achieved in several patients treated with intra-arterial 5-fluorouracil and 5-iodo-2'-deoxyuridine. The authors therefore consider combined, concurrent radiation therapy and intra-arterially administered chemotherapeutic agents worthy of further clinical investigation as a means of treating massive malignancies. They also suggest that the best chance of optimizing the therapeutic ratio of such therapy is dependent primarily on a proper understanding of clinical tumour vascularity and of its subsequent effect on drug and oxygen distributions within the radiation treatment volume. Accordingly, tumour vascularity has been clinically evaluated by the use of intra-arterially administered radiopharmaceuticals. Such clinical data, in conjunction with radiobiological data, might in the future be utilized to optimize both low and high LET combined therapy by allowing for correction of the physical isodose for drug and oxygen concentration variations. (author)

Chemotherapeutic targets in parasites: contemporary strategies

National Research Council Canada - National Science Library

Mansour, Tag E; Mansour, Joan MacKinnon

2002-01-01

... identify effective antiparasitic agents. An introduction to the early development of parasite chemotherapy is followed by an overview of biophysical techniques and genomic and proteomic analyses. Several chapters are devoted to specific types of chemotherapeutic agents and their targets in malaria, trypanosomes, leishmania, and amitochondrial...

Pyrimidine nucleoside analogues, potential chemotherapeutic agents, and substrates/inhibitors in various enzyme systems

International Nuclear Information System (INIS)

Kulikowski, T.; Bretner, M.; Felczak, K.; Drabikowska, A.; Shugar, D.

1998-01-01

Full text. Pyrimidine nucleoside analogues are an important class of compounds with antimetabolic (antitumor, antiparasitic and antiviral) properties. The synthesis of thiated nucleoside and nucleotide analogues, determination of structures, conformation and dissociation constans, their potential chemotherapeutic activities, and their substrate/inhibitor properties in various enzyme systems, with emphasis on enzymes related to chemotherapeutic activities, were investigated. In the series of thionated inhibitors of thymidylate synthase (TS), potential antitumor agents, regioselective syntheses were elaborated for 2- and 4-thio, and 2,4-dithio derivatives of 2'-deoxyuridine (dUrd), 5-fluoro-2'-deoxyuridine (FdUrd), and several other 5-fluoro-, 5-bromo- and 5-trifluoromethyl congeners, and the 2-thio derivatives of FdUrd and its α-anomer, which proved to be selective agents with high cytotoxicities correlated with the inhibitory activities vs TS of their corresponding 5'-monophosphates. Regioslective syntheses were also elaborated for 2'-deoxycytidin e and 5-fluoro-2'-deoxycitidine derivatives. Solution conformation of these nucleosides were deduced from high-resolution (500 MHz) 1 H NMR spectra. Substrate/inhibitor properties of 2-thio-2'-deoxycitidine (S 2 dCyd) and 5-fluoro-2-thio-2'-deoxycitidine ( S 2 FdCyd) with respect to human leukemic spleen deoxycytidine kinase have been examined. Both are substrates, and also good inhibitors, of phosphorylation of 2'-deoxycitidine and 2'-deoxyadenosine. Particular attention was directed to the specificity of t he NTP phosphate donor for several nucleoside kinases, and procedures have been developed for distinguishing between ATP and other NTP donors, a problem of importance in chemotherapy with nucleoside analogues. Biological properties of the newly synthetize d thiated pyrimidine 2',3'-dideoxy-3'-fluoronucleosides, S 2 ,3'-FddUrd and S 2 ,3'-FddThd, were also investigated. Thiated 3'-fluoronucleosides were moderate

Optimal Classes of Chemotherapeutic Agents Sensitized by Specific Small-Molecule Inhibitors of Akt In Vitro and In Vivo

Directory of Open Access Journals (Sweden)

Yan Shi

2005-11-01

Full Text Available Akt is a serine/threonine kinase that transduces survival signals from survival/growth factors. Deregulation and signal imbalance in cancer cells make them prone to apoptosis. Upregulation or activation of Akt to aid the survival of cancer cells is a common theme in human malignancies. We have developed small-molecule Akt inhibitors that are potent and specific. These Akt inhibitors can inhibit Akt activity and block phosphorylation by Akt on multiple downstream targets in cells. Synergy in apoptosis induction was observed when Akt inhibitors were combined with doxorubicin or camptothecin. Akt inhibitor-induced enhancement of topoisomerase inhibitor cytotoxicity was also evident in long-term cell survival assay. Synergy with paclitaxel in apoptosis induction was evident in cells pretreated with paclitaxel, and enhancement of tumor delay by paclitaxel was demonstrated through cotreatment with Akt inhibitor Compound A (A-443654. Combination with other classes of chemotherapeutic agents did not yield any enhancement of cytotoxicity. These findings provide important guidance in selecting appropriate classes of chemotherapeutic agents for combination with Akt inhibitors in cancer treatment.

Radiation recall cutaneous induced by chlorambucil. Case report

International Nuclear Information System (INIS)

Dei-Cas, Ignacio; Wright, Dolores; Rigo, Bettina; Cohen Sabban, Emilia; Lacasagne, Jorgelina; Pietropaolo, Nelida; Cabo, Horacio; Molina, Malena

2005-01-01

Radiation recall refers to a tissue reaction produced by the use of certain drugs, usually chemotherapeutic agents, in a previously irradiated area. We report a patient with cutaneous radiation recall associated with chlorambucil, drug previously unreported as a causative agent in the literature. (author) [es

Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

Directory of Open Access Journals (Sweden)

Li X

2015-12-01

Full Text Available Xiaoyu Li, Meiying Wu, Limin Pan, Jianlin Shi State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, People’s Republic of China Abstract: To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4 and a chemotherapeutic drug (doxorubicin and conjugate with targeting molecules (iRGD peptide for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. Keywords: mesoporous silica nanoparticles, drug delivery, tumor vasculatures targeting, antiangiogenic agent

PET studies of potential chemotherapeutic agents: Pt. 10; Synthesis of ''no-carrier-added'' ( sup 11 C)-HECNU: the hydroxyethyl analog of the chemotherapeutic agent BCNU

Energy Technology Data Exchange (ETDEWEB)

Conway, T.; Diksic, M. (Montreal Neurological Inst. and Hospital, PQ (Canada). McConnell Brain Imaging Centre McGill Univ., Montreal, PQ (Canada). Dept. of Neurology and Neurosurgery)

1991-01-01

Carbon-11-labeled HECNU (1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea) a potential chemotherapeutic agent, has been prepared by the nitrosation of the corresponding carbon-11-labeled urea, HECU, (1-(2-chloroethyl)-3-(2-hydroxyethyl) urea). The isomeric byproduct of nitrosation, 1-(2-chloroethyl)-3-nitroso-3-(2-hydroxyethyl) urea can be efficiently removed by preparative scale HPLC on a Partisil column. ({sup 11}C)-HECU was prepared by reacting ethanolamine with ({sup 11}C)-2-chloroethyl-isocyanate which was itself prepared by reacting ({sup 11}C)-phosgene with 2-chloroethylamine hydrochloride suspended in dioxane at 60-65{sup o}C. This synthesis yielded ({sup 11}C)-HECNU with an average radiochemical purity of 98% in an average radiochemical yield of 18% relative to the radioactivity measured at the end of the {sup 11}C-phosgene introduction. (author).

Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells

Directory of Open Access Journals (Sweden)

Coffey Matthew C

2009-07-01

Full Text Available Abstract Background Reovirus type 3 Dearing strain (ReoT3D has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers. Its human safety and potential efficacy are currently being investigated in early clinical trials. In this study, we investigated the in vitro combination effects of ReoT3D and chemotherapeutic agents against human non-small cell lung cancer (NSCLC. Results ReoT3D alone exerted significant cytolytic activity in 7 of 9 NSCLC cell lines examined, with the 50% effective dose, defined as the initial virus dose to achieve 50% cell killing after 48 hours of infection, ranging from 1.46 ± 0.12 ~2.68 ± 0.25 (mean ± SD log10 pfu/cell. Chou-Talalay analysis of the combination of ReoT3D with cisplatin, gemcitabine, or vinblastine demonstrated strong synergistic effects on cell killing, but only in cell lines that were sensitive to these compounds. In contrast, the combination of ReoT3D and paclitaxel was invariably synergistic in all cell lines tested, regardless of their levels of sensitivity to either agent. Treatment of NSCLC cell lines with the ReoT3D-paclitaxel combination resulted in increased poly (ADP-ribose polymerase cleavage and caspase activity compared to single therapy, indicating enhanced apoptosis induction in dually treated NSCLC cells. NSCLC cells treated with the ReoT3D-paclitaxel combination showed increased proportions of mitotic and apoptotic cells, and a more pronounced level of caspase-3 activation was demonstrated in mitotically arrested cells. Conclusion These data suggest that the oncolytic activity of ReoT3D can be potentiated by taxanes and other chemotherapeutic agents, and that the ReoT3D-taxane combination most effectively achieves synergy through accelerated apoptosis triggered by prolonged mitotic arrest.

Susceptibility of ATM-deficient pancreatic cancer cells to radiation.

Science.gov (United States)

Ayars, Michael; Eshleman, James; Goggins, Michael

2017-05-19

Ataxia telangiectasia mutated (ATM) is inactivated in a significant minority of pancreatic ductal adenocarcinomas and may be predictor of treatment response. We determined if ATM deficiency renders pancreatic cancer cells more sensitive to fractionated radiation or commonly used chemotherapeutics. ATM expression was knocked down in three pancreatic cancer cell lines using ATM-targeting shRNA. Isogenic cell lines were tested for sensitivity to several chemotherapeutic agents and radiation. DNA repair kinetics were analyzed in irradiated cells using the comet assay. We find that while rendering pancreatic cancer cells ATM-deficient did not significantly change their sensitivity to several chemotherapeutics, it did render them exquisitely sensitized to radiation. Pancreatic cancer ATM status may help predict response to radiotherapy.

Suppression of NRF2–ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells

International Nuclear Information System (INIS)

Peng, Hui; Wang, Huihui; Xue, Peng; Hou, Yongyong; Dong, Jian; Zhou, Tong; Qu, Weidong; Peng, Shuangqing; Li, Jin; Carmichael, Paul L.; Nelson, Bud; Clewell, Rebecca; Zhang, Qiang; Andersen, Melvin E.; Pi, Jingbo

2016-01-01

Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the antioxidant response element (ARE)-dependent transcription, plays a pivotal role in chemical detoxification in normal and tumor cells. Consistent with previous findings that NRF2–ARE contributes to chemotherapeutic resistance of cancer cells, we found that stable knockdown of NRF2 by lentiviral shRNA in human acute monocytic leukemia (AML) THP-1 cells enhanced the cytotoxicity of several chemotherapeutic agents, including arsenic trioxide (As 2 O 3 ), etoposide and doxorubicin. Using an ARE-luciferase reporter expressed in several human and mouse cells, we identified a set of compounds, including isonicotinic acid amides, isoniazid and ethionamide, that inhibited NRF2–ARE activity. Treatment of THP-1 cells with ethionamide, for instance, significantly reduced mRNA expression of multiple ARE-driven genes under either basal or As 2 O 3 -challenged conditions. As determined by cell viability and cell cycle, suppression of NRF2–ARE by ethionamide also significantly enhanced susceptibility of THP-1 and U937 cells to As 2 O 3 -induced cytotoxicity. In THP-1 cells, the sensitizing effect of ethionamide on As 2 O 3 -induced cytotoxicity was highly dependent on NRF2. To our knowledge, the present study is the first to demonstrate that ethionamide suppresses NRF2–ARE signaling and disrupts the transcriptional network of the antioxidant response in AML cells, leading to sensitization to chemotherapeutic agents. - Highlights: • Identification of novel inhibitors of ARE-dependent transcription • Suppression of NRF2–ARE sensitizes THP-1 cells to chemotherapy. • Ethionamide suppresses ARE-dependent transcriptional activity. • Ethionamide and isoniazid increase the cytotoxicity of As 2 O 3 in AML cells. • Sensitization of THP-1 cells to As 2 O 3 toxicity by ethionamide is NRF2-dependent.

Investigation of the interaction of radiation and cardiotoxic anticancer agents using a fetal mouse heart organ culture system

International Nuclear Information System (INIS)

Kimler, B.F.; Rethorst, R.D.; Cox, G.G.

1985-01-01

The fetal mouse heart organ culture was utilized in an attempt to predict the cardiotoxic effects of combinations of radiation, Adriamycin (ADR), and Dihydroxyanthraquinone (DHAQ), antineoplastic agents which have been shown to produce clinical cardiomyopathy. Seventeen-day fetal hearts were removed and placed in a culture system of micro-titer plates. A single heart was placed in each well on a piece of aluminum mesh to keep the heart above the culture medium but bathed by capillary action. The plates were then placed in a 100% oxygen environment at 37 0 C. Treatments were performed on day 1 after culture: radiation doses (Cs-137) of 10, 20, or 40 Gy; drug treatment with 10, 30, or 100 μg/ml of ADR; 5, 20, or 50 μg/ml of DHAQ; and combinations and sequences of drug and radiation. Hearts were checked every day for functional activity as evidenced by a continuous heart beat. Untreated hearts beat rhythmically for up to 9 days; treated hearts stopped beating earlier. Using an endpoint of functional retention time, dose response curves were obtained for all individual agents and for combinations of agents. This system may help to predict the cardiotoxic effects that result from the use of these drugs and radiation. It may also aid in the development of new anthracycline chemotherapeutic agents that lack cardiotoxicity

Radiation Recall Reaction: Two Case Studies Illustrating an Uncommon Phenomenon Secondary to Anti-Cancer Agents

International Nuclear Information System (INIS)

Zhu, Su-yu; Yuan, Yuan; Xi, Zhen

2012-01-01

Radiation recall phenomenon is a tissue reaction that develops throughout a previously irradiated area, precipitated by the administration of certain drugs. Radiation recall is uncommon and easily neglected by physicians; hence, this phenomenon is underreported in literature. This manuscript reports two cases of radiation recall. First, a 44-year-old man with nasopharyngeal carcinoma was treated with radiotherapy in 2010 and subsequently developed multi-site bone metastases. A few days after the docetaxel-based chemotherapy, erythema and papules manifested dermatitis, as well as swallowing pain due to pharyngeal mucositis, developed on the head and neck that strictly corresponded to the previously irradiated areas. Second, a 19-year-old man with recurrent nasal NK/T cell lymphoma initially underwent radiotherapy followed by chemotherapy after five weeks. Erythema and edema appeared only at the irradiated skin. Both cases were considered chemotherapeutic agents that incurred radiation recall reactions. Clinicians should be knowledgeable of and pay attention to such rare phenomenon

African indigenous plants with chemotherapeutic potentials and ...

African Journals Online (AJOL)

Herbal-based and plant-derived products can be exploited with sustainable comparative and competitive advantage. This review presents some indigenous African plants with chemotherapeutic properties and possible ways of developing them into potent pharmacological agents using biotechnological approaches.

Participation of MT3 melatonin receptors in the synergistic effect of melatonin on cytotoxic and apoptotic actions evoked by chemotherapeutics.

Science.gov (United States)

Pariente, Roberto; Bejarano, Ignacio; Espino, Javier; Rodríguez, Ana B; Pariente, José A

2017-11-01

Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant actions. Therefore, melatonin may be useful in the treatment of tumors in association with chemotherapy drugs. This study was performed to study the role of melatonin receptors on the cytotoxicity and apoptosis induced by the chemotherapeutic agents cisplatin and 5-fluorouracil in two tumor cell lines, such as human colorectal cancer HT-29 cells and cervical cancer HeLa cells. We found that both melatonin and the two chemotherapeutic agents tested induced a decrease in HT-29 and HeLa cell viability. Furthermore, melatonin significantly increased the cytotoxic effect of chemotherapeutic agents, particularly, in 5-fluorouracil-challenged cells. Stimulation of cells with either of the two chemotherapeutic agents in the presence of melatonin further increased caspase-3 activation. Concomitant treatments with melatonin and chemotherapeutic agents augmented the population of apoptotic cells compared to the treatments with chemotherapeutics alone. Blockade of MT1 and/or MT2 receptors with luzindole or 4-P-PDOT was unable to reverse the enhancing effects of melatonin on both cytotoxicity, caspase-3 activation and the amount of apoptotic cells evoked by the chemotherapeutic agents, whereas when MT3 receptors were blocked with prazosin, the synergistic effect of melatonin with chemotherapy on cytotoxicity and apoptosis was reversed. Our findings provided evidence that in vitro melatonin strongly enhances chemotherapeutic-induced cytotoxicity and apoptosis in two tumor cell lines, namely HT-29 and HeLa cells and, this potentiating effect of melatonin is mediated by MT3 receptor stimulation.

[Relationship between sensitivity of tumor cells to chemotherapeutic agent in vivo and in vitro: experiment with mouse lymphoma cells].

Science.gov (United States)

Li, Chuan-gang; Li, Mo-lin; Shu, Xiao-hong; Jia, Yu-jie; Liu, Yong-ji; Li, Ming

2007-06-12

To study the relationship of the sensitivity of tumor cells to chemotherapeutic agent between in vivo and in vitro. Mouse lymphoma cells of the line E14 were cultured and melphalan resistant EL4 cell line (EL4/melphalan) was established by culturing EL4 cells with continuous low-concentration and intermittent gradually-increasing-concentration of melphalan in vitro. MTT assay was used to evaluate the drug sensitivity and the resistance index of the EL4/melphalan cells to melphalan was calculated. EL4/melphalan and EL4 cells of the concentration of 5 x 10(8)/L were inoculated separately into 20 C57BL/6 mice subcutaneously. 12 days later, the EL4 and EL4/melphalan tumor-bearing mice were randomly divided into 2 groups respectively, 5 mice in each group. Treatment groups were given 7.5 mg/kg melphalan intraperitoneally, and control groups were given the same volume of normal saline. The tumor size was observed every other day. Compared with the EL4 cells, the EL4/melphalan cells had no obvious changes morphologically. They could grow in RPMI 1640 medium containing 5 mg/ml melphalan. The resistance index was 2.87 against melphalan. After the treatment of melphalan of the dose 7.5 mg/kg, the tumor sizes of the treatment groups and control groups inoculated with both EL4 cells and the EL4/melphalan cells gradually decreased at the similar speed, and about one week later all tumors disappeared. However, the tumors of the control groups grew progressively and all the mice died at last. The chemotherapeutic effects of tumors in vivo have nothing to do with the effects of the chemotherapeutic agents on tumor cells in vitro. The tumor cells resistant to melphalan in vitro remain sensitive to the drug in vivo.

Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice

Science.gov (United States)

Foley, John J.; Clark-Vetri, Rachel; Raffa, Robert B.

2011-01-01

Rationale A number of cancer chemotherapeutic agents have been associated with a loss of memory in breast cancer patients although little is known of the causality of this effect. Objectives To assess the potential cognitive effects of repeated exposure to chemotherapeutic agents, we administered the selective estrogen receptor modulator tamoxifen or the antimetabolite chemotherapy, methotrexate, and 5-fluorouracil, alone and in combination to mice and tested them in a learning and memory assay. Methods Swiss-Webster male mice were injected with saline, 32 mg/kg tamoxifen, 3.2 or 32 mg/kg methotrexate, 75 mg/kg 5-fluorouracil, 3.2 or 32 mg/kg methotrexate in combination with 75 mg/kg 5-fluorouracil once per week for 3 weeks. On days 23 and 24, mice were tested for acquisition and retention of a nose-poke response in a learning procedure called autoshaping. In addition, the acute effects of tamoxifen were assessed in additional mice in a similar procedure. Results The chemotherapeutic agents alone and in combination reduced body weight relative to saline treatment over the course of 4 weeks. Repeated treatment with tamoxifen produced both acquisition and retention effects relative to the saline-treated group although acute tamoxifen was without effect except at a behaviorally toxic dose. Repeated treatment with methotrexate in combination with 5-fluorouracil produced effects on retention, but the magnitude of these changes depended on the methotrexate dose. Conclusions These data demonstrate that repeated administration of tamoxifen or certain combination of methotrexate and 5-fluorouracil may produce deficits in the acquisition or retention of learned responses which suggest potential strategies for prevention or remediation might be considered in vulnerable patient populations. PMID:21537942

Suppression of NRF2–ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells

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Peng, Hui [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC (United States); Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing (China); Wang, Huihui [School of Public Health, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang (China); Xue, Peng [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC (United States); Key Laboratory of the Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai (China); Hou, Yongyong [School of Public Health, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang (China); Dong, Jian [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC (United States); Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan (China); Zhou, Tong [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC (United States); Qu, Weidong [Key Laboratory of the Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai (China); Peng, Shuangqing [Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing (China); Li, Jin; Carmichael, Paul L. [Unilever, Safety & Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ (United Kingdom); Nelson, Bud; Clewell, Rebecca; Zhang, Qiang; Andersen, Melvin E. [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC (United States); Pi, Jingbo, E-mail: jpi@mail.cmu.edu.cn [School of Public Health, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang (China); The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC (United States)

2016-02-01

Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the antioxidant response element (ARE)-dependent transcription, plays a pivotal role in chemical detoxification in normal and tumor cells. Consistent with previous findings that NRF2–ARE contributes to chemotherapeutic resistance of cancer cells, we found that stable knockdown of NRF2 by lentiviral shRNA in human acute monocytic leukemia (AML) THP-1 cells enhanced the cytotoxicity of several chemotherapeutic agents, including arsenic trioxide (As{sub 2}O{sub 3}), etoposide and doxorubicin. Using an ARE-luciferase reporter expressed in several human and mouse cells, we identified a set of compounds, including isonicotinic acid amides, isoniazid and ethionamide, that inhibited NRF2–ARE activity. Treatment of THP-1 cells with ethionamide, for instance, significantly reduced mRNA expression of multiple ARE-driven genes under either basal or As{sub 2}O{sub 3}-challenged conditions. As determined by cell viability and cell cycle, suppression of NRF2–ARE by ethionamide also significantly enhanced susceptibility of THP-1 and U937 cells to As{sub 2}O{sub 3}-induced cytotoxicity. In THP-1 cells, the sensitizing effect of ethionamide on As{sub 2}O{sub 3}-induced cytotoxicity was highly dependent on NRF2. To our knowledge, the present study is the first to demonstrate that ethionamide suppresses NRF2–ARE signaling and disrupts the transcriptional network of the antioxidant response in AML cells, leading to sensitization to chemotherapeutic agents. - Highlights: • Identification of novel inhibitors of ARE-dependent transcription • Suppression of NRF2–ARE sensitizes THP-1 cells to chemotherapy. • Ethionamide suppresses ARE-dependent transcriptional activity. • Ethionamide and isoniazid increase the cytotoxicity of As{sub 2}O{sub 3} in AML cells. • Sensitization of THP-1 cells to As{sub 2}O{sub 3} toxicity by ethionamide is NRF2-dependent.

Hyperthermia and chemotherapy agent

International Nuclear Information System (INIS)

Roizin-Towle, L.; Hall, E.J.

1981-01-01

The use of chemotherapeutic agents for the treatment of cancer dates back to the late 19th century, but the modern era of chemotherapy drugs was ushered in during the 1940's with the development of the polyfunctional alkylating agent. Since then, numerous classes of drugs have evolved and the combined use of antineoplastic agents with other treatment modalities such as radiation or heat, remains a large relatively unexplored area. This approach, combining local hyperthermia with chemotherapy agents affords a measure of targeting and selective toxicity not previously available for drugs. In this paper, the effects of adriamycin, bleomycin and cis-platinum are examined. The adjuvant use of heat may also reverse the resistance of hypoxic cells noted for some chemotherapy agents

Combined Effects of Fe3O4 Nanoparticles and Chemotherapeutic Agents on Prostate Cancer Cells In Vitro

Directory of Open Access Journals (Sweden)

Kanako Kojima

2018-01-01

Full Text Available Patients with metastatic castration-resistant prostate cancer (mCRPC have poor outcomes. Docetaxel (DTX-based therapy is a current standard treatment for patients with mCRPC. Approaches combining conventional chemotherapeutic agents and nanoparticles (NPs, particularly iron oxide NPs, may overcome the serious side effects and drug resistance, resulting in the establishment of new therapeutic strategies. We previously reported the combined effects of Fe3O4 nanoparticles (Fe3O4 NPs with DTX on prostate cancer cells in vitro. In this study, we investigated the combined effects of Fe3O4 NPs and rapamycin or carboplatin on prostate cancer cells in vitro. Treatment of DU145 and PC-3 cells with Fe3O4 NPs increased intracellular reactive oxygen species (ROS levels in a concentration-dependent manner. Treatment of both cell lines with 100 μg/mL Fe3O4 NPs for 72 h resulted in significant inhibition of cell viability with a different inhibitory effect. Combination treatments with 100 µg/mL Fe3O4 NPs and 10 µM carboplatin or 10 nM rapamycin in DU145 and PC-3 cells significantly decreased cell viability. Synergistic effects on apoptosis were observed in PC-3 cells treated with Fe3O4 NPs and rapamycin and in DU145 cells with Fe3O4 NPs and carboplatin. These results suggest the possibility of combination therapy with Fe3O4 NPs and various chemotherapeutic agents as a novel therapeutic strategy for patients with mCRPC.

1,3-Bis(2-chloroethyl)-1-nitrosourea-loaded bovine serum albumin nanoparticles with dual magnetic resonance-fluorescence imaging for tracking of chemotherapeutic agents.

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Wei, Kuo-Chen; Lin, Feng-Wei; Huang, Chiung-Yin; Ma, Chen-Chi M; Chen, Ju-Yu; Feng, Li-Ying; Yang, Hung-Wei

To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2). These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1) of FITC-BSA-Gd/BCNU NPs was 3.25 mM(-1) s(-1), which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM(-1) s(-1)). The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy.

Effect of time intervals between irradiation and chemotherapeutic agents on the normal tissue damage. Comparison between in vivo and in vitro experiments

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Ito, Hisao; Nakayama, Toshitake; Hashimoto, Shozo (Keio Univ., Tokyo (Japan). School of Medicine)

1989-05-01

Experiments have been carried out to determine the effect on the cell survivals at different time intervals between irradiation and chemotherapeutic agents (BLM, cisDDP, ADM and ACNU) in either the in vivo or the in vitro system. The intestinal epithelial assay was applied on the in vivo system. The clonogenic cell survivals of V/sub 79/ cells, both in the proliferative and the plateau phases, were determined in the in vitro system. The V/sub 79/ cells in the plateau phase were more sensitive to BLM, cisDDP and ACNU than those in the proliferative phase, however, the result was reverse with ADM. When BLM, cisDDP or ACNU was combined with irradiation at different time intervals, the response of the plateau phase V/sub 79/ cells to combination therapies were very similar to those of the intestinal epithelial cells. On the other hand, V/sub 79/ cells in the proliferative phase, which were treated with ADM and irradiation, showed the similar response as the intestinal cells. These results suggest that studies of chemo-radiotherapy with cultured cells which are sensitive to chemotherapeutic agents might be suitable to expect the in vivo damage of the normal tissue. (author).

The use of chemotherapeutics for the treatment of keloid scars

Directory of Open Access Journals (Sweden)

Christopher David Jones

2015-05-01

Full Text Available Keloid scars are pathological scars, which develop as a result of exaggerated dermal tissue proliferation following cutaneous injury and often cause physical, psychological and cosmetic problems. Various theories regarding keloidogenesis exist, however the precise pathophysiological events remain unclear. Many different treatment modalities have been implicated in their management, but currently there is no entirely satisfactory method for treating all keloid lesions. We review a number of different chemotherapeutic agents which have been proposed for the treatment of keloid and hypertrophic scars while giving insight into some of the novel chemotherapeutic drugs which are currently being investigated. Non-randomized trials evaluating the influence of different chemotherapeutic agents, such as 5-fluorouracil (5-FU; mitomycin C; bleomycin and steroid injection, either alone or in combination with other chemotherapeutic agents or alternative treatment modalities, for the treatment of keloids were identified using a predefined PubMed search strategy. Twenty seven papers were identified. Scar improvement ≥50% was found in the majority of cases treated with 5-FU, with similar results found for mitomycin C, bleomycin and steroid injection. Combined intralesional 5-FU and steroid injection produced statistically significant improvements when compared to monotherapy. Monotherapy recurrence rates ranged from 0-47% for 5-FU, 0-15% for bleomycin and 0-50% for steroid injection. However, combined therapy in the form of surgical excision and adjuvant 5-FU or steroid injections demonstrated lower recurrence rates; 19% and 6% respectively. Currently, most of the literature supports the use of combination therapy (usually surgery and adjuvant chemotherapy as the mainstay treatment of keloids, however further investigation is necessary to determine success rates over longer time frames. Furthermore, there is the potential for novel therapies, but further

Suspension culture combined with chemotherapeutic agents for sorting of breast cancer stem cells

International Nuclear Information System (INIS)

Li, Hai-zhi; Yi, Tong-bo; Wu, Zheng-yan

2008-01-01

Cancer stem cell (CSC) hypothesis has not been well demonstrated by the lack of the most convincing evidence concerning a single cell capable of giving rise to a tumor. The scarcity in quantity and improper approaches for isolation and purification of CSCs have become the major obstacles for great development in CSCs. Here we adopted suspension culture combined with anticancer regimens as a strategy for screening breast cancer stem cells (BrCSCs). BrCSCs could survive and be highly enriched in non-adherent suspension culture while chemotherapeutic agents could destroy most rapidly dividing cancer cells and spare relatively quiescent BrCSCs. TM40D murine breast cancer cells were cultured in serum-free medium. The expression of CD44 + CD24 - was measured by flow cytometry. Cells of passage 10 were treated in combination with anticancer agents pacilitaxel and epirubicin at different peak plasma concentrations for 24 hours, and then maintained under suspension culture. The rate of apoptosis was examined by flow cytometry with Annexin-V fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining method. Selected cells in different amounts were injected subcutaneously into BALB/C mice to observe tumor formation. Cells of passage 10 in suspension culture had the highest percentage of CD44 + CD24 - (about 77 percent). A single tumor cell in 0.35 PPC could generate tumors in 3 of 20 BALB/C mice. Suspension culture combined with anticancer regimens provides an effective means of isolating, culturing and purifying BrCSCs

Polymeric micelles with ionic cores containing biodegradable cross-links for delivery of chemotherapeutic agents.

Science.gov (United States)

Kim, Jong Oh; Sahay, Gaurav; Kabanov, Alexander V; Bronich, Tatiana K

2010-04-12

Novel functional polymeric nanocarriers with ionic cores containing biodegradable cross-links were developed for delivery of chemotherapeutic agents. Block ionomer complexes (BIC) of poly(ethylene oxide)-b-poly(methacylic acid) (PEO-b-PMA) and divalent metal cations (Ca(2+)) were utilized as templates. Disulfide bonds were introduced into the ionic cores by using cystamine as a biodegradable cross-linker. The resulting cross-linked micelles with disulfide bonds represented soft, hydrogel-like nanospheres and demonstrated a time-dependent degradation in the conditions mimicking the intracellular reducing environment. The ionic character of the cores allowed to achieve a very high level of doxorubicin (DOX) loading (50% w/w) into the cross-linked micelles. DOX-loaded degradable cross-linked micelles exhibited more potent cytotoxicity against human A2780 ovarian carcinoma cells as compared to micellar formulations without disulfide linkages. These novel biodegradable cross-linked micelles are expected to be attractive candidates for delivery of anticancer drugs.

Enterobacter and Klebsiella species isolated from fresh vegetables marketed in Valencia (Spain) and their clinically relevant resistances to chemotherapeutic agents.

Science.gov (United States)

Falomir, María Pilar; Rico, Hortensia; Gozalbo, Daniel

2013-12-01

Occurrence of antibiotic-resistant pathogenic or commensal enterobacteria in marketed agricultural foodstuffs may contribute to their incorporation into the food chain and constitutes an additional food safety concern. In this work, we have determined the clinically relevant resistances to 11 common chemotherapeutic agents in Enterobacter and Klebsiella isolates from fresh vegetables from various sources (supermarkets and greengrocers' shops in Valencia, Spain). A total of 96 isolates were obtained from 160 vegetables analyzed (50% positive samples): 68 Enterobacter isolates (59 E. cloacae, two E. aerogenes, two E. cancerogenus, one E. gergoviae, and four E. sakazakii, currently Cronobacter spp.), and 28 Klebsiella isolates (19 K. oxytoca and 9 K. pneumoniae). Only seven isolates were susceptible to all agents tested, and no resistances to ceftazidime, ciprofloxacin, gentamicin, and chloramphenicol were detected. Most isolates were resistant to amoxicillin/clavulanic acid (74 [58 Enterobacter and 16 Klebsiella]) or to ampicillin (80 [55/25]). Other resistances were less frequent: nitrofurantoin (13 isolates [12/1]), tetracycline (6 [5/1]), co-trimoxazole (3 [3/0]), cefotaxime (1 [1/0]), and streptomycin (2 [1/1]). Multiresistant isolates to two (56 [41/15]), three (10 E. cloacae isolates), four (one E. cloacae and one K. pneumoniae isolate), and five (two E. cloacae isolates) chemotherapeutic agents were also detected. The presence of potential pathogens points to marketed fresh produce, which often is eaten raw, as a risk factor for consumer health. In addition, these results support the usefulness of these bacterial species as indicators of the spreading of antibiotic resistances into the environment, particularly in the food chain, and suggest their role as carriers of resistance determinants from farms to consumers, which may constitute an additional "silent" food safety concern. Therefore, there is a need to improve the hygienic quality of marketed fresh

Role of Reactive Oxygen Species and Nitric Oxide in Mediating Chemotherapeutic Drug Induced Bystander Response in Human Cancer Cells Exposed In-Vitro

Science.gov (United States)

Chinnadurai, Mani; Rao, Bhavna S; Deepika, Ramasamy; Paul, Solomon F.D.; Venkatachalam, Perumal

2012-01-01

Background The intention of cancer chemotherapy is to control the growth of cancer cells using chemical agents. However, the occurrence of second malignancies has raised concerns, leading to re-evaluation of the current strategy in use for chemotherapeutic agents. Although the mechanisms involved in second malignancy remain ambiguous, therapeutic-agent-induced non-DNA targeted effects like bystander response and genomic instability cannot be eliminated completely. Hence, Bleomycin (BLM) and Neocarzinostatin (NCS), chemotherapeutic drugs with a mode of action similar to ionizing radiation, were used to study the mechanism of bystander response in human cancer cells (A549, CCRF-CEM and HL-60) by employing co-culture methodology. Methods Bystander effect was quantified using micronucleus (MN) assay and in-situ immunofluorescence(γH2AX assay).The role of reactive oxygen species (ROS) and nitric oxide (NO) in mediating the bystander response was explored by pre-treating bystander cells with dimethylsulphoxide (DMSO) and C-PTIO respectively. Results Bystander response was observed only in CCRF-CEM and A549 cells (P bystander response on treatment with DMSO, suggests that ROS has a more significant role in mediating the bystander response.Since the possibility of the ROS and NO in mediating these bystander effect was confirmed, mechanistic control of these signaling molecules could either reduce radiation damage and potential carcinogenicity of normal tissues (by reducing bystander signaling) or maximize cell sterilization during chemotherapy (by amplifying bystander responses in tumors). PMID:29147282

Experimental studies on interactions of radiation and cancer chemotherapeutic drugs in normal tissues and a solid tumour

International Nuclear Information System (INIS)

Maase, H. van der

1986-01-01

The interactions of radiation and seven cancer chemotherapeutic drugs have been investigated in four normal tissues and in a solid C 3 H mouse mammary carcinoma in vivo. The investigated drugs were adriamycin (ADM), bleomycin (BLM), cyclophosphamide (CTX), 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin C (MM-C) and cis-diamminedichloroplatinum(II) (cis-DDP). The drugs enhanced the radiation response in most cases. However, signs of radioprotection was observed for CTX in skin and for MTX in haemopoietic tissue. The interval and the sequence of the two treatment modalities were of utmost importance for the normal tissue reactions. In general, the most serious interactions occurred when drugs were administered simultaneously with or a few hours before radiation. The radiation-modifying effect of the drugs deviated from this pattern in the haemopoietic tissue as the radiation response was most enhanced on drug administration 1-3 days after radiation. Enhancement of the radiation response was generally less pronounced in the tumour model than in the normal tissues. The combined drug-radiation effect was apparently less time-dependent in the tumour than in the normal tissues. (Auth.)

Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

Energy Technology Data Exchange (ETDEWEB)

Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J. (CSIRO/MSE); (CSIRO/LW)

2014-09-24

We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

Characterization of the response of a human breast carcinoma cell line (T-47D) to radiation and chemotherapeutic agents

International Nuclear Information System (INIS)

Prager, A.; Ben-Hur, E.; Riklis, E.

1981-01-01

The response of a human breast carcinoma cell line (T-47D) to various antitumour agents, gamma irradiation, UV light and heat was studied, using the colony-forming ability technique. Combinations of radiation with drugs and heat were also tested. The resulting survival curves corresponded to one of five patterns: simple exponential, biphasic exponential, threshold exponential, exponential plateau and ineffectual. Whereas the cells were particularly sensitive to gamma irradiation, the response to UV light was normal. The patient from whom this cell line originated did not respond to METHOTREXATEsup(R) therapy. The in vitro results correlated with this observation. (author)

Co-delivery of chemotherapeutics and proteins for synergistic therapy.

Science.gov (United States)

He, Chaoliang; Tang, Zhaohui; Tian, Huayu; Chen, Xuesi

2016-03-01

Combination therapy with chemotherapeutics and protein therapeutics, typically cytokines and antibodies, has been a type of crucial approaches for synergistic cancer treatment. However, conventional approaches by simultaneous administration of free chemotherapeutic drugs and proteins lead to limitations for further optimizing the synergistic effects, due to the distinct in vivo pharmacokinetics and distribution of small drugs and proteins, insufficient tumor selectivity and tumor accumulation, unpredictable drug/protein ratios at tumor sites, short half-lives, and serious systemic adverse effects. Consequently, to obtain optimal synergistic anti-tumor efficacy, considerable efforts have been devoted to develop the co-delivery systems for co-incorporating chemotherapeutics and proteins into a single carrier system and subsequently releasing the dual or multiple payloads at desired target sites in a more controllable manner. The co-delivery systems result in markedly enhanced blood stability and in vivo half-lives of the small drugs and proteins, elevated tumor accumulation, as well as the capability of delivering the multiple agents to the same target sites with rational drug/protein ratios, which may facilitate maximizing the synergistic effects and therefore lead to optimal antitumor efficacy. This review emphasizes the recent advances in the co-delivery systems for chemotherapeutics and proteins, typically cytokines and antibodies, for systemic or localized synergistic cancer treatment. Moreover, the proposed mechanisms responsible for the synergy of chemotherapeutic drugs and proteins are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics.

Science.gov (United States)

Garg, Abhishek D; More, Sanket; Rufo, Nicole; Mece, Odeta; Sassano, Maria Livia; Agostinis, Patrizia; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2017-01-01

The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

GTP depletion synergizes the anti-proliferative activity of chemotherapeutic agents in a cell type-dependent manner

International Nuclear Information System (INIS)

Lin, Tao; Meng, Lingjun; Tsai, Robert Y.L.

2011-01-01

Highlights: → Strong synergy between mycophenolic acid (MPA) and 5-FU in MDA-MB-231 cells. → Cell type-dependent synergy between MPA and anti-proliferative agents. → The synergy of MPA on 5-FU is recapitulated by RNA polymerase-I inhibition. → The synergy of MPA on 5-FU requires the expression of nucleostemin. -- Abstract: Mycophenolic acid (MPA) depletes intracellular GTP by blocking de novo guanine nucleotide synthesis. GTP is used ubiquitously for DNA/RNA synthesis and as a signaling molecule. Here, we made a surprising discovery that the anti-proliferative activity of MPA acts synergistically with specific chemotherapeutic agents in a cell type-dependent manner. In MDA-MB-231 cells, MPA shows an extremely potent synergy with 5-FU but not with doxorubicin or etoposide. The synergy between 5-FU and MPA works most effectively against the highly tumorigenic mammary tumor cells compared to the less tumorigenic ones, and does not work in the non-breast cancer cell types that we tested, with the exception of PC3 cells. On the contrary, MPA shows the highest synergy with paclitaxel but not with 5-FU in SCC-25 cells, derived from oral squamous cell carcinomas. Mechanistically, the synergistic effect of MPA on 5-FU in MDA-MB-231 cells can be recapitulated by inhibiting the RNA polymerase-I activity and requires the expression of nucleostemin. This work reveals that the synergy between MPA and anti-proliferative agents is determined by cell type-dependent factors.

Radiation protective agents possessing anti-oxidative properties

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Anzai, Kazunori; Ueno, Emi; Yoshida, Akira; Furuse, Masako; Ikota, Nobuo [National Inst. of Radiological Sciences, Research Center for Radiation Safety, Chiba, Chiba (Japan)

2005-11-15

The purpose of studies is to see mechanisms of radiation protection of agents possessing anti-oxidative properties because the initial step resulting in radiation hazard is the formation of radicals by water radiolysis. Agents were commercially available or synthesized proxyl derivatives (spin prove agents), commercially available spin-trapping agents, edaravone and TMG (a tocopherol glycoside). Mice and cultured cells were X-irradiated by Shimadzu Pantak HF-320 or 320S. Survivals of cells were determined by colony assay and of mice, to which the agents were given intraperitoneally before or after X-irradiation, within 30 days post irradiation. Plasma and marrow concentrations of proxyls were estimated by electron spin resonance (ESR) spectrometry. Mechanisms of their radiation protective effects were shown different from agent to agent. TMG was found effective even post irradiation, which suggests a possibility for a new drug development. Some (spin trapping agents and TMG), virtually ineffective at the cell level, were found effective in the whole body, suggesting the necessity of studies on their disposition and metabolism. (S.I.)

Radiation protective agents possessing anti-oxidative properties

International Nuclear Information System (INIS)

Anzai, Kazunori; Ueno, Emi; Yoshida, Akira; Furuse, Masako; Ikota, Nobuo

2005-01-01

The purpose of studies is to see mechanisms of radiation protection of agents possessing anti-oxidative properties because the initial step resulting in radiation hazard is the formation of radicals by water radiolysis. Agents were commercially available or synthesized proxyl derivatives (spin prove agents), commercially available spin-trapping agents, edaravone and TMG (a tocopherol glycoside). Mice and cultured cells were X-irradiated by Shimadzu Pantak HF-320 or 320S. Survivals of cells were determined by colony assay and of mice, to which the agents were given intraperitoneally before or after X-irradiation, within 30 days post irradiation. Plasma and marrow concentrations of proxyls were estimated by electron spin resonance (ESR) spectrometry. Mechanisms of their radiation protective effects were shown different from agent to agent. TMG was found effective even post irradiation, which suggests a possibility for a new drug development. Some (spin trapping agents and TMG), virtually ineffective at the cell level, were found effective in the whole body, suggesting the necessity of studies on their disposition and metabolism. (S.I.)

APC selectively mediates response to chemotherapeutic agents in breast cancer

International Nuclear Information System (INIS)

VanKlompenberg, Monica K.; Bedalov, Claire O.; Soto, Katia Fernandez; Prosperi, Jenifer R.

2015-01-01

The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in up to 70 % of sporadic breast cancers depending on subtype; however, the effects of APC mutation on tumorigenic properties remain unexplored. Using the Apc Min/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we identified enhanced breast tumorigenesis and alterations in genes critical in therapeutic resistance independent of Wnt/β-catenin signaling. Apc mutation changed the tumor histopathology from solid to squamous adenocarcinomas, resembling the highly aggressive human metaplastic breast cancer. Mechanistic studies in tumor-derived cell lines demonstrated that focal adhesion kinase (FAK)/Src/JNK signaling regulated the enhanced proliferation downstream of Apc mutation. Despite this mechanistic information, the role of APC in mediating breast cancer chemotherapeutic resistance is currently unknown. We have examined the effect of Apc loss in MMTV-PyMT mouse breast cancer cells on gene expression changes of ATP-binding cassette transporters and immunofluorescence to determine proliferative and apoptotic response of cells to cisplatin, doxorubicin and paclitaxel. Furthermore we determined the added effect of Src or JNK inhibition by PP2 and SP600125, respectively, on chemotherapeutic response. We also used the Aldefluor assay to measure the population of tumor initiating cells. Lastly, we measured the apoptotic and proliferative response to APC knockdown in MDA-MB-157 human breast cancer cells after chemotherapeutic treatment. Cells obtained from MMTV-PyMT;Apc Min/+ tumors express increased MDR1 (multidrug resistance protein 1), which is augmented by treatment with paclitaxel or doxorubicin. Furthermore MMTV-PyMT;Apc Min/+ cells are more resistant to cisplatin and doxorubicin-induced apoptosis, and show a larger population of ALDH positive cells. In the human metaplastic breast cancer cell line MDA-MB-157, APC knockdown led to paclitaxel and cisplatin

TTFields alone and in combination with chemotherapeutic agents effectively reduce the viability of MDR cell sub-lines that over-express ABC transporters

International Nuclear Information System (INIS)

Schneiderman, Rosa S; Shmueli, Esther; Kirson, Eilon D; Palti, Yoram

2010-01-01

Exposure of cancer cells to chemotherapeutic agents may result in reduced sensitivity to structurally unrelated agents, a phenomenon known as multidrug resistance, MDR. The purpose of this study is to investigate cell growth inhibition of wild type and the corresponding MDR cells by Tumor Treating Fields - TTFields, a new cancer treatment modality that is free of systemic toxicity. The TTFields were applied alone and in combination with paclitaxel and doxorubicin. Three pairs of wild type/MDR cell lines, having resistivity resulting from over-expression of ABC transporters, were studied: a clonal derivative (C11) of parental Chinese hamster ovary AA8 cells and their emetine-resistant sub-line Emt R1 ; human breast cancer cells MCF-7 and their mitoxantrone-resistant sub lines MCF-7/Mx and human breast cancer cells MDA-MB-231 and their doxorubicin resistant MDA-MB-231/Dox cells. TTFields were applied for 72 hours with and without the chemotherapeutic agents. The numbers of viable cells in the treated cultures and the untreated control groups were determined using the XTT assay. Student t-test was applied to asses the significance of the differences between results obtained for each of the three cell pairs. TTFields caused a similar reduction in the number of viable cells of wild type and MDR cells. Treatments by TTFields/drug combinations resulted in a similar increased reduction in cell survival of wild type and MDR cells. TTFields had no effect on intracellular doxorubicin accumulation in both wild type and MDR cells. The results indicate that TTFields alone and in combination with paclitaxel and doxorubicin effectively reduce the viability of both wild type and MDR cell sub-lines and thus can potentially be used as an effective treatment of drug resistant tumors

Sensitization of human carcinoma cells to alkylating agents by small interfering RNA suppression of 3-alkyladenine-DNA glycosylase.

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Paik, Johanna; Duncan, Tod; Lindahl, Tomas; Sedgwick, Barbara

2005-11-15

One of the major cytotoxic lesions generated by alkylating agents is DNA 3-alkyladenine, which can be excised by 3-alkyladenine DNA glycosylase (AAG). Inhibition of AAG may therefore result in increased cellular sensitivity to chemotherapeutic alkylating agents. To investigate this possibility, we have examined the role of AAG in protecting human tumor cells against such agents. Plasmids that express small interfering RNAs targeted to two different regions of AAG mRNA were transfected into HeLa cervical carcinoma cells and A2780-SCA ovarian carcinoma cells. Stable derivatives of both cell types with low AAG protein levels were sensitized to alkylating agents. Two HeLa cell lines with AAG protein levels reduced by at least 80% to 90% displayed a 5- to 10-fold increase in sensitivity to methyl methanesulfonate, N-methyl-N-nitrosourea, and the chemotherapeutic drugs temozolomide and 1,3-bis(2-chloroethyl)-1-nitrosourea. These cells showed no increase in sensitivity to UV light or ionizing radiation. After treatment with methyl methanesulfonate, AAG knockdown HeLa cells were delayed in S phase but accumulated in G2-M. Our data support the hypothesis that ablation of AAG activity in human tumor cells may provide a useful strategy to enhance the efficacy of current chemotherapeutic regimens that include alkylating agents.

Reações tegumentares adversas relacionadas aos agentes antineoplásicos: parte II Adverse mucocutaneous reactions related to chemotherapeutic agents: part II

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Paulo Ricardo Criado

2010-10-01

Full Text Available Os eventos e reações envolvendo quimioterapia são frequentes na prática oncológica. Agentes quimioterápicos são uma modalidade de tratamento amplamente utilizada. Efeitos colaterais podem variar de frequência e também ser confundidos com outras manifestações tegumentares do tratamento oncológico. Este artigo objetiva expor as informações sobre reações cutâneas à quimioterapia, em especial, aqueles para os quais o dermatologista é requisitado a emitir parecer e a comentar sobre a segurança e a viabilidade da readministração de uma droga específica. Os autores descrevem os aspectos associados a esses eventos, fazendo uma análise detalhada de cada um deles.Events and reactions involving chemotherapy are common in clinical oncology. Chemotherapeutic agents are widely used in therapy. Side effects range from the common to the rare and may be confused with other mucocutaneous manifestations resulting from the oncological treatment. The objective of this paper was to present data on skin reactions to chemotherapy, particularly those cases in which the dermatologist is requested to issue a report and asked to comment on the safety and viability of readministration of a specific drug. The authors describe aspects associated with these events, presenting a detailed analysis of each one of them.

Chemotherapy Agents: A Primer for the Interventional Radiologist

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Mihlon, Frank; Ray, Charles E.; Messersmith, Wells

2010-01-01

In this article, the authors review the basic principles of cancer chemotherapy and provide an overview of each of the general classes of chemotherapeutic agents with a target audience of interventional radiologists in mind. Special attention is paid to agents used in regional chemotherapy as well as agents commonly included in systemic chemotherapeutic regimens for patients who also require regional chemotherapy.

Studies on uptake and distribution of chemotherapeutic agents to malignant tumors of the head and neck in rabbits, 2

International Nuclear Information System (INIS)

Yamada, Ryuichi

1981-01-01

Experiments were performed to investigate incorporation and distribution of chemotherapeutic agents into malignant tumors of the head and neck by microautoradiographic and electron microscopic-autoradiographic observations of VX2 carcinoma transplanted in the lower genial region of rabbits after injection of 3 H-Adriamycin as a tracer. The following findings were obtained. 1. On microautoradiograms, 3 H-Adriamycin was distributed predominantly in the nucleoplasm, rather than in the cytoplasm, of tumor tissues. 2. At the ultrastructural level, 3 H-Adriamycin was localized in the nuclear membrane and nucleoli within the nucleoplasm and in the rough endoplasmic reticulum and secretory granules within the cytoplasm. 3. These findings seem to indicate that Adriamycin may inhibit the synthesis of DNA and RNA in the nucleoplasm. (author)

Synergistic Effects of Secretory Phospholipase A2 from the Venom of Agkistrodon piscivorus piscivorus with Cancer Chemotherapeutic Agents

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Jennifer Nelson

2013-01-01

Full Text Available Healthy cells typically resist hydrolysis catalyzed by snake venom secretory phospholipase A2. However, during various forms of programmed cell death, they become vulnerable to attack by the enzyme. This observation raises the question of whether the specificity of the enzyme for dying cells could be used as a strategy to eliminate tumor cells that have been intoxicated but not directly killed by chemotherapeutic agents. This idea was tested with S49 lymphoma cells and a broad range of antineoplastic drugs: methotrexate, daunorubicin, actinomycin D, and paclitaxel. In each case, a substantial population of treated cells was still alive yet vulnerable to attack by the enzyme. Induction of cell death by these agents also perturbed the biophysical properties of the membrane as detected by merocyanine 540 and trimethylammonium-diphenylhexatriene. These results suggest that exposure of lymphoma cells to these drugs universally causes changes to the cell membrane that render it susceptible to enzymatic attack. The data also argue that the snake venom enzyme is not only capable of clearing cell corpses but can aid in the demise of tumor cells that have initiated but not yet completed the death process.

1,3-Bis(2-chloroethyl-1-nitrosourea-loaded bovine serum albumin nanoparticles with dual magnetic resonance–fluorescence imaging for tracking of chemotherapeutic agents

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Wei KC

2016-08-01

Full Text Available Kuo-Chen Wei,1 Feng-Wei Lin,2 Chiung-Yin Huang,1 Chen-Chi M Ma,3 Ju-Yu Chen,1 Li-Ying Feng,1 Hung-Wei Yang2 1Department of Neurosurgery, Chang Gung Memorial Hospital, School of Medicine, Chang Gung University, Taoyuan, 2Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, 3Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, Republic of China Abstract: To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA-based nanoparticles (NPs with dual magnetic resonance (MR and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl-1-nitrosourea [BCNU] NPs to deliver BCNU for inhibition of brain tumor cells (MBR 261-2. These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1 of FITC-BSA-Gd/BCNU NPs was 3.25 mM-1 s-1, which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM-1 s-1. The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy. Keywords: drug tracking, fluorescence imaging, MR imaging, BSA nanoparticles, cancer therapy

Use of the dog spleen for studying effects of irradiation and chemotherapeutic agents, with suggested uses of other organs

International Nuclear Information System (INIS)

Wilcox, L.D.; De Rose, G.; Cooke, D.

1976-01-01

The irradiation of the exteriorized spleen of the dog, with the animal lead-shielded, produced constant changes in the white blood cells. The time of recovery from the irradiation effect was determined. The normal canine spleen could handle live pneumococci injected into the splenic artery, as proven by sterile cultures of splenic vein samples. The size of the bolus used was determined by repeated trials and proved to be one billion pneumococci per pound of body weight. The capacity of the irradiated spleen to handle this number of pneumococci was impaired. It was found that whole body irradiation, nitrogen mustard, thio-tepa, cyclophosphamide, methotrexate, 5-fluorouracil, vinblastine, and azothioprine all impaired this capacity of the spleen. The dose of the chemotherapeutic agent was the same in milligrams per kilogram as that used in the cancer clinic. A method for determining the recovery time following the use of one or more agents was developed with the repeated use of the spleen model. By extending the methods used with the spleen it was found that similar use could be made, usually without surgery, of the liver, gut, and lungs

Effect of mutagens, chemotherapeutic agents and defects in DNA repair genes on recombination in F' partial diploid Escherichia coli

International Nuclear Information System (INIS)

Norin, A.J.; Goldschmidt, E.P.

1979-01-01

The ability of mutagenic agents, nonmutagenic substances and defects in DNA repair to alter the genotype of F' partial diploid (F30) Escherichia coli was determined. The frequency of auxotrophic mutants and histidine requiring (His - ) haploid colonies was increased by mutagen treatment but Hfr colonies were not detected in F30 E. coli even with specific selection techniques. Genotype changes due to nonreciprocal recombination were determined by measuring the frequency of His - homogenotes, eg. F' hisC780, hisI + /hisC780, hisI + , arising from a His + heterogenote, F' hisC780 hisI + /hisC + , his1903. At least 75% of the recombinants were homozygous for histidine alleles which were present on the F' plasmid (exogenote) of the parental hetergenote rather than for histidine alleles on the chromosome. Mutagens, chemotherapeutic agents which block DNA synthesis and a defective DNA polymerase I gene, polA1, were found to increase the frequency of nonreciprocal recombination. A defect in the ability to excise thymine dimers, uvrC34, did not increase spontaneous nonreciprocal recombination. However, UV irradiation but not methyl methanesulfonate (MMS) induced greater recombination in this excision-repair defective mutant than in DNA-repair-proficient strains. (Auth.)

The cell's nucleolus: an emerging target for chemotherapeutic intervention.

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Pickard, Amanda J; Bierbach, Ulrich

2013-09-01

The transient nucleolus plays a central role in the up-regulated synthesis of ribosomal RNA (rRNA) to sustain ribosome biogenesis, a hallmark of aberrant cell growth. This function, in conjunction with its unique pathohistological features in malignant cells and its ability to mediate apoptosis, renders this sub-nuclear structure a potential target for chemotherapeutic agents. In this Minireview, structurally and functionally diverse small molecules are discussed that have been reported to either interact with the nucleolus directly or perturb its function indirectly by acting on its dynamic components. These molecules include all major classes of nucleic-acid-targeted agents, antimetabolites, kinase inhibitors, anti-inflammatory drugs, natural product antibiotics, oligopeptides, as well as nanoparticles. Together, these molecules are invaluable probes of structure and function of the nucleolus. They also provide a unique opportunity to develop novel strategies for more selective and therefore better-tolerated chemotherapeutic intervention. In this regard, inhibition of RNA polymerase-I-mediated rRNA synthesis appears to be a promising mechanism for killing cancer cells. The recent development of molecules targeted at G-quadruplex-forming rRNA gene sequences, which are currently undergoing clinical trials, seems to attest to the success of this approach. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer.

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Kelly H Salter

Full Text Available A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective.Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%. When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06. Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8% of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04, representing a viable alternative therapy.Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding micro

Immunological detection and quantification of DNA components structurally modified by alkylating carcinogens, mutagens and chemotherapeutic agents

International Nuclear Information System (INIS)

Rajewsky, M.F.

1983-01-01

The detection and quantification of defined reaction products of chemical mutagens and carcinogens (and of many cancer chemotherapeutic agents) with DNA require highly sensitive analytical techniques. The exceptional capability of immunoglobulins to recognize subtle alterations of molecular structure (especially when monoclonal antibodies are used to maximize specificity), outstanding sensitivity of immunoanalysis by high-affinity antibodies, and the fact that radioactively-labelled agents are not required suggest the utility of a radioimmunoassay to recognize and quantitate alkylated DNA products. We have recently developed a set of high-affinity monoclonal antibodies (secreted by mouse x mouse as well as by rat x rat hybridomas; antibody affinity constants, 10 9 to > 10 10 lmol) specifically directed against several DNA alkylation products with possible relevance in relation to both mutagenesis and malignant transformation of mammalian cells. These alkylation products include 0 6 -N-butyldeoxyguanosine, and 0 4 -ethyldeoxythymidine. When used in a radioimmunassay, an antibody specific for 0 6 -ethyldeoxyguanosine, for example, will detect this product at an 0 6 -ethyldeoxyguanosine/deoxyguanosine molar ratio of approx. 3 x 10 -7 in a hydrolysate of 100 ug of DNA. The limit of detection can be lowered further if the respective alkyldeoxynucleosides are separated by HPLC from the DNA hydrolysate prior to the RIA. The anti-alkyldeoxynucleoside monoclonal antibodies can also be used to visualize, by immunostaining and fluorescence microscopy combined with electronic image intensification, specific alkylation products in the nuclear DNA of individual cells, and to localize structurally modified bases in double-stranded DNA molecules by transmission electron microscopy

Ixabepilone: a new chemotherapeutic option for refractory metastatic breast cancer

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Shannon Puhalla

2008-09-01

Full Text Available Shannon Puhalla, Adam BrufskyUPMC Magee-Womens Cancer Program, University of Pittsburgh, Pittsburgh, Pennsylvania, USAAbstract: Taxane therapy is commonly used in the treatment of metastatic breast cancer. However, most patients will eventually become refractory to these agents. Ixabepilone is a newly approved chemotherapeutic agent for the treatment of metastatic breast cancer. Although it targets microtubules similarly to docetaxel and paclitaxel, ixabepilone has activity in patients that are refractory to taxanes. This review summarizes the pharmacology of ixapebilone and clinical trials with the drug both as a single agent and in combination. Data were obtained using searches of PubMed and abstracts of the annual meetings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium from 1995 to 2008. Ixapebilone is a semi-synthetic analog of epothilone B that acts to induce apoptosis of cancer cells via the stabilization of microtubules. Phase I clinical trials have employed various dosing schedules ranging from daily to weekly to 3-weekly. Dose-limiting toxicites included neuropathy and neutropenia. Responses were seen in a variety of tumor types. Phase II studies verified activity in taxane-refractory metastatic breast cancer. The FDA has approved ixabepilone for use as monotherapy and in combination with capecitabine for the treatment of metastatic breast cancer. Ixabepilone is an efficacious option for patients with refractory metastatic breast cancer. The safety profile is similar to that of taxanes, with neuropathy and neutropenia being dose-limiting. Studies are ongoing with the use of both iv and oral formulations and in combination with other chemotherapeutic and biologic agents.Keywords: ixabepilone, epothilone, metastatic breast cancer, taxane-refractory

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

International Nuclear Information System (INIS)

Durdux, C.

2004-01-01

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

The chemotherapeutic agent paclitaxel selectively impairs reversal learning while sparing prior learning, new learning and episodic memory.

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Panoz-Brown, Danielle; Carey, Lawrence M; Smith, Alexandra E; Gentry, Meredith; Sluka, Christina M; Corbin, Hannah E; Wu, Jie-En; Hohmann, Andrea G; Crystal, Jonathon D

2017-10-01

Chemotherapy is widely used to treat patients with systemic cancer. The efficacy of cancer therapies is frequently undermined by adverse side effects that have a negative impact on the quality of life of cancer survivors. Cancer patients who receive chemotherapy often experience chemotherapy-induced cognitive impairment across a variety of domains including memory, learning, and attention. In the current study, the impact of paclitaxel, a taxane derived chemotherapeutic agent, on episodic memory, prior learning, new learning, and reversal learning were evaluated in rats. Neurogenesis was quantified post-treatment in the dentate gyrus of the same rats using immunostaining for 5-Bromo-2'-deoxyuridine (BrdU) and Ki67. Paclitaxel treatment selectively impaired reversal learning while sparing episodic memory, prior learning, and new learning. Furthermore, paclitaxel-treated rats showed decreases in markers of hippocampal cell proliferation, as measured by markers of cell proliferation assessed using immunostaining for Ki67 and BrdU. This work highlights the importance of using multiple measures of learning and memory to identify the pattern of impaired and spared aspects of chemotherapy-induced cognitive impairment. Copyright © 2017 Elsevier Inc. All rights reserved.

Studies on uptake and distribution of chemotherapeutic agents to malignant tumors of the head and neck in rabbits, 2. /sup 3/H-Adriamycin

Energy Technology Data Exchange (ETDEWEB)

Yamada, R. (Gifu Univ. (Japan). Faculty of Medicine)

1981-09-01

Experiments were performed to investigate incorporation and distribution of chemotherapeutic agents into malignant tumors of the head and neck by microautoradiographic and electron microscopic-autoradiographic observations of VX2 carcinoma transplanted in the lower genial region of rabbits after injection of /sup 3/H-Adriamycin as a tracer. The following findings were obtained. 1. On microautoradiograms, /sup 3/H-Adriamycin was distributed predominantly in the nucleoplasm, rather than in the cytoplasm, of tumor tissues. 2. At the ultrastructural level, /sup 3/H-Adriamycin was localized in the nuclear membrane and nucleoli within the nucleoplasm and in the rough endoplasmic reticulum and secretory granules within the cytoplasm. 3. These findings seem to indicate that Adriamycin may inhibit the synthesis of DNA and RNA in the nucleoplasm.

The electron affinity of some radiotherapeutic agents used in cancer therapy

International Nuclear Information System (INIS)

Wold, E.; Kaalhus, O.; Johansen, E.S.; Ekse, A.T.

1980-01-01

In order to evaluate whether chemotherapeutic compounds applied in cancer treatment might interact with radiation as anoxic cell sensitizers, the electron-affinic properties of DTIC (5-(3,3-dimethyl-1-triazeno)imidazole-4 carboxamide) AIC 4(5)-aminoimidazole-5(4)-carboxamide, hydroxyurea, busulfan and cyclophosphamide were studied by pulse radiolysis. Reaction rates with hydrated electrons were determined for all these compounds. With the exception of DTIC, they all reacted much more slowly with electrons than do most electron-affinic sensitizers. One-electron reduction potentials were determined for DTIC, AIC and hydroxyurea. The values were all in the region for the onset of sensitization, with hydroxyurea as the most promising (E 7 1 = -0.552 V). For busulfan and cyclophosphamide no value could be determined, but these compounds are probably less electron-affinic than hydroxyurea. A possible application of chemotherapeutic agents as radiosensitizers is discussed. (author)

Cytotoxic effects of chemotherapeutic drugs and heterocyclic compounds at application on the cells of primary culture of neuroepithelium tumors.

Science.gov (United States)

Kulchitsky, Vladimir A; Potkin, Vladimir I; Zubenko, Yuri S; Chernov, Alexander N; Talabaev, Michael V; Demidchik, Yuri E; Petkevich, Sergei K; Kazbanov, Vladimir V; Gurinovich, Tatiana A; Roeva, Margarita O; Grigoriev, Dmitry G; Kletskov, Alexei V; Kalunov, Vladimir N

2012-01-01

Neuroepithelial tumor cells were cultured in vitro. The biopsy material was taken from 93 children at removal of the brain tumors during neurosurgical operations. The individual features of the cells sensitivity of primary cultures in respect to protocol-approved chemotherapy drugs and changes in the Interleukin-6 (Il-6) level in the culture medium after the application of chemotherapy were established. The initial level of Il-6 exceeded 600.0 pg/ml in the cultural medium with histologically verified pilomyxoid astrocytoma cells, and ranged from 100.0 to 200.0 pg/ml in the medium at cultivation of ganglioneuroblastoma and pilocytic astrocytoma. A decrease in the Il-6 level in the medium culture of primary tumors cells was observed after the application of chemotherapeutic agents on the cells of pilomyxoid astrocytoma, astrocytomas, and pilocytic desmoplastic/nodular medulloblastoma. The production of Il-6 increased after application of cytostatic drugs on the cells of oligoastrocytomas. A decrease in Il-6 level after application of Cisplatin and Methotrexate and a 5-10 fold increase in the level of Il-6 after application of Etoposide, Carboplatin, Cytarabine, and Gemcitabine were registered in the medium with ganglioneuroblastoma. To improve the cytotoxic action of chemotherapeutic agents, the combined application of cytostatics with heterocyclic compounds was carried out. A computer modeling of ligand-protein complexes of carbamide using the Dock 6.4 and USF Chimera program packages was performed with molecular mechanics method. Special attention was drawn to the ability of several isoxazole heterocycles and isothiazolyl to inhibit the tyrosine kinase. It was proved in vitro that the joint application of chemotherapeutic agents and heterocyclic compounds could reduce the concentration of the cytostatic factor by 10 or more times, having maintained the maximum cytotoxic effect. It was assumed that the target amplification of cytotoxic action of chemotherapeutic

Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium

International Nuclear Information System (INIS)

Konno, T.

1990-01-01

Arterially administered Lipiodol Ultrafluid contrast medium selectively remained in various malignant solid tumors because of the difference in time required for the removal of Lipiodol contrast medium from normal capillaries and tumor neovasculature. Although blood flow was maintained in the tumor, even immediately after injection Lipiodol contrast medium remained in the neovasculature of the tumor. To target anti-cancer agents to tumors by using Lipiodol contrast medium as a carrier, the characteristics of the agents were examined. Anti-cancer agents had to be soluble in Lipiodol, be stable in it, and separate gradually from it so that the anti-cancer agents would selectively remain in the tumor. These conditions were found to be necessary on the basis of the measurement of radioactivity in VX2 tumors implanted in the liver of 16 rabbits that received arterial injections of 14C-labeled doxorubicin. Antitumor activities and side effects of arterial injections of two types of anti-cancer agents were compared in 76 rabbits with VX2 tumors. Oily anti-cancer agents that had characteristics essential for targeting were compared with simple mixtures of anti-cancer agents with Lipiodol contrast medium that did not have these essential characteristics. Groups of rabbits that received oily anti-cancer agents responded significantly better than groups that received simple mixtures, and side effects were observed more frequently in the groups that received the simple mixtures. These results suggest that targeting of the anti-cancer agent to the tumor is important for treatment of solid malignant tumors

Modification of in vitro and in vivo BCG cell wall-induced immunosuppression by treatment with chemotherapeutic agents or indomethacin

International Nuclear Information System (INIS)

DeSilva, M.A.; Wepsic, H.T.; Mizushima, Y.; Nikcevich, D.A.; Larson, C.H.

1985-01-01

The in vitro inhibition of spleen cell blastogenesis response and the in vivo enhancement of tumor growth are phenomena associated with BCG cell wall (BCGcw) immunization. What effect treatment with chemotherapeutic agents and the prostaglandin inhibitor indomethacin would have on the in vitro and in vivo responses to BCGcw immunization was evaluated. In vitro blastogenesis studies showed that chemotherapy pretreatment prior to immunization with BCGcw resulted in a restoration of the spleen cell blastogenesis response. In blastogenesis addback studies, where BCGcw-induced irradiated splenic suppressor cells were admixed with normal cells, less inhibition of blastogenesis occurred when spleen cells were obtained from rats that had received the combined treatment of chemotherapy and BCGcw immunization versus only BCGcw immunization. The cocultivation of spleen cells from BCGcw-immunized rats with indomethacin resulted in a 30-40% restoration of the blastogenesis response. In vivo studies showed that BCGcw-mediated enhancement of intramuscular tumor growth of the 3924a ACI rat tumor could be abrogated by either pretreatment with busulfan or mitomycin or by the feeding of indomethacin

Comparative studies on the effect of radiation-sensitizing agents used in radiating VX2 Carcinoma

International Nuclear Information System (INIS)

Migita, Hidenobu

1975-01-01

The effects of 5-Fu and BUdR as radiation-sensitizing agents macroscopically were investigated in 122 VX2 Carcinomas transplanted into the calves of the hind legs of rabbits. Experimental groups and contrast groups are divided into six as follows: A: No treatment, B: 5-Fu infusion, C: BUdR+Antimetabolite infusion, D: Radiation, E: 5-Fu infusion and radiation, and F: BUdR+Antimetabolite infusion and radiation. The amount of agent given to each was 5 mg/kg/day of 5-Fu and 50 mg/kg/day of BUdR, and the amount of radiation was 300 rad/day. 5-Fu was used as the Antimetabolite, and its amount was one-tenth of that in the 5-Fu Infusion Group. The agent and the radiation were given for five days. 1. In the 300 rad/day Group, the radiation was not enough to result in a complete cure. 2. In the two Agent Infusion Group, 5-Fu and BUdR+Antimetabolite proved to be anti-cancer, but neither of them resulted in effective treatment. 3. The 5-Fu Infusion and Radiation Group, showed a strong degenerative change in the tumor cell and a radiosensitive effect from 5-Fu, but the tumor was not lessened. 4. In the BUdR-Antimetabolite Infusion and Radiation Group, the tumor began to reduce on the third day. On the seventh and fourteenth days, necrosis of the greater part of tumor was seen, and the rest of the tumor cells were found to be in degenerative change. On the twenty first day, no live tumor cell was found, only dead remains of tumor cells. The results were confirmed both macroscopically and histopathologically. 5. BUdR can be expected to be effective in clinical application to oral malignant tumors. (Evans, J.)

Development of a novel, physiologically relevant cytotoxicity model: Application to the study of chemotherapeutic damage to mesenchymal stromal cells

International Nuclear Information System (INIS)

May, Jennifer E.; Morse, H. Ruth; Xu, Jinsheng; Donaldson, Craig

2012-01-01

There is an increasing need for development of physiologically relevant in-vitro models for testing toxicity, however determining toxic effects of agents which undergo extensive hepatic metabolism can be particularly challenging. If a source of such metabolic enzymes is inadequate within a model system, toxicity from prodrugs may be grossly underestimated. Conversely, the vast majority of agents are detoxified by the liver, consequently toxicity from such agents may be overestimated. In this study we describe the development of a novel in-vitro model, which could be adapted for any toxicology setting. The model utilises HepG2 liver spheroids as a source of metabolic enzymes, which have been shown to more closely resemble human liver than traditional monolayer cultures. A co-culture model has been developed enabling the effect of any metabolised agent on another cell type to be assessed. This has been optimised to enable the study of damaging effects of chemotherapy on mesenchymal stem cells (MSC), the supportive stem cells of the bone marrow. Several optimisation steps were undertaken, including determining optimal culture conditions, confirmation of hepatic P450 enzyme activity and ensuring physiologically relevant doses of chemotherapeutic agents were appropriate for use within the model. The developed model was subsequently validated using several chemotherapeutic agents, both prodrugs and active drugs, with resulting MSC damage closely resembling effects seen in patients following chemotherapy. Minimal modifications would enable this novel co-culture model to be utilised as a general toxicity model, contributing to the drive to reduce animal safety testing and enabling physiologically relevant in-vitro study. -- Highlights: ► An in vitro model was developed for study of drugs requiring hepatic metabolism ► HepG2 spheroids were utilised as a physiologically relevant source of liver enzymes ► The model was optimised to enable study of chemotherapeutic

Development of a novel, physiologically relevant cytotoxicity model: Application to the study of chemotherapeutic damage to mesenchymal stromal cells

Energy Technology Data Exchange (ETDEWEB)

May, Jennifer E., E-mail: Jennifer2.May@uwe.ac.uk; Morse, H. Ruth, E-mail: Ruth.Morse@uwe.ac.uk; Xu, Jinsheng, E-mail: Jinsheng.Xu@uwe.ac.uk; Donaldson, Craig, E-mail: Craig.Donaldson@uwe.ac.uk

2012-09-15

There is an increasing need for development of physiologically relevant in-vitro models for testing toxicity, however determining toxic effects of agents which undergo extensive hepatic metabolism can be particularly challenging. If a source of such metabolic enzymes is inadequate within a model system, toxicity from prodrugs may be grossly underestimated. Conversely, the vast majority of agents are detoxified by the liver, consequently toxicity from such agents may be overestimated. In this study we describe the development of a novel in-vitro model, which could be adapted for any toxicology setting. The model utilises HepG2 liver spheroids as a source of metabolic enzymes, which have been shown to more closely resemble human liver than traditional monolayer cultures. A co-culture model has been developed enabling the effect of any metabolised agent on another cell type to be assessed. This has been optimised to enable the study of damaging effects of chemotherapy on mesenchymal stem cells (MSC), the supportive stem cells of the bone marrow. Several optimisation steps were undertaken, including determining optimal culture conditions, confirmation of hepatic P450 enzyme activity and ensuring physiologically relevant doses of chemotherapeutic agents were appropriate for use within the model. The developed model was subsequently validated using several chemotherapeutic agents, both prodrugs and active drugs, with resulting MSC damage closely resembling effects seen in patients following chemotherapy. Minimal modifications would enable this novel co-culture model to be utilised as a general toxicity model, contributing to the drive to reduce animal safety testing and enabling physiologically relevant in-vitro study. -- Highlights: ► An in vitro model was developed for study of drugs requiring hepatic metabolism ► HepG2 spheroids were utilised as a physiologically relevant source of liver enzymes ► The model was optimised to enable study of chemotherapeutic

FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

Science.gov (United States)

Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D.; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie N.; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A.; Collis, Spencer J.

2014-01-01

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome. PMID:25071006

New Insights into the Mechanism Underlying the Synergistic Action of Ionizing Radiation With Platinum Chemotherapeutic Drugs: The Role of Low-Energy Electrons

Energy Technology Data Exchange (ETDEWEB)

Rezaee, Mohammad, E-mail: Mohammad.Rezaee@USherbrooke.ca; Hunting, Darel John; Sanche, Léon

2013-11-15

Purpose: To investigate the efficiencies of platinum chemotherapeutic drugs (Pt-drugs) in the sensitization of DNA to the direct effects of ionizing radiation and to determine the role of low-energy electrons (LEEs) in this process. Methods and Materials: Complexes of supercoiled plasmid DNA covalently bound to either cisplatin, carboplatin, or oxaliplatin were prepared in different molar ratios. Solid films of DNA and DNA modified by Pt-drugs were irradiated with either 10-KeV or 10-eV electrons. Damages to DNA were quantified by gel electrophoresis, and the yields for damage formation were obtained from exposure–response curves. Results: The presence of an average of 2 Pt-drug–DNA adducts (Pt-adducts) in 3199-bp plasmid DNA increases the probability of a double-strand break by factors of 3.1, 2.5, and 2.4 for carboplatin, cisplatin, and oxaliplatin, respectively. Electrons with energies of 10 eV and 10 KeV interact with Pt-adducts to preferentially enhance the formation of cluster lesions. The maximum increase in radiosensitivity per Pt-adduct is found at ratios up to 3.1 × 10{sup −4} Pt-adducts per nucleotide, which is equivalent to an average of 2 adducts per plasmid. Carboplatin and oxaliplatin show higher efficiencies than cisplatin in the radiosensitization of DNA. Because carboplatin and cisplatin give rise to identical reactive species that attach to DNA, carboplatin must be considered as a better radiosensitizer for equal numbers of Pt-adducts. Conclusion: Platinum chemotherapeutic drugs preferentially enhance the formation of cluster damage to DNA induced by the direct effect of ionizing radiation, and LEEs are the main species responsible for such an enhancement via the formation of electron resonances.

New Insights into the Mechanism Underlying the Synergistic Action of Ionizing Radiation With Platinum Chemotherapeutic Drugs: The Role of Low-Energy Electrons

International Nuclear Information System (INIS)

Rezaee, Mohammad; Hunting, Darel John; Sanche, Léon

2013-01-01

Purpose: To investigate the efficiencies of platinum chemotherapeutic drugs (Pt-drugs) in the sensitization of DNA to the direct effects of ionizing radiation and to determine the role of low-energy electrons (LEEs) in this process. Methods and Materials: Complexes of supercoiled plasmid DNA covalently bound to either cisplatin, carboplatin, or oxaliplatin were prepared in different molar ratios. Solid films of DNA and DNA modified by Pt-drugs were irradiated with either 10-KeV or 10-eV electrons. Damages to DNA were quantified by gel electrophoresis, and the yields for damage formation were obtained from exposure–response curves. Results: The presence of an average of 2 Pt-drug–DNA adducts (Pt-adducts) in 3199-bp plasmid DNA increases the probability of a double-strand break by factors of 3.1, 2.5, and 2.4 for carboplatin, cisplatin, and oxaliplatin, respectively. Electrons with energies of 10 eV and 10 KeV interact with Pt-adducts to preferentially enhance the formation of cluster lesions. The maximum increase in radiosensitivity per Pt-adduct is found at ratios up to 3.1 × 10 −4 Pt-adducts per nucleotide, which is equivalent to an average of 2 adducts per plasmid. Carboplatin and oxaliplatin show higher efficiencies than cisplatin in the radiosensitization of DNA. Because carboplatin and cisplatin give rise to identical reactive species that attach to DNA, carboplatin must be considered as a better radiosensitizer for equal numbers of Pt-adducts. Conclusion: Platinum chemotherapeutic drugs preferentially enhance the formation of cluster damage to DNA induced by the direct effect of ionizing radiation, and LEEs are the main species responsible for such an enhancement via the formation of electron resonances

Study on the application of sensitizing and protective agent in the process of radiation chemistry

International Nuclear Information System (INIS)

Kamal, Z.

1976-01-01

The role of sensitizing agent and protective agent in the process of radiation chemistry is studied. Direct and indirect radiation effects on bio molecules, molecular and sensitizing agent mechanism, electron activities as the basis for sensitizing agent mechanism, protective agent mechanism on irradiated macro molecules, and kinds of protective and sensitizing agents, are discussed. (RUW)

Induction of cell death by chemotherapeutic methylating agents

International Nuclear Information System (INIS)

Quiros Barrantes, Steve

2012-01-01

The mechanism of cell death induced by O 6 MeG has been investigated and inhibition of homologous recombination as a strategy for sensitization of tumor cells against methylating agents S N 1. Dependence of the cell cycle was determined toxic responses triggered by O''6 MeG and evaluated by proliferation assays if apoptotic cells have originated exclusively from the second post-treatment cycle. Dependence of O''6 MeG was found at DSB formation. The activation of the control points of the cell cycle and induction of apoptosis is generated during the second cell cycle. Additionally, a portion of the cells has been determined that triggers apoptosis in subsequent generations in the second cell cycle. Inhibition of homologous recombination has been a reasonable strategy to increase S N 1 alkylating agent effectiveness. Evidence has been provided in NHEJ dependent inhibition of DNA-PK that not significantly sensitizes the glioblastoma cells against temozolomide [es

Sensitivity to ionizing radiation and chemotherapeutic agents in gemcitabine-resistant human tumor cell lines

International Nuclear Information System (INIS)

Bree, Chris van; Kreder, Natasja Castro; Loves, Willem J.P.; Franken, Nicolaas A.P.; Peters, Godefridus J.; Haveman, Jaap

2002-01-01

Purpose: To determine cross-resistance to anti-tumor treatments in 2',2'difluorodeoxycytidine (dFdC, gemcitabine)-resistant human tumor cells. Methods and Materials: Human lung carcinoma cells SW-1573 (SWp) were made resistant to dFdC (SWg). Sensitivity to cisplatin (cDDP), paclitaxel, 5-fluorouracil (5-FU), methotrexate (MTX), cytarabine (ara-C), and dFdC was measured by a proliferation assay. Radiosensitivity and radioenhancement by dFdC of this cell panel and the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000 were determined by clonogenic assay. Bivariate flowcytometry was performed to study cell cycle changes. Results: In the SWg, a complete deoxycytidine kinase (dCK) deficiency was found on mRNA and protein level. This was accompanied by a 10-fold decrease in dCK activity which resulted in the >1000-fold resistance to dFdC. Sensitivity to other anti-tumor drugs was not altered, except for ara-C (>100-fold resistance). Radiosensitivity was not altered in the dFdC-resistant cell lines SWg and AG6000. High concentrations (50-100 μM dFdC) induced radioenhancement in the dFdC-resistant cell lines similar to the radioenhancement obtained at lower concentrations (10 nM dFdC) in the parental lines. An early S-phase arrest was found in all cell lines after dFdC treatment where radioenhancement was achieved. Conclusions: In the dFdC-resistant lung tumor cell line SWg, the deficiency in dCK is related to the resistance to dFdC and ara-C. No cross-resistance was observed to other anti-tumor drugs used for the treatment in lung cancer. Sensitivity to ionizing radiation was not altered in two different dFdC-resistant cell lines. Resistance to dFdC does not eliminate the ability of dFdC to sensitize cells to radiation

The effects of artificially induced hyperglycaemia on the response of the Lewis lung carcinoma to radiation and cyclophosphamide

International Nuclear Information System (INIS)

Chaplin, D.J.

1984-01-01

In the treatment of any malignancy it is essential to utilize all known physiological differences that exist between tumour and normal tissue. One well established difference is that tumours, in both rodents and man, have a lower pH than normal tissue. Further reduction in tumour pH occurs in non-vascularised necrotic regions. It is now widely believed that cells, close to necrotic regions, distant from blood vessels are protected from the effects of radiation and chemotherapeutic agents by their hypoxia and reduced rate of proliferation, thus providing the foci for tumour regrowth. Yet, since these cells are situated in an acidic environment they should be the ones most susceptible to exploitation or modification of the tumour's acid:base status. Hyperglycaemia is known to increase tumour acidosis. The effect of such treatment on the tumour response to radiation or to chemotherapeutic agents is being assessed. Initial results indicate that hyperglycaemia can increase or reduce the response of the Lewis lung carcinoma to cyclophosphamide. The type of response obtained is dependent on the duration, level and timing of glucose treatments. Further work is now in progress

Rapid selection and proliferation of CD133+ cells from cancer cell lines: chemotherapeutic implications.

Directory of Open Access Journals (Sweden)

Sarah E Kelly

2010-04-01

Full Text Available Cancer stem cells (CSCs are considered a subset of the bulk tumor responsible for initiating and maintaining the disease. Several surface cellular markers have been recently used to identify CSCs. Among those is CD133, which is expressed by hematopoietic progenitor cells as well as embryonic stem cells and various cancers. We have recently isolated and cultured CD133 positive [CD133+] cells from various cancer cell lines using a NASA developed Hydrodynamic Focusing Bioreactor (HFB (Celdyne, Houston, TX. For comparison, another bioreactor, the rotary cell culture system (RCCS manufactured by Synthecon (Houston, TX was used. Both the HFB and the RCCS bioreactors simulate aspects of hypogravity. In our study, the HFB increased CD133+ cell growth from various cell lines compared to the RCCS vessel and to normal gravity control. We observed a +15-fold proliferation of the CD133+ cellular fraction with cancer cells that were cultured for 7-days at optimized conditions. The RCCS vessel instead yielded a (-4.8-fold decrease in the CD133+cellular fraction respect to the HFB after 7-days of culture. Interestingly, we also found that the hypogravity environment of the HFB greatly sensitized the CD133+ cancer cells, which are normally resistant to chemo treatment, to become susceptible to various chemotherapeutic agents, paving the way to less toxic and more effective chemotherapeutic treatment in patients. To be able to test the efficacy of cytotoxic agents in vitro prior to their use in clinical setting on cancer cells as well as on cancer stem cells may pave the way to more effective chemotherapeutic strategies in patients. This could be an important advancement in the therapeutic options of oncologic patients, allowing for more targeted and personalized chemotherapy regimens as well as for higher response rates.

Cdt1 is differentially targeted for degradation by anticancer chemotherapeutic drugs.

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Athanasia Stathopoulou

Full Text Available BACKGROUND: Maintenance of genome integrity is crucial for the propagation of the genetic information. Cdt1 is a major component of the pre-replicative complex, which controls once per cell cycle DNA replication. Upon DNA damage, Cdt1 is rapidly targeted for degradation. This targeting has been suggested to safeguard genomic integrity and prevent re-replication while DNA repair is in progress. Cdt1 is deregulated in tumor specimens, while its aberrant expression is linked with aneuploidy and promotes tumorigenesis in animal models. The induction of lesions in DNA is a common mechanism by which many cytotoxic anticancer agents operate, leading to cell cycle arrest and apoptosis. METHODOLOGY/PRINCIPAL FINDING: In the present study we examine the ability of several anticancer drugs to target Cdt1 for degradation. We show that treatment of HeLa and HepG2 cells with MMS, Cisplatin and Doxorubicin lead to rapid proteolysis of Cdt1, whereas treatment with 5-Fluorouracil and Tamoxifen leave Cdt1 expression unaffected. Etoposide affects Cdt1 stability in HepG2 cells and not in HeLa cells. RNAi experiments suggest that Cdt1 proteolysis in response to MMS depends on the presence of the sliding clamp PCNA. CONCLUSION/SIGNIFICANCE: Our data suggest that treatment of tumor cells with commonly used chemotherapeutic agents induces differential responses with respect to Cdt1 proteolysis. Information on specific cellular targets in response to distinct anticancer chemotherapeutic drugs in different cancer cell types may contribute to the optimization of the efficacy of chemotherapy.

Enhanced killing of mammalian cells by radiation combined with m-AMSA

International Nuclear Information System (INIS)

Roberts, P.B.; Millar, B.C.

1980-01-01

m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected. m-AMSA increased radiation lethality throughout the cell cycle, but a contribution to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended. (author)

Enhanced killing of mammalian cells by radiation combined with m-AMSA

Energy Technology Data Exchange (ETDEWEB)

Roberts, P B; Millar, B C [Institute of Cancer Research, Sutton (UK). Surrey Branch

1980-11-01

m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30 min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected. m-AMSA increased radiation lethality throughout the cell cycle, but a contribution to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended.

Training strategic community agents in health effects of ionizing radiation

International Nuclear Information System (INIS)

Leite, Teresa C.S.B.; Silva, IIson P.M. da; Jannuzzi, Denise M.S.; Maurmo, Alexandre M.

2013-01-01

The main motivation for the development of training was the need to train agents (opinion makers) with proximity and credibility among the population, to clarify the most frequently asked questions in relation to ionizing radiation, the operation of nuclear power plants, emergency plans and about the possibility of there effects of radiation on the health of inhabitants in regions close to the central Nuclear Almirante Alvaro Alberto - CNAAA. The project has a target audience of 420 agents, 60 of them have already been trained in a pilot project . The results indicate that the topics of training were adequate and the agents have expanded their knowledge. On the other hand, the information passed on to communities by agents, recognized by this population as ' the most reliable people', is of greater credibility and likelihood of success in communicating important issues for the population living in the vicinity of the CNAAA. (author)

Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

Science.gov (United States)

Roy Chaudhuri, Tista

An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre

The Paracrine Induction of TRAIL by Genotoxic Agents

National Research Council Canada - National Science Library

Spalding, Aaron

2002-01-01

TNF related apoptosis inducing ligand, TRAIL, is a recently cloned cytokine that has been shown to induce apoptosis in a synergistic fashion with chemotherapeutic agents on several cancer cell lines...

Base excision repair of chemotherapeutically-induced alkylated DNA damage predominantly causes contractions of expanded GAA repeats associated with Friedreich's ataxia.

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Yanhao Lai

Full Text Available Expansion of GAA·TTC repeats within the first intron of the frataxin gene is the cause of Friedreich's ataxia (FRDA, an autosomal recessive neurodegenerative disorder. However, no effective treatment for the disease has been developed as yet. In this study, we explored a possibility of shortening expanded GAA repeats associated with FRDA through chemotherapeutically-induced DNA base lesions and subsequent base excision repair (BER. We provide the first evidence that alkylated DNA damage induced by temozolomide, a chemotherapeutic DNA damaging agent can induce massive GAA repeat contractions/deletions, but only limited expansions in FRDA patient lymphoblasts. We showed that temozolomide-induced GAA repeat instability was mediated by BER. Further characterization of BER of an abasic site in the context of (GAA20 repeats indicates that the lesion mainly resulted in a large deletion of 8 repeats along with small expansions. This was because temozolomide-induced single-stranded breaks initially led to DNA slippage and the formation of a small GAA repeat loop in the upstream region of the damaged strand and a small TTC loop on the template strand. This allowed limited pol β DNA synthesis and the formation of a short 5'-GAA repeat flap that was cleaved by FEN1, thereby leading to small repeat expansions. At a later stage of BER, the small template loop expanded into a large template loop that resulted in the formation of a long 5'-GAA repeat flap. Pol β then performed limited DNA synthesis to bypass the loop, and FEN1 removed the long repeat flap ultimately causing a large repeat deletion. Our study indicates that chemotherapeutically-induced alkylated DNA damage can induce large contractions/deletions of expanded GAA repeats through BER in FRDA patient cells. This further suggests the potential of developing chemotherapeutic alkylating agents to shorten expanded GAA repeats for treatment of FRDA.

Efficacy Comparison of Six Chemotherapeutic Combinations for Osteosarcoma and Ewing's Sarcoma Treatment: A Network Meta-Analysis.

Science.gov (United States)

Zhang, Tao; Zhang, Song; Yang, Feifei; Wang, Lili; Zhu, Sigang; Qiu, Bing; Li, Shunhua; Deng, Zhongliang

2018-01-01

This study aimed to address the insufficiency of traditional meta-analysis and provide improved guidelines for the clinical practice of osteosarcoma treatment. The heterogeneity of the fixed-effect model was calculated, and when necessary, a random-effect model was adopted. Furthermore, the direct and indirect evidence was pooled together and exhibited in the forest plot and slash table. The surface under the cumulative ranking curve (SUCRA) value was also measured to rank each intervention. Finally, heat plot was introduced to demonstrate the contribution of each intervention and the inconsistency between direct and indirect comparisons. This network meta-analysis included 32 trials, involving a total of 5,626 subjects reported by 28 articles. All the treatments were classified into six chemotherapeutic combinations: dual agent with or without ifosfamide (IFO), multi-agent with or without IFO, and dual agent or multi-agent with IFO and etoposide. For the primary outcomes, both overall survival (OS) and event-free survival (EFS) rates were considered. The multi-agent integrated with IFO and etoposide showed an optimal performance for 5-year OS, 10-year OS, 3-year EFS, 5-year EFS, and 10-year EFS when compared with placebo. The SUCRA value of this treatment was also the highest of these six interventions. However, multi-drug with IFO alone had the highest SUCRA value of 0.652 and 0.516 when it came to relapse and lung-metastasis. It was efficient to some extent, but no significant difference was observed in both outcomes. Chemotherapy, applied as induction or adjuvant treatment with radiation therapy or surgery, is able to increase the survival rate of patients, especially by combining multi-drug with IFO and etoposide, which demonstrated the best performance in both OS and EFS. As for relapse and the lung-metastasis, multiple agents with IFO alone seemed to have the optimal efficiency, although no significant difference was observed here. J. Cell. Biochem. 119: 250

Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

Science.gov (United States)

Ranchoux, Benoît; Günther, Sven; Quarck, Rozenn; Chaumais, Marie-Camille; Dorfmüller, Peter; Antigny, Fabrice; Dumas, Sébastien J; Raymond, Nicolas; Lau, Edmund; Savale, Laurent; Jaïs, Xavier; Sitbon, Olivier; Simonneau, Gérald; Stenmark, Kurt; Cohen-Kaminsky, Sylvia; Humbert, Marc; Montani, David; Perros, Frédéric

2015-02-01

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans.

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Heather E Wheeler

Full Text Available Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4. Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3. Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05, including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.

A Potential Adjuvant Agent of Chemotherapy: Sepia Ink Polysaccharides

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Fangping Li

2018-03-01

Full Text Available Sepia ink polysaccharide (SIP isolated from squid and cuttlefish ink is a kind of acid mucopolysaccharide that has been identified in three types of primary structures from squid (Illex argentinus and Ommastrephes bartrami, cuttlefish Sepiella maindroni, and cuttlefish Sepia esculenta ink. Although SIP has been proved to be multifaceted, most of the reported evidence has illuminated its chemopreventive and antineoplastic activities. As a natural product playing a role in cancer treatment, SIP may be used as chemotherapeutic ancillary agent or functional food. Based on the current findings on SIP, we have summarized four topics in this review, including: chemopreventive, antineoplastic, chemosensitive, and procoagulant and anticoagulant activities, which are correlative closely with the actions of anticancer agents on cancer patients, such as anticancer, toxicity and thrombogenesis, with the latter two actions being common causes of death in cancer cases exposed to chemotherapeutic agents.

[Alkylating agents].

Science.gov (United States)

Pourquier, Philippe

2011-11-01

With the approval of mechlorethamine by the FDA in 1949 for the treatment of hematologic malignancies, alkylating agents are the oldest class of anticancer agents. Even though their clinical use is far beyond the use of new targeted therapies, they still occupy a major place in specific indications and sometimes represent the unique option for the treatment of refractory diseases. Here, we are reviewing the major classes of alkylating agents and their mechanism of action, with a particular emphasis for the new generations of alkylating agents. As for most of the chemotherapeutic agents used in the clinic, these compounds are derived from natural sources. With a complex but original mechanism of action, they represent new interesting alternatives for the clinicians, especially for tumors that are resistant to conventional DNA damaging agents. We also briefly describe the different strategies that have been or are currently developed to potentiate the use of classical alkylating agents, especially the inhibition of pathways that are involved in the repair of DNA lesions induced by these agents. In this line, the development of PARP inhibitors is a striking example of the recent regain of interest towards the "old" alkylating agents.

Hypertension induced by chemotherapeutic and immunosuppresive agents: a new challenge.

Science.gov (United States)

Abi Aad, Simon; Pierce, Matthew; Barmaimon, Guido; Farhat, Fadi S; Benjo, Alexandre; Mouhayar, Elie

2015-01-01

Hypertension is a common adverse effect of certain anti neoplastic therapy. The incidence and severity of hypertension are dependent mainly on the type and the dose of the drug. We reviewed the literature for studies that reported the effect of anti neoplastic agents on blood pressure in patients with malignancies. The medical databases of PubMed, MEDLINE and EMBASE were searched for articles published in English between 1955 and June 2012. The effects of specific agents on blood pressure were analyzed. Hypertension is a prevalent adverse effect of many of the new chemotherapy agents such as VEGF inhibitors. Approximately 30% of patients treated for cancer will have concomitant hypertension, and crucial chemotherapy can sometimes be stopped due to new onset or worsening severe hypertension. The importance of a timely diagnosis and optimal management of HTN in this group of patients is related to the facts that HTN is a well established risk factor for chemotherapy-induced cardiotoxicity and if left untreated, can alter cancer management and result in dose reductions or termination of anti-cancer treatments as well as life-threatening end organ damage. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Augmentation of radiation response with the vascular targeting agent ZD6126

International Nuclear Information System (INIS)

Hoang Tien; Huang Shyhmin; Armstrong, Eric; Eickhoff, Jens C.; Harari, Paul M.

2006-01-01

Purpose: To examine the antivascular and antitumor activity of the vascular targeting agent ZD6126 in combination with radiation in lung and head-and-neck (H and N) cancer models. The overall hypothesis was that simultaneous targeting of tumor cells (radiation) and tumor vasculature (ZD6126) might enhance tumor cell killing. Methods and Materials: A series of in vitro studies using human umbilical vein endothelial cells (HUVEC) and in vivo studies in athymic mice bearing human lung (H226) and H and N (squamous cell carcinoma [SCC]1, SCC6) tumor xenografts treated with ZD6126 and/or radiation were performed. Results: ZD6126 inhibited the capillary-like network formation in HUVEC. Treatment of HUVEC with ZD6126 resulted in cell cycle arrest in G2/M, with decrease of cells in S phase and proliferation inhibition in a dose-dependent manner. ZD6126 augmented the cell-killing effect of radiation and radiation-induced apoptosis in HUVEC. The combination of ZD6126 and radiation further decreased tumor vascularization in an in vivo Matrigel angiogenesis assay. In tumor xenografts, ZD6126 enhanced the antitumor activity of radiation, resulting in tumor growth delay. Conclusions: These preclinical studies suggest that ZD6126 can augment the radiation response of proliferating endothelial H and N and lung cancer cells. These results complement recent reports suggesting the potential value of combining radiation with vascular targeting/antiangiogenic agents

Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy

DEFF Research Database (Denmark)

Stenvang, Jan; Kümler, Iben; Nygård, Sune Boris

2013-01-01

-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1...

Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression

International Nuclear Information System (INIS)

McDonald, Gail T.; Sullivan, Richard; Pare, Genevieve C.; Graham, Charles H.

2010-01-01

Approaches to overcome chemoresistance in cancer cells have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present study determined the effect of PI3K inhibition on the clonogenic survival of human cancer cells following exposure to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in increased survival of MDA-MB-231 breast carcinoma cells after exposure to doxorubicin, etoposide, 5-fluorouracil, and vincristine. Increased survival following PI3K inhibition was also observed in DU-145 prostate, HCT-116 colon and A-549 lung carcinoma cell lines exposed to doxorubicin. Increased cell survival mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G 1 phase of the cell cycle. Inhibition of PI3K signaling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21 Waf1/Cip1 and p27 Kip1 ; and knockdown of p27 kip1 with siRNA attenuated resistance to doxorubicin in cells treated with LY294002. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle; however, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) may be a critical determinant of chemosensitivity.

Radiation hardenable impregnating agents for the consolidating conservation of wooden objects

International Nuclear Information System (INIS)

Schaudy, R.

1985-01-01

Radiation hardenable impregnating agents offer some advantages over the conventional agents. At the author's institution objects up to 110 cm length can be impregnated for conservation. More than 200 monomers and resins have been investigated. The procedure of impregnation is outlined and some kinds of wooden objects conserved in this way listed. (G.W.)

Study of enteroparasites infection frequency and chemotherapeutic agents used in pediatric patients in a community living in Porto Alegre, RS, Brazil

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Morrone Fernanda B.

2004-01-01

Full Text Available Parasitic infections caused by intestinal protozoan and helminths affect more than two billion people worldwide and chemotherapy is the most commonly used therapeutic procedure. Considering the problems created by parasitic infections and the incorrect use of drugs, the aim of this work was to detect the frequency of enteroparasites infection and to estimate the use of chemotherapeutic agents in children living in the periphery of the city of Porto Alegre, RS, Brazil. Ninety-six preschool age children, who had parasitological exams and who used antiparasitic drugs, were analyzed. The efficacy of treatment was evaluated by stool examination repeated six months after treatment. The same diagnostic test was used to evaluate parasitological cure, which was defined as absence of eggs and cysts in the stool. From these children, 79 (82.3% were contaminated by some species of parasite, the most prevalent were Ascaris lumbricoides, Trichuris trichiura and Giardia lamblia. The most commonly used drugs were mebendazole (86% of prescriptions and metronidazole (30.3%. The cure rate in the 79 children, examined 6 months after treatment, was 65.3% for A. lumbricoides and 66.1% for T. trichiura. This study suggests that a continuous education program regarding the prevention and treatment of parasitic infections is an essential tool for their eradication.

Herbal radiation countermeasure agents: promising role in the management of radiological/nuclear exigencies

International Nuclear Information System (INIS)

Arora, Rajesh; Sharma, A.; Kumar, R.; Tripathi, R.P.

2008-01-01

In the future, there is a need to substantially boost biomass production and employ elicitors/precursors for improving the production of radioprotective compounds from such alternative sources for ensuring a sustainable supply of the high-value, low volume radioprotective molecules. Chemical fingerprinting, identification and characterization of bioactive constituents using modem analytical techniques and evaluation of their multifaceted mode of action at genomic/proteomic level is also the need of the hour. Such data will help in the development of novel, safe and effective radiation countermeasure agents for human use. Herbal radiation countermeasure agents, including several dietary agents, are likely to find large-scale acceptance in most countries in view of their widespread acceptance, holistic mode of action, less toxicity and economical nature. Endeavours made at INMAS in this direction are likely to fructify in coming years and radiation countermeasure agents from several of these herbal sources would become available, possibly several would be obtainable over-the-counter, for use by civilians, military personnel, first emergency responders and other rescue and recovery personnel. (author)

Validation and use of microdialysis for determination of pharmacokinetic properties of the chemotherapeutic agent mitomycin C - an experimental study

International Nuclear Information System (INIS)

Sørensen, Olaf; Andersen, Anders; Olsen, Harald; Alexandr, Kristian; Ekstrøm, Per Olaf; Giercksky, Karl-Erik; Flatmark, Kjersti

2010-01-01

Mitomycin C is a chemotherapeutic agent used in the treatment of peritoneal surface malignancies, administered as hyperthermic intraperitoneal chemotherapy after cytoreductive surgery. Pharmacokinetic studies have been based on analyses of blood, urine and abdominal perfusate, but actual tissue concentrations of the drug have never been determined. Microdialysis is an established method for continuous monitoring of low-molecular substances in tissues, and in the present study microdialysis of mitomycin C was studied in vitro and in vivo. Using in vitro microdialysis, relative recovery was determined when varying drug concentration, temperature and perfusion flow rate. In vivo microdialysis was performed in rats to verify long-term stability of relative recovery in four compartments (vein, peritoneum, extraperitoneal space and hind leg muscle). Subsequently, intravenous and intraperitoneal bolus infusion experiments were performed and pharmacokinetic parameters were calculated. In vitro, compatibility of mitomycin C and microdialysis equipment was demonstrated, and relative recovery was stable over an adequate concentration range, moderately increased by raising medium temperature and increased when flow rate was reduced, all according to theory. In vivo, stable relative recovery was observed over seven hours. Mitomycin C exhibited fast and even distribution in rat tissues, and equal bioavailability was achieved by intravenous and intraperitoneal infusion. The half-life of mitomycin C calculated after intravenous infusion was 40 minutes. Mitomycin C concentration can be reliable monitored in vivo using microdialysis, suggesting that this technique can be used in pharmacokinetic studies of this drug during hyperthermic intraperitoneal chemotherapy

Agentes antineoplásicos biorredutíveis: uma nova alternativa para o tratamento de tumores sólidos

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Oliveira Renata Barbosa de

2002-01-01

Full Text Available A problem often encountered in cancer therapy is the presence of tumor cell subpopulation that are resistant to treatment. Solid tumors frequently contain hypoxic cells that are resistant to killing by ionizing radiation and also by many chemotherapeutic agents. However, these hypoxic cells can be exploited for therapy by non-toxic hypoxic-activated prodrugs. Bioreductive drugs require metabolic reduction to generate cytotoxic metabolites. This process is facilitated by appropriate reductases and the lower oxygen conditions present in solid tumors. The unique presence of hypoxic cells in human tumors provides an important target for selective cancer therapy.

Mutagenic effect of ionizing radiation and chemical and environmental agents in Tradescantia

International Nuclear Information System (INIS)

Cebulska-Wasilewska, A.

1988-01-01

The studies covered the following problems: an influence of some environmental agents on the mutagenic effectiveness of ionizing radiation, interaction between ionizing radiation and chemical mutagens in the induction of somatic mutations and also an application of Tradescantia model system for biological monitoring. The studies showed that the pretreatment of Tradescantia plants with sodium fluoride or the modification of the soil composition with dolomite admixture, visibly influences plants radiosensitivity. The analysis of the changes in the dose-response curves suggested that the employed agents were influencing in different ways the repair processes of the DNA. The studies on the interaction between agents proved that the synergistic effect occurs in case of combined action of ionizing radiation with such chemical mutagens as ethyl methansulfonate or 1,2 dibromomethane. It was also discovered that in the range of low doses the effect was proportional to radiation dose and total exposition to chemical mutagen. The field application of Tradescantia method defined the mutagenicity of air pollution in the Cracow area. The highest frequencies of mutations were detected after the Chernobyl accident and after the damage of the filters in the Pharmaceutical Plant. The applied method was evaluated in respect of its usefulness for biological monitoring of environmental pollution. 163 refs. (author)

Applying radiation approaches to the control of public risks from chemical agents

International Nuclear Information System (INIS)

Alexander, R.E.

1989-01-01

IF a hazardous agent has a threshold, prevention is the obvious measure of success. To the eyes of this author, success is also achieveable for a hazardous agent that may have no threshold and that causes its effects in a probabilistic manner. First, the technical people responsible for protection must be given a reasonable, well defined risk objective by governmental authorities. To the extent that they meet that objective (1) without unnecessarily increasing operational costs, (2) without interfering unnecessarily with operational activities, and (3) without diverting resources away from greater risks, they are successful. Considering these three qualifications, radiation protection for members of the public can hardly be presented as the panacea for other hazardous agents. It would be an error to dismiss the improvement opportunities discussed above as being of acdemic interest only. Decades of experience with radiation have demonstrated that these problems are both real adn significant. In the US the axioms discussed above are accepted as scientific fact for radiation by many policy makers, the news media and the public. For any operation the collective dose is calculated using zero dose as the lower limit of integration, the results are converted to cancer deaths using the risk coefficients, and decisions are made as though these deaths would actually occur without governmental intervention. As a result, billions of dollars and a very large number of highly skilled persons are being expended to protect against radiation doses far smaller than geographical variations in the natural radiation background. These expenditures are demanded by, and required for well-meaning, nontechnical people who have been misled. It is often stated by knowledgeable people that if the degree of protection required for radiation were also to be requested for the other hazards, human progress would come to a halt. If the radiation approaches are to be used in the control of public

Training strategic community agents in health effects of ionizing radiation; Capacitacao de agentes comunitarios de saude em efeitos das radiacoes ionizantes

Energy Technology Data Exchange (ETDEWEB)

Leite, Teresa C.S.B.; Silva, IIson P.M. da; Jannuzzi, Denise M.S. [Fundacao Eletronuclear de Assistencia Medica (CIRA/FEAM), Angra dos Reis, RJ (Brazil). Centro de Informacoes em Radioepidemiologia; Maurmo, Alexandre M., E-mail: ammaurmo@gmail.com [Fundacao Eletronuclear de Assistencia Medica (CMRl/CTNV/FEAM), Angra dos Reis, RJ (Brazil). Centro de Treinamento Prof. Nelson Valverde. Centro de Medicina das Radiacoes Ionizantes

2013-11-01

The main motivation for the development of training was the need to train agents (opinion makers) with proximity and credibility among the population, to clarify the most frequently asked questions in relation to ionizing radiation, the operation of nuclear power plants, emergency plans and about the possibility of there effects of radiation on the health of inhabitants in regions close to the central Nuclear Almirante Alvaro Alberto - CNAAA. The project has a target audience of 420 agents, 60 of them have already been trained in a pilot project . The results indicate that the topics of training were adequate and the agents have expanded their knowledge. On the other hand, the information passed on to communities by agents, recognized by this population as ' the most reliable people', is of greater credibility and likelihood of success in communicating important issues for the population living in the vicinity of the CNAAA. (author)

Comparative studies on the effect of radiation-sensitizing agents used in radiating VX2 Carcinoma. With reference to 5-bromodeoxyuridine (BUdR)

Energy Technology Data Exchange (ETDEWEB)

Migita, H [Kyushu Dental Coll., Kitakyushu, Fukuoka (Japan)

1975-11-01

The effects of 5-Fu and BUdR as radiation-sensitizing agents macroscopically were investigated in 122 VX2 Carcinomas transplanted into the calves of the hind legs of rabbits. Experimental groups and contrast groups are divided into six as follows: A: No treatment, B: 5-Fu infusion, C: BUdR+Antimetabolite infusion, D: Radiation, E: 5-Fu infusion and radiation, and F: BUdR+Antimetabolite infusion and radiation. The amount of agent given to each was 5 mg/kg/day of 5-Fu and 50 mg/kg/day of BUdR, and the amount of radiation was 300 rad/day. 5-Fu was used as the Antimetabolite, and its amount was one-tenth of that in the 5-Fu Infusion Group. The agent and the radiation were given for five days. 1. In the 300 rad/day Group, the radiation was not enough to result in a complete cure. 2. In the two Agent Infusion Group, 5-Fu and BUdR+Antimetabolite proved to be anti-cancer, but neither of them resulted in effective treatment. 3. The 5-Fu Infusion and Radiation Group, showed a strong degenerative change in the tumor cell and a radiosensitive effect from 5-Fu, but the tumor was not lessened. 4. In the BUdR-Antimetabolite Infusion and Radiation Group, the tumor began to reduce on the third day. On the seventh and fourteenth days, necrosis of the greater part of tumor was seen, and the rest of the tumor cells were found to be in degenerative change. On the twenty first day, no live tumor cell was found, only dead remains of tumor cells. The results were confirmed both macroscopically and histopathologically. 5. BUdR can be expected to be effective in clinical application to oral malignant tumors.

Effect of dihydroxyanthraquinone (DHAQ) and radiation on the survival of cultured Chinese hamster ovary cells

International Nuclear Information System (INIS)

Kimler, B.F.

1983-01-01

Dihydroxyanthraquinone (DHAQ) is currently being tested as a cancer chemotherapeutic agent because of its structural similarity to Adriamycin (ADR) and other DNA-intercalating antibiotics. The interaction of DHAQ and ionizing radiation on the induction of cell lethality was investigated in Chinese hamster ovary cells in culture. In asynchronous populations of cells, DHAQ produced a slight enhancement of radiation-induced cell lethality as evidenced by changes in both shoulder and slope of the radiation dose-survival curves. However, DHAQ had no effect on either the extent or time course of recovery from sublethal radiation damage. In synchronous populations of cells treated at various times before or after selection in mitosis, the combination of DHAQ and radiation produced greater cell killing than that predicted based on simple additivity of effect, with a decided enhancement for cells treated during S phase. These results indicate that DHAQ is similar to other DNA-intercalating antibiotics in regard to the interaction with ionizing radiation to produce cell lethality

Low environmental radiation background impairs biological defence of the yeast Saccharomyces cerevisiae to chemical radiomimetic agents

International Nuclear Information System (INIS)

Satta, L.; Augusti-Tocco, G.; Ceccarelli, R.; Paggi, P.; Scarsella, G.; Esposito, A.; Fiore, M.; Poggesi, I.; Ricordy, R.; Cundari, E.

1995-01-01

Background radiation is likely to constitute one of the factors involved in biological evolution since radiations are able to affect biological processes. Therefore, it is possible to hypothesize that organisms are adapted to environmental background radiation and that this adaptation could increase their ability to respond to the harmful effects of ionizing radiations. In fact, adaptive responses to alkylating agents and to low doses of ionizing radiation have been found in many organisms. In order to test for effects of adaptation, cell susceptibility to treatments with high doses of radiomimetic chemical agents has been studied by growing them in a reduced environmental radiation background. The experiment has been performed by culturing yeast cells (Saccharomyces cerevisiae D7) in parallel in a standard background environment and in the underground Gran Sasso National Laboratory, with reduced environmental background radiation. After a conditioning period, yeast cells were exposed to recombinogenic doses of methyl methanesulfonate. The yeast cells grown in the Gran Sasso Laboratory showed a higher frequency of radiomimetic induced recombination as compared to those grown in the standard environment. This suggests that environmental radiation may act as a conditioning agent

Differential impact of diverse anticancer chemotherapeutics on the Cdc25A-degradation checkpoint pathway

International Nuclear Information System (INIS)

Agner, Jeppe; Falck, Jacob; Lukas, Jiri; Bartek, Jiri

2005-01-01

When exposed to DNA-damaging insults such as ionizing radiation (IR) or ultraviolet light (UV), mammalian cells activate checkpoint pathways to halt cell cycle progression or induce cell death. Here we examined the ability of five commonly used anticancer drugs with different mechanisms of action to activate the Chk1/Chk2-Cdc25A-CDK2/cyclin E cell cycle checkpoint pathway, previously shown to be induced by IR or UV. Whereas exposure of human cells to topoisomerase inhibitors camptothecin, etoposide, or adriamycin resulted in rapid (within 1 h) activation of the pathway including degradation of the Cdc25A phosphatase and inhibition of cyclin E/CDK2 kinase activity, taxol failed to activate this checkpoint even after a prolonged treatment. Unexpectedly, although the alkylating agent cisplatin also induced degradation of Cdc25A (albeit delayed, after 8-12 h), cyclin E/CDK2 activity was elevated and DNA synthesis continued, a phenomena that correlated with increased E2F1 protein levels and consequently enhanced expression of cyclin E. These results reveal a differential impact of various classes of anticancer chemotherapeutics on the Cdc25A-degradation pathway, and indicate that the kinetics of checkpoint induction, and the relative balance of key components within the DNA damage response network may dictate whether the treated cells arrest their cell cycle progression

Sensitivity to TOP2 targeting chemotherapeutics is regulated by Oct1 and FILIP1L.

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Huarui Lu

Full Text Available Topoisomerase II (TOP2 targeting drugs like doxorubicin and etoposide are frontline chemotherapeutics for a wide variety of solid and hematological malignancies, including breast and ovarian adenocarcinomas, lung cancers, soft tissue sarcomas, leukemias and lymphomas. These agents cause a block in DNA replication leading to a pronounced DNA damage response and initiation of apoptotic programs. Resistance to these agents is common, however, and elucidation of the mechanisms causing resistance to therapy could shed light on strategies to reduce the frequency of ineffective treatments. To explore these mechanisms, we utilized an unbiased shRNA screen to identify genes that regulate cell death in response to doxorubicin treatment. We identified the Filamin A interacting protein 1-like (FILIP1L gene as a crucial mediator of apoptosis triggered by doxorubicin. FILIP1L shares significant similarity with bacterial SbcC, an ATPase involved in DNA repair. FILIP1L was originally described as DOC1, or "down-regulated in ovarian cancer" and has since been shown to be downregulated in a wide variety of human tumors. FILIP1L levels increase markedly through transcriptional mechanisms following treatment with doxorubicin and other TOP2 poisons, including etoposide and mitoxantrone, but not by the TOP2 catalytic inhibitors merbarone or dexrazoxane (ICRF187, or by UV irradiation. This induction requires the action of the OCT1 transcription factor, which relocalizes to the FILIP1L promoter and facilitates its expression following doxorubicin treatment. Our findings suggest that the FILIP1L expression status in tumors may influence the response to anti-TOP2 chemotherapeutics.

Chemotherapeutic Drugs and Mitochondrial Dysfunction: Focus on Doxorubicin, Trastuzumab, and Sunitinib

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Stefania Gorini

2018-01-01

Full Text Available Many cancer therapies produce toxic side effects whose molecular mechanisms await full elucidation. The most feared and studied side effect of chemotherapeutic drugs is cardiotoxicity. Also, skeletal muscle physiology impairment has been recorded after many chemotherapeutical treatments. However, only doxorubicin has been extensively studied for its side effects on skeletal muscle. Chemotherapeutic-induced adverse side effects are, in many cases, mediated by mitochondrial damage. In particular, trastuzumab and sunitinib toxicity is mainly associated with mitochondria impairment and is mostly reversible. Vice versa, doxorubicin-induced toxicity not only includes mitochondria damage but can also lead to a more robust and extensive cell injury which is often irreversible and lethal. Drugs interfering with mitochondrial functionality determine the depletion of ATP reservoirs and lead to subsequent reversible contractile dysfunction. Mitochondrial damage includes the impairment of the respiratory chain and the loss of mitochondrial membrane potential with subsequent disruption of cellular energetic. In a context of increased stress, AMPK has a key role in maintaining energy homeostasis, and inhibition of the AMPK pathway is one of the proposed mechanisms possibly mediating mitochondrial toxicity due to chemotherapeutics. Therapies targeting and protecting cell metabolism and energy management might be useful tools in protecting muscular tissues against the toxicity induced by chemotherapeutic drugs.

Technical advances in radiation therapy

International Nuclear Information System (INIS)

Sause, W.T.

1986-01-01

Substantial advances have been made in radiation therapy. Many of these advances can be applied in most radiation therapy departments without expensive improvements in equipment. Changes in radiation fractionation, chemotherapeutic sensitization, intraoperative radiation, and interstitial implants can be performed with experience and improved physician training in most medium-sized departments. Advances that require investments in expensive equipment such as particle radiation and hyperthermia will need to be evaluated at designated treatment centers. 106 references

A review on the chemotherapeutic potential of fisetin: In vitro evidences.

Science.gov (United States)

Sundarraj, Kiruthika; Raghunath, Azhwar; Perumal, Ekambaram

2018-01-01

During the past five decades, cancer cell lines are being successfully used as an in vitro model to discover the anti-cancer potential of plant secondary metabolites. Fisetin - the most popular polyphenol from fruits and vegetables, exhibits a repertoire of promising pharmacological features. Such versatile properties make fisetin an excellent anticancer agent and its efficacy as a chemotherapeutic agent against tumor heterogeneity from in vitro studies are encouraging. Fisetin is like a Pandora's box, as more research studies are being carried out, it reveals its new molecules within the cancer cells as therapeutic targets. These molecular targets orchestrate processes such as apoptosis, autophagic cell death, cell cycle, invasion, metastasis and angiogenesis in cancer cells. Besides apoptotic elicitation, fisetin's ability to induce autophagic cell death in cancer cells has been reported. This review examines the various molecular mechanisms of action elicited by fisetin leading to apoptosis and autophagic cell death as evidenced from cancer cell lines. In addition, the increased bioavailability and sustained release of fisetin improved through conjugation and enhanced effect of fisetin through synergism on various cancers are also highlighted. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Radiation-curable impregnating agents for the conservation of archaeologic wooden objects. Part 2

International Nuclear Information System (INIS)

Schaudy, R.; Wendrinsky, J.; Kalteis, H.; Grienauer, W.

1982-12-01

As a continuation of the work described in OEFZS Ber. No. 4165, impregnating agents curable by ionizing radiation, such as free radical polymerizable monomers or artificial resins, have been investigated. Specific weight and viscosity of the liquid mixtures have been as well determined as the specific weight and gel content of the gamma radiation-cured samples. Hardness and elastic behaviour have been estimated only. The shrinkage during hardening was found to be 5 to 12 % for low viscous mixtures (up to 600 mPa.s) and 3 to 8 % for higher viscous impregnating agents. The results are to be discussed. (Author) [de

A trial of ACNU and radiation therapy with sensitizing agents for malignant gliomas

Energy Technology Data Exchange (ETDEWEB)

Kawano, Hirokazu; Hayashi, Minoru; Satoh, Kazufumi; Ishii, Hisamasa; Nakatsugawa, Shigekazu; Ishii, Yasushi (Fukui Medical School, Yoshida, Fukui (Japan))

1989-11-01

Twelve cases of malignant gliomas (anaplastic astrocytoma 4, glioblatoma 8, recurrent 3, primary 9) were treated with ACNU and radiation with sensitizing agents after the surgical removal of the tumor. BUdR, Vidarabine (Ara-A), Aciclovir (ACV) were applied for sensitizing agents. BUdR was administrated intraarterially prior to radiation (380 rad, two times a week), and Ara-A and ACV intravenously during and after the radiation. Total dosage of the radiation was 50-60 Grey for each case. All recurrent and eight primary patients died. The mean survival time of the recurrent patients was 17.7 months, while that of the primary patients was 13.4 months. One of the primary patients was glioblastoma and is still surviving more than 24 months by now. The complete response (CR) rate of the primary tumor patients observed by computerized tomography (CT) scan was 5/9. We can expect the availability of this trial for malignant gliomas because of high CR rate in primary tumor cases. (author).

Toxic agent and radiation control: meeting the 1990 objectives for the nation

International Nuclear Information System (INIS)

Rall, D.P.

1984-01-01

Toxic agent and radiation control is 1 of the 15 health priority areas addressed through the Public Health Service's Objectives for the Nation. Several gains in moving toward the 1990 goals for toxic agent and radiation control have been recorded. Research and technical assistance, combined with legislation to reduce the amount of lead in gasoline, have contributed to a decrease in the mean blood lead level of the general population. New testing procedures have been developed to evaluate both reproductive and developmental toxicities of chemicals. Educational implementation of pelvimetry referral criteria in a multiyear study involving approximately 200 U.S. hospitals has resulted in a 50 percent reduction in the number of pelvimetries performed. Health-related responses have been given to environmental problems such as exposures to polychlorinated biphenyls (PCBs) in Massachusetts and Florida and exposures to dioxin in Missouri and New Jersey. Chemical records for some 1000 compounds likely to occur in chemical dumps or in bulk transit are being either created or updated to enhance online data retrieval services. For the foreseeable future, however, improvement of knowledge of the potential health risk posed by toxic chemicals and radiation must remain one of the most important priorities. To control toxic agents, development of surveillance systems and data bases are equally important

Study of qinolones usage in prevention and therapy of septic complications of radiation damage

International Nuclear Information System (INIS)

Petyrek, P.; Spelda, S.

1994-01-01

A standard model of experimental sepsis was elaborated at rats in dependence on a gamma irradiation dose and a time interval between irradiation and application infectious agents E. coli O 83:K 24:H 31. For a development of experimental sepsis was proved that it is not decisive in these laboratory animals when infectious agents is i.v. or i.p. applicated. Such amount of organisms (1-20.10 7-8 ) was applicated in particular not to develop sepsis in non-irradiated laboratory animals. Laboratory animals were irradiated with sublethal doses and approximately. LD 50-30 doses of gamma radiation. The laboratory animals were treated only in experiments and qinolone drug ofloxacin was used in the treatment of experimental sepsis. Ofloxacin perorally administrated in the dose of 40 mg/kg in an hour after application of infectious agents and its administration for 5 days in the 24-h intervals confirmed in fact 100% therapeutic effectiveness in irradiated experimental animals. In non-treated experimental groups, animals died in 24-28 hours interval after application of infectious agents and sepsis was a cause of death. In treated experimental groups, animal survived by day 30 after irradiation with sublethal doses or died during the period typical for a bone marrow syndrome of acute radiation injury after irradiation with lethal doses of gamma radiation. Acquired experimental outcomes may suggest that fluorochinolone chemotherapeuticals in the respect of their essential pharmacokinetic properties will be used for a prevention of infectious complications in acute radiation injury. (author)

Effects of chemotherapeutics on organotypic corticostriatal slice cultures identified by a panel of fluorescent and immunohistochemical markers

DEFF Research Database (Denmark)

Nørregaard, Annette; Jensen, Stine Skov; Kolenda, Jesper

2012-01-01

no toxicity was observed. Corresponding immunostaining showed loss of MAP2 and increased expression of GFAP and p25α for cultures exposed to 1,000 nM VCR. Cultures exposed to high concentrations of ACNU and IM disintegrated, leaving no tissue for histology. In conclusion, corticostriatal slice cultures...... specific neuronal and glial degeneration induced by chemotherapeutics in organotypic rat corticostriatal slice cultures. The slice cultures were exposed to the alkylating agents temozolomide (TMZ) and nimustine (ACNU), the tyrosine kinase inhibitor imatinib mesylate (IM) and the microtubule...

Reaction of a chemotherapeutic agent, 6-mercaptopurine, with a direct-acting, electrophilic carcinogen, benzo[a]pyrene-7,8-diol 9,10-epoxide.

Science.gov (United States)

MacLeod, M C; Stewart, E; Daylong, A; Lew, L K; Evans, F E

1991-01-01

The chemotherapeutic agent 6-mercaptopurine (6-MP) has been shown to react covalently with the ultimate carcinogenic metabolite of benzo[a]pyrene, 7-r,8-t-dihydroxy-9-t,10-t-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), in aqueous solution, forming a single adduct. NMR studies of the HPLC-purified product were consistent with its identification as 10(S)-(6'-mercaptopurinyl)-7,8,9-trihydroxy-7,8,9,10- tetrahydrobenzo[a]pyrene. Reaction kinetics were analyzed by using both HPLC separation of the products formed and a spectrophotometric assay for adduct formation. A simple model in which direct reaction between 6-MP and BPDE takes place without formation of a physical complex was found to adequately predict the dependence of product ratios on 6-MP concentration. Variations in the observed rate constant for this reaction with changes in temperature, pH, and buffer concentration were determined and compared to the effects of these variables on the observed rate constant for BPDE hydrolysis. In each case, the processes were affected quite differently, suggesting that different rate-determining steps are involved. The data suggest that the reaction mechanism involves SN2 attack of the anion of 6-MP, formed by ionization of the sulfhydryl group, on carbon 10 of BPDE, resulting in a trans-9,10 reaction product.

Oncogenic transformation with radiation and chemicals: review

International Nuclear Information System (INIS)

Hall, E.J.; Hei, T.K.

1985-01-01

Quantitative in vitro assay systems for oncogenic transformation are a powerful research tool. They may be based on short-term cultures of hamster embryo cells, or established cell lines of mouse origin. While X-ray-induced transformation of human cells has been demonstrated, it has proved difficult to develop quantitative assay systems based on cells of human origin. The presently available quantitative assays have two quite distinct basic uses. First, they may be useful to accumulate data which is essentially pragmatic in nature. For example, they may be used to compare and contrast the oncogenic potential of chemotherapeutic agents or hypoxic cell sensitizers used or proposed in the clinic. They may be used to identify compounds that inhibit or suppress the transformation incidence resulting from known oncogenic agents, or they may be used to demonstrate the interaction between two different agents, such as radiation and asbestos. Second, they may prove to be invaluable in the study of the basic mechanisms of carcinogenesis, inasmuch as they represent models of tumourigenesis in which the various steps can be manipulated and modified more readily and in a controlled way. (author)

Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells.

Science.gov (United States)

Nojima, Kuniharu; Hochegger, Helfrid; Saberi, Alihossein; Fukushima, Toru; Kikuchi, Koji; Yoshimura, Michio; Orelli, Brian J; Bishop, Douglas K; Hirano, Seiki; Ohzeki, Mioko; Ishiai, Masamichi; Yamamoto, Kazuhiko; Takata, Minoru; Arakawa, Hiroshi; Buerstedde, Jean-Marie; Yamazoe, Mitsuyoshi; Kawamoto, Takuo; Araki, Kasumi; Takahashi, Jun A; Hashimoto, Nobuo; Takeda, Shunichi; Sonoda, Eiichiro

2005-12-15

Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polzeta, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy.

A rapid method for testing in vivo the susceptibility of different strains of Trypanosoma cruzi to active chemotherapeutic agents

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Leny S. Filardi

1984-06-01

Full Text Available A method is described which permits to determine in vivo an in a short period of time (4-6 hours the sensitivity of T. cruzo strains to known active chemotherapeutic agents. By using resistant- and sensitive T. cruzi stains a fairly good correlation was observed between the results obtained with this rapid method (which detects activity against the circulating blood forms and those obtained with long-term schedules which involve drug adminstration for at least 20 consecutive days and a prolonged period of assessment. This method may be used to characterize susceptibility to active drugs used clinically, provide infomation on the specific action against circulating trypomastigotes and screen active compounds. Differences in the natural susceptibility of Trypanosoma cruzi strains to active drugs have been already reported using different criteria, mostly demanding long-term study of the animal (Hauschka, 1949; Bock, Gonnert & Haberkorn, 1969; Brener, Costa & Chiari, 1976; Andrade & Figueira, 1977; Schlemper, 1982. In this paper we report a method which detects in 4-6 hours the effect of drugs on bloodstream forms in mice with established T. cruzi infections. The results obtained with this method show a fairly good correlation with those obtained by prolonged treatment schedules used to assess the action of drugs in experimental Chagas' disease and may be used to study the sensitivity of T. cruzi strains to active drugs.No presente trabalho descreve-se um metodo que permite determinar in vivo e em curto espaço de tempo (4-6 horas a sensibilidade de cepas de T. cruzi a agentes terapeuticos ativos na doença de Chagas. Usando-se cepas sensíveis e resistentes aos medicamentos foi possível observar uma boa correlação entre os resultados obtidos com o método rápido (que detecta atividade contra as formas circulantes do parasita e aqueles obtidos com esquema de acao prolongada que envolve a administração da droga por 20 dias e posterior avalia

Protection against radiation-induced oxidative stress in cultured human epithelial cells by treatment with antioxidant agents

International Nuclear Information System (INIS)

Wan, X. Steven; Ware, Jeffrey H.; Zhou, Zhaozong; Donahue, Jeremiah J.; Guan, Jun; Kennedy, Ann R.

2006-01-01

Purpose: To evaluate the protective effects of antioxidant agents against space radiation-induced oxidative stress in cultured human epithelial cells. Methods and Materials: The effects of selected concentrations of N-acetylcysteine, ascorbic acid, sodium ascorbate, co-enzyme Q10, α-lipoic acid, L-selenomethionine, and vitamin E succinate on radiation-induced oxidative stress were evaluated in MCF10 human breast epithelial cells exposed to radiation with X-rays, γ-rays, protons, or high mass, high atomic number, and high energy particles using a dichlorofluorescein assay. Results: The results demonstrated that these antioxidants are effective in protecting against radiation-induced oxidative stress and complete or nearly complete protection was achieved by treating the cells with a combination of these agents before and during the radiation exposure. Conclusion: The combination of antioxidants evaluated in this study is likely be a promising countermeasure for protection against space radiation-induced adverse biologic effects

Plant-Derived Urease Inhibitors as Alternative Chemotherapeutic Agents.

Science.gov (United States)

Hassan, Sherif T S; Žemlička, Milan

2016-07-01

Inhibition of the metalloenzyme urease has important pharmacologic applications in the field of antiulcer and antigastric cancer agents. Urease is involved in many serious infections caused by Helicobacter pylori in the gastric tract as well as by Proteus and related species in the urinary tract. Although numerous studies have described several novel urease inhibitors (UIs) used for the treatment of gastric and urinary infections, all these compounds have exhibited severe side effects, toxicity, and instability. Therefore, to overcome such problems, it is necessary to search for new sources of UIs, such as natural products, that provide reduced side effects, low toxicity, greater stability, and bioavailability. As limited studies have been conducted on plant-derived UIs, this paper aims to highlight and summarize the most promising compounds isolated and identified from plants, such as terpenoids, phenolic compounds, alkaloids, and other substances with inhibitory activities against plant and bacterial ureases; these are in vitro and in vivo studies with an emphasis on structure-activity relationship studies and types of inhibition that show high and promising levels of anti-urease activity. This will aid medicinal chemists in the design and synthesis of novel and pharmacologically potent UIs useful for the development of antiulcer drugs. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pharmacological agents and impairment of fracture healing: what is the evidence?

NARCIS (Netherlands)

Pountos, I.; Georgouli, T.; Blokhuis, T.J.; Pape, H.C.; Giannoudis, P.V.

2008-01-01

Bone healing is an extremely complex process which depends on the coordinated action of several cell lineages on a cascade of biological events, and has always been a major medical concern. The use of several drugs such as corticosteroids, chemotherapeutic agents, non-steroidal anti-inflammatory

Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

Science.gov (United States)

Tsen, Andrew R; Long, Patrick M; Driscoll, Heather E; Davies, Matthew T; Teasdale, Benjamin A; Penar, Paul L; Pendlebury, William W; Spees, Jeffrey L; Lawler, Sean E; Viapiano, Mariano S; Jaworski, Diane M

2014-03-15

Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors. © 2013 UICC.

Persistence of DNA adducts, hypermutation and acquisition of cellular resistance to alkylating agents in glioblastoma.

Science.gov (United States)

Head, R J; Fay, M F; Cosgrove, L; Y C Fung, K; Rundle-Thiele, D; Martin, J H

2017-12-02

Glioblastoma is a lethal form of brain tumour usually treated by surgical resection followed by radiotherapy and an alkylating chemotherapeutic agent. Key to the success of this multimodal approach is maintaining apoptotic sensitivity of tumour cells to the alkylating agent. This initial treatment likely establishes conditions contributing to development of drug resistance as alkylating agents form the O 6 -methylguanine adduct. This activates the mismatch repair (MMR) process inducing apoptosis and mutagenesis. This review describes key juxtaposed drivers in the balance between alkylation induced mutagenesis and apoptosis. Mutations in MMR genes are the probable drivers for alkylation based drug resistance. Critical to this interaction are the dose-response and temporal interactions between adduct formation and MMR mutations. The precision in dose interval, dose-responses and temporal relationships dictate a role for alkylating agents in either promoting experimental tumour formation or inducing tumour cell death with chemotherapy. Importantly, this resultant loss of chemotherapeutic selective pressure provides opportunity to explore novel therapeutics and appropriate combinations to minimise alkylation based drug resistance and tumour relapse.

Ecological effects of various toxic agents on the aquatic microcosm in comparison with acute ionizing radiation

International Nuclear Information System (INIS)

Fuma, S.; Ishii, N.; Takeda, H.; Miyamoto, K.; Yanagisawa, K.; Ichimasa, Y.; Saito, M.; Kawabata, Z.; Polikarpov, G.G.

2003-01-01

The purpose of this study was an evaluation of the effect levels of various toxic agents compared with acute doses of ionizing radiation for the experimental model ecosystem, i.e., microcosm mimicking aquatic microbial communities. For this purpose, the authors used the microcosm consisting of populations of the flagellate alga Euglena gracilis as a producer, the ciliate protozoan Tetrahymena thermophila as a consumer and the bacterium Escherichia coli as a decomposer. Effects of aluminum and copper on the microcosm were investigated in this study, while effects of γ-rays, ultraviolet radiation, acidification, manganese, nickel and gadolinium were reported in previous studies. The microcosm could detect not only the direct effects of these agents but also the community-level effects due to the interspecies interactions or the interactions between organisms and toxic agents. The authors evaluated doses or concentrations of each toxic agent which had the following effects on the microcosm: (1) no effects; (2) recognizable effects, i.e., decrease or increase in the cell densities of at least one species; (3) severe effects, i.e., extinction of one or two species; and (4) destructive effects, i.e., extinction of all species. The resulting effects data will contribute to an ecological risk assessment of the toxic agents compared with acute doses of ionizing radiation

Repurposing the FDA-approved pinworm drug pyrvinium as a novel chemotherapeutic agent for intestinal polyposis.

Directory of Open Access Journals (Sweden)

Bin Li

Full Text Available Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP and 85% of spontaneous colorectal cancers (CRC. FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes.

Alterations of nutritional status: impact of chemotherapy and radiation therapy

International Nuclear Information System (INIS)

Donaldson, S.S.; Lenon, R.A.

1979-01-01

The nutritional status of a cancer patient may be affected by the tumor, the chemotherapy and/or radiation therapy directed against the tumor, and by complications associated with that therapy. Chemotherpay-radiotherapy is not confined exclusively to malignant cell populations; thus, normal tissues may also be affected by the therapy and may contribute to specific nutritional problems. Impaired nutrition due to anorexia, mucositis, nausea, vomiting, and diarrhea may be dependent upon the specific chemotherapeutic agent, dose, or schedule utilized. Similar side effects from radiation therapy depend upon the dose, fractionation, and volume irradiated. When combined modality treatment is given the nutritional consequences may be magnified. Prospective, randomized clinical trials are underway to investigate the efficacy of nutritional support during chemotherapy-radiotherapy on tolerance to treatment, complications from treatment, and response rates to treatment. Preliminary results demonstrate that the administration of total parenteral nutrition is successful in maintaining weight during radiation therapy and chemotherapy, but that weight loss occurs after discontinuation of nutritional support. Thus, longterm evaluation is mandatory to learn the impact of nutritional support on survival, diease-free survival, and complication rates, as well as on the possible prevention of morbidity associated with aggressive chemotherapy-radiation therapy

HFE polymorphisms influence the response to chemotherapeutic agents via induction of p16INK4A.

Science.gov (United States)

Lee, Sang Y; Liu, Siying; Mitchell, Ryan M; Slagle-Webb, Becky; Hong, Young-Soo; Sheehan, Jonas M; Connor, James R

2011-11-01

HFE is a protein that impacts cellular iron uptake. HFE gene variants are identified as risk factors or modifiers for multiple diseases. Using HFE stably transfected human neuroblastoma cells, we found that cells carrying the C282Y HFE variant do not differentiate when exposed to retinoic acid. Therefore, we hypothesized HFE variants would impact response to therapeutic agents. Both the human neuroblastoma and glioma cells that express the C282Y HFE variant are resistant to Temodar, geldanamycin and γ-radiation. A gene array analysis revealed that p16INK4A (p16) expression was increased in association with C282Y expression. Decreasing p16 protein by siRNA resulted in increased vulnerability to all of the therapeutic agents suggesting that p16 is responsible for the resistance. Decreasing HFE expression by siRNA resulted in a 85% decrease in p16 expression in the neuroblastoma cells but not the astrocytoma cells. These data suggest a potential direct relationship between HFE and p16 that may be cell specific or mediated by different pathways in the different cell types. In conclusion, the C282Y HFE variant impacts the vulnerability of cancer cells to current treatment strategies apparently by increasing expression of p16. Although best known as a tumor suppressor, there are multiple reports that p16 is elevated in some forms of cancer. Given the frequency of the HFE gene variants, as high as 10% of the Caucasian population, these data provide compelling evidence that the C282Y HFE variant should be part of a pharmacogenetic strategy for evaluating treatment efficacy in cancer cells. Copyright © 2011 UICC.

Conservation experiments applying radiation-curable impregnating agents to intact and artifically decayed wood samples

International Nuclear Information System (INIS)

Schaudy, R.; Slais, E.

1983-02-01

Conservation experiments have been performed applying 10 selected impregnating agents to intact and chemically as well as biologically decayed wood samples. The quality of the radiation-curable impregnating agents could be valued by determination of the monomer uptake, the alteration of dimensions and volume and the deformation of the samples. The results are to be discussed. (Author) [de

Human toxoplasmosis-Searching for novel chemotherapeutics.

Science.gov (United States)

Antczak, Magdalena; Dzitko, Katarzyna; Długońska, Henryka

2016-08-01

The protozoan Toxoplasma gondii, an obligate intracellular parasite, is an etiological agent of human and animal toxoplasmosis. Treatment regimens for T. gondii-infected patients have not essentially changed for years. The most common chemotherapeutics used in the therapy of symptomatic toxoplasmosis are a combination of pyrimethamine and sulfadiazine plus folinic acid or a combination of pyrimethamine with lincosamide or macrolide antibiotics. To protect a fetus from parasite transplacental transmission, therapy of pregnant women is usually based on spiramycin, which is quite safe for the organism, but not efficient in the treatment of infected children. Application of recommended drugs limits replication of T. gondii, however, it may be associated with numerous an severe adverse effects. Moreover, medicines have no impact on the tissue cysts of the parasite located predominantly in a brain and muscles. Thus, there is urgent need to develop new drugs and establish "gold standard" treatment. In this review classical treatment of toxoplasmosis as well as potential compounds active against T. gondii have been discussed. For two last decades studies on the development of new anti-T. gondii medications have been focused on both natural and novel synthetic compounds based on existing chemical scaffolds. They have revealed several promising drug candidates characterized by a high selectivity, the low IC50 (the half maximal inhibitory concentration) and low cytotoxicity towards host cells. These drugs are expected to replace or supplement current anti-T. gondii drug arsenal soon. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Synergism in mutations induction in Tradescantia by plants protection agents acting jointly with ionizing radiation

International Nuclear Information System (INIS)

Cebulska-Wasilewska, A.; Smagala, J.

1990-01-01

Tradescantia was first treated by plants protection agents such as: Ambusz, Afalton, Ripcord, Decis, deltametryne and after that irradiated with X radiation. The synergism of both factors was observed. The mutation frequency dependence on radiation doses was studied. 7 figs., 4 refs. (A.S.)

Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents Against Lung Cancer

Science.gov (United States)

2014-10-01

pol eta when replicating damaged DNA. 1S. SUBJECT TERMS: Mutagenesis, DNA polymerases, nucleoside analogs, chemotherapeutic agents 16. SECURITY ...such as polymerase eta, iota , and kappa that are involved in replicating damaged DNA. Our kinetic data obtained under Task 1B indicates that pol eta

Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours

International Nuclear Information System (INIS)

Horsman, M.

1996-01-01

Oxygen deficient hypoxic cells, which are resistant to sparsely ionising radiation, have now been identified in most animal and some human solid tumours and will influence the response of those tumours to radiation treatment. This hypoxia can be either chronic, arising from an oxygen diffusion limitation, or acute, resulting from transient stoppages in microregional blood flow. Extensive experimental studies, especially in the last decade, have shown that nicotinamide and structurally related analogs can effectively sensitize murine tumours to both single and fractionated radiation treatments and that they do so in preference to the effects seen in mouse normal tissues. The earliest studies suggested that this enhancement of radiation damage was the result of an inhibition of the repair mechanisms. However, recent studies in mouse tumours have shown that these drugs prevent transient cessations in blood flow, thus inhibiting the development of acute hypoxia. This novel discovery led to the suggestion that the potential role of these agents as radiosensitizers would be when combined with treatments that overcame chronic hypoxia. The combined nicotinamide with hyperthermia proved that the enhancement of radiation damage by both agents together was greater than that seen with each agent alone. Similar results were later seen for nicotinamide combined with a perfluorochemical emulsion, carbogen breathing, and pentoxifylline, and in all these studies the effects in tumours were always greater than those seen in appropriate normal tissues. Of all the analogs, it is nicotinamide itself which has been the most extensively studied as a radiosensitizer in vivo and the one that shows the greatest effect in animal tumours. It is also an agent that has been well established clinically, with daily doses of up to 6 g, associated with a low incidence of side effects. This human dose is equivalent to 100-200 mg/kg in mice and such doses will maximally sensitize murine tumours to

Possible involvement of the Sigma-1 receptor chaperone in chemotherapeutic-induced neuropathic pain.

Science.gov (United States)

Tomohisa, Mori; Junpei, Ohya; Aki, Masumoto; Masato, Harumiya; Mika, Fukase; Kazumi, Yoshizawa; Teruo, Hayashi; Tsutomu, Suzuki

2015-11-01

Previous studies have shown that ligands of the sigma-1 receptor chaperone (Sig-1R) regulate pain-related behaviors. Clinical use of chemotherapeutics is often compromised due to their adverse side effects, particularly those related to neuropathy. Previous studies have shown that repeated administration of oxaliplatin and paclitaxel produces neuropathy in rodents. Therefore, the aim of the present study was to clarify the involvement of the Sig-1R in chemotherapeutic-induced neuropathy by examining the effects of oxaliplatin and paclitaxel on the Sig-1R levels in the spinal cord, and by examining the effects of Sig-1R agonist and antagonist on oxaliplatin- and paclitaxel-induced neuropathy in rats. Chemotherapeutic-induced neuropathic pain was accompanied by a significant reduction of the Sig-1R level in the spinal cord. Furthermore, the administration of paclitaxel to CHO cells that stably overexpressed Sig-1Rs induced the clustering of Sig-1Rs. We also found that the Sig-1R agonist SA4503 potently inhibited the neuropathy induced by oxaliplatin- and paclitaxel, whereas this action was abolished by the Sig-1R antagonist NE-100. These results suggest that the reduction of Sig-1R activity is involved in chemotherapeutic-induced neuropathy, and the Sig-1R agonist SA4503 could serve as a potential candidate for the treatment of chemotherapeutic-induced neuropathy. © 2015 Wiley Periodicals, Inc.

166Ho-chitosan as a radiation synovectomy agent - biocompatibility study of 166Ho-chitosan in rabbits

International Nuclear Information System (INIS)

Kim, Sug Jun; Lee, Soo Yong; Jeon, Dae Geun; Lee Jong Seok

1997-01-01

Radiation synovectomy is a noninvasive therapy that has been investigated as an alternative to surgical synovectomy. It is been successfully employed in the treatment of synovitis in rheumatoid arthrits and other inflammatory arthropathies. We developed the 166 Ho-chitosan complex for possible use as a radiation synovectomy agent. Holmium is the more practical isotope based on its higher radioactivity and logner half-life. And isotope based on its higher radioactivity and logner half-life. And chitosan is ideal and suitable particles based on its soluble and biodegradable characteristics. So we investigated the biocompatibility of the 166 Ho-chitosan complex to evaluated the suitability as a radiation synovectomy agent. In this study, we performed in vivo and in vitro stability test and biodistribution test. Our results indicate that 166 Ho-chitosan may be an effective radiopharmaceutical for radiation synovectomy. (author). 30 refs., 7 tabs

Radiation proctitis in the rat. Sequential changes and effects of anti-inflammatory agents

Energy Technology Data Exchange (ETDEWEB)

Northway, M.G.; Scobey, M.W.; Geisinger, K.R.

1988-11-01

Female Wistar rats were treated with single exposure irradiation to 2 cm of distal colon to cause radiation proctitis. All animals were evaluated by examination, colonoscopy and histologic evaluation for changes post-irradiation. Exposures of 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5 and 30 Gy caused dose-related clinical and histologic changes peaking at 7 to 15 days post-exposure. Rats treated with 20 Gy were colonoscoped and biopsied daily and showed sequential post-irradiation endoscopic changes ranging from mucosal edema and mild inflammatory changes to erosion and ulcers. Histologically, crypt abscess and mural wall necrosis similar to changes found in the human rectum after radiotherapy were noted. Treatment with nonsteroidal anti-inflammatory agents, (aspirin, indomethacin, piroxicam), misoprostol (a prostaglandin E1 analogue), or sucralfate (an anti-ulcer agent) did not ameliorate nor exacerbate radiation proctitis in rats exposed to 22.5 Gy. We conclude from these data that the female Wistar rat is a good model for studying radiation proctitis because endoscopic, histologic, and clinical changes seen post-exposure closely resemble those found in man.

Radiation proctitis in the rat. Sequential changes and effects of anti-inflammatory agents

International Nuclear Information System (INIS)

Northway, M.G.; Scobey, M.W.; Geisinger, K.R.

1988-01-01

Female Wistar rats were treated with single exposure irradiation to 2 cm of distal colon to cause radiation proctitis. All animals were evaluated by examination, colonoscopy and histologic evaluation for changes post-irradiation. Exposures of 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5 and 30 Gy caused dose-related clinical and histologic changes peaking at 7 to 15 days post-exposure. Rats treated with 20 Gy were colonoscoped and biopsied daily and showed sequential post-irradiation endoscopic changes ranging from mucosal edema and mild inflammatory changes to erosion and ulcers. Histologically, crypt abscess and mural wall necrosis similar to changes found in the human rectum after radiotherapy were noted. Treatment with nonsteroidal anti-inflammatory agents, (aspirin, indomethacin, piroxicam), misoprostol (a prostaglandin E1 analogue), or sucralfate (an anti-ulcer agent) did not ameliorate nor exacerbate radiation proctitis in rats exposed to 22.5 Gy. We conclude from these data that the female Wistar rat is a good model for studying radiation proctitis because endoscopic, histologic, and clinical changes seen post-exposure closely resemble those found in man

Efficacy of continuous treatment with radiation in a rat brain-tumor model

International Nuclear Information System (INIS)

Wheeler, K.T.; Kaufman, K.

1981-01-01

Rats bearing intracerebral 9L/Ro tumors were treated with 10 daily fractions of cesium-137 gamma-rays, BCNU, or combinations of these to agents beginning on either Day 10 or Day 12 after implantation. The treatments were administered either 5 days/week for 2 weeks, with the weekend off, or 10 consecutive days. The median day of death for untreated tumor-bearing rats was Day 15, so Day 12 tumors can be considered late tumors and Day 10 tumors can be considered moderately early. Although all single- and multiple-agent treatments significantly (p less than 0.05) increased the lifespan of tumor-bearing rats over that of the untreated controls, and all multiple-agent schedules significantly (p less than 0.05) increased the lifespan over that of the single-agent therapies, none of the 10 consecutive day schedules increased the lifespan of tumor-bearing rats significantly (p less than 0.2) over that obtained with the 5-day/week schedules. Thus, the evidence from this tumor model suggests that no significant improvement in lifespan would be expected if malignant brain tumors were treated with radiation 7 days a week, either alone or in combination with chemotherapeutic agents such as BCNU

Clinical effect of Cystenosine on leukocytopenia at the time of therapy with radiation and antineoplastic agents

International Nuclear Information System (INIS)

Sato, Kazuhide; Usui, Ryu; Inoue, Hiroshi; Mihashi, Norio; Niibe, Hideo.

1977-01-01

Out of 62 cases, 25 cases received only radiotherapy, 11 cases received both radiotherapy and antineoplastic agents, and 26 cases received only antineoplastic agents. Total dose of x-ray ranges from 3000 to 6200 rad in 18 of 36 cases of the former two groups, and 2600 to 6260 rad of 60 Co dose were irradiated to 18 cases of the rest. This agent was administered 9 tablets per a day (one tablet contains 200 mg of inosine and 20 mg of cystine) for 19 to 142 days. Its effects on leukocytopenia showed marked effectiveness in 9 out of 25 cases treated with only radiation, effectiveness in 8 cases, and ineffectiveness in 3 cases. Its effective rate was 72.8%. The effective rate was 65.4% in the cases treated with only antineoplastic agents, and was 67.7% in all cases. A certain relationship between dose and the effective rate was not recognized. Radiation sickness, such as loss of appetite general fatigue and mausea, decreased gradually by using this agent. Side effect was not recognized particularly. (Kanao. N.)

Evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma

NARCIS (Netherlands)

Kremer, Marijke E B; Derikx, Joep P M; Kremer, Leontien C M; van Baren, Robertine; Heij, Hugo A.; Wijnen, Marc H W A; Wijnen, René M H; van der Zee, David C.; van Heurn, L. W Ernest

2016-01-01

Purpose: The impact of chemotherapeutic sequelae on long-term quality of life (QoL) for survivors of malignant sacrococcygeal teratoma (SCT) is unknown. The incidence of chemotherapeutic toxicity in patients treated for malignant SCT and possible effects on the QoL were analyzed. Methods:

N-acetylaspartate (NAA) induces neuronal differentiation of SH-SY5Y neuroblastoma cell line and sensitizes it to chemotherapeutic agents.

Science.gov (United States)

Mazzoccoli, Carmela; Ruggieri, Vitalba; Tataranni, Tiziana; Agriesti, Francesca; Laurenzana, Ilaria; Fratello, Angelo; Capitanio, Nazzareno; Piccoli, Claudia

2016-05-03

Neuroblastoma is the most commonly extra-cranial solid tumor of childhood frequently diagnosed. The nervous system-specific metabolite N-acetylaspartate (NAA) is synthesized from aspartate and acetyl-CoA in neurons, it is among the most abundant metabolites present in the central nervous system (CNS) and appears to be involved in many CNS disorders. The functional significance of the high NAA concentration in the brain remains uncertain, but it confers to NAA a unique clinical significance exploited in magnetic resonance spectroscopy. In the current study, we show that treatment of SH-SY5Y neuroblastoma-derived cell line with sub-cytotoxic physiological concentrations of NAA inhibits cell growth. This effect is partly due to enhanced apoptosis, shown by decrease of the anti-apoptotic factors survivin and Bcl-xL, and partly to arrest of the cell-cycle progression, linked to enhanced expression of the cyclin-inhibitors p53, p21Cip1/Waf1 and p27Kip1. Moreover, NAA-treated SH-SY5Y cells exhibited morphological changes accompanied with increase of the neurogenic markers TH and MAP2 and down-regulation of the pluripotency markers OCT4 and CXCR4/CD184. Finally, NAA-pre-treated SH-SY5Y cells resulted more sensitive to the cytotoxic effect of the chemotherapeutic drugs Cisplatin and 5-fluorouracil.To our knowledge, this is the first study demonstrating the neuronal differentiating effects of NAA in neuroblastoma cells. NAA may be a potential preconditioning or adjuvant compound in chemotherapeutic treatment.

Radiosensitizers: rationale and potential

International Nuclear Information System (INIS)

Brown, J.M.

1981-01-01

This paper briefly reviews agents that are capable of sensitizing hypoxic cells to radiation and chemotherapeutic agents. The first part is a synopsis of the development of hypoxic radiosensitizers, which concludes that misonidazole can be effective against human tumors. Unfortunately, neurotoxicity limits its effectiveness in humans because the dose that can be given in conjunction with daily fractionated radiation is five to ten times lower than is required for full radiosensitization of the hypoxic cells. The second part covers our recent efforts to develop a drug that does not produce such limiting neurotoxicity. The primary rationale of our program was to synthesize a drug with a short plasma half-life that was too hydrophilic to cross the blood-brain barrier but was able to penetrate tumors and radiosensitize hypoxic cells. From this program, a new drug, SR-2508, has been found that is as efficient as misonidazole in its radiosensitizing ability, but is four to ten times less toxic. Finally, the potential of radiosensitizers not only as agents that can sensitize tumor cells to radiation, but also as agents that can specifically sensitize tumors to chemotherapeutic agents, is discussed. In addition, these drugs may be potential cytotoxic agents that produce toxicity only in solid tumors

Chemotherapeutic drug delivery by tumoral extracellular matrix targeting

NARCIS (Netherlands)

Raavé , R.; Kuppevelt, T.H. van; Daamen, W.F.

2018-01-01

Systemic chemotherapy is a primary strategy in the treatment of cancer, but comes with a number of limitations such as toxicity and unfavorable biodistribution. To overcome these issues, numerous targeting systems for specific delivery of chemotherapeutics to tumor cells have been designed and

Balancing repair and tolerance of DNA damage caused by alkylating agents.

Science.gov (United States)

Fu, Dragony; Calvo, Jennifer A; Samson, Leona D

2012-01-12

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity.

Delivery of chemotherapeutic drugs in tumour cell-derived microparticles.

Science.gov (United States)

Tang, Ke; Zhang, Yi; Zhang, Huafeng; Xu, Pingwei; Liu, Jing; Ma, Jingwei; Lv, Meng; Li, Dapeng; Katirai, Foad; Shen, Guan-Xin; Zhang, Guimei; Feng, Zuo-Hua; Ye, Duyun; Huang, Bo

2012-01-01

Cellular microparticles are vesicular plasma membrane fragments with a diameter of 100-1,000 nanometres that are shed by cells in response to various physiological and artificial stimuli. Here we demonstrate that tumour cell-derived microparticles can be used as vectors to deliver chemotherapeutic drugs. We show that tumour cells incubated with chemotherapeutic drugs package these drugs into microparticles, which can be collected and used to effectively kill tumour cells in murine tumour models without typical side effects. We describe several mechanisms involved in this process, including uptake of drug-containing microparticles by tumour cells, synthesis of additional drug-packaging microparticles by these cells that contribute to the cytotoxic effect and the inhibition of drug efflux from tumour cells. This study highlights a novel drug delivery strategy with potential clinical application.

Fresh garlic extract inhibits Staphylococcus aureus biofilm formation under chemopreventive and chemotherapeutic conditions

Directory of Open Access Journals (Sweden)

Panan Ratthawongjirakul

2016-08-01

Full Text Available Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA are the leading aetiological pathogens of nosocomial infections worldwide. These bacteria form biofilms on both biotic and abiotic surfaces causing biofilm-associated infections. Within the biofilm, these bacteria might develop persistent and antimicrobial resistant characteristics resulting in chronic infections and treatment failures. Garlic exhibits broad pharmaceutical properties and inhibitory activities against S. aureus. We investigated the effects of aqueous fresh garlic extract on biofilm formation in S. aureus ATCC25923 and MRSA strains under chemopreventive and chemotherapeutic conditions. The viable bacteria and biofilm levels were quantified through colony count and crystal violet staining, respectively. The use of fresh garlic extract under both conditions significantly inhibited biofilm formation in S. aureus strains ATCC25923 and MRSA. Garlic could be developed as either a prophylactic or therapeutic agent to manage S. aureus biofilm-associated infections.

Gamma radiation effect on sisal / polyurethane composites without coupling agents

Energy Technology Data Exchange (ETDEWEB)

Vasco, Marina Cardoso; Claro Neto, Salvador; Nascimento, Eduardo Mauro; Azevedo, Elaine, E-mail: marina.mcv@gmail.com [University of Patras (Greece); Universidade de Sao Paulo (USP) Sao Carlos, SP (Brazil); Universidade Tecnologica Federal do Parana (UTFPR), Curitiba, PR (Brazil)

2017-04-15

Natural fibers and polyurethane based composites may present chemical bonding between the components of the polymer and the lignin of the fiber. The incidence of radiation can cause degradation of the polymeric material and alter its mechanical properties. The objective of this study was to obtain and characterize cold pressed composites from polyurethane derived from castor oil and sisal fibers, without coupling agents, through thermogravimetric and mechanical tests, before and after the incidence of 25 kGy dose of gamma radiation. Woven composites that were not irradiated had maximum values of 4.40 GPa for flexural elastic modulus on three point flexural test and dispersed fiber composite that were not irradiated had maximum values of 2.25 GPa. These materials are adequate for use in non-structural applications in radiotherapy and radiodiagnostic rooms. (author)

A novel chemotherapeutic sensitivity-testing system based on collagen gel droplet embedded 3D-culture methods for hepatocellular carcinoma.

Science.gov (United States)

Hou, Jun; Hong, Zhixian; Feng, Fan; Chai, Yantao; Zhang, Yunkai; Jiang, Qiyu; Hu, Yan; Wu, Shunquan; Wu, Yingsong; Gao, Xunian; Chen, Qiong; Wan, Yong; Bi, Jingfeng; Zhang, Zheng

2017-11-08

Patients suffering from advanced stage hepatocellular carcinoma (HCC) often exhibit a poor prognosis or dismal clinical outcomes due to ineffective chemotherapy or a multi-drug resistance (MDR) process. Thus, it is urgent to develop a new chemotherapeutic sensitivity testing system for HCC treatment. The presence study investigated the potential application of a novel chemotherapeutic sensitivity-testing system based on a collagen gel droplet embedded 3D-culture system (CD-DST). Primary cells were separating from surgical resection specimens and then tested by CD-DST. To identify whether HCC cell lines or cells separating from clinical specimens contain MDR features, the cells were treated with an IC 50 (half maximal inhibitory concentration) or IC max (maximal inhibitory concentration) concentration of antitumor agents, e.g., 5-furuolouracil (5-FU), paclitaxel (PAC), cisplatin (CDDP), epirubicin (EPI), or oxaliplatin (L-OHP), and the inhibitory rates (IRs) were calculated. HepG2 cells were sensitive to 5-FU, PAC, CDDP, EPI, or L-OHP; the IC 50 value is 0.83 ± 0.45 μg/ml, 0.03 ± 0.02 μg/ml, 1.15 ± 0.75 μg/ml, 0.09 ± 0.03 μg/ml, or 1.76 ± 0.44 μg/ml, respectively. Only eight (8/26), nine (9/26), or five (5/26) patients were sensitive to the IC max concentration of CDDP, EPI, or L-OHP; whereas only three (3/26), four (4/26), or two (2/26) patients were sensitive to the IC 50 concentration of CDDP, EPI, or L-OHP. No patients were sensitive to 5-FU or PAC. The in vitro drug sensitivity exanimation revealed the MDR features of HCC and examined the sensitivity of HCC cells from clinical specimens to anti-tumor agents. CD-DST may be a useful method to predict the potential clinical benefits of anticancer agents for HCC patients.

Recent advances in nanoformulations for co-delivery of curcumin and chemotherapeutic drugs

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Maryam Hashemi

2017-01-01

Full Text Available The application of chemotherapy in cancer treatment has been limited due to cause side effects such as toxicity against normal cells and drug resistance. In recent years, numerous studies have been focused on using natural products with chemotherapeutic drugs to enhance therapeutic efficiency and reduce cytotoxicity. On the other hand, encapsulation of drugs into nanoparticles (NPs can improve solubility of hydrophobic drug; circulation time in blood and the residence at the pathological site by enhance permeation and retention (EPR effect. It has been shown that curcumin (CUR has  wide range of pharmacological activities against many diseases such as cancer. CUR has been demonstrated to be a potent chemosensitizer that can induce additive or synergistic effects with chemotherapeutic drugs against different cancer cell lines.  Recently, various types of nanocarriers have been investigated for CUR.  In this review, different co-formulations containing Cur and chemotherapeutic drugs used in cancer therapy are discussed with emphasis on their pharmaceutical properties.

Plant-Derived Agents for Counteracting Cisplatin-Induced Nephrotoxicity

OpenAIRE

Ojha, Shreesh; Venkataraman, Balaji; Kurdi, Amani; Mahgoub, Eglal; Sadek, Bassem; Rajesh, Mohanraj

2016-01-01

Cisplatin (CSP) is a chemotherapeutic agent commonly used to treat a variety of malignancies. The major setback with CSP treatment is that its clinical efficacy is compromised by its induction of organ toxicity, particular to the kidneys and ears. Despite the significant strides that have been made in understanding the mechanisms underlying CSP-induced renal toxicity, advances in developing renoprotective strategies are still lacking. In addition, the renoprotective approaches described in th...

Innovative agents in cancer prevention.

Science.gov (United States)

Manson, Margaret M; Farmer, Peter B; Gescher, Andreas; Steward, William P

2005-01-01

There are many facets to cancer prevention: a good diet, weight control and physical activity, a healthy environment, avoidance of carcinogens such as those in tobacco smoke, and screening of populations at risk to allow early detection. But there is also the possibility of using drugs or naturally occurring compounds to prevent initiation of, or to suppress, tumour growth. Only a few such agents have been used to date in the clinic with any success, and these include non-steroidal anti-inflammatory drugs for colon, finasteride for prostate and tamoxifen or raloxifene for breast tumours. An ideal chemopreventive agent would restore normal growth control to a preneoplastic or cancerous cell population by modifying aberrant signalling pathways or inducing apoptosis (or both) in cells beyond repair. Characteristics for such an agent include selectivity for damaged or transformed cells, good bioavailability and more than one mechanism of action to foil redundancy or crosstalk in signalling pathways. As more research effort is being targeted towards this area, the distinction between chemotherapeutic and chemopreventive agents is blurring. Chemotherapeutic drugs are now being designed to target over- or under-active signalling molecules within cancer cells, a philosophy which is just as relevant in chemoprevention. Development of dietary agents is particularly attractive because of our long-standing exposure to them, their relative lack of toxicity, and encouraging indications from epidemiology. The carcinogenic process relies on the cell's ability to proliferate abnormally, evade apoptosis, induce angiogenesis and metastasise to distant sites. In vitro studies with a number of different diet-derived compounds suggest that there are molecules capable of modulating each of these aspects of tumour growth. However, on the negative side many of them have rather poor bioavailability. The challenge is to uncover their multiple mechanisms of action in order to predict their

Radiation treatment of brain tumors: Concepts and strategies

International Nuclear Information System (INIS)

Marks, J.E.

1989-01-01

Ionizing radiation has demonstrated clinical value for a multitude of CNS tumors. Application of the different physical modalities available has made it possible for the radiotherapist to concentrate the radiation in the region of the tumor with relative sparing of the surrounding normal tissues. Correlation of radiation dose with effect on cranial soft tissues, normal brain, and tumor has shown increasing effect with increasing dose. By using different physical modalities to alter the distribution of radiation dose, it is possible to increase the dose to the tumor and reduce the dose to the normal tissues. Alteration of the volume irradiated and the dose delivered to cranial soft tissues, normal brain, and tumor are strategies that have been effective in improving survival and decreasing complications. The quest for therapeutic gain using hyperbaric oxygen, neutrons, radiation sensitizers, chemotherapeutic agents, and BNCT has met with limited success. Both neoplastic and normal cells are affected simultaneously by all modalities of treatment, including ionizing radiation. Consequently, one is unable to totally depopulate a tumor without irreversibly damaging the normal tissues. In the case of radiation, it is the brain that limits delivery of curative doses, and in the case of chemical additives, it is other organ systems, such as bone marrow, liver, lung, kidneys, and peripheral nerves. Thus, the major obstacle in the treatment of malignant gliomas is our inability to preferentially affect the tumor with the modalities available. Until it is possible to directly target the neoplastic cell without affecting so many of the adjacent normal cells, the quest for therapeutic gain will go unrealized.72 references

Chemotherapeutic agents attenuate CXCL12-mediated migration of colon cancer cells by selecting for CXCR4-negative cells and increasing peptidase CD26

International Nuclear Information System (INIS)

Cutler, Murray J.; Lowthers, Erica L.; Richard, Cynthia L.; Hajducek, Dagmar M.; Spagnuolo, Paul A.; Blay, Jonathan

2015-01-01

Recurrence of colorectal cancer (CRC) may arise due to the persistence of drug-resistant and cancer-initiating cells that survive exposure to chemotherapy. Proteins responsible for this recurrence include the chemokine receptor CXCR4, which is known to enable CRC metastasis, as well as the cancer-initiating cell marker and peptidase CD26, which terminates activity of its chemokine CXCL12. We evaluated the expression and function of CXCR4 and CD26 in colon cancer cell lines and xenografts following treatment with common chemotherapies using radioligand binding, flow cytometry, immunofluorescence, and enzymatic assays. 5-Fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan), as well as cisplatin, methotrexate and vinblastine, each caused decreases in cell-surface CXCR4 and concomitant increases in CD26 on HT-29, T84, HRT-18, SW480 and SW620 CRC cell lines. Flow cytometry indicated that the decline in CXCR4 was associated with a significant loss of CXCR4+/CD26- cells. Elevations in CD26 were paralleled by increases in both the intrinsic dipeptidyl peptidase activity of CD26 as well as its capacity to bind extracellular adenosine deaminase. Orthotopic HT-29 xenografts treated with standard CRC chemotherapeutics 5-fluorouracil, irinotecan, or oxaliplatin showed dramatic increases in CD26 compared to untreated tumors. Consistent with the loss of CXCR4 and gain in CD26, migratory responses to exogenous CXCL12 were eliminated in cells pretreated with cytotoxic agents, although cells retained basal motility. Analysis of cancer-initiating cell CD44 and CD133 subsets revealed drug-dependent responses of CD26/CD44/CD133 populations, suggesting that the benefits of combining standard chemotherapies 5-fluoruracil and oxaliplatin may be derived from their complementary elimination of cell populations. Our results indicate that conventional anticancer agents may act to inhibit chemokine-mediated migration through eradication of CXCR4+ cells and attenuation of

Studies on the effects of ionizing radiation and chemotherapeutic agents on hematopoiesis according to the stem-cell kinetics

International Nuclear Information System (INIS)

Hirashima, Kunitake

1975-01-01

The fundamental problem of the effects of ionizing radiation and antineoplastic drugs on hematopoiesis can be explained by the kinetic study on the hematopoietic stem-cell population. Quantitative comparison of a single x-irradiation and a single administration of several antineoplastic drugs on the stem-cell population was performed by the splenic colony-forming method. The repopulation pattern of stem-cells in mice after a single 150 rad irradiation was compared with that after the administration of corresponding dose of cyclophosphamide. It was demonstrated that the additional administration of cyclophosphamide immediately after the x-irradiation significantly accelerated repopulation of the stem-cell compartment. The mechanism of repopulation of the stem-cell compartment after partial irradiation was also studied according to the immigration theory of stem-cells. An in vitro colony-forming technique for the human bone marrow cells was introduced and compared with other assay methods for stem-cells. From the hematological observations of accidentally irradiated patients, it was determined that the thromboelastogram values were regarded as one of the most useful indicators for detecting the earliest recovery sign of the hematopoietic stem-cells. (Evans, J.)

Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells.

Directory of Open Access Journals (Sweden)

Shan Wan

Full Text Available Low doses of anticancer drugs have been shown to enhance antitumor immune response and increase the efficacy of immunotherapy. The molecular basis for such effects remains elusive, although selective depletion of T regulatory cells has been demonstrated. In the current studies, we demonstrate that topotecan (TPT, a topoisomerase I-targeting drug with a well-defined mechanism of action, stimulates major histocompatibility complex class I (MHC I expression in breast cancer cells through elevated expression/secretion of interferon-β (IFN-β and activation of type I IFN signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-naïve recipient cells, suggesting the involvement of cytokines and/or other secreted molecules. Consistently, TPT-treated cells exhibit elevated expression of multiple cytokines such as IFN-β, TNF-α, IL-6 and IL-8. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1 or addition of neutralizing antibody against IFN-β results in reduced MHC I expression in TPT-treated cells. Together, these results suggest that TPT induces increased IFN-β autocrine/paracrine signaling through type I IFN receptor, resulting in the elevated MHC I expression in tumor cells. Studies have also demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine similarly induce increased IFN-β secretion and elevated MHC I expression. In addition, conditioned media from γ-irradiated donor cells are shown to induce IFN-β-dependent MHC I expression in unirradiated recipient cells. In the aggregate, our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through MHC I, which could represent a common mechanism for enhanced antitumor immune response through

Gamma radiation effect on sisal / polyurethane composites without coupling agents

Directory of Open Access Journals (Sweden)

Marina Cardoso Vasco

Full Text Available Abstract Natural fibers and polyurethane based composites may present chemical bonding between the components of the polymer and the lignin of the fiber. The incidence of radiation can cause degradation of the polymeric material and alter its mechanical properties. The objective of this study was to obtain and characterize cold pressed composites from polyurethane derived from castor oil and sisal fibers, without coupling agents, through thermogravimetric and mechanical tests, before and after the incidence of 25 kGy dose of gamma radiation. Woven composites that were not irradiated had maximum values of 4.40 GPa for flexural elastic modulus on three point flexural test and dispersed fiber composite that were not irradiated had maximum values of 2.25 GPa. These materials are adequate for use in non-structural applications in radiotherapy and radiodiagnostic rooms.

Radiation- and Photo-induced Activation of 5-Fluorouracil Prodrugs as a Strategy for the Selective Treatment of Solid Tumors

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Sei-ichi Nishimoto

2008-10-01

Full Text Available 5-Fluorouracil (5-FU is used widely as an anticancer drug to treat solid cancers, such as colon, breast, rectal, and pancreatic cancers, although its clinical application is limited because 5-FU has gastrointestinal and hematological toxicity. Many groups are searching for prodrugs with functions that are tumor selective in their delivery and can be activated to improve the clinical utility of 5-FU as an important cancer chemotherapeutic agent. UV and ionizing radiation can cause chemical reactions in a localized area of the body, and these have been applied in the development of site-specific drug activation and sensitization. In this review, we describe recent progress in the development of novel 5-FU prodrugs that are activated site specifically by UV light and ionizing radiation in the tumor microenvironment. We also discuss the chemical mechanisms underlying this activation.

Radiobiological aspects of application of interleucine as agents for the first aid under strong radiation action

International Nuclear Information System (INIS)

Rozhdestvensij, L.M.

1997-01-01

The paper substantiates the application of the interleucine-1 beta (IL-1) as an emergency medical care agent in case of the acute emergency exposure of a human being. During simulation experiments a human recombinant IL-1 was added to suspension of the affected bony marrow-cells extracted a few minutes following the total 5 Gy exposure of Fi male-mice (CBAxC57B1). Recombinant mouse IL-3 and GM-CSF agents (produced by Bering company, Germany) were used for comparison purpose (agent concentration constituted 100-10000 unit/ml). The incubated bony marrow cells were tested for trunk potencies in mice-recipients irradiated by 8.5 Gy dose during 24 h. Following nine days the colonies in their spleen and bony marrow cellular texture were estimated. IL-1 was shown to have the protective effect both on separated trunk type hemopoietic cells and on the whole body irradiated hemopoietic system. IL-1 turned to be similar to radiation-protective agents of polysaccharide nature and to radiation-protective EIR procedure. It is pointed out that IL-1 has no whole body toxic or any other by effects [ru

Experimental FT-IR, Laser-Raman and DFT spectroscopic analysis of a potential chemotherapeutic agent 6-(2-methylpropyl)-4-oxo-2-sulfanylidene-1,2,3,4-tetrahydropyrimidine-5-carbonitrile.

Science.gov (United States)

Sert, Yusuf; Al-Turkistani, Abdulghafoor A; Al-Deeb, Omar A; El-Emam, Ali A; Ucun, Fatih; Çırak, Çağrı

2014-01-01

In this study, the experimental and theoretical vibrational frequencies of a newly synthesized potential chemotherapeutic agent namely, 6-(2-methylpropyl)-4-oxo-2-sulfanylidene-1,2,3,4-tetrahydropyrimidine-5-carbonitrile have been investigated. The experimental FT-IR (4000-400 cm(-1)) and Laser-Raman spectra (4000-100 cm(-1)) of the molecule in solid phase have been recorded. The theoretical vibrational frequencies and optimized geometric parameters (bond lengths and bond angles) have been calculated by using density functional theory (DFT/B3LYP: Becke, 3-parameter, Lee-Yang-Parr) and M06-2X (the highly parametrized, empirical exchange correlation function) quantum chemical methods with 6-311++G(d,p) basis set by Gaussian 09 W software, for the first time. The assignments of the vibrational frequencies have been done by potential energy distribution (PED) analysis by using VEDA 4 software. The theoretical optimized geometric parameters and vibrational frequencies have been found to be in good agreement with the corresponding experimental data, and with the results in the literature. In addition, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies and the other related molecular energy values have been calculated and depicted. Copyright © 2013 Elsevier B.V. All rights reserved.

CYB5D2 requires heme-binding to regulate HeLa cell growth and confer survival from chemotherapeutic agents.

Directory of Open Access Journals (Sweden)

Anthony Bruce

Full Text Available The cytochrome b5 domain containing 2 (CYB5D2; Neuferricin protein has been reported to bind heme, however, the critical residues responsible for heme-binding are undefined. Furthermore, the relationship between heme-binding and CYB5D2-mediated intracellular functions remains unknown. Previous studies examining heme-binding in two cytochrome b5 heme-binding domain-containing proteins, damage-associated protein 1 (Dap1; Saccharomyces cerevisiae and human progesterone receptor membrane component 1 (PGRMC1, have revealed that conserved tyrosine (Y 73, Y79, aspartic acid (D 86, and Y127 residues present in human CYB5D2 may be involved in heme-binding. CYB5D2 binds to type b heme, however, only the substitution of glycine (G at D86 (D86G within its cytochrome b5 heme-binding (cyt-b5 domain abolished its heme-binding ability. Both CYB5D2 and CYB5D2(D86G localize to the endoplasmic reticulum. Ectopic CYB5D2 expression inhibited cell proliferation and anchorage-independent colony growth of HeLa cells. Conversely, CYB5D2 knockdown and ectopic CYB5D2(D86G expression increased cell proliferation and colony growth. As PGRMC1 has been reported to regulate the expression and activities of cytochrome P450 proteins (CYPs, we examined the role of CYB5D2 in regulating the activities of CYPs involved in sterol synthesis (CYP51A1 and drug metabolism (CYP3A4. CYB5D2 co-localizes with cytochrome P450 reductase (CYPOR, while CYB5D2 knockdown reduced lanosterol demethylase (CYP51A1 levels and rendered HeLa cells sensitive to mevalonate. Additionally, knockdown of CYB5D2 reduced CYP3A4 activity. Lastly, CYB5D2 expression conferred HeLa cell survival from chemotherapeutic agents (paclitaxel, cisplatin and doxorubicin, with its ability to promote survival being dependent on its heme-binding ability. Taken together, this study provides evidence that heme-binding is critical for CYB5D2 in regulating HeLa cell growth and survival, with endogenous CYB5D2 being required to

{sup 166}Ho-chitosan as a radiation synovectomy agent - biocompatibility study of {sup 166}Ho-chitosan in rabbits

Energy Technology Data Exchange (ETDEWEB)

Kim, Sug Jun; Lee, Soo Yong; Jeon, Dae Geun; Seok, Lee Jong [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

1997-01-01

Radiation synovectomy is a noninvasive therapy that has been investigated as an alternative to surgical synovectomy. It is been successfully employed in the treatment of synovitis in rheumatoid arthrits and other inflammatory arthropathies. We developed the {sup 166}Ho-chitosan complex for possible use as a radiation synovectomy agent. Holmium is the more practical isotope based on its higher radioactivity and logner half-life. And isotope based on its higher radioactivity and logner half-life. And chitosan is ideal and suitable particles based on its soluble and biodegradable characteristics. So we investigated the biocompatibility of the {sup 166}Ho-chitosan complex to evaluated the suitability as a radiation synovectomy agent. In this study, we performed in vivo and in vitro stability test and biodistribution test. Our results indicate that {sup 166}Ho-chitosan may be an effective radiopharmaceutical for radiation synovectomy. (author). 30 refs., 7 tabs.

1 ALPHA-Hydroxyvitamin D5 as a Chemotherapeutic and Possibly Chemopreventive Agent

Science.gov (United States)

2004-09-01

cancer cells. TTT TG. The primer -for the housekeeping gene G3PDH was purchased from ClonTech. The touchdown 3.2. Induction of differentiation of breast...the housekeeping gene The effects of vitamin D analogues as differentiating G3PDH (C) was identical for all the cDNAs, indicating . agents and...control housekeeping gene. "* G. Lazzaro et al. / European Journal of Cancer 36 (2000) 780-786 785 levels of VDR, do not respond to active vitamin D p53

Effective chemotherapy of acute myelocytic leukemia occurring after alkylating agent or radiation therapy for prior malignancy

International Nuclear Information System (INIS)

Vaughan, W.P.; Karp, J.E.; Burke, P.J.

1983-01-01

Eleven consecutive patients with acute myelocytic leukemia occurring as a second malignancy were treated with high-dose, timed, sequential chemotherapy. Eight of the patients were felt to have ''secondary'' acute leukemia because they had received an alkylating agent or radiation therapy. The other three patients were considered controls. Despite a median age of 65, four of the eight secondary leukemia patients achieved complete remission with this regimen. One of the three control patients also achieved complete remission. This remission rate and duration are comparable to what was achieved with this treatment of ''primary'' acute myelocytic leukemia during the same period of time. These results suggest that patients with leukemia occurring after an alkylating agent or radiation therapy are not at especially high risk if treated aggressively

Toxic agent and radiation control: progress toward objectives for the nation for the year 1990

International Nuclear Information System (INIS)

Rall, D.P.

1988-01-01

In 1980, the Department of Health and Human Services set national prevention objectives for 1990 in 15 health priority areas, 1 of which is the control of toxic agents and radiation. Ten objectives related to this area are priorities for the national control effort. Progress is reviewed on those priorities within the responsibilities of the Public Health Service. Six key program elements, or types of support activities, are deemed essential to preventing, identifying, and controlling toxic agent and radiation threats. Significant progress has been made toward achieving objectives for which all key program elements have been successfully implemented to provide the requisite know-how, manpower, and tools. Important advances have been made in reducing the blood lead levels of the population, reducing unnecessary exposure to medical X-rays, evaluating the toxicities of chemicals in toxic waste dumps, and improving the scientific and technical information base and its availability for prevention and control efforts. The most important priority for the forseeable future will be to expand our knowledge of potential health risks posed by toxic agents and radiation. Expanded surveillance systems and data bases are essential to determining the extent of the problems in terms of human health effects and for measuring the impact of prevention programs. Emphasis on the activities embodied in the key elements will encourage the expansion of the knowledge base and its effective application to prevention and control problems

Oxygen carrying perfluorochemical emulsion as an adjuvant to radiation therapy

International Nuclear Information System (INIS)

Teicher, B.A.; Rose, C.M.

1984-01-01

The potential of a perfluorochemical emulsion which as an excellent carrying capacity for oxygen to enhance the ability of radiation therapy to delay the growth of Lewis lung tumor was examined. There was a highly significant effect produced by the addition of perfluorochemical emulsion and carbogen breathing in combination with irradiation. With single dose x-ray treatment the dose of perfluorochemical emulsion was varied from 0.05-0.6 ml addition to the blood volume of the animals. The dose response effect was very broad peaking at 0.3-0.4 ml which gave a dose modifying effect of 2.8 +- 0.6 with 1000 rad of x-rays. The addition of 0.3 ml of perfluorochemical free annex solution with carbogen breathing produced a small enhancement in tumor growth delay addition of the same volume of the complete emulsion increased the tumor growth delay time about 3-fold compared to the annex solution. When the perfluorochemical emulsion was added to a fractionated course of radiation therapy a dose modifying effect of 1.8 +- 0.3 was obtained. Oxygen carrying perfluorochemical emulsions may provide a nontoxic clinically useful means of increasing the effectiveness of radiation therapy and of certain chemotherapeutic agents

Gemcitabine concurrent with radiation therapy for locally advanced ...

African Journals Online (AJOL)

Background: Management of advanced head and neck carcinoma is a challenging proposition. Presently concomitant chemoirradiation has become the standard of care in such patients. Many chemotherapeutic drugs have shown radio-sensitising effects when used concomitantly along with radiation. The present study ...

Arsenic trioxide synergistically enhances radiation response in human cervical cancer cells through ROS-dependent p38 MAPK and JNK signalling pathway

Energy Technology Data Exchange (ETDEWEB)

Kang, Young-Hee; Park, Seung-Moo; Kim, Min-Jeong [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)] (and others)

2006-07-01

Many factors affect susceptibility of tumor cells to ionizing radiation. Among them intrinsic apoptosis sensitivity or resistancy seems to play an important role. The use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic efficacy by overcoming a high apoptotic threshold. Several recent studies demonstrated additive effects of As{sub 2}O{sub 3} with conventional chemotherapeutic agents such as cisplatin, adriamycin, and etoposide, but no synergism. Previously, we have shown for the first time that As{sub 2}O{sub 3} sensitize human cervical cancer cells to ionizing radiation. Treatment of As{sub 2}O{sub 3} in combination of ionizing radiation has synergistic effects in decreasing clonogenic survival and in the regression of tumor growth in xenografts. We also have shown that the combination treatment enhanced apoptotic cell death through a reactive oxygen species-dependent pathway in human cervical cancer cells. In this study, we investigated the regulatory mechanism of ROS-mediated mitochondrial apoptotic cell death induced by combination treatment with As{sub 2}O{sub 3} and ionizing radiation in human cervical cancer cells.

Role of secondary low energy electrons in radiobiology and chemoradiation therapy of cancer

Science.gov (United States)

Sanche, Léon

2009-05-01

With the chemotherapeutic agent cisplatin bound to DNA, damage to the molecule by electrons of low and high energies increases by factors varying from 1.3 to 4.4. The enhancement in bond dissociation is triggered by modifications of the interaction of low energy electrons with DNA. From our understanding of the latter, the present Letter attempts to explain the basic radiation-damage mechanism responsible for the efficiency of the concomitant chemoradiation treatment of cancer. Such a basic comprehension of the direct effects of radiation may have implications in the design of new chemotherapeutic and radiosensitizing drugs, as well as in the development of more efficient protocols in chemoradiation therapy.

8-aminoadenosine enhances radiation-induced cell death in human lung carcinoma A549 cells

International Nuclear Information System (INIS)

Meike, Shunsuke; Yamamori, Tohru; Yasui, Hironobu; Eitaki, Masato; Inanami, Osamu; Matsuda, Akira

2011-01-01

The combination of a chemotherapeutic agent and radiation is widely applied to enhance cell death in solid tumor cells in cancer treatment. The purine analogue 8-aminoadenosine (8-NH 2 -Ado) is known to be a transcription inhibitor that has proved very effective in multiple myeloma cell lines and primary indolent leukemia cells. In this report, to examine whether 8-NH 2 -Ado had the ability to enhance the radiation-induced cell killing in solid tumor cells, human lung adenocarcinoma A549 cells were irradiated in the presence and absence of 8-NH 2 -Ado. 8-NH 2 -Ado significantly increased reproductive cell death and apoptosis in A549 cells exposed to X-rays. When peptide inhibitors against caspase-3, -8, and -9 were utilized to evaluate the involvement of caspases, all inhibitors suppressed the enhancement of radiation-induced apoptosis, suggesting that not only mitochondria-mediated apoptotic signal transduction pathways but also death receptor-mediated pathways were involved in this enhancement of apoptosis. In addition, in the cells exposed to the treatment combining X-irradiation and 8-NH 2 -Ado, reduction of the intracellular ATP concentration was essential for survival, and down-regulation of the expression of antiapoptotic proteins such as survivin and X-linked inhibitor of apoptosis protein (XIAP) was observed. These results indicate that 8-NH 2 -Ado has potential not only as an anti-tumor drug for leukemia and lymphoma but also as a radiosensitizing agent for solid tumors. (author)

The synthesis of potential chemotherapeutic agents based on leads from nature

International Nuclear Information System (INIS)

Brimble, M.A.

2001-01-01

Our research group has developed an efficient synthesis of several simpler members of pyranonaphthoquinone antibiotics using a novel annulation of a 2-acetylnaphthoquinone using 2- trimethylsilyloxyfuran to afford a furonaphthofuran ring system that then underwent oxidative rearrangement to the desired pyranonaphthoquinone ring system. This methodology was then successfully applied to the synthesis of the spiroacetal-containing pyranonaphthoquinone, griseusin A, and the C-glycosidic pyranonaphthoquinone, medermycin, which is effective against neoplastic cells in vitro, antibiotic resistant cell lines of L5178Y lymphoblastoma, and inhibits human leukaemia K 562 cells as well as platelet aggregation. The first efficient synthesis of a dimeric pyranonaphthoquinone as present in the antiviral agent, crisamycin A and γ-actinorhodin, has also been successfully effected using an efficient double furofuran-oxidative rearrangement strategy starting from a bis(2-acetyl-1,4-naphthoquinone)

Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields)

International Nuclear Information System (INIS)

Kirson, Eilon D; Goldsher, Dorit; Wasserman, Yoram; Palti, Yoram; Schneiderman, Rosa S; Dbalý, Vladimír; Tovaryš, František; Vymazal, Josef; Itzhaki, Aviran; Mordechovich, Daniel; Gurvich, Zoya; Shmueli, Esther

2009-01-01

The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial. Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients. The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1). The sensitivity to chemotherapeutic treatment was increased by 1–3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 – 1316). Similar findings were seen in an animal tumor model. Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year. No TTFields related systemic toxicity was observed in any of these patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment. In newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months. These results indicate that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment related toxicity

Cell cycle kinetics and radiation therapy

International Nuclear Information System (INIS)

Mendelsohn, M.L.

1975-01-01

Radiation therapy as currently practiced involves the subtle largely empirical art of balancing the recurrence of cancer due to undertreatment against severe damage to local tissues due to overtreatment. Therapeutic results too often fall short of desired success rates; yet, the therapist is continually tantalized to the likelihood that a slight shift of therapeutic ratio favoring normal tissue over cancer would have a profoundly beneficial effect. The application of cell cycle kinetics to radiation therapy is one hope for improving the therapeutic ratio; but, as I will try to show, kinetic approaches are complex, poorly understood, and presently too elusive to elicit confidence or to be used clinically. Their promise lies in their diversity and in the magnitude of our ignorance about how they work and how they should be used. Potentially useful kinetic approaches to therapy can be grouped into three classes. The first class takes advantage of intracyclic differential sensitivity, an effect involving the metabolism and biology of the cell cycle; its strategies are based on synchronization of cells over intervals of hours to days. The second class involves the distinction between cycling and noncycling cells; its strategies are based on the resistance of noncycling cells to cycle-linked radiation sensitizers and chemotherapeutic agents. The third class uses cell repopulation between fractions; its strategies are based on the relative growth rates of tumor and relevant normal tissue before and after perturbation

MicroRNA-101 regulates T-cell acute lymphoblastic leukemia progression and chemotherapeutic sensitivity by targeting Notch1.

Science.gov (United States)

Qian, Lu; Zhang, Wanggang; Lei, Bo; He, Aili; Ye, Lianhong; Li, Xingzhou; Dong, Xin

2016-11-01

The present study aimed to investigate the role of microRNA (miR)-101 in acute lymphoblastic leukemia progression and chemoresistance. Furthermore, a novel target gene of miR-101 was identified. Here, we confirmed that miR-101 was significantly downregulated in the blood samples of patients with T-cell acute lymphoblastic leukemia (T-ALL) compared with the healthy controls, as determined by reverse transcription quantitative polymerase chain reaction (RTqPCR) analysis. The in vitro experiments demonstrated that miR-101 significantly repressed the proliferation and invasion, and induced potent apoptosis in Jurkat cells, as determined by CCK-8, flow cytometer and cell invasion assays. Luciferase assay confirmed that Notch1 was a target gene of miR-101, and western blotting showed that miR-101 suppressed the expression of Notch1 at the protein level. Moreover, functional restoration assays revealed that Notch1 mediates the effects of miR-101 on Jurkat cell proliferation, apoptosis and invasion. miR-101 enhanced the sensitivity of Jurkat cells to the chemotherapeutic agent adriamycin. Taken together, our results show for the first time that miR-101 acts as a tumor suppressor in T-cell acute lymphoblastic leukaemia and it could enhance chemotherapeutic sensitivity. Furthermore, Notch1 was identified to be a novel target of miR-101. This study indicates that miR-101 may represent a potential therapeutic target for T-cell acute lymphoblastic leukemia intervention.

Pilot study on developing a decision support tool for guiding re-administration of chemotherapeutic agent after a serious adverse drug reaction

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Chew Lita

2011-07-01

Full Text Available Abstract Background Currently, there are no standard guidelines for recommending re-administration of a chemotherapeutic drug to a patient after a serious adverse drug reaction (ADR incident. The decision on whether to rechallenge the patient is based on the experience of the clinician and is highly subjective. Thus the aim of this study is to develop a decision support tool to assist clinicians in this decision making process. Methods The inclusion criteria for patients in this study are: (1 had chemotherapy at National Cancer Centre Singapore between 2004 to 2009, (2 suffered from serious ADRs, and (3 were rechallenged. A total of 46 patients fulfilled the inclusion criteria. A genetic algorithm attribute selection method was used to identify clinical predictors for patients' rechallenge status. A Naïve Bayes model was then developed using 35 patients and externally validated using 11 patients. Results Eight patient attributes (age, chemotherapeutic drug, albumin level, red blood cell level, platelet level, abnormal white blood cell level, abnormal alkaline phosphatase level and abnormal alanine aminotransferase level were identified as clinical predictors for rechallenge status of patients. The Naïve Bayes model had an AUC of 0.767 and was found to be useful for assisting clinical decision making after clinicians had identified a group of patients for rechallenge. A platform independent version and an online version of the model is available to facilitate independent validation of the model. Conclusion Due to the limited size of the validation set, a more extensive validation of the model is necessary before it can be adopted for routine clinical use. Once validated, the model can be used to assist clinicians in deciding whether to rechallenge patients by determining if their initial assessment of rechallenge status of patients is accurate.

Maximum standard uptake value on pre-chemotherapeutic FDG-PET is a significant parameter for disease progression of newly diagnosed lymphoma

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Eo, Jae Seon; Lee, Won Woo; Chung, June Key; Lee, Myung Chul; Kim, Sang Eun

2005-01-01

F-18 FDG-PET is useful for detection and staging of lymphoma. We investigated the prognostic significance of maximum standard uptake (maxSUV) value of FDG-PET for newly diagnosed lymphoma patients before chemotherapy. Twenty-seven patients (male: female = 17: 10: age: 49±19 years) with newly diagnosed lymphoma were enrolled. Nine-teen patients suffered from B cell lymphoma, 6 Hodgkins disease and 2 T cell lymphoma. One patient was stage I, 9 stage II, 3 stage III, 1 stage IV and 13 others. All patients underwent FDG-PET before initiation of chemotherapy. MaxSUV values using lean body weight were obtained for main and largest lesion to represent maxSUV of the patients. The disease progression was defined as total change of the chemotherapeutic regimen or addition of new chemotherapeutic agent during follow up period. The observed period was 389±224 days. The value of maxSUV ranged from 3 to 18 (mean±SD = 10.6±4.4). The disease progressions occurred in 6 patients. Using Cox proportional-hazard regression analysis, maxSUV was identified as a significant parameter for the disease progression free survival (p=0.044). Kaplan-Meier survival curve analysis revealed that the group with higher maxSUV (=10.6, n=5) suffered from shorter disease progression free survival (median 299 days) than the group with lower maxSUV (<10.6, n = 22) (median 378 days, p=0.0146). We found that maxSUV on pre-chemotherapeutic F-18 FDG-PET for newly diagnosed lymphoma patients is a significant parameter for disease progression. Lymphoma patients can be stratified before initiation of chemotherapy in terms of disease progression by the value of maxSUV 10.6

SERIES: Genomic instability in cancer Balancing repair and tolerance of DNA damage caused by alkylating agents

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Fu, Dragony; Calvo, Jennifer A.; Samson, Leona D

2013-01-01

Alkylating agents comprise a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER), and mismatch repair (MMR) respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for an organism's favorable response to alkylating agents. Furthermore, an individual's response to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity. PMID:22237395

The combination of novel targeted molecular agents and radiation in the treatment of pediatric gliomas

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Tina eDasgupta

2013-05-01

Full Text Available Brain tumors are the most common solid pediatric malignancy. For high-grade, recurrent or refractory pediatric brain tumors, radiation therapy (XRT is an integral treatment modality. In the era of personalized cancer therapy, molecularly targeted agents have been designed to inhibit pathways critical to tumorigenesis. Our evolving knowledge of genetic aberrations in low-grade gliomas is being exploited with targeted inhibitors. These agents are also being combined with XRT to increase their efficacy. In this review, we discuss novel agents targeting three different pathways in low-grade gliomas, and their potential combination with XRT. B-Raf is a kinase in the Ras/Raf/MAPK kinase pathway, which is integral to cellular division, survival and metabolism. In low-grade pediatric gliomas, point mutations in BRAF (BRAF V600E or a BRAF fusion mutation (KIAA1549:BRAF causes overactivation of the MEK/MAPK pathway. Pre-clinical data shows cooperation between XRT and tagrgeted inhibitors of BRAF V600E, and MEK and mTOR inhibitors in the gliomas with the BRAF fusion. A second important signaling cascade in pediatric glioma pathogenesis is the PI3 kinase (PI3K/mTOR pathway. Dual PI3K/mTOR inhibitors are poised to enter studies of pediatric tumors. Finally, many brain tumors express potent stimulators of angiogenesis. Several inhibitors of immunomodulators are currently being evaluated in in clinical trials for the treatment of recurrent or refractory pediatric central nervous system (CNS tumors. In summary, combinations of these targeted inhibitors with radiation are currently under investigation in both translational bench research and early clinical trials. We summarize the molecular rationale for, and the pre-clinical data supporting the combinations of these targeted agents with other anti-cancer agents and XRT in pediatric gliomas. Parallels are drawn to adult gliomas, and the molecular mechanisms underlying the efficacy of these agents is discussed

Ecological effects of ionizing radiation and other toxic agents on the aquatic microcosm

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Fuma, Shoichi; Ishii, Nobuyoshi; Tanaka, Nobuyuki; Takeda, Hiroshi; Miyamoto, Kiriko; Yanagisawa, Kei; Kawabata, Zen'ichiro

2004-01-01

The purpose of this study was comparative evaluation of effects of ionizing radiation and other various toxic agents on aquatic microbial communities. For this purpose, the authors investigated effects of γ-rays, ultraviolet (UV) radiation, acidification, aluminum, manganese, nickel, copper and gadolinium on the microcosm, i.e., the experimental model ecosystem consisting of populations of the flagellate alga Euglena gracilis as a producer, the ciliate protozoan Tetrahymena thermophila as a consumer and the bacterium Eseherichia coli as a decomposer. Effects of toxic agents in the microcosm were not only direct effects but also community-level effects due to interactions among the constituting species or between organisms and toxic agents. In general, the degrees of effects observed in the microcosm could be categorized as follows: no effects; recognizable effects, i.e., decrease or increase in the cell densities of at least one species; severe effects, i.e., extinction of one or two species; and destructive effects, i.e., extinction of all species. These results were analyzed by the ecological effect index (EEI), in which differences in the cell densities between exposed and control microcosm were represented by the Euclidean distance function. A 50% effect doses for the microcosm (ED M50 ), at which the EEI became 50%, were evaluated to be 530 Gy for γ-rays, 2100 J m -2 for UV, 4100 μM for manganese, 45 μM for nickel, 110 μM for copper and 250 μM for gadolinium. (author)

Root Canal Irrigation: Chemical Agents and Plant Extracts Against Enterococcus faecalis

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Borzini, Letizia; Condò, Roberta; De Dominicis, Paolo; Casaglia, Adriano; Cerroni, Loredana

2016-01-01

Background: There are various microorganisms related to intra and extra-radicular infections and many of these are involved in persistent infections. Bacterial elimination from the root canal is achieved by means of the mechanical action of instruments and irrigation as well as the antibacterial effects of the irrigating solutions. Enterococcus faecalis can frequently be isolated from root canals in cases of failed root canal treatments. Antimicrobial agents have often been developed and optimized for their activity against endodontic bacteria. An ideal root canal irrigant should be biocompatible, because of its close contact with the periodontal tissues during endodontic treatment. Sodium hypoclorite (NaOCl) is one of the most widely recommended and used endodontic irrigants but it is highly toxic to periapical tissues. Objectives: To analyze the literature on the chemotherapeutic agent and plant extracts studied as root canal irrigants. In particularly, the study is focused on their effect on Enterococcus faecalis. Method: Literature search was performed electronically in PubMed (PubMed Central, MEDLINE) for articles published in English from 1982 to April 2015. The searched keywords were “endodontic irrigants” and “Enterococcus faecalis” and “essential oil” and “plant extracts”. Results: Many of the studied chemotherapeutic agents and plant extracts have shown promising results in vitro. Conclusion: Some of the considered phytotherapic substances, could be a potential alternative to NaOCl for the biomechanical treatment of the endodontic space. PMID:28217184

Balancing repair and tolerance of DNA damage caused by alkylating agents

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Fu, Dragony; Calvo, Jennifer A.; Samson, Leona D.

2012-01-01

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial ...

Effect of radiation and alkylating agents on chromatin degradation in normal and malignant lymphoid cells

International Nuclear Information System (INIS)

Ryabchenko, N.I.; Yurashkova, V.; Ivannik, B.P.; Konov, A.V.; Drashil, V.

1991-01-01

Regularities of chromatin degradation in thymocytes and LS/BL tumor cells have been investigated. It has been shown that the rate of DNA degradation by Ca/Mg-dependent endonuclease in LS/BL tumor cells is 25 times lower than that in thymocytes, and radiation does not induce chormatin degradation. The alkylating agent TS 160 causes chromatin degradation in both LS/Bl cells and thymocytes. In contrast to radiation TS 160 inhibits the endogenous chromatin degradation by Ca/Mg-dependent endonuclease in thymocytes

The role of radiation therapy in pediatric oncology as assessed by cooperative clinical trials

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D'Angio, G.J.

1985-01-01

Major advances have been made in pediatric oncology, and many are due to the advent of the cooperative clinical trial. This important research tool was originally developed for the testing of various therapeutic strategies for the management of children with acute leukemia. Such trials were eminently successful, as the consistently better long-term survival rates for children with this hitherto uniformly lethal disease can attest. The method soon found favor for the investigation of patients with so-called solid tumors. These trails were originally concerned with the elucidation of the value of various chemotherapeutic agents. Radiation therapists soon became involved, however, and this discipline became more heavily represented in study design and data analyses. Much radiation therapy information has been gained, some through prospective, randomized clinical investigations and some through retrospective reviews of roentgen therapy as it was employed in protocols accenting other aspects of care. Voluminous, important radiation therapy data have been deduced through the latter retrospective kinds of analyses, but this review will be confined largely to the published results of prospective, randomized cooperative clinical trials where radiation therapy was a governing variable. Certain investigations of historical interest will also be cited together with other results that established important principles even though not so rigorous in design

Regorafenib overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter in colorectal cancer: In vitro and in vivo study.

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Wang, Yi-Jun; Zhang, Yun-Kai; Zhang, Guan-Nan; Al Rihani, Sweilem B; Wei, Meng-Ning; Gupta, Pranav; Zhang, Xiao-Yu; Shukla, Suneet; Ambudkar, Suresh V; Kaddoumi, Amal; Shi, Zhi; Chen, Zhe-Sheng

2017-06-28

Chemotherapeutic multidrug resistance (MDR) is a significant challenge to overcome in clinic practice. Several mechanisms contribute to MDR, one of which is the augmented drug efflux induced by the upregulation of ABCB1 in cancer cells. Regorafenib, a multikinase inhibitor targeting the RAS/RAF/MEK/ERK pathway, was approved by the FDA to treat metastatic colorectal cancer and gastrointestinal stromal tumors. We investigated whether and how regorafenib overcame MDR mediated by ABCB1. The results showed that regorafenib reversed the ABCB1-mediated MDR and increased the accumulation of [ 3 H]-paclitaxel in ABCB1-overexpressing cells by suppressing efflux activity of ABCB1, but not altering expression level and localization of ABCB1. Regorafenib inhibited ATPase activity of ABCB1. In mice bearing resistant colorectal tumors, regorafenib raised the intratumoral concentration of paclitaxel and suppressed the growth of resistant colorectal tumors. But regorafenib did not induce cardiotoxicity/myelosuppression of paclitaxel in mice. Strategy to reposition one FDA-approved anticancer drug regorafenib to overcome the resistance of another FDA-approved, widely used chemotherapeutic paclitaxel, may be a promising direction for the field of adjuvant chemotherapy. This study provides clinical rationale for combination of conventional chemotherapy and targeted anticancer agents. Copyright © 2017 Elsevier B.V. All rights reserved.

Residual injury to the hemopoietic microenvironment following sequential radiation and alkylating agents

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Wathen, L.M.K.

1981-01-01

To assess the hemopoietic impact following combined therapy, mice received intraperitoneal doses of cyclophosphamide one week after 1500 rad leg irradiation. This treatment inhibited repopulation of endogenous nucleated cells to less than 60% of normal. Leg irradiation alone repressed the repopulation to about 75% of normal and cyclophosphamide alone suppressed to 80% of normal. Differential marrow counts revealed that marrow stromal cells were suppressed to less than 30% normal for 3 months following combined modality treatment. Studies were initiated to determine whether busulfan, an alkylating agent known to produce aplastic anemia, would cause microenvironmental damage similar to that seen following cyclophosphamide. The mice received intraperitoneal doses of busulfan one week after 1500 rad leg irradation. In general, the pattern of hemopoietic suppression was similar to that following sequential radiation and cyclophosphamide. However, at 4 and 6 months post-irradiation, the busulfan treated mice had a more severe suppression of CFU-S, CFU-C, and marrow stromal cells than mice treated with cyclophosphamide alone. In addition, an excessive number of myeloid blast cells and a severe erythroid depletion suggested that the BU-treated mice were preleukemic. Vascular patency was studied by injecting 51 Cr labeled autologous red blood cells into mice treated with the radiation and busulfan regimen. Combined modality therapy inhibited the ingress of 51 Cr labeled erythrocytes into the irradiated femur but either modality alone did not cause inhibition. It was concluded that a portion of the microenvironmental defect seen in the combined radiation and alkylating agent studies was the result of microvascular damage and that a portion was due to marrow stromal cell insufficiency

New in vitro system to predict chemotherapeutic efficacy of drug combinations in fresh tumor samples

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Frank Christian Kischkel

2017-03-01

Full Text Available Background To find the best individual chemotherapy for cancer patients, the efficacy of different chemotherapeutic drugs can be predicted by pretesting tumor samples in vitro via the chemotherapy-resistance (CTR-Test®. Although drug combinations are widely used among cancer therapy, so far only single drugs are tested by this and other tests. However, several first line chemotherapies are combining two or more chemotherapeutics, leading to the necessity of drug combination testing methods. Methods We established a system to measure and predict the efficacy of chemotherapeutic drug combinations with the help of the Loewe additivity concept in combination with the CTR-test. A combination is measured by using half of the monotherapy’s concentration of both drugs simultaneously. With this method, the efficacy of a combination can also be calculated based on single drug measurements. Results The established system was tested on a data set of ovarian carcinoma samples using the combination carboplatin and paclitaxel and confirmed by using other tumor species and chemotherapeutics. Comparing the measured and the calculated values of the combination testings revealed a high correlation. Additionally, in 70% of the cases the measured and the calculated values lead to the same chemotherapeutic resistance category of the tumor. Conclusion Our data suggest that the best drug combination consists of the most efficient single drugs and the worst drug combination of the least efficient single drugs. Our results showed that single measurements are sufficient to predict combinations in specific cases but there are exceptions in which it is necessary to measure combinations, which is possible with the presented system.

Chemotherapeutic Impact Of Natural Antioxidant Flavonoids Gallic Acid Rutin Quercetin And Mannitol On Pathogenic Microbes And Their Synergistic Effect

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Ganesh Ghosh

2015-08-01

Full Text Available Several studies suggest that natural flavonoids with antioxidants and can influence the response to chemotherapy as well as the development of adverse side effects that results from treatment with antineoplastic agents and Its prevalence over Multi drug resistant bacterial strain revived interest on Flavonoids. Synergistic effect is defined as passive interaction arises when two agents combine and together they exert an inhibitory effect that is greater than the sum of individual effect The new Synergistic therapy so that antioxidant are more effective in combination on multi drug resistant bacterial strain. Interaction between natural antioxidants and topoisomerase enzyme can be seen through Quercetin as a potent antimicrobial compound alone and in combination with other natural antioxidant like rutin. MICMBC result show antibacterial activity of the flavonoids were enhanced when used in combination against Staphylococcus aureus Bacillus cereus Bacillus subtilis Klebsiella pneumonae Escherichia coli as the test bacteria. The combination of rutin and quercetin rutin and gallic acid mannitol and gallic acid were much more effective than either flavonoid alone. Furthermore Its gave a good relation between these antioxidant compound and antimicrobial activity. Flavonoids as a chemotherapeutic agent and its Synergistic effect can be solution for various microbial disease conditions.

Prevalence and sunlight photolysis of controlled and chemotherapeutic drugs in aqueous environments

International Nuclear Information System (INIS)

Lin, Angela Yu-Chen; Lin, Yen-Ching; Lee, Wan-Ning

2014-01-01

This study addresses the occurrences and natural fates of chemotherapeutics and controlled drugs when found together in hospital effluents and surface waters. The results revealed the presence of 11 out of 16 drugs in hospital effluents, and the maximum detected concentrations were at the μg L −1 level in the hospital effluents and the ng L −1 level in surface waters. The highest concentrations corresponded to meperidine, morphine, 5-fluorouracil and cyclophosphamide. The sunlight photolysis of the target compounds was investigated, and the results indicated that morphine and codeine can be significantly attenuated, with half-lives of 0.27 and 2.5 h, respectively, in natural waters. Photolysis can lower the detected environmental concentrations, also lowering the estimated environmental risks of the target drugs to human health. Nevertheless, 5-fluorouracil and codeine were found to have a high risk quotient (RQ), demonstrating the high risks of directly releasing hospital wastewater into the environment. - Highlights: • High occurrence of chemotherapeutics and controlled substances in aqueous systems. • Photolysis lowers the detected concentrations of morphine and codeine. • 5-fluorouracil and codeine in hospital effluents have high risk quotients. - Chemotherapeutics and controlled drugs occur at significant levels in hospital effluents and surface waters. Natural sunlight photolysis reduces their environmental occurrence

Cytotoxic Autophagy in Cancer Therapy

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Khushboo Sharma

2014-06-01

Full Text Available Autophagy is a process of cellular self-digestion, whereby the cell degrades subcellular materials in order to generate energy and metabolic precursors in order to prolong survival, classically under conditions of nutrient deprivation. Autophagy can also involve the degradation of damaged or aged organelles, and misfolded or damaged proteins to eliminate these components that might otherwise be deleterious to cellular survival. Consequently, autophagy has generally been considered a prosurvival response. Many, if not most chemotherapeutic drugs and radiation also promote autophagy, which is generally considered a cytoprotective response, in that its inhibition frequently promotes apoptotic cells death. Furthermore, it has been shown that conventional chemotherapeutic drugs and radiation alone rarely induce a form of autophagy that leads to cell death. However, there are multiple examples in the literature where newer chemotherapeutic agents, drug combinations or drugs in combination with radiation promote autophagic cell death. This review will describe autophagic cell death induced in breast tumor cells, lung cancer cells as well as glioblastoma, demonstrating that it cannot be concluded that stress induced autophagy is, of necessity, cytoprotective in function.

Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

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Braidwood L

2013-12-01

Full Text Available Lynne Braidwood,1 Sheila V Graham,2 Alex Graham,1 Joe Conner11Virttu Biologics Ltd, Department of Neurology, Southern General Hospital, Glasgow, UK; 2MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Jarrett Building, University of Glasgow, Glasgow, UKAbstract: Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVexGM-CSF], is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report

Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase.

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Shiraishi, A; Sakumi, K; Sekiguchi, M

2000-10-01

O(6)-methylguanine-DNA methyltransferase plays vital roles in preventing induction of mutations and cancer as well as cell death related to alkylating agents. Mice defective in the MGMT: gene, encoding the methyltransferase, were used to evaluate cell death-inducing and tumorigenic activities of therapeutic agents which have alkylation potential. MGMT(-/-) mice were considerably more sensitive to dacarbazine, a monofunctional triazene, than were wild-type mice, in terms of survival. When dacarbazine was administered i.p. to 6-week-old mice and survival at 30 days was enumerated, LD(50) values of MGMT(-/-) and MGMT(+/+) mice were 20 and 450 mg/kg body wt, respectively. Increased sensitivity of MGMT(-/-) mice to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosou rea (ACNU), a bifunctional nitrosourea, was also noted. On the other hand, there was no difference in survival of MGMT(+/+) and MGMT(-/-) mice exposed to cyclophosphamide, a bifunctional nitrogen mustard. It appears that dacarbazine and ACNU produce O(6)-alkylguanine as a major toxic lesion, while cyclophosphamide yields other types of modifications in DNA which are not subjected to the action of the methyltransferase. MGMT(-/-) mice seem to be less refractory to the tumor-inducing effect of dacarbazine than are MGMT(+/+) mice. Thus, the level of O(6)-methylguanine-DNA methyltransferase activity is an important factor when determining susceptibility to drugs with the potential for alkylation.

Nitric oxide donors attenuate clongenic potential in rat C6 glioma cells treated with alkylating chemotherapeutic agents.

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Yang, Jir-Jei; Yin, Jiu-Haw; Yang, Ding-I

2007-05-11

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) kills tumor cells via multiple actions including alkylation and carbamoylation. Previously, we have reported that formation of S-nitrosoglutathione (GSNO) in glioma cells overexpressing inducible nitric oxide synthase (iNOS) contributed to nitric oxide (NO)-dependent carbamoylating chemoresistance against BCNU. To further characterize the effects of NO on alkylating cytotoxicity, colony formation assay was applied to evaluate the effects of various NO donors on rat C6 glioma cells challenged with alkylating agents. We demonstrate that NO donors including GSNO, diethylamine NONOate (DEA/NO), and sodium nitroprusside (SNP) substantially reduced the extent of colony formation in glioma cells treated with alkylating agents, namely methyl methanesulfonate (MMS), N-methyl-N-nitrosourea (MNU), and N-ethyl-N-nitrosourea (ENU). Without alkylating agents these NO-releasing agents alone had no effects on clongenic potential of rat C6 glioma cells. Among these three NO donors used, the effectiveness in potentiating alkylating cytotoxicity is in the order of "GSNO>DEA/NO>SNP" when applied at the same dosages. GSNO also exerted similar synergistic actions reducing the extents of colony formation when co-administrated with 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-hydrazine (compound #1), another alkylating agent that mimics the chloroethylating action of BCNU. Together with our previous findings, we propose that NO donors may be used as adjunct chemotherapy with alkylating agents for such malignant brain tumors as glioblastoma multiforme (GBM). In contrast, production of NO as a result of iNOS induction, such as that occurring after surgical resection of brain tumors, may compromise the efficacy of carbamoylating chemotherapy.

Multimodal treatment combining chemotherapy, hyperthermia and radiotherapy for ovarian cancer

International Nuclear Information System (INIS)

Nagashima, Kei

1992-01-01

There has been increasing interest in the use of heat in the treatment of cancer. Theoretically cells are the most sensitive to ionizing radiation at mitosis, whereas the cycle phase that is the most resistant to ionizing radiation namely late in the DNA. Synthetic phase (late S) is the most sensitive to hyperthermia. Hyperthermia has been reported to enhance the cytocidal effects of several active chemotherapeutic agents. When thermal potentiation of chemotherapeutic agents against malignant cells is contemplated, normal tissues have a relatively high ambient blood flow which increases in response to thermal stress, thereby dissipating heat, compared to tumors. Tumors, with relatively poor blood flow and a responsive neovasculature, are in capable of augmenting flow and acting as a heat reservoir. This is the phenomenon of a heat reservoir which is one factor to enhance the cytocidal effects of several active anticancer agents for enhancing the uptake in tumor. The importance is in the adjuvant chemotherapy treated for post operative, advanced and recurrent ovarian cancer. Heating enhances the effects of radiotherapy and chemotherapy. Thirty patients with ovarian cancer were subjected to the multidisciplinary treatment with combination of hyperthermochemotherapy and radiation. The 30 patients consisted of 18 with endometrioid adenocarcinoma and 7 with serious post operative or recurrent status. Two types of equipments with rediofrequencies of 70 MHz (BSD-1000) or 434 MHZ (TAG MED·HS 434) were used for hyperthermia. Chemotherapeutic agents such as adriamycin, cis DDP, cyclophosphamide and etoposide were injected intravenously. Arterial infusion with reservoir was very effective in advanced stage of ovarian cancer. No severe or fatal side effects were observed. Hyperthermochemotherapy is useful and effective for the postoperative management or the treatment of recurrent cancer of the ovary. (J.P.N.)

Comparison of the efficacy among multiple chemotherapeutic interventions combined with radiation therapy for patients with cervix cancer after surgery: A network meta-analysis.

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Chang, Lei; Guo, Ruixia

2017-07-25

Cervix cancer was the second most common cancer in female. However, there was no network meta-analysis (NMA) comparing the efficacy of the multiple chemotherapeutic interventions combined with radiation therapy in patients after operation. Randomized controlled trials were retrieved from PubMed, Embase and Cochrane Library. Overall survival (OS), recurrence-free survival (RFS), incidence of recurrence and distant metastasis were the main outcomes, particularly 5-year OS and PFS were considered as primary outcomes. Furthermore, the hazard ratio (HR) or odds ratio (OR) and their 95% credible intervals (CrIs) were extracted. The surface under cumulative ranking curve (SUCRA) was also used in this NMA. A total of 39 eligible trials with 8,952 patients were included and 22 common chemotherapies were evaluated in this meta-analysis. For OS, cisplatin+fluorouracil+hydroxyurea, fluorouracil+mitomycin C, cisplatin and cisplatin+fluorouracil were better than placebo. As for RFS, cisplatin+fluorouracil, fluorouracil+mitomycin C, and cisplatin alone had the significant superiority compared with placebo. In terms of incidence of recurrence, the optimal drug combination was cisplatin+ifosfamide (0.93) based on SUCRA. Moreover, epirubicin (OR = 0.28, 95% CrI: 0.08-0.91) was the only one had the distinguished potency in reducing the occurrence of distant metastasis with a SUCRA rank probability of 0.88. We recommended cisplatin+fluorouracil+hydroxyurea and cisplatin+docetaxel for their good efficacy in long term survival. Meanwhile, the combination of multiple drugs with different mechanisms worked better.

Nanospheric Chemotherapeutic and Chemoprotective Agents

Science.gov (United States)

2008-09-01

Rutgers scientists led by Prof. Joachim Kohn and TyRx Pharma, Inc., announced the FDA’s clearance of a new medical device for hernia repair that...significant decrease of the cell metabolic activity of KB cervical carcinoma cells was detected, confirming that these nanospheres do not induce any short...term cytotoxicity. Cell viability was analyzed by MTS colorimetric assay after 3 days. Figure 11: Metabolic activity of KB cervical carcinoma cells

Combined effect of environmental radiation and other agents: Is there a synergism trap?

International Nuclear Information System (INIS)

Hornhardt, S.; Jung, T.; Burkart, W.

2002-01-01

Most assessments of possible deleterious outcomes from environmental and occupational exposures concentrate on single agents and neglect the potential for combined effects, i.e. synergisms or antagonisms. Biomechanistic considerations based on multistep processes such as carcinogenesis indicate the potential for highly detrimental interactions, if two or more consecutive rate limiting steps are specifically effected by different agents. However, low specificity towards molecular structure or DNA-sequence - and therefore exchangeability - of many genotoxic agents indicate little functional specificity and therefore little vulnerability towards synergism at most occupational and environmental exposure situations. The low potential for significant combined effects for those common low exposure situations where non-genotoxic agents with highly non-linear dose effect relationships and apparent thresholds are involved, is also evident. Nevertheless, a quantitative assessment of the contribution of synergistic interactions to the total detriment from natural and man-made toxicants based on experimental data is far away. The existing database on combined effects is rudimentary, mainly descriptive and rarely covers exposure ranges large enough to make direct inferences to present day low dose exposure situations. In view of the multitude of possible interactions between the large number of potentially harmful agents in the human environment, descriptive approaches will have to be supplemented by the use of mechanistic models for critical health endpoints such as cancer. Finally an important question considering the shape of dose effect relationships for ionizing radiation arises from the unresolved question whether real or apparent thresholds may be used for any genotoxic agent separately or only one time for an exposed genome. (author)

Effects of some nonsteroidal anti-inflammatory agents on experimental radiation pneumonitis

Energy Technology Data Exchange (ETDEWEB)

Gross, N.J.; Holloway, N.O.; Narine, K.R. (Medical Radiology Service, Hines VA Hospital, Maywood, IL (United States))

1991-09-01

Corticosteroids have previously been found to be protective against the mortality of radiation pneumonitis in mice, even when given well after lethal lung irradiation. The authors explored the possibility that this effect was due to their well-known anti-inflammatory actions by giving various nonsteroidal inhibitors of arachidonate metabolism to groups of mice that had received 19 Gy to the thorax (bilaterally). Treatments of four cyclooxygenase inhibitors, one lipoxygenase inhibitor, and one leukotriene receptor antagonist, given by various routes in various doses, were commenced 10 weeks after irradiation or sham irradiation and continued throughout the period when death from radiation pneumonitis occurs, 11-26 weeks after irradiation. Each of the treatments had the appropriate effect on arachidonate metabolism in the lungs as assessed by LTB4 and PGE2 levels in lung lavage fluid. The principal end point was mortality. The 5-lipoxygenase inhibitor diethylcarbamazine and the LTD4/LTE4 receptor antagonist LY 171883 markedly reduced mortality in dose-response fashion. The effects of cyclooxygenase inhibitors were divergent; piroxicam and ibuprofen were marginally protective, indomethacin in all doses accelerated mortality, and aspirin reduced mortality in a dose-response fashion. These results suggest that the protective effect of corticosteroids in radiation pneumonitis can be tentatively attributed to their anti-inflammatory actions, and that nonsteroidal anti-inflammatory agents, particularly those that affect lipoxygenase products, may offer equal or better protection than corticosteroids against mortality due to radiation pneumonitis.

Effects of some nonsteroidal anti-inflammatory agents on experimental radiation pneumonitis

International Nuclear Information System (INIS)

Gross, N.J.; Holloway, N.O.; Narine, K.R.

1991-01-01

Corticosteroids have previously been found to be protective against the mortality of radiation pneumonitis in mice, even when given well after lethal lung irradiation. The authors explored the possibility that this effect was due to their well-known anti-inflammatory actions by giving various nonsteroidal inhibitors of arachidonate metabolism to groups of mice that had received 19 Gy to the thorax (bilaterally). Treatments of four cyclooxygenase inhibitors, one lipoxygenase inhibitor, and one leukotriene receptor antagonist, given by various routes in various doses, were commenced 10 weeks after irradiation or sham irradiation and continued throughout the period when death from radiation pneumonitis occurs, 11-26 weeks after irradiation. Each of the treatments had the appropriate effect on arachidonate metabolism in the lungs as assessed by LTB4 and PGE2 levels in lung lavage fluid. The principal end point was mortality. The 5-lipoxygenase inhibitor diethylcarbamazine and the LTD4/LTE4 receptor antagonist LY 171883 markedly reduced mortality in dose-response fashion. The effects of cyclooxygenase inhibitors were divergent; piroxicam and ibuprofen were marginally protective, indomethacin in all doses accelerated mortality, and aspirin reduced mortality in a dose-response fashion. These results suggest that the protective effect of corticosteroids in radiation pneumonitis can be tentatively attributed to their anti-inflammatory actions, and that nonsteroidal anti-inflammatory agents, particularly those that affect lipoxygenase products, may offer equal or better protection than corticosteroids against mortality due to radiation pneumonitis

Self-assembled Nanomaterials for Chemotherapeutic Applications

Science.gov (United States)

Shieh, Aileen

The self-assembly of short designed peptides into functional nanostructures is becoming a growing interest in a wide range of fields from optoelectronic devices to nanobiotechnology. In the medical field, self-assembled peptides have especially attracted attention with several of its attractive features for applications in drug delivery, tissue regeneration, biological engineering as well as cosmetic industry and also the antibiotics field. We here describe the self-assembly of peptide conjugated with organic chromophore to successfully deliver sequence independent micro RNAs into human non-small cell lung cancer cell lines. The nanofiber used as the delivery vehicle is completely non-toxic and biodegradable, and exhibit enhanced permeability effect for targeting malignant tumors. The transfection efficiency with nanofiber as the delivery vehicle is comparable to that of the commercially available RNAiMAX lipofectamine while the toxicity is significantly lower. We also conjugated the peptide sequence with camptothecin (CPT) and observed the self-assembly of nanotubes for chemotherapeutic applications. The peptide scaffold is non-toxic and biodegradable, and drug loading of CPT is high, which minimizes the issue of systemic toxicity caused by extensive burden from the elimination of drug carriers. In addition, the peptide assembly drastically increases the solubility and stability of CPT under physiological conditions in vitro, while active CPT is gradually released from the peptide chain under the slight acidic tumor cell environment. Cytotoxicity results on human colorectal cancer cells and non-small cell lung cancer cell lines display promising anti-cancer properties compared to the parental CPT drug, which cannot be used clinically due to its poor solubility and lack of stability in physiological conditions. Moreover, the peptide sequence conjugated with 5-fluorouracil formed a hydrogel with promising topical chemotherapeutic applications that also display

Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents.

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Francia, Giulio; Green, Shane K; Bocci, Guido; Man, Shan; Emmenegger, Urban; Ebos, John M L; Weinerman, Adina; Shaked, Yuval; Kerbel, Robert S

2005-10-01

Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion-mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.

Organoruthenium Complexes with CN Ligands are Highly Potent Cytotoxic Agents that Act by a New Mechanism of Action

Czech Academy of Sciences Publication Activity Database

Novohradský, Vojtěch; Yellol, J.; Stuchlíková, O.; Santana, M.D.; Kostrhunová, Hana; Yellol, G.; Kašpárková, Jana; Bautista, D.; Ruiz, J.; Brabec, Viktor

2017-01-01

Roč. 23, č. 61 (2017), s. 15294-15299 ISSN 0947-6539 R&D Projects: GA ČR(CZ) GA17-05302S Institutional support: RVO:68081707 Keywords : chemotherapeutic-agents * ruthenium(ii) complexes * iridium(iii) complexes Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 5.317, year: 2016

A critical ethnography of communication processes involving the management of oral chemotherapeutic agents by patients with a primary diagnosis of colorectal cancer: study protocol.

Science.gov (United States)

Mitchell, Gary; Porter, Sam; Manias, Elizabeth

2015-04-01

To describe the protocol used to examine the processes of communication between health professionals, patients and informal carers during the management of oral chemotherapeutic medicines to identify factors that promote or inhibit medicine concordance. Ideally communication practices about oral medicines should incorporate shared decision-making, two-way dialogue and an equality of role between practitioner and patient. While there is evidence that healthcare professionals are adopting these concordant elements in general practice there are still some patients who have a passive role during consultations. Considering oral chemotherapeutic medications, there is a paucity of research about communication practices which is surprising given the high risk of toxicity associated with chemotherapy. A critical ethnographic design will be used, incorporating non-participant observations, individual semi-structured and focus-group interviews as several collecting methods. Observations will be carried out on the interactions between healthcare professionals (physicians, nurses and pharmacists) and patients in the outpatient departments where prescriptions are explained and supplied and on follow-up consultations where treatment regimens are monitored. Interviews will be conducted with patients and their informal carers. Focus-groups will be carried out with healthcare professionals at the conclusion of the study. These several will be analysed using thematic analysis. This research is funded by the Department for Employment and Learning in Northern Ireland (Awarded February 2012). Dissemination of these findings will contribute to the understanding of issues involved when communicating with people about oral chemotherapy. It is anticipated that findings will inform education, practice and policy. © 2014 John Wiley & Sons Ltd.

Radiation exposure and contrast agent use related to radial versus femoral arterial access during percutaneous coronary intervention (PCI)—Results of the FERARI study

Energy Technology Data Exchange (ETDEWEB)

Becher, Tobias, E-mail: Tobias.Becher@umm.de [First Department of Medicine, University Medical Centre Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim (Germany); DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim (Germany); Behnes, Michael; Ünsal, Melike; Baumann, Stefan; El-Battrawy, Ibrahim; Fastner, Christian; Kuschyk, Jürgen; Papavassiliu, Theano; Hoffmann, Ursula [First Department of Medicine, University Medical Centre Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim (Germany); DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim (Germany); Mashayekhi, Kambis [Division of Cardiology and Angiology II, University Heart Center Freiburg Bad Krozingen, Bad Krozingen (Germany); Borggrefe, Martin; Akin, Ibrahim [First Department of Medicine, University Medical Centre Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim (Germany); DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim (Germany)

2016-12-15

Summary: Background: Data regarding radiation exposure related to radial versus femoral arterial access in patients undergoing percutaneous coronary intervention (PCI) remain controversial. This study aims to evaluate patients enrolled in the FERARI study regarding radiation exposure, fluoroscopy time and contrast agent use. Methods: The Femoral Closure versus Radial Compression Devices Related to Percutaneous Coronary Interventions (FERARI) study evaluated prospectively 400 patients between February 2014 and May 2015 undergoing PCI either using the radial or femoral access. In these 400 patients, baseline characteristics, procedural data such as procedural duration, fluoroscopy time, dose–area product (DAP) as well as the amount of contrast agent used were documented and analyzed. Results: Median fluoroscopy time was not significantly different in patients undergoing radial versus femoral access (12.2 vs. 9.8 min, p = 0.507). Furthermore, median DAP (54.5 vs. 52.0 Gycm2, p = 0.826), procedural duration (46.0 vs. 45.0 min, p = 0.363) and contrast agent use (185.5 vs. 199.5 ml, p = 0.742) were also similar in radial and femoral PCI. Conclusion: There was no difference regarding median fluoroscopy time, procedural duration, radiation dose or contrast agent use between radial versus femoral arterial access in PCI. - Highlights: • Data comparing radiation exposure in radial versus femoral PCI remain controversial. • 400 enrolled in the FERARI study were prospectively evaluated. • There was no difference regarding radiation exposure in radial versus femoral access. • Furthermore, there was no significant difference regarding contrast agent use.

Radiation exposure and contrast agent use related to radial versus femoral arterial access during percutaneous coronary intervention (PCI)—Results of the FERARI study

International Nuclear Information System (INIS)

Becher, Tobias; Behnes, Michael; Ünsal, Melike; Baumann, Stefan; El-Battrawy, Ibrahim; Fastner, Christian; Kuschyk, Jürgen; Papavassiliu, Theano; Hoffmann, Ursula; Mashayekhi, Kambis; Borggrefe, Martin; Akin, Ibrahim

2016-01-01

Summary: Background: Data regarding radiation exposure related to radial versus femoral arterial access in patients undergoing percutaneous coronary intervention (PCI) remain controversial. This study aims to evaluate patients enrolled in the FERARI study regarding radiation exposure, fluoroscopy time and contrast agent use. Methods: The Femoral Closure versus Radial Compression Devices Related to Percutaneous Coronary Interventions (FERARI) study evaluated prospectively 400 patients between February 2014 and May 2015 undergoing PCI either using the radial or femoral access. In these 400 patients, baseline characteristics, procedural data such as procedural duration, fluoroscopy time, dose–area product (DAP) as well as the amount of contrast agent used were documented and analyzed. Results: Median fluoroscopy time was not significantly different in patients undergoing radial versus femoral access (12.2 vs. 9.8 min, p = 0.507). Furthermore, median DAP (54.5 vs. 52.0 Gycm2, p = 0.826), procedural duration (46.0 vs. 45.0 min, p = 0.363) and contrast agent use (185.5 vs. 199.5 ml, p = 0.742) were also similar in radial and femoral PCI. Conclusion: There was no difference regarding median fluoroscopy time, procedural duration, radiation dose or contrast agent use between radial versus femoral arterial access in PCI. - Highlights: • Data comparing radiation exposure in radial versus femoral PCI remain controversial. • 400 enrolled in the FERARI study were prospectively evaluated. • There was no difference regarding radiation exposure in radial versus femoral access. • Furthermore, there was no significant difference regarding contrast agent use

Cytotoxic effects of radiation and docetaxel in human tumour cells

International Nuclear Information System (INIS)

Dunne, A.L.

2000-12-01

Data from both single institutions and from randomised multicentre trials have demonstrated that the combination of chemotherapy with radiotherapy can increase the survival of cancer patients. Treatment regimens consisting of taxanes (paclitaxel and docetaxel), a potent class of new chemotherapeutic agents, combined with radiotherapy have recently undergone preclincal investigation. Overall, these studies show that taxanes can enhance the radiation sensitivity of tumour cells. However, data on docetaxel is very limited and the mechanism of radiosensitisation by docetaxel remains largely unknown. The chief purpose of this thesis was to investigate the ability of docetaxel to radiosensitise human tumour cells and investigate potential mechanisms for radiosensitisation. The results reported here for docetaxel indicate that for the cell fines examined this drug does have a synergistic effect and is thus a radiosensitising agent. The degree of radiosensitisation seen seems to be largely dependent on drug concentration. A mechanism involving docetaxel potentiation of radiation-induced apoptosis is also suggested. The second purpose of this thesis is to investigate the potential usefulness of an apoptosis assay and the comet assay as biological indicators for cellular radiosensitivity. Many scientists and clinicans have highlighted the need for development of new rapid, predictive assays of radiation responses. If the radiosensitivity of tumours could be predicted, it may eventually allow the individualisation of patient treatment by radiotherapy. In summary, initial DNA damage measured using the comet assay was successful in predicting the radiosensitivity of colorectal tumour cells. The results suggest that the comet assay appears more suitable than the detection of apoptosis for the prediction of radiosensitivity. We conclude that the results obtained from this thesis will contribute to the current attempts to improve the radiotherapeutic management of cancer. (author)

Up-regulated Ectonucleotidases in Fas-Associated Death Domain Protein- and Receptor-Interacting Protein Kinase 1-Deficient Jurkat Leukemia Cells Counteract Extracellular ATP/AMP Accumulation via Pannexin-1 Channels during Chemotherapeutic Drug-Induced Apoptosis.

Science.gov (United States)

Boyd-Tressler, Andrea M; Lane, Graham S; Dubyak, George R

2017-07-01

Pannexin-1 (Panx1) channels mediate the efflux of ATP and AMP from cancer cells in response to induction of extrinsic apoptosis by death receptors or intrinsic apoptosis by chemotherapeutic agents. We previously described the accumulation of extracellular ATP /AMP during chemotherapy-induced apoptosis in Jurkat human leukemia cells. In this study, we compared how different signaling pathways determine extracellular nucleotide pools in control Jurkat cells versus Jurkat lines that lack the Fas-associated death domain (FADD) or receptor-interacting protein kinase 1 (RIP1) cell death regulatory proteins. Tumor necrosis factor- α induced extrinsic apoptosis in control Jurkat cells and necroptosis in FADD-deficient cells; treatment of both lines with chemotherapeutic drugs elicited similar intrinsic apoptosis. Robust extracellular ATP/AMP accumulation was observed in the FADD-deficient cells during necroptosis, but not during apoptotic activation of Panx1 channels. Accumulation of extracellular ATP/AMP was similarly absent in RIP1-deficient Jurkat cells during apoptotic responses to chemotherapeutic agents. Apoptotic activation triggered equivalent proteolytic gating of Panx1 channels in all three Jurkat cell lines. The differences in extracellular ATP/AMP accumulation correlated with cell-line-specific expression of ectonucleotidases that metabolized the released ATP/AMP. CD73 mRNA, and α β -methylene-ADP-inhibitable ecto-AMPase activity were elevated in the FADD-deficient cells. In contrast, the RIP1-deficient cells were defined by increased expression of tartrate-sensitive prostatic acid phosphatase as a broadly acting ectonucleotidase. Thus, extracellular nucleotide accumulation during regulated tumor cell death involves interplay between ATP/AMP efflux pathways and different cell-autonomous ectonucleotidases. Differential expression of particular ectonucleotidases in tumor cell variants will determine whether chemotherapy-induced activation of Panx1 channels

DMH1 (4-[6-(4-isopropoxyphenylpyrazolo[1,5-a]pyrimidin-3-yl]quinoline inhibits chemotherapeutic drug-induced autophagy

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Yue Sheng

2015-07-01

Full Text Available Our previous work found that DMH1 (4-[6-(4-isopropoxyphenylpyrazolo [1,5-a]pyrimidin-3-yl]quinoline was a novel autophagy inhibitor. Here, we aimed to investigate the effects of DMH1 on chemotherapeutic drug-induced autophagy as well as the efficacy of chemotherapeutic drugs in different cancer cells. We found that DMH1 inhibited tamoxifen- and cispcis-diaminedichloroplatinum (II (CDDP-induced autophagy responses in MCF-7 and HeLa cells, and potentiated the anti-tumor activity of tamoxifen and CDDP for both cells. DMH1 inhibited 5-fluorouracil (5-FU-induced autophagy responses in MCF-7 and HeLa cells, but did not affect the anti-tumor activity of 5-FU for these two cell lines. DMH1 itself did not induce cell death in MCF-7 and HeLa cells, but inhibited the proliferation of these cells. In conclusion, DMH1 inhibits chemotherapeutic drug-induced autophagy response and the enhancement of efficacy of chemotherapeutic drugs by DMH1 is dependent on the cell sensitivity to drugs.

Drug/radiation interactions and central nervous system injury

International Nuclear Information System (INIS)

DeAngelis, L.M.; Shapiro, W.R.

1991-01-01

Central nervous system (CNS) injury caused by combined treatment with cranial radiation therapy (CRT) and chemotherapy is a complicated and difficult problem. Interactions between the two modalities at the cellular level, the effect of treatment sequencing, and chemotherapy and RT dosages are all poorly understood. While this is generally true and applicable to toxicities expressed in multiple organs and tissue types, it is particularly true for the brain. There are many clinical descriptions and situations that strongly implicate an enhanced neurotoxic potential for combined treatment compared to either therapy alone; there is a paucity of definitive experimental evidence, however, and few animal models that can be used to elucidate the nature and pathophysiology of this clinical association. This paper addresses the neurotoxic potential of a specific chemotherapeutic drug when combined with CRT; outlines whose drugs known to cause CNS injury when combined with CRT. Although many of the clinical situations are complicated because multiple cytotoxic agents have been used, usually only one is thought to contribute to the CNS injury. The authors discuss each drug separately

Overexpression of metallothionein in CHO cells and its effect on cell killing by ionizing radiation and alkylating agents

International Nuclear Information System (INIS)

Lohrer, H.; Robson, T.

1989-01-01

Metallothionein protein protects cells from the toxic effects of heavy metal ions. To establish its protective function against ionizing radiation and alkylating agents, a model system was created by transfecting two CHO cell lines (wild-type, K1-2 and X-ray sensitive, xrs-2 subclone Bc11) with the human metallothionein II-A (hMTII-A) gene integrated in a bovine papilloma derived autonomously replicating vector. The isolated transfectants are cadmium-resistant (Cd 1 ), due to the overexpression of the hMTII-A gene. Their steady-state level of hMTII-A mRNA can be increased up to 40-fold after Cd treatment and 20-fold after induction with ionizing radiation. The transfected cell lines proved to be as sensitive as the recipient cell lines to ionizing radiation and bleomycin but the transfectants were significantly more resistant to N-methyl-nitro-nitrosoguanidine (MNNG) and mitomycin C (MMC). These results lead to the conclusion that the MT protein does provide a defence mechanism to protect cells from monofunctional alkylating and cross-linking agents but not from free radicals. (author)

Overexpression of metallothionein in CHO cells and its effect on cell killing by ionizing radiation and alkylating agents

Energy Technology Data Exchange (ETDEWEB)

Lohrer, H.; Robson, T. (Newcastle upon Tyne Univ. (UK). Cancer Research Unit)

1989-12-01

Metallothionein protein protects cells from the toxic effects of heavy metal ions. To establish its protective function against ionizing radiation and alkylating agents, a model system was created by transfecting two CHO cell lines (wild-type, K1-2 and X-ray sensitive, xrs-2 subclone Bc11) with the human metallothionein II-A (hMTII-A) gene integrated in a bovine papilloma derived autonomously replicating vector. The isolated transfectants are cadmium-resistant (Cd{sup 1}), due to the overexpression of the hMTII-A gene. Their steady-state level of hMTII-A mRNA can be increased up to 40-fold after Cd treatment and 20-fold after induction with ionizing radiation. The transfected cell lines proved to be as sensitive as the recipient cell lines to ionizing radiation and bleomycin but the transfectants were significantly more resistant to N-methyl-nitro-nitrosoguanidine (MNNG) and mitomycin C (MMC). These results lead to the conclusion that the MT protein does provide a defence mechanism to protect cells from monofunctional alkylating and cross-linking agents but not from free radicals. (author).

Histopathologic and Radiologic Assessment of Chemotherapeutic Response in Ewing's Sarcoma: A Review.

Science.gov (United States)

García-Castellano, José M; Atallah Yordi, Nagib; Reyes, Carolina; Healey, John H

2012-01-01

Ewing's sarcoma is a highly malignant tumor that metastasizes rapidly and is thus associated with a low survival rate. The intensification of chemotherapy has been shown to improve the overall survival of patients with Ewing's sarcoma. However, intensified chemotherapy can lead to increased toxicity or even the development of secondary malignancies. The stratification of patients with Ewing's sarcoma into "good" and "poor" responders may help guide the administration of progressively more intensified chemotherapy. Thus, an accurate assessment of the chemotherapeutic response, as well as the extent of chemotherapy-induced tumor necrosis, is critical for avoiding potential treatment-related complications in these patients. This paper reviews the methods currently used to evaluate chemotherapeutic response in Ewing's sarcoma, focusing specifically on histopathologic and imaging analyses, and discusses novel therapies and imaging methods that may help improve the overall survival of these patients.

Study of arsenic trioxide-induced vascular shutdown and enhancement with radiation in solid tumor

International Nuclear Information System (INIS)

Monzen, Hajime; Griffin, R.J.; Williams, B.W.; Amamo, Morikazu; Ando, Satoshi; Hasegawa, Takeo

2004-01-01

Arsenic trioxide (ATO) has been reported to be an effective chemotherapeutic agent for acute promyelocytic leukemia (APL), and, recently, anti-tumor effect has been demonstrated in solid tumors. However, little is known about the mechanism of action of the ATO effect on solid tumor. We investigated the anti-vascular effect of ATO and the potential of combining ATO with radiation therapy. We studied the anti-vascular effect of ATO and radiosensitization of squamous cell carcinoma (SCC) VII murine tumors of C3H mice. The anti-vascular effect was examined using magnetic resonance imaging (MRI), and radiosensitivity was studied by clonogenic assay and tumor growth delay. Histopathological changes of the tumors after various treatments were also observed with hematoxylin and eosin (H and E) staining. Necrosis and blood flow changes in the central region of tumors in the hind limbs of the animals were observed on T2-weighted imaging after an intraperitoneal (i.p.) injection of 8 mg/kg of ATO alone. ATO exposure followed by radiation decreased the clonogenic survival of SCC VII cells compared with either treatment alone. Tumor growth delay after 10-20 Gy of radiation alone was increased slightly compared with control tumors, but the combination of ATO injection 2 hours before exposure to 20 Gy of radiation significantly prolonged tumor growth delay by almost 20 days. The results suggest that ATO and radiation can enhance the radiosensitivity of solid tumor. (author)

DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells.

Science.gov (United States)

Klaus, Christine R; Iwanowicz, Dorothy; Johnston, Danielle; Campbell, Carly A; Smith, Jesse J; Moyer, Mikel P; Copeland, Robert A; Olhava, Edward J; Scott, Margaret Porter; Pollock, Roy M; Daigle, Scott R; Raimondi, Alejandra

2014-09-01

EPZ-5676 [(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol], a small-molecule inhibitor of the protein methyltransferase DOT1L, is currently under clinical investigation for acute leukemias bearing MLL-rearrangements (MLL-r). In this study, we evaluated EPZ-5676 in combination with standard of care (SOC) agents for acute leukemias as well as other chromatin-modifying drugs in cellular assays with three human acute leukemia cell lines: MOLM-13 (MLL-AF9), MV4-11 (MLL-AF4), and SKM-1 (non-MLL-r). Studies were performed to evaluate the antiproliferative effects of EPZ-5676 combinations in a cotreatment model in which the second agent was added simultaneously with EPZ-5676 at the beginning of the assay, or in a pretreatment model in which cells were incubated for several days in the presence of EPZ-5676 prior to the addition of the second agent. EPZ-5676 was found to act synergistically with the acute myeloid leukemia (AML) SOC agents cytarabine or daunorubicin in MOLM-13 and MV4-11 MLL-r cell lines. EPZ-5676 is selective for MLL-r cell lines as demonstrated by its lack of effect either alone or in combination in the nonrearranged SKM-1 cell line. In MLL-r cells, the combination benefit was observed even when EPZ-5676 was washed out prior to the addition of the chemotherapeutic agents, suggesting that EPZ-5676 sets up a durable, altered chromatin state that enhances the chemotherapeutic effects. Our evaluation of EPZ-5676 in conjunction with other chromatin-modifying drugs also revealed a consistent combination benefit, including synergy with DNA hypomethylating agents. These results indicate that EPZ-5676 is highly efficacious as a single agent and synergistically acts with other chemotherapeutics, including AML SOC drugs and DNA hypomethylating agents in MLL-r cells. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Enhancement of the photo-electric effect with pharmacological agents in synchrotron radiation based anti-cancer radiotherapy: a methodological study

International Nuclear Information System (INIS)

Corde, Stephanie

2002-01-01

Anti-cancer therapy rests on three main principles: 1) anatomic confinement of irradiation; 2) temporal fractioning of treatment; 3) treatment of tissues that are more sensitive to radiation than surrounding healthy tissue. Under those principles hides the goal of radiotherapy: to deposit more of the X-ray energy in the tumor while preserving the surrounding healthy tissues. This goal is hard to reach since one of the causes of the failures in radiotherapy is the continuing evolution of the tumor. Could synchrotron radiation be more effective as an X-ray source for radiotherapy? The variation of the radiation-matter interaction cross-sections as a function of X-ray energy and atomic number of the medium show that certain energies and certain elements are more suitable to obtain the largest number of interactions and the largest amount of deposited energy. Synchrotron radiation allows to select precisely those energies because of its high spectral intensity. Its spectral characteristics (energy of the photons between 10 and 100 keV) allow to trigger the photoelectric effect with a maximum of probability on heavy elements introduced close to cancerous cells. It has been shown that: 1) synchrotron radiation based tomodensitometry is a quantitative imaging technique, potentially powerful for radiotherapy since it insures in-vivo the measurement of intra-tumoral concentration of contrast agent (I or Gd); 2) in the presence of iodinated contrast agent the lethal effect of X-rays on cell survival is increased and the gain in radio sensitivity depends on X-ray energy; 3) at the cellular scale the lethality of irradiation can be optimised again by transporting heavy atoms (I, Pt) inside the DNA, which is the biological target of the irradiation. This reinforcement of the killing efficiency of low energy X-rays using a physical mechanism aimed at a pharmacological agent is an original concept in anti-cancer radiotherapy. (author) [fr

The influence of toxicity constraints in models of chemotherapeutic protocol escalation

KAUST Repository

Boston, E. A. J.

2011-04-06

The prospect of exploiting mathematical and computational models to gain insight into the influence of scheduling on cancer chemotherapeutic effectiveness is increasingly being considered. However, the question of whether such models are robust to the inclusion of additional tumour biology is relatively unexplored. In this paper, we consider a common strategy for improving protocol scheduling that has foundations in mathematical modelling, namely the concept of dose densification, whereby rest phases between drug administrations are reduced. To maintain a manageable scope in our studies, we focus on a single cell cycle phase-specific agent with uncomplicated pharmacokinetics, as motivated by 5-Fluorouracil-based adjuvant treatments of liver micrometastases. In particular, we explore predictions of the effectiveness of dose densification and other escalations of the protocol scheduling when the influence of toxicity constraints, cell cycle phase specificity and the evolution of drug resistance are all represented within the modelling. For our specific focus, we observe that the cell cycle and toxicity should not simply be neglected in modelling studies. Our explorations also reveal the prediction that dose densification is often, but not universally, effective. Furthermore, adjustments in the duration of drug administrations are predicted to be important, especially when dose densification in isolation does not yield improvements in protocol outcomes. © The author 2011. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

The SOS Chromotest applied for screening plant antigenotoxic agents against ultraviolet radiation.

Science.gov (United States)

Fuentes, J L; García Forero, A; Quintero Ruiz, N; Prada Medina, C A; Rey Castellanos, N; Franco Niño, D A; Contreras García, D A; Córdoba Campo, Y; Stashenko, E E

2017-09-13

In this work, we investigated the usefulness of the SOS Chromotest for screening plant antigenotoxic agents against ultraviolet radiation (UV). Fifty Colombian plant extracts obtained by supercritical fluid (CO 2 ) extraction, twelve plant extract constituents (apigenin, carvacrol, β-caryophyllene, 1,8-cineole, citral, p-cymene, geraniol, naringenin, pinocembrin, quercetin, squalene, and thymol) and five standard antioxidant and/or photoprotective agents (curcumin, epigallocatechin gallate, resveratrol, α-tocopherol, and Trolox®) were evaluated for their genotoxicity and antigenotoxicity against UV using the SOS Chromotest. None of the plant extracts, constituents or agents were genotoxic in the SOS Chromotest at tested concentrations. Based on the minimal extract concentration that significantly inhibited UV-genotoxicity (CIG), five plant extracts were antigenotoxic against UV as follows: Baccharis nítida (16 μg mL -1 ) = Solanum crotonifolium (16 μg mL -1 ) > Hyptis suaveolens (31 μg mL -1 ) = Persea caerulea (31 μg mL -1 ) > Lippia origanoides (62 μg mL -1 ). Based on CIG values, the flavonoid compounds showed the highest antigenotoxic potential as follows: apigenin (7 μM) > pinocembrin (15 μM) > quercetin (26 μM) > naringenin (38 μM) > epigallocatechin gallate (108 μM) > resveratrol (642 μM). UV-genotoxicity inhibition with epigallocatechin gallate, naringenin and resveratrol was related to its capability for inhibiting protein synthesis. A correlation analysis between compound antigenotoxicity estimates and antioxidant activity evaluated by the oxygen radical absorbance capacity (ORAC) assay showed that these activities were not related. The usefulness of the SOS Chromotest for bioprospecting of plant antigenotoxic agents against UV was discussed.

Assessment of genetic integrity, splenic phagocytosis and cell death potential of (Z-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl amino-4-oxobut-2-enoic acid and its effect when combined with commercial chemotherapeutics

Directory of Open Access Journals (Sweden)

Rodrigo Juliano Oliveira

2018-02-01

Full Text Available Abstract The increased incidence of cancer and its high treatment costs have encouraged the search for new compounds to be used in adjuvant therapies for this disease. This study discloses the synthesis of (Z-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl amino-4-oxobut-2-enoic acid (IR-01 and evaluates not only the action of this compound on genetic integrity, increase in splenic phagocytosis and induction of cell death but also its effects in combination with the commercial chemotherapeutic agents doxorubicin, cisplatin and cyclophosphamide. IR-01 was designed and synthesized based on two multifunctionalyzed structural fragments: 4-aminoantipyrine, an active dipyrone metabolite, described as an antioxidant and anti-inflammatory agent; and the pharmacophore fragment 1,4-dioxo-2-butenyl, a cytotoxic agent. The results indicated that IR-01 is an effective chemoprotector because it can prevent clastogenic and/or aneugenic damage, has good potential to prevent genomic damage, can increase splenic phagocytosis and lymphocyte frequency and induces cell death. However, its use as an adjuvant in combination with chemotherapy is discouraged since IR-01 interferes in the effectiveness of the tested chemotherapeutic agents. This is a pioneer study as it demonstrates the chemopreventive effects of IR-01, which may be associated with the higher antioxidant activity of the precursor structure of 4-aminoantipyrine over the effects of the 1,4-dioxo-2-butenyl fragment.

Evaluation of image quality and radiation dose using gold nanoparticles and other clinical contrast agents in dual-energy Computed Tomography (CT): CT abdomen phantom

Science.gov (United States)

Zukhi, J.; Yusob, D.; Tajuddin, A. A.; Vuanghao, L.; Zainon, R.

2017-05-01

The aim of this study was to evaluate the image quality and radiation dose using commercial gold nanoparticles and clinical contrast agents in dual-energy Computed Tomography (CT). Five polymethyl methacrylate (PMMA) tubes were used in this study, where four tubes were filled with different contrast agents (barium, iodine, gadolinium, and gold nanoparticles). The fifth tube was filled with water. Two optically stimulated luminescence dosimeters (OSLD) were placed in each tube to measure the radiation dose. The tubes were placed in a fabricated adult abdominal phantom of 32 cm in diameter using PMMA. The phantom was scanned using a DECT at low energy (80 kV) and high energy (140 kV) with different pitches (0.6 mm and 1.0 mm) and different slice thickness (3.0 mm and 5.0 mm). The tube current was applied automatically using automatic exposure control (AEC) and tube current modulation recommended by the manufacturer (CARE Dose 4D, Siemens, Germany). The contrast-to-noise ratio (CNR) of each contrast agent was analyzed using Weasis software. Gold nanoparticles has highest atomic number (Z = 79) than barium (Z = 56), iodine (Z = 53) and gadolinium (Z = 64). The CNR value of each contrast agent increases when the slice thickness increases. The radiation dose obtained from this study decreases when the pitch increases. The optimal imaging parameters for gold nanoparticles and other clinical contrast agents is obtained at pitch value of 1.0 mm and slice thickness of 5.0 mm. Low noise and low radiation dose obtained at these imaging parameters. The optimal imaging parameters obtained in this study can be applied in multiple contrast agents imaging.

Evaluation of image quality and radiation dose using gold nanoparticles and other clinical contrast agents in dual-energy Computed Tomography (CT): CT abdomen phantom

International Nuclear Information System (INIS)

Zukhi, J; Yusob, D; Vuanghao, L; Zainon, R; Tajuddin, A A

2017-01-01

The aim of this study was to evaluate the image quality and radiation dose using commercial gold nanoparticles and clinical contrast agents in dual-energy Computed Tomography (CT). Five polymethyl methacrylate (PMMA) tubes were used in this study, where four tubes were filled with different contrast agents (barium, iodine, gadolinium, and gold nanoparticles). The fifth tube was filled with water. Two optically stimulated luminescence dosimeters (OSLD) were placed in each tube to measure the radiation dose. The tubes were placed in a fabricated adult abdominal phantom of 32 cm in diameter using PMMA. The phantom was scanned using a DECT at low energy (80 kV) and high energy (140 kV) with different pitches (0.6 mm and 1.0 mm) and different slice thickness (3.0 mm and 5.0 mm). The tube current was applied automatically using automatic exposure control (AEC) and tube current modulation recommended by the manufacturer (CARE Dose 4D, Siemens, Germany). The contrast-to-noise ratio (CNR) of each contrast agent was analyzed using Weasis software. Gold nanoparticles has highest atomic number (Z = 79) than barium (Z = 56), iodine (Z = 53) and gadolinium (Z = 64). The CNR value of each contrast agent increases when the slice thickness increases. The radiation dose obtained from this study decreases when the pitch increases. The optimal imaging parameters for gold nanoparticles and other clinical contrast agents is obtained at pitch value of 1.0 mm and slice thickness of 5.0 mm. Low noise and low radiation dose obtained at these imaging parameters. The optimal imaging parameters obtained in this study can be applied in multiple contrast agents imaging. (paper)

Combining radiation with hyperthermochemotherapy (Cis-DDP) for advanced, recurrent esophageal cancer

International Nuclear Information System (INIS)

Endou, Masaru; Suzuki, Hirotoshi; Nakashima, Yukihiro

1991-01-01

We treated 20 cases of squamous cell carcinoma of the esophagus, combining radiation, chemotherapy and hyperthermia. Hyperthermia combining chemotherapy consisting of cis-dichlorodiamine platinum (25∼75 mg/body, every week) in the form continuous intravenous infusion was given. The hyperthermochemotherapy only had limited effectiveness but good response was noted for post-operative and post-irradiative adjuvant hyperthermochemotherapy. Heating could alleviate some chemotherapeutic side effects, especially renal damage or audiometric disturbance. Furthermore, hyperthermia relieved some radiation side effects, such as radiation-induced scleroderma probably due to hypercirculation. We believe that combining hyperthermochemotherapy with radiation is promising for advanced, recurrent esophageal cancer. (author)

Combining radiation with hyperthermochemotherapy (Cis-DDP) for advanced, recurrent esophageal cancer

Energy Technology Data Exchange (ETDEWEB)

Endou, Masaru; Suzuki, Hirotoshi; Nakashima, Yukihiro (Saint Marianna Univ., Kawasaki, Kanagawa (Japan). School of Medicine) (and others)

1991-10-01

We treated 20 cases of squamous cell carcinoma of the esophagus, combining radiation, chemotherapy and hyperthermia. Hyperthermia combining chemotherapy consisting of cis-dichlorodiamine platinum (25{approx}75 mg/body, every week) in the form continuous intravenous infusion was given. The hyperthermochemotherapy only had limited effectiveness but good response was noted for post-operative and post-irradiative adjuvant hyperthermochemotherapy. Heating could alleviate some chemotherapeutic side effects, especially renal damage or audiometric disturbance. Furthermore, hyperthermia relieved some radiation side effects, such as radiation-induced scleroderma probably due to hypercirculation. We believe that combining hyperthermochemotherapy with radiation is promising for advanced, recurrent esophageal cancer. (author).

Enhanced radiation response in radioresistant MCF-7 cells by targeting peroxiredoxin II

Directory of Open Access Journals (Sweden)

Diaz AJG

2013-10-01

Full Text Available Anthony Joseph Gomez Diaz,1 Daniel Tamae,2 Yun Yen,3 JianJian Li,4 Tieli Wang1 1Department of Chemistry and Biochemistry, California State University at Dominguez Hills, Carson, CA, 2Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, 3Department of Clinical and Molecular Pharmacology, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA, 4Department of Radiation Oncology, University of California Davis, Sacramento, CA, USA Abstract: In our previous study, we identified that a protein target, peroxiredoxin II (PrxII, is overexpressed in radioresistant MCF+FIR3 breast-cancer cells and found that its expression and function is associated with breast-cancer radiation sensitivity or resistance. Small interference RNA (siRNA targeting PrxII gene expression was able to sensitize MCF+FIR3 radioresistant breast-cancer cells to ionizing radiation. The major focus of this work was to investigate how the radiation response of MCF+FIR3 radioresistant cells was affected by the siRNA that inhibits PrxII gene expression. Our results, presented here, show that silencing PrxII gene expression increased cellular toxicity by altering cellular thiol status, inhibiting Ca2+ efflux from the cells, and perturbing the intracellular Ca2+ homeostasis. By combining radiotherapy and siRNA technology, we hope to develop new therapeutic strategies that may have potential to enhance the efficacy of chemotherapeutic agents due to this technology's property of targeting to specific cancer-related genes. Keywords: siRNA, PrxII, radiation resistance, Ca2+, MCF+FIR3

Histopathologic and Radiologic Assessment of Chemotherapeutic Response in Ewing's Sarcoma: A Review

Directory of Open Access Journals (Sweden)

José M. García-Castellano

2012-01-01

Full Text Available Ewing’s sarcoma is a highly malignant tumor that metastasizes rapidly and is thus associated with a low survival rate. The intensification of chemotherapy has been shown to improve the overall survival of patients with Ewing’s sarcoma. However, intensified chemotherapy can lead to increased toxicity or even the development of secondary malignancies. The stratification of patients with Ewing’s sarcoma into “good” and “poor” responders may help guide the administration of progressively more intensified chemotherapy. Thus, an accurate assessment of the chemotherapeutic response, as well as the extent of chemotherapy-induced tumor necrosis, is critical for avoiding potential treatment-related complications in these patients. This paper reviews the methods currently used to evaluate chemotherapeutic response in Ewing’s sarcoma, focusing specifically on histopathologic and imaging analyses, and discusses novel therapies and imaging methods that may help improve the overall survival of these patients.

Limit values for exposure to physical agents

International Nuclear Information System (INIS)

Anon.

1983-01-01

The limit values for exposure to thermal environments adopted by the French AFNOR and by the ISO Working Group (AFNOR Standard X 35-201 and ISO Standard 7243, and AFNOR Standard X 35-204). The limit values for exposure to other physical agents established by the American ACGIH for 1982. The following agents are covered: - laser radiation (ocular and skin exposure); - ultraviolet radiation; - visible and near-infrared radiation (retinal thermal and photochemical injury); - airborne and upper sonic and ultrasonic acoustic radiation; - radiofrequency radiation [fr

Cooperative biological effects between ionizing radiation and other physical and chemical agents.

Science.gov (United States)

Manti, Lorenzo; D'Arco, Annalisa

2010-01-01

Exposure to ionizing radiation (IR), at environmentally and therapeutically relevant doses or as a result of diagnostics or accidents, causes cyto- and genotoxic damage. However, exposure to IR alone is a rare event as it occurs in spatial and temporal combination with several physico-chemical agents. Some of these are of known noxiousness, as is the case with chemical compounds at high dose, hence additive/synergistic effects can be expected or have been demonstrated. Conversely, the cellular toxicity of other agents, such as non-ionizing electromagnetic fields (EMFs), is only presumed and their short- and long-term cooperation on IR-induced damage remains undetermined. In this review, we shall examine evidence in support of the interplay between spatially and/or temporally related environmentally relevant stressors. In vitro or animal-based studies as well as epidemiological surveys have generally examined the combined action of no more than a couple of known or potentially DNA-damaging agents. Moreover, most existing research mainly focused on short-term effects of combined exposures. Hence, it is important that quantitative research addresses the issue of the possible cooperation between chronic exposure to environmental trace contaminants and exposure to EMFs, examining not only the modulation of damage acutely induced by IR but also long-term genome stability. 2010 Elsevier B.V. All rights reserved.

Combination of vascular targeting agents with thermal or radiation therapy

International Nuclear Information System (INIS)

Horsman, Michael R.; Murata, Rumi

2002-01-01

Purpose: The most likely clinical application of vascular targeting agents (VTAs) is in combination with more conventional therapies. In this study, we report on preclinical studies in which VTAs were combined with hyperthermia and/or radiation. Methods and Materials: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was treated when at 200 mm 3 in size. The VTAs were combretastatin A-4 disodium phosphate (CA4DP, 25 mg/kg), flavone acetic acid (FAA, 150 mg/kg), and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, 20 mg/kg), and were all injected i.p. Hyperthermia and radiation were locally administered to tumors of restrained, nonanesthetized mice, and response was assessed using either a tumor growth or tumor control assay. Results: Heating tumors at 41.5 degree sign C gave rise to a linear relationship between the heating time and tumor growth with a slope of 0.02. This slope was increased to 0.06, 0.09, and 0.08, respectively, by injecting the VTAs either 30 min (CA4DP), 3 h (FAA), or 6 h (DMXAA) before heating. The radiation dose (±95% confidence interval) that controls 50% of treated tumors (the TCD 50 value) was estimated to be 53 Gy (51-55 Gy) for radiation alone. This was decreased to 48 Gy (46-51 Gy), 45 Gy (41-49 Gy), and 42 Gy (39-45 Gy), respectively, by injecting CA4DP, DMXAA, or FAA 30-60 min after irradiating. These values were further decreased to around 28-33 Gy if the tumors of VTA-treated mice were also heated to 41.5 degree sign C for 1 h, starting 4 h after irradiation, and this effect was much larger than the enhancement seen with either 41.5 degree sign C or even 43 degree sign C alone. Conclusions: Our preclinical studies and those of others clearly demonstrate that VTAs can enhance tumor response to hyperthermia and/or radiation and support the concept that such combination studies should be undertaken clinically for the full potential of VTAs to be realized

Enhancing the radiation response of tumors but not early or late responding normal tissues using a vascular disrupting agent

DEFF Research Database (Denmark)

Horsman, Michael R

2017-01-01

INTRODUCTION: Vascular disrupting agents (VDAs) damage tumor vasculature and enhance tumor radiation response. In this pre-clinical study, we combined radiation with the leading VDA in clinical development, combretastatin A-4 phosphate (CA4P), and compared the effects seen in tumors and relevant...... normal tissues. MATERIAL AND METHODS: Radiation was applied locally to tissues in CDF1 mice to produce full radiation dose-response curves. CA4P (250 mg/kg) was intraperitoneally (i.p.) injected within 30 minutes after irradiating. Response of 200 mm3 foot implanted C3H mammary carcinomas was assessed......% increase in ventilation rate measured by plethysmography within 9 months). A Chi-squared test was used for statistical comparisons (significance level of p 4P. The radiation...

Biological effects of radiation in combination with other physical, chemical or biological agents. Annex L

International Nuclear Information System (INIS)

1982-01-01

This Annex considers the combined action of radiation with potentially important environmental conditions. Since there is a scarcity of systematic data on which an analysis of combined effects can be based, this Annex will be more hypothetical and will attempt to suggest definitions, to identify suitable methods of analysis, to select from a large amount of diffuse information the conditions and the data of importance for further consideration and to provide suggestions for future research. For humans in environmental circumstances the UNSCEAR Committee has been unable to document any clear case of synergistic interaction between radiation and other agents, which could lead to substantial modifications of the risk estimates for significant sections of the population.

Oxidative metabolism of monensin in rat liver microsomes and interactions with tiamulin and other chemotherapeutic agents: evidence for the involvement of cytochrome P-450 3A subfamily.

Science.gov (United States)

Nebbia, C; Ceppa, L; Dacasto, M; Carletti, M; Nachtmann, C

1999-09-01

Monensin (MON) is an ionophore antibiotic widely used in veterinary practice as a coccidiostatic or a growth promoter. The aims of this study were to characterize the P-450 isoenzyme(s) involved in the biotransformation of the ionophore and to investigate how this process may be affected by tiamulin and other chemotherapeutic agents known to produce toxic interactions with MON when administered concurrently in vivo. In liver microsomes from untreated rats (UT) or from rats pretreated, respectively, with ethanol (ETOH), beta-naphthoflavone (betaNAF), phenobarbital (PB), pregnenolone 16alpha-carbonitrile (PCN), or dexamethasone (DEX), the rate of MON O-demethylation was the following: DEX > PCN > PB > UT = ETOH > betaNAF; similar results were obtained by measuring total MON metabolism. In addition, the extent of triacetyloleandomycin-mediated P-450 complexes was greatly reduced by the prior addition of 100 microM MON. In DEX-treated microsomes, MON O-demethylation was found to fit monophasic Michaelis-Menten kinetics (K(M) = 67.6 +/- 0.01 microM; V(max) = 4.75 +/- 0.76 nmol/min/mg protein). Tiamulin markedly inhibited this activity in an apparent competitive manner, with a calculated K(i) (Dixon plot) of 8.2 microM and an IC(50) of about 25 microM. At the latter concentration, only ketoconazole or metyrapone, which can bind P-450 3A, inhibited MON O-demethylase to a greater extent than tiamulin, whereas alpha-naphthoflavone, chloramphenicol, or sulphametasine was less effective. These results suggest that P-450 3A plays an important role in the oxidative metabolism of MON and that compounds capable of binding or inhibiting this isoenzyme could be expected to give rise to toxic interactions with the ionophore.

Radiation exposure and contrast agent use related to radial versus femoral arterial access during percutaneous coronary intervention (PCI)-Results of the FERARI study.

Science.gov (United States)

Becher, Tobias; Behnes, Michael; Ünsal, Melike; Baumann, Stefan; El-Battrawy, Ibrahim; Fastner, Christian; Kuschyk, Jürgen; Papavassiliu, Theano; Hoffmann, Ursula; Mashayekhi, Kambis; Borggrefe, Martin; Akin, Ibrahim

2016-12-01

Data regarding radiation exposure related to radial versus femoral arterial access in patients undergoing percutaneous coronary intervention (PCI) remain controversial. This study aims to evaluate patients enrolled in the FERARI study regarding radiation exposure, fluoroscopy time and contrast agent use. The Femoral Closure versus Radial Compression Devices Related to Percutaneous Coronary Interventions (FERARI) study evaluated prospectively 400 patients between February 2014 and May 2015 undergoing PCI either using the radial or femoral access. In these 400 patients, baseline characteristics, procedural data such as procedural duration, fluoroscopy time, dose-area product (DAP) as well as the amount of contrast agent used were documented and analyzed. Median fluoroscopy time was not significantly different in patients undergoing radial versus femoral access (12.2 vs. 9.8min, p=0.507). Furthermore, median DAP (54.5 vs. 52.0 Gycm2, p=0.826), procedural duration (46.0 vs. 45.0min, p=0.363) and contrast agent use (185.5 vs. 199.5ml, p=0.742) were also similar in radial and femoral PCI. There was no difference regarding median fluoroscopy time, procedural duration, radiation dose or contrast agent use between radial versus femoral arterial access in PCI. Copyright © 2016 Elsevier Inc. All rights reserved.

ERC/mesothelin as a marker for chemotherapeutic response in patients with mesothelioma.

Science.gov (United States)

Tajima, Ken; Hirama, Michihiro; Shiomi, Kazu; Ishiwata, Toshiji; Yoshioka, Masataka; Iwase, Akihiko; Iwakami, Shinichiro; Yamazaki, Mariko; Toba, Michie; Tobino, Kazunori; Sugano, Koji; Ichikawa, Masako; Hagiwara, Yoshiaki; Takahashi, Kazuhisa; Hino, Okio

2008-01-01

It has been recently reported that soluble mesothelin-related protein (SMRP), serum mesothelin, and osteopontin (OPN) are considered as relevant biomarkers for the diagnosis of mesothelioma. The aim of this study was to investigate whether serum N-ERC/mesothelin, an NH3-terminal fragment of mesothelin, and plasma OPN reflect chemotherapeutic effect in patients with mesothelioma. Serum N-ERC/mesothelin and plasma osteopontin were determined with a sandwich enzyme-linked immunosorbent assay (ELISA) system. The average N-ERC ratio, determined by dividing the N-ERC levels following chemotherapy by those prior to chemotherapy, in the partial response (PR) group was significantly lower than that of the stable disease (SD)/progressive disease (PD) group. In contrast, the average OPN ratio, determined by dividing the OPN levels following chemotherapy by those prior to chemotherapy, in the PR group was not statistically different from that of the SD/PD group. N-ERC/mesothelin is considered as relevant in monitoring chemotherapeutic response in patients with mesothelioma.

WE-D-210-04: Radiation-Induced Polymerization of Ultrasound Contrast Agents in View of Non-Invasive Dosimetry in External Beam Radiation Therapy

Energy Technology Data Exchange (ETDEWEB)

Callens, M; Verboven, E; Van Den Abeele, K [Department of Physics, Wave Propagation and Signal Processing, KU Leuven KULAK, Kortrijk (Belgium); D’Agostino, E [DoseVue NV, Hasselt (Belgium); Pfeiffer, H [Department of Materials Engineering, KU Leuven, Leuven (Belgium); D’hooge, J [Department of Cardiovascular Sciences, Bio-Medical Science Group, KU Leuven, Leuven (Belgium)

2015-06-15

Purpose: Ultrasound contrast agents (UCA’s) based on gas-filled microbubbles encapsulated by an amphiphilic shell are well established as safe and effective echo-enhancers in diagnostic imaging. In view of an alternative application of UCA’s, we investigated the use of targeted microbubbles as radiation sensors for external beam radiation therapy. As radiation induces permanent changes in the microbubble’s physico-chemical properties, a robust measure of these changes can provide a direct or indirect estimate of the applied radiation dose. For instance, by analyzing the ultrasonic dispersion characteristics of microbubble distributions before and after radiation treatment, an estimate of the radiation dose at the location of the irradiated volume can be made. To increase the radiation sensitivity of microbubbles, polymerizable diacetylene molecules can be incorporated into the shell. This study focuses on characterizing the acoustic response and quantifying the chemical modifications as a function of radiation dose. Methods: Lipid/diacetylene microbubbles were irradiated with a 6 MV photon beam using dose levels in the range of 0–150 Gy. The acoustic response of the microbubbles was monitored by ultrasonic through-transmission measurements in the range of 500 kHz to 20 MHz, thereby providing the dispersion relations of the phase velocity, attenuation and nonlinear coefficient. In addition, the radiation-induced chemical modifications were quantified using UV-VIS spectroscopy. Results: UV-VIS spectroscopy measurements indicate that ionizing radiation induces the polymerization of diacetylenes incorporated in the microbubble shell. The polymer yield strongly depends on the shell composition and the radiation-dose. The acoustic response is inherently related to the visco-elastic properties of the shell and is strongly influenced by the shell composition and the physico-chemical changes in the environment. Conclusion: Diacetylene-containing microbubbles are

Labelled chemotherapeutic drugs and neurotransmitter precursors

International Nuclear Information System (INIS)

Diksic, M.

1989-01-01

The authors have synthesized several chemotherapeutic drugs and their analogs labelled with 11 C or 18 F positron emitting radionuclides. The pharmacokinetics of several of these, 1,3-bis-2-chloroethylnitroso [ 11 C] urea [ 11 C-BCNU] and sarcosinamide congenerate of BCNU [SarCNU] were studied in animals and humans. This evaluation permitted them to have a better understanding of the tissue trapping of nitrosoureas and also the opportunity to do biological modelling permitting a better schedule of chemotherapy for these drugs. They have also been working on an analog of tryptophan, α-methyl-L-tryptophan, the compound studied for the past 15 years. An introduction of 11 C-label permitted in vivo evaluation of that compound and in conjunction with biochemical measurements done with 14 C-compound estimates of the rate of the brain serotonin synthesis without any metabolic manipulation

Contrast agent choice for intravenous coronary angiography

International Nuclear Information System (INIS)

Zeman, H.D.; Siddons, D.P.

1990-01-01

The screening of the general population for coronary artery disease would be practical if a method existed for visualizing the extent of occlusion after an intravenous injection of contrast agent. Measurements performed with monochromatic synchrotron radiation X-rays and an iodine-containing contrast agent at the Stanford Synchrotron Radiation Laboratory have shown that such an intravenous angiography procedure would be possible with an adequately intense monochromatic X-ray source. Because of the size and cost of synchrotron radiation facilities it would be desirable to make the most efficient use of the intensity available, while reducing as much as possible the radiation dose experienced by the patient. By choosing contrast agents containing elements with a higher atomic number than iodine, it is possible to both improve the image quality and reduce the patient radiation dose, while using the same synchrotron radiation source. By using Si monochromator crystals with a small mosaic spread, it is possible to increase the X-ray flux available for imaging by over an order of magnitude, without any changes in the storage ring or wiggler magnet. The most critical imaging task for intravenous coronary angiography utilizing synchrotron radiation X-rays is visualizing a coronary artery through the left ventricle or aorta which also contain contrast agent. Calculations have been made of the signal to noise ratio expected for this imaging task for various contrast agents with atomic numbers between that of iodine and bismuth. The X-ray energy spectrum of the X-17 superconduction wiggler beam line at the National Synchrotron Light Source at Brookhaven National Laboratory has been used for these calculations. Both perfect Si crystals and Si crystals with a small mosaic spread are considered as monochromators. Contrast agents containing Gd or Yb seem to have about the optimal calculated signal to noise ratio. (orig./HSI)

Radiation dosimetry of iodine-123 HEAT, an alpha-1 receptor imaging agent

International Nuclear Information System (INIS)

Thomas, K.D.; Greer, D.M.; Couch, M.W.; Williams, C.M.

1987-01-01

Biologic distribution data in the rat were obtained for the alpha-1 adrenoceptor imaging agent (+/-) 2-[beta-(iodo-4-hydroxyphenyl)ethylaminomethyl]tetralone (HEAT) labeled with [ 123 I]. The major excretory routes were through the liver (67%) and the kidney (33%). Internal radiation absorbed dose estimates to nine source organs, total body, the GI tract, gonads, and red bone marrow were calculated for the human using the physical decay data for [ 123 I]. The critical organ was found to be the lower large intestine, receiving 1.1 rad per mCi of [ 123 I]HEAT administered. The total-body dose was found to be 58 mrad per mCi

Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma

International Nuclear Information System (INIS)

Lee, Jong Cheol; Lee, Won Hyeok; Min, Young Joo; Cha, Hee Jeong; Han, Myung Woul; Chang, Hyo Won; Kim, Sun-A; Choi, Seung-Ho; Kim, Seong Who; Kim, Sang Yoon

2014-01-01

Purpose: There are limited therapeutic options for patients with recurrent head and neck cancer after radiation therapy failure. To assess the use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as a salvage chemotherapeutic agent for recurrent cancer after radiation failure, we investigated the effect of clinically relevant cumulative irradiation on TRAIL-induced apoptosis. Methods and Materials: Using a previously established HN3 cell line from a laryngeal carcinoma patient, we generated a chronically irradiated HN3R isogenic cell line. Viability and apoptosis in HN3 and HN3R cells treated with TRAIL were analyzed with MTS and PI/annexin V-FITC assays. Western blotting and flow cytometry were used to determine the underlying mechanism of TRAIL resistance. DR4 expression was semiquantitatively scored in a tissue microarray with 107 laryngeal cancer specimens. Methylation-specific polymerase chain reaction and bisulfite sequencing for DR4 were performed for genomic DNA isolated from each cell line. Results: HN3R cells were more resistant than HN3 cells to TRAIL-induced apoptosis because of significantly reduced levels of the DR4 receptor. The DR4 staining score in 37 salvage surgical specimens after radiation failure was lower in 70 surgical specimens without radiation treatment (3.03 ± 2.75 vs 5.46 ± 3.30, respectively; P<.001). HN3R cells had a methylated DR4 CpG island that was partially demethylated by the DNA demethylating agent 5-aza-2′-deoxycytidine. Conclusion: Epigenetic silencing of the TRAIL receptor by hypermethylation of a DR4 CpG island might be an underlying mechanism for TRAIL resistance in recurrent laryngeal carcinoma treated with radiation

In vitro study of cytotoxicity by U.V. radiation and differential sensitivity in combination with alkylating agents on established cell systems

International Nuclear Information System (INIS)

Ramudu, K.

1991-01-01

The effect of U.V. radiation or alkylating agents, such as actinomycin-D, cycloheximide and mitomycin-C (MMC), was studied on CHO, BHK and HeLa cells. U.V. radiation caused DNA ssb and dsb and were prevented by cycloheximide and actinomycin-D. MMC is known to be cytotoxic in CHO/BHK cells by forming free radical generation. MMC in combination with U.V. radiation enhanced DNA ssb ampersand dsb in these cell types. However, HeLa cells were insensitive to U.V. radiation. This insensitivity to U.V. radiation could be ascribed to the presence of glutathione transferase which is absent in CHO/BHK cell line

Contrast agent choice for intravenous coronary angiography

International Nuclear Information System (INIS)

Zeman, H.D.; Siddons, D.P.

1989-01-01

The screening of the general population for coronary artery disease would be practical if a method existed for visualizing the extent of occlusion after an intravenous injection of contrast agent. Measurements performed with monochromatic synchrotron radiation x-rays and an iodine containing contrast agent at the Stanford Synchrotron Radiation Laboratory have shown that such an intravenous angiography procedure would be possible with an adequately intense monochromatic x-ray source. Because of the size and cost of synchrotron radiation facilities it would be desirable to make the most efficient use of the intensity available, while reducing as much as possible the radiation dose experienced by the patient. By choosing contrast agents containing elements with a higher atomic number than iodine, it is possible to both improve the image quality and reduce the patient radiation dose, while using the same synchrotron source. By using Si monochromator crystals with a small mosaic spread, it is possible to increase the x-ray flux available for imaging by over an order of magnitude, without any changes in the storage ring or wiggler magnet. The most critical imaging task for intravenous coronary angiography utilizing synchrotron radiation x-rays is visualizing a coronary artery through the left ventricle or aorta which also contains a contrast agent. Calculations have been made of the signal to noise ratio expected for this imaging task for various contrast agents with atomic numbers between that of iodine and bismuth

Targeting inflammatory pathways by dietary agents for prevention and treatment of cancer

International Nuclear Information System (INIS)

Aggarwal, Bharat B.

2016-01-01

Chronic infections, obesity, alcohol, tobacco, radiation, environmental pollutants and high-calorie diet have been recognized as major risk factors for the most common types of cancer. All these risk factors are linked to cancer through inflammation. While acute inflammation that persists for short-term mediates host defense against infections, chronic inflammation that lasts for long-term can predispose the host to various chronic illnesses, including cancer. Linkage between cancer and inflammation is indicated by numerous lines of evidence; first, transcription factors NF-kB and STAT3, two major pathways for inflammation, are activated by most cancer risk factors; second, an inflammatory condition precedes most cancers; third, NFkB and STAT3 are constitutively active in most cancers; fourth, hypoxia and acidic conditions found in solid tumors activate NF-kB; fifth, chemotherapeutic agents and γ-irradiation activate NF-kB and lead to chemoresistance and radioresistance; sixth, most gene products linked to inflammation, survival, proliferation, invasion, angiogenesis and metastasis are regulated by NF-kB and STAT3; seventh, suppression of NF-kB and STAT3 inhibits the proliferation and invasion of tumors; and eighth, most chemopreventive agents mediate their effects through inhibition of NF-kB and STAT3 activation pathways. Thus, the suppression of these proinflammatory pathways may provide opportunities for both prevention and treatment of cancer. We will discuss the potential of nutraceuticals derived from spices and from traditional Indian medicine in suppression of inflammatory pathways and their role inprevention and therapy of cancer. (author)

Sensitivity to ionizing radiation and chemotherapeutic agents in gemcitabine-resistant human tumor cell lines

NARCIS (Netherlands)

van Bree, Chris; Castro Kreder, Natasja; Loves, Willem J. P.; Franken, Nicolaas A. P.; Peters, Godefridus J.; Haveman, Jaap

2002-01-01

Purpose: To determine cross-resistance to anti-tumor treatments in 2',2'difluorodeoxycytidine (dFdC, gemcitabine)-resistant human tumor cells. Methods and Materials: Human lung carcinoma cells SW-1573 (SWp) were made resistant to dFdC (SWg). Sensitivity to cisplatin (cDDP), paclitaxel,

A dual energy CT study on vascular effects of gold nanoparticles in radiation therapy

Science.gov (United States)

Ashton, Jeffrey R.; Hoye, Jocelyn; Deland, Katherine; Whitley, Melodi; Qi, Yi; Moding, Everett; Kirsch, David G.; West, Jennifer; Badea, Cristian T.

2016-03-01

Gold nanoparticles (AuNPs) are emerging as promising agents for both cancer therapy and CT imaging. AuNPs are delivered to tumors via the enhanced permeability and retention effect and they preferentially accumulate in close proximity to the tumor blood vessels. AuNPs produce low-energy, short-range photoelectrons during external beam radiation therapy (RT), boosting dose. This work is focused on understanding how tumor vascular permeability is influenced by AuNP-augmented radiation therapy (RT), and how this knowledge can potentially improve the delivery of additional nanoparticle-based chemotherapeutics. We use dual energy (DE) CT to detect accumulation of AuNPs and increased vascular permeability to liposomal iodine (i.e. a surrogate for chemotherapeutics with liposome encapsulation) following RT. We used sarcoma tumors generated in LSL-KrasG12D; p53FL/FL conditional mutant mice. A total of n=37 mice were used in this study. The treated mice were injected with 20 mg AuNP (0.1 ml/25 g mouse) 24 hours before delivery of 5 Gy RT (n=5), 10 Gy RT (n=3) or 20 Gy RT (n=6). The control mice received no AuNP injection and either no RT (n=6), 5 Gy RT (n=3), 10 Gy RT (n=3), 20 Gy RT (n=11). Twenty four hours post-RT, the mice were injected with liposomal iodine (0.3 ml/25 mouse) and imaged with DE-CT three days later. The results suggest that independent of any AuNP usage, RT levels of 10 Gy and 20 Gy increase the permeability of tumor vasculature to liposomal iodine and that the increase in permeability is dose-dependent. We found that the effect of RT on vasculature may already be at its maximum response i.e. saturated at 20 Gy, and therefore the addition of AuNPs had almost no added benefit. Similarly, at 5 Gy RT, our data suggests that there was no effect of AuNP augmentation on tumor vascular permeability. However, by using AuNPs with 10 Gy RT, we observed an increase in the vascular permeability, however this is not yet statistically significant due to the small

New therapeutic agent for radiation synovectomy - preparation of 166Ho-EDTMP-HA particle

International Nuclear Information System (INIS)

Bai, H.; Jin, X.; Du, J.; Wang, F.; Chen, D.; Fan, H.; Cheng, Z.; Zhang, J.

1997-01-01

In order to prepare new therapeutical agent for radiation synovectomy, Hydroxyapatite (HA) was labelled with 166 Ho by EDTMP that had high affinity to HA particles. Radiolabelling of HA particles was divided into two steps, 166 Ho-EDTMP was prepared first; then mixed with HA particles completely and vibrated for 15 minutes on the micromixer at room temperature, washed 3 times with deionized water. Radiolabelling particle was separated from free 166 Ho via centrifugation to determine its radiolabelling efficiency. 166 Ho-EDTMP-HA and 166 Ho-EDTMP were injected into knee joint of normal rabbits respectively, every group was killed at different time postinjection, took out major organ and collected urine and blood, then weighted and determined their radio counts. HA particles, as a natural component of bone was known to have good compatibility with soft tissue and biodegrade into calcium and phosphate in vivo. It was readily prepared from common chemical and formed into particles of desired size range in a controlled process, it had high stability in vitro and vivo. Radiolabelling of HA particle with 166 Ho by EDTMP was simple to perform and provides an excellent labelling yield that was more than 95% under the optimal labelling condition. The optimal labelling condition at room temperature was pH 6.0-8.0 and vibration time 15 minutes. The absorbed capacity of HA particle was 5 mg Ho/g HA particle and size of radiolabelling particle was at range of 2-5,μm that is suitable for therapy of radiation synovectomy. 166 Ho-EDTMP-HA particle demonstrated high in vitro stability in either normal saline or 1% BSA solution, but instability under extremely acidic condition (pH 1-2). The control studies performed with 166 Ho-EDTMP not bound to HA particle provided information on the distribution of radioactivity that would occur upon leakage of the radiochemical compound from joint. Its short half-life, its extremely low leakage from the joint and its even distribution throughout

Breast cancer chemopreventive and chemotherapeutic effects of Camellia Sinensis (green tea): an updated review.

Science.gov (United States)

Rafieian-Kopaei, Mahmoud; Movahedi, Mino

2017-02-01

Camellia sinensis belongs to the plant family of Theaceae, native to East Asia, the Indian Subcontinent and Southeast Asia, but naturalized in many parts of the world. The aim of this study was to overview its anti-breast cancer chemopreventive and chemotherapeutic effects. This review article is aimed to overview breast cancer chemopreventive and chemotherapeutic effects of Camellia sinensis (green tea). This review article was carried out by searching studies in PubMed, Medline, Web of Science, and IranMedex databases. The initial search strategy identified around 108 references. In this study, 68 studies were accepted for further screening, and met all our inclusion criteria [in English, full text, chemopreventive and chemotherapeutic effects of Camellia sinensis and dated mainly from the year 1999 to 2016. The search terms were Camellia sinensis, chemopreventive, chemotherapeutic properties, pharmacological effects. The result of this study suggested that the catechin available in Camellia sinensis has properties which can prevent and treat breast cancer. It has also been shown to inhibit proliferation of breast cancer cells and to block carcinogenesis. It was found that increased Camellia sinensis consumption may lower the risk of breast cancer. Camellia sinensis intake was shown to reduce the risk of breast cancer incidence. In addition, potential breast cancer chemopreventive effect of Camellia sinensis both in vivo and in vitro was highly confirmed. However, the evidence of low effect and no effect was observed. More clinical trial studies are needed to prove its anti-breast cancer activity decisively. Camellia sinensis is broadly utilized as a part of customary medication since antiquated time because of its cost adequacy, and fewer reaction properties. The studies demonstrated anti-breast cancer activity of Camellia sinensis and its component by adjusting cell signaling pathways such as angiogenesis, apoptosis, and transcription factor. Furthermore

Lethal and mutagenic effects of radiation and alkylating agents on two strains of mouse L5178Y cells

International Nuclear Information System (INIS)

Evans, H.H.; Horng, M.; Beer, J.Z.

1986-01-01

The two closely related strains of L5178Y (LY) mouse lymphoma cells, LY-R and LY-S, have been shown to differ in their sensitivity to UV and ionizing radiation. In the present work, the lethal and mutagenic effects of ethyl methanesulfonate (EMS), methyl nitrosourea (MNU) and UV radiation (254 nm) were compared in the two strains. Mutability at the Na + /K + -ATPase locus as well as the HGPRT locus was determined. The authors found strain LY-S to be more resistant than strain LY-R to the lethal effects of UV radiation. In contrast, strain LY-S was more sensitive to the cytotoxic effects of the two alkylating agents. In spite of these differences in sensitivity, the authors found strain LY-S to be less mutable than strain LY-R by all 3 agents at the HGPRT locus. At the Na + /K + -ATPase locus, strain LY-S was also less mutable than strain LY-R by equal concentrations of EMS and UV radiation and by equitoxic concentrations of MNU. However, the difference between the strains was much more pronounced at the HGPRT locus than at the Na + /K + -ATPase locus. The authors have suggested that the interaction of unrepaired lesions in strain LY-S tends to cause an excess of deletions and multilocus effects, which in turn result in a locus-dependent decrease in the recovery of viable LY-S mutant cells. (Auth.)

Comparison of alkylating agent and radiation carcinogenesis: some aspects of the possible involvement of effects on DNA

International Nuclear Information System (INIS)

Lawley, P.D.

1976-01-01

A series of alkylating agents was classified in terms of increasing relative ability to react at O-atom sites in DNA, MMS 6 -alkylguanines are directly miscoding bases. This series of agents was also used in a study of comparative carcinogenicity with respect to induction of thymic lymphoma in mice, a system in which x-irradiation yields tumors. A positive correlation between ability of agents to alkylate O-6 of guanine in DNA of thymus and carcinogenic potency was found. Although MMS was not active in this system, it was noted that it can induce tumors in other systems. The relationship between repair of alkylation and radiation induced damage in DNA was briefly discussed. The methylating agents induce single-strand breaks in DNA, and the principal repair system appears to fall into the category of short repair as denoted by Regan and Setlow (1974). These single-strand breaks may result from spontaneous hydrolytic depurinations of 3- and 7-methylpurines, or from enzymatic depurinations, e.g., of 3-alkyladenine and O 6 -alkylguanine. Aralkylating agents, which are also carcinogens, can evoke an alternative repair response of the uvr type

Long-term exposure to estrogen enhances chemotherapeutic efficacy potentially through epigenetic mechanism in human breast cancer cells.

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Yu-Wei Chang

Full Text Available Chemotherapy is the most common clinical option for treatment of breast cancer. However, the efficacy of chemotherapy depends on the age of breast cancer patients. Breast tissues are estrogen responsive and the levels of ovarian estrogen vary among the breast cancer patients primarily between pre- and post-menopausal age. Whether this age-dependent variation in estrogen levels influences the chemotherapeutic efficacy in breast cancer patients is not known. Therefore, the objective of this study was to evaluate the effects of natural estrogen 17 beta-estradiol (E2 on the efficacy of chemotherapeutic drugs in breast cancer cells. Estrogen responsive MCF-7 and T47D breast cancer cells were long-term exposed to 100 pg/ml estrogen, and using these cells the efficacy of chemotherapeutic drugs doxorubicin and cisplatin were determined. The result of cell viability and cell cycle analysis revealed increased sensitivities of doxorubicin and cisplatin in estrogen-exposed MCF-7 and T47D cells as compared to their respective control cells. Gene expression analysis of cell cycle, anti-apoptosis, DNA repair, and drug transporter genes further confirmed the increased efficacy of chemotherapeutic drugs in estrogen-exposed cells at molecular level. To further understand the role of epigenetic mechanism in enhanced chemotherapeutic efficacy by estrogen, cells were pre-treated with epigenetic drugs, 5-aza-2-deoxycytidine and Trichostatin A prior to doxorubicin and cisplatin treatments. The 5-aza-2 deoxycytidine pre-treatment significantly decreased the estrogen-induced efficacy of doxorubicin and cisplatin, suggesting the role of estrogen-induced hypermethylation in enhanced sensitivity of these drugs in estrogen-exposed cells. In summary, the results of this study revealed that sensitivity to chemotherapy depends on the levels of estrogen in breast cancer cells. Findings of this study will have clinical implications in selecting the chemotherapy strategies for

In vitro testing of chemotherapeutic drug combinations in acute myelocytic leukaemia using the fluorometric microculture cytotoxicity assay (FMCA).

Science.gov (United States)

Larsson, R; Fridborg, H; Kristensen, J; Sundström, C; Nygren, P

1993-05-01

The fluorometric microculture cytotoxicity assay (FMCA) was employed for analysing the effect of different chemotherapeutic drug combinations and their single constituents in 44 cases of acute myelocytic leukaemia (AML). A large heterogeneity with respect to cell kill was observed for all combinations tested, the interactions ranging from antagonistic to synergistic in terms of the multiplicative concept for drug interactions. However, an 'additive' model provided a significantly better fit of the data compared to the effect of the most active single agent of the combination (Dmax) for several common antileukaemic drug combinations. When the two interaction models were related to treatment outcome 38% of the non-responders showed preference for the additive model whereas the corresponding figure for responders was 80%. Overall, in 248 of 290 (85%) tests performed with drug combinations, there was an agreement between the effect of the combination and that of the most active single component. Direct comparison of Dmax and the combination for correlation with clinical outcome demonstrated only minor differences in the ability to predict drug resistance. The results show that FMCA appear to report drug interactions in samples from patients with AML in accordance with clinical experience. Furthermore, testing single agents as a substitute for drug combinations may be adequate for detection of clinical drug resistance to combination therapy in AML.

In vitro therapy study combined with low doses of radiation (Rn-222) and chemotherapy (taxol)

International Nuclear Information System (INIS)

Soto, J.; Sainz, C.; Cos, S.; Gonzalez-Lamuno, D.

2004-01-01

A study was carried out to test the possibility that breast cancer cells show increased sensitivity to the chemotherapeutic agent taxol when they have been treated with low radiation doses from the gas radon. To this end, the cells were cultivated in a medium containing dissolved radon and then in a second medium containing a concentration of taxol. After the culture phase the surviving cells were counted and their viability was assessed. The results obtained indicate that the cells treated with low doses of radon exhibit increased sensitivity when treated with certain concentrations of taxol; in particular a lower survival rate and lower viability were observed in cells treated with radon and 50 nM of taxol in cells treated with the same concentration of taxol alone. These effects seem to result from the influence of the radon on the expression of apoptosis -related genes, which is complementary to the action of taxol on bcl-x related genes. (author)

SERIES: Genomic instability in cancer Balancing repair and tolerance of DNA damage caused by alkylating agents

OpenAIRE

Fu, Dragony; Calvo, Jennifer A.; Samson, Leona D

2012-01-01

Alkylating agents comprise a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER), and mismatch repair (MMR) respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial fo...

Studies of antibiotic resistant mutants of Bacteroides fragilis obtained by Cs-137 ionizing radiation

International Nuclear Information System (INIS)

Azghani, A.O.

1986-01-01

The genus Bacteroides is an obligate anaerobic bacillus normally found in the upper respiratory tract, the colon, and the genitourinary system. The project reported here was undertaken because of the high frequency of hospital infections attributed to B. fragilis, and the increased resistance of the bacteria to commonly used antibiotics. Cs-137 gamma irradiation was used to induce antibiotic resistant mutants in B. fragilis in the presence of Escherichia coli B/r membrane fragments, employed as reducing agent. Based on a dose-survival curve, an effective radiation dose of 1.54 x 10 4 R (3.99 C/Kg) was used to induce mutations to rifampicin and tetracycline resistance in the test organism. The antibiotic resistant mutants of B. fragilis were utilized to reveal the mechanism by which this group of organisms becomes resistant to select chemotherapeutic agents. Studies on tetracycline resistant mutants of B. fragilis isolated after irradiation, suggest that the resistance to this antibiotic is associated with the outer membrane permeability. The difference in inhibitory action of rifampicin on RNA polymerase activity, from rifampicin sensitive and resistant strains of B. fragilis, reveals that this enzyme is a possible suitable target for inhibition of bacterial growth in anaerobes by rifampicin

Sodium butyrate affects the cytotoxic and mutagenic response of V79 Chinese hamster cells to the genotoxic agents, daunorubicin and U.V. radiation

International Nuclear Information System (INIS)

Pani, B.; Babudri, N.; Giancotti, V.; Russo, E.

1984-01-01

It has been suggested that conditions which lead to modifications in the chromatin structure could be responsible for an increased accessibility of DNA to genotoxic agents in eukaryotic cells. With this in mind, the cytotoxic and mutagenic activity of the anthracycline antibiotic, daunorubicin, and of UV radiation was assayed on V79 Chinese hamster cells pretreated or not with 5 mM sodium butyrate, an agent known to induce modifications in the chromatin structure: this treatment in fact proved to induce the hyperacetylation of the core histones, and moreover to enhance the cytotoxic response of the cells to both daunorubicin and UV radiation and the mutagenic response to daunorubicin. (orig.)

Downregulation of hPMC2 imparts chemotherapeutic sensitivity to alkylating agents in breast cancer cells.

Science.gov (United States)

Krishnamurthy, Nirmala; Liu, Lili; Xiong, Xiahui; Zhang, Junran; Montano, Monica M

2015-01-01

Triple negative breast cancer cell lines have been reported to be resistant to the cyotoxic effects of temozolomide (TMZ). We have shown previously that a novel protein, human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2) has a role in the repair of estrogen-induced abasic sites. Our present study provides evidence that downregulation of hPMC2 in MDA-MB-231 and MDA-MB-468 breast cancer cells treated with temozolomide (TMZ) decreases cell survival. This increased sensitivity to TMZ is associated with an increase in number of apurinic/apyrimidinic (AP) sites in the DNA. We also show that treatment with another alkylating agent, BCNU, results in an increase in AP sites and decrease in cell survival. Quantification of western blot analyses and immunofluorescence experiments reveal that treatment of hPMC2 downregulated cells with TMZ results in an increase in γ-H2AX levels, suggesting an increase in double strand DNA breaks. The enhancement of DNA double strand breaks in TMZ treated cells upon downregulation of hPCM2 is also revealed by the comet assay. Overall, we provide evidence that downregulation of hPMC2 in breast cancer cells increases cytotoxicity of alkylating agents, representing a novel mechanism of treatment for breast cancer. Our data thus has important clinical implications in the management of breast cancer and brings forth potentially new therapeutic strategies.

Peptide carrier-mediated non-covalent delivery of unmodified cisplatin, methotrexate and other agents via intravenous route to the brain.

Directory of Open Access Journals (Sweden)

Gobinda Sarkar

Full Text Available BACKGROUND: Rapid pre-clinical evaluation of chemotherapeutic agents against brain cancers and other neurological disorders remains largely unattained due to the presence of the blood-brain barrier (BBB, which limits transport of most therapeutic compounds to the brain. A synthetic peptide carrier, K16ApoE, was previously developed that enabled transport of target proteins to the brain by mimicking a ligand-receptor system. The peptide carrier was found to generate transient BBB permeability, which was utilized for non-covalent delivery of cisplatin, methotrexate and other compounds to the brain. APPROACH: Brain delivery of the chemotherapeutics and other agents was achieved either by injecting the carrier peptide and the drugs separately or as a mixture, to the femoral vein. A modification of the method comprised injection of K16ApoE pre-mixed with cetuximab, followed by injection of a 'small-molecule' drug. PRINCIPAL FINDINGS: Seven-of-seven different small molecules were successfully delivered to the brain via K16ApoE. Depending on the method, brain uptake with K16ApoE was 0.72-1.1% for cisplatin and 0.58-0.92% for methotrexate (34-50-fold and 54-92 fold greater for cisplatin and methotrexate, respectively, with K16ApoE than without. Visually intense brain-uptake of Evans Blue, Light Green SF and Crocein scarlet was also achieved. Direct intracranial injection of EB show locally restricted distribution of the dye in the brain, whereas K16ApoE-mediated intravenous injection of EB resulted in the distribution of the dye throughout the brain. Experiments with insulin suggest that ligand-receptor signaling intrinsic to the BBB provides a natural means for passive transport of some molecules across the BBB. SIGNIFICANCE: The results suggest that the carrier peptide can non-covalently transport various chemotherapeutic agents to the brain. Thus, the method offers an avenue for pre-clinical evaluation of various small and large therapeutic molecules

Mutagenic interactions between near-ultraviolet (365 nm) radiation and alkylating agents in Escherichia coli

International Nuclear Information System (INIS)

Moraes, E.C. de; Tyrell, R.M.

1981-01-01

The mutagenic interaction between near-ultrviolet (365 nm) radiation and the alkylting agents ehtyl methanesulponate (EMS) and methyl methanesulphonate (MMS) was studied in a repair-component and an excision-deficient stram of Escherichia coli. Near-UV raditation modified the metabolic response of of exposure to these chemicals and either reduced or increased their mutagenic efficiency. Based on these results, an experimental model was formulated to explain the mutagenic interactions that occur between near-UV and various agents that induce prototrophic reverants cia error-prone repair of DNA. According to this model, low doses of near-UV provoke conditions for mutation frequency decline (MFI) and lead to a mutagenic antagonism. With increasing near-Uv doses, damage to constitutive error-free repairs system increases, favouring the error-prone system and inhibiting the MFD. Under these conditions there will be a progressive decrease in antagonism until at high doses an enhancement of mutation frequency (positive interaction) will occur. (orig.)

Comparison of radiation dosimetry for several potential myocardial imaging agents

International Nuclear Information System (INIS)

Watson, E.E.; Stabin, M.G; Goodman, M.M.; Knapp, F.F. Jr.; Srivastava, P.C.

1986-01-01

Although myocardial imaging is currently dominated by Tl-201, several alternative agents with improved physiologic or radionuclidic properties have been proposed. Based on human and animal studies in the literature, the metabolism of several of these compounds was studied for the purpose of generating radiation dose estimates. Dose estimates are listed for several I-123-labeled free fatty acids, an I-123-labeled phosphonium compound, Rb-82, Cu-64, F-18 FDG (all compounds which are taken up by the normal myocardium), and for Tc-99m pyrophosphate (PYP) (which localizes in myocardial infarcts). Dose estimates could not be generated for C-11 palmitate, but his compound was included in a comparison of myocardial retention times. For the I-123-labeled compounds, I-124 was included as a contaminant in generating the dose estimates. Radiation doses were lowest for Rb-82 (gonads 0.3-0.4 Gy/MBq, kidneys 8.6 Gy/MBq). Doses for the I-123-labeled fatty acids were similar to one another, with IPPA being the lowest (gonads 15 Gy/MBq, heart wall 18 Gy/MBq). Doses for Tc-99m PYP were also low (gonads 4-7 Gy/MBq, heart wall 4 Gy/MBq, skeleton 15 Gy/MBq). The desirability of these compounds is discussed briefly, considering half-life, imaging mode and energy, and dosimetry, including a comparison of the effective whole body dose equivalents. 37 references, 11 tables

Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers.

Science.gov (United States)

Dahan, Arik; Wolk, Omri; Yang, Peihua; Mittal, Sachin; Wu, Zhiqian; Landowski, Christopher P; Amidon, Gordon L

2014-12-01

The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r(2) = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r(2) = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI₅₀ = 261 μM) compared to that in SK-MEL-5 cells (GI₅₀ = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.

Prediction of chemotherapeutic response in bladder cancer using K-means clustering of dynamic contrast-enhanced (DCE)-MRI pharmacokinetic parameters.

Science.gov (United States)

Nguyen, Huyen T; Jia, Guang; Shah, Zarine K; Pohar, Kamal; Mortazavi, Amir; Zynger, Debra L; Wei, Lai; Yang, Xiangyu; Clark, Daniel; Knopp, Michael V

2015-05-01

To apply k-means clustering of two pharmacokinetic parameters derived from 3T dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the chemotherapeutic response in bladder cancer at the mid-cycle timepoint. With the predetermined number of three clusters, k-means clustering was performed on nondimensionalized Amp and kep estimates of each bladder tumor. Three cluster volume fractions (VFs) were calculated for each tumor at baseline and mid-cycle. The changes of three cluster VFs from baseline to mid-cycle were correlated with the tumor's chemotherapeutic response. Receiver-operating-characteristics curve analysis was used to evaluate the performance of each cluster VF change as a biomarker of chemotherapeutic response in bladder cancer. The k-means clustering partitioned each bladder tumor into cluster 1 (low kep and low Amp), cluster 2 (low kep and high Amp), cluster 3 (high kep and low Amp). The changes of all three cluster VFs were found to be associated with bladder tumor response to chemotherapy. The VF change of cluster 2 presented with the highest area-under-the-curve value (0.96) and the highest sensitivity/specificity/accuracy (96%/100%/97%) with a selected cutoff value. The k-means clustering of the two DCE-MRI pharmacokinetic parameters can characterize the complex microcirculatory changes within a bladder tumor to enable early prediction of the tumor's chemotherapeutic response. © 2014 Wiley Periodicals, Inc.

Effect of ionizing radiation on mechanical and thermal properties of low-density polyethylene containing pro-degradant agents

International Nuclear Information System (INIS)

Bardi, Marcelo A.G.; Kodama, Yasko; Machado, Luci D.B.; Giovedi, Claudia; Rosa, Derval S.

2009-01-01

The wide use of plastics on packages of short-lifetime products has presented harmful consequences for the environment due to their low degradation rate. By this way, improved results to the bio-assimilation of polyolefins have been achieved by the incorporation of pro-oxidant components. The aim of this work is to evaluate the mechanical and thermal behavior of low-density polyethylene (LDPE) modified by those agents and submitted to ionizing radiation by gamma rays. LDPE was modified using a masterbatch containing calcium stearate (CaSt), or magnesium stearate (MgSt) or Clariant R commercial metallic complex. The final amount of stearate in modified LDPE was 0.2%. The films were obtained by compression molding. Samples were gamma irradiated at absorbed doses of 15 kGy and 100 kGy. Differential scanning calorimetry (DSC) and thermogravimetry (TG) were performed on samples, as well as mechanical analysis by universal testing machine. Thermal properties of samples presenting pro-degradant agents were affected by the ionizing radiation in the dose range studied, and some of the mechanical properties were clearly modified by reducing their values of tensile strength at break and elongation at break. (author)

Effect of ionizing radiation on mechanical and thermal properties of low-density polyethylene containing pro-degradant agents

Energy Technology Data Exchange (ETDEWEB)

Bardi, Marcelo A.G.; Kodama, Yasko; Machado, Luci D.B., E-mail: magbardi@ipen.b, E-mail: ykodama@ipen.b, E-mail: lmachado@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Giovedi, Claudia, E-mail: giovedi@ctmsp.mar.mil.b [Centro Tecnologico da Marinha em Sao Paulo (CTMSP), Sao Paulo, SP (Brazil); Rosa, Derval S., E-mail: derval.rosa@ufabc.edu.b [Universidade Federal do ABC (UFABC), Santo Andre, SP (Brazil)

2009-07-01

The wide use of plastics on packages of short-lifetime products has presented harmful consequences for the environment due to their low degradation rate. By this way, improved results to the bio-assimilation of polyolefins have been achieved by the incorporation of pro-oxidant components. The aim of this work is to evaluate the mechanical and thermal behavior of low-density polyethylene (LDPE) modified by those agents and submitted to ionizing radiation by gamma rays. LDPE was modified using a masterbatch containing calcium stearate (CaSt), or magnesium stearate (MgSt) or Clariant{sup R} commercial metallic complex. The final amount of stearate in modified LDPE was 0.2%. The films were obtained by compression molding. Samples were gamma irradiated at absorbed doses of 15 kGy and 100 kGy. Differential scanning calorimetry (DSC) and thermogravimetry (TG) were performed on samples, as well as mechanical analysis by universal testing machine. Thermal properties of samples presenting pro-degradant agents were affected by the ionizing radiation in the dose range studied, and some of the mechanical properties were clearly modified by reducing their values of tensile strength at break and elongation at break. (author)

Systemic use of tumor necrosis factor alpha as an anticancer agent

Science.gov (United States)

Roberts, Nicholas J.; Zhou, Shibin; Diaz, Luis A.; Holdhoff, Matthias

2011-01-01

Tumor necrosis factor-α (TNF-α) has been discussed as a potential anticancer agent for many years, however initial enthusiasm about its clinical use as a systemic agent was curbed due to significant toxicities and lack of efficacy. Combination of TNF-α with chemotherapy in the setting of hyperthermic isolated limb perfusion (ILP), has provided new insights into a potential therapeutic role of this agent. The therapeutic benefit from TNF-α in ILP is thought to be not only due to its direct anti-proliferative effect, but also due to its ability to increase penetration of the chemotherapeutic agents into the tumor tissue. New concepts for the use of TNF-α as a facilitator rather than as a direct actor are currently being explored with the goal to exploit the ability of this agent to increase drug delivery and to simultaneously reduce systemic toxicity. This review article provides a comprehensive overview on the published previous experience with systemic TNF-α. Data from 18 phase I and 10 phase II single agent as well as 18 combination therapy studies illustrate previously used treatment and dose schedules, response data as well as the most prominently observed adverse effects. Also discussed, based on recent preclinical data, is a potential future role of systemic TNF-α in combination with liposomal chemotherapy to facilitate increased drug uptake into tumors. PMID:22036896

Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKK? inhibition

OpenAIRE

Tse, Anfernee Kai-Wing; Chen, Ying-Jie; Fu, Xiu-Qiong; Su, Tao; Li, Ting; Guo, Hui; Zhu, Pei-Li; Kwan, Hiu-Yee; Cheng, Brian Chi-Yan; Cao, Hui-Hui; Lee, Sally Kin-Wah; Fong, Wang-Fun; Yu, Zhi-Ling

2017-01-01

Nitrosourea represents one of the most active classes of chemotherapeutic alkylating agents for metastatic melanoma. Treatment with nitrosoureas caused severe systemic side effects which hamper its clinical use. Here, we provide pharmacological evidence that reactive oxygen species (ROS) induction and IKKβ inhibition cooperatively enhance nitrosourea-induced cytotoxicity in melanoma cells. We identified SC-514 as a ROS-inducing IKKβ inhibitor which enhanced the function of nitrosoureas. Eleva...

Reactivating p53 and Inducing Tumor Apoptosis (RITA) Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin.

Science.gov (United States)

Wiegering, Armin; Matthes, Niels; Mühling, Bettina; Koospal, Monika; Quenzer, Anne; Peter, Stephanie; Germer, Christoph-Thomas; Linnebacher, Michael; Otto, Christoph

2017-04-01

oxaliplatin to enhance the antiproliferative response to both chemotherapeutic agents. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Carboplatin enhances the production and persistence of radiation-induced DNA single-strand breaks

International Nuclear Information System (INIS)

Yang, L.; Douple, E.B.; O'Hara, J.A.; Wang, H.J.

1995-01-01

Fluorometric analysis of DNA unwinding and alkaline elution were used to investigate the production and persistence of DNA single-strand breaks (SSBs) in Chinese hamster V79 and xrs-5 cells treated with the chemotherapeutic agent carboplatin in combination with radiation. Carboplatin was administered to cells before irradiation in hypoxic conditions, or the drug was added immediately after irradiation during the postirradiation recovery period in air. The results of DNA unwinding studies suggest that carboplatin enhances the production of radiation-induced SSBs in hypoxic V79 cells and xrs-5 cells by a factor of 1.86 and 1.83, respectively, when combined with radiation compared to the SSBs produced by irradiation alone. Carboplatin alone did not produce a measureable number of SSBs. Alkaline elution profiles also indicated that the rate of elution of SSBs was higher in cells treated with the carboplatin is present after irradiation and during the postirradiation recovery period, the rejoining of radiation-induced SSBs by a factor of 1.46 in V79 cells with 20 Gy irradiation and by a factor of 2.02 in xrs-5 cells with 20 Gy irradiation. When carboplatin is present after irradiation and during the postirradiation recovery period, the rejoining of radiation-induced SSBs is inhibited during this postirradiation incubation period (radiopotentiation) with a relative inhibition factor at 1 h postirradiation of 1.25 in V79 cells and 1.15 in xrs-5 cells. An increased production and persistence of SSBs resulting from the interaction of carboplatin with radiation may be an important step in the mechanism responsible for the potentiated cell killing previously from studies in animal tumors and in cultured cells. 31 refs., 7 figs

Frequency and spectrum of chlorophyll-deficient mutations in rice after treatment with radiation and alkylating agents

International Nuclear Information System (INIS)

Bhan, A.K.; Kaul, M.L.H.

1976-01-01

Three varieties of rice were treated with gamma rays and two alkylating agents EMS and DES, separately and in combinations, with a view to finding out the frequency and spectrum of chlorophyll mutations in relation to the genotype and the nature of the mutagen. Chlorophyll mutation frequency was enhanced with increasing dose but dropped at very high doses (doses that induced over 90% seeding lethality in M 1 ). The fall was attributed to either the increased mutated sector and diplontic selection after exposure to very high doses or relatively high resistance of some of the seeds. Among chlorophyll mutants in M 2 induced by radiations as well as alkylating agents, the albina type formed the majority class. EMS induced a significantly higher proportion of albinas than did gamma rays

Integrated effect of gamma radiation and biocontrol agent on quality parameters of apple fruit: An innovative commercial preservation method

International Nuclear Information System (INIS)

Ahari Mostafavi, Hossein; Mahyar Mirmajlessi, Seyed; Fathollahi, Hadi; Shahbazi, Samira; Mohammad Mirjalili, Seyed

2013-01-01

Effects of gamma irradiation and biocontrol agent (Pseudomonas fluorescens) on the physico-chemical parameters (including moisture, total soluble solids, antioxidant activity, phenolic content and firmness) of cv. Golden Delicious apples were investigated for their ability to avoid the post-harvest blue mold caused by Penicillium expansum during cold storage. Freshly harvested apples were inoculated with P. expansum. Treated fruits were irradiated at doses of 0, 200, 400, 600 and 800 Gy and then inoculated with P. fluorescens suspension. Samples were evaluated at 3 month intervals. The results demonstrated a clear link between antioxidant activity and phenolic content, so that dose range of 200–400 Gy significantly increased phenolic content and antioxidant activity. Effect of P. fluorescens was similar to irradiation at 200 and 400 Gy that could prevent lesion diameter in pathogen-treated apples. As dose and storage time increased firmness decreased but, combination of P. fluorescens as well as irradiation (at 200–400 Gy) could decrease softening apple fruits during storage. In all parameters, P. fluorescens (as biocontrol agent) inhibited P. expansum similar to irradiation at 200–400 Gy. So, integrated treatment of irradiation and biocontrol agent explored the potential dual benefit of low doses (200 and 400 Gy) as a suitable method to sustain physico-chemical quality and conclusively reduce apple fruits losses during post-harvest preservation. - Highlights: • A suitable method to reduce apple quality losses during 9 month storage period. • Effects of γ radiation in combination with biocontrol agent on physico-chemical parameters of the apple fruits during cold storage. • The potential dual benefit of low irradiation dose combined with biocontrol agent. • Radiation dose determination for Penicillium expansum (postharvest pathogen) control

Epidemiology and quantitation of environmental risk in humans from radiation and other agents

International Nuclear Information System (INIS)

Castellani, Amleto

1985-01-01

The identification and quantitation of environmental risk in humans is one of the main problems to be solved in order to improve the protection of individuals and of human populations against physical and chemical pollutants. Epidemiology plays a central role in the evaluation of health risk directly in human populations. In this volume are collected 33 lectures presented at the AS! course on ''Epidemiology and quantitation of environmental risk in humans from radiation and other agents: potential and limitations'', sponsored by NATO and Italian Association of Radiobiology and organized by ENEA. The course has been devoted to a number of aspects of environmental risk analysis and evaluation based on epidemiological investigation. Basic epidemiological concepts and methods have been reviewed. Fundamentals of dosimetry and microdosimetry were presented in relation to the contribution of epidemiology in defining the dose effect relationships for radiation carcinogenesis and its relation with age, sex and ethnicity. The mechanisms of carcinogenesis as a multi-stage process were illustrated. One of the main topics was 'cancer epidemiology' and its correlation with: - occupational and non-occupational exposure to radiation - diagnostic and therapeutic irradiation - cancer proneness - hereditary and familiar diseases - abnormal response to carcinogens - environmental pollution in air and water - exposure to radon in mines and in building material - atomic bomb explosion - chemotherapy - dioxin and related compounds

Interpretation of interspecies differences in the biodistribution of radioactive agents

International Nuclear Information System (INIS)

McAfee, J.G.; Subramanian, G.

1981-01-01

The biodistribution of some radioactive agents is anomalous and unpredictable from one species to another. However, many agents follow a general pattern of rapid clearance from the blood and total body in small rodents, intermediate clearance in the dog and monkey and slower clearance in man. A major determinant of this interspecies difference is the shorter mean circulation time (blood volume/cardiac output) in smaller animals. To permit comparisons between mammals of varying size, many physiological and metabolic parameters, and stable drug effects have been expressed as power functions with exponents less than 1 (rather than linear functions) of body weight W, or body surface area. Frequency functions such as heart and respiratory rates have been correlated with negative power functions of body weight. The plasma clearances of chemotherapeutic agents in different species has been successfully normalized by altering the time dimension according to power functions of body weight. A similar procedure has been explored to normalize blood and total body clearances of various diagnostic radioactive agents in animals and man. Time equivalent units were derived from W 33 animal / W 33 man. The method failed, however for agents with a predominantly intracellular localization or undergoing active cellular transport (such as T1-201 or I-131 Hippuran). Nonetheless, this approach appears useful in distinguishing interspecies variability merely due to body size from interspecies metabolic variations

Biodistribution and radiation dosimetry of {sup 11}C-labelled docetaxel in cancer patients

Energy Technology Data Exchange (ETDEWEB)

Veldt, Astrid A.M. van der; Mooijer, Martien P.J.; Rijnders, Anneloes Y.; Windhorst, Albert D.; Lammertsma, Adriaan A.; Lubberink, Mark [VU University Medical Center, Department of Nuclear Medicine and PET Research, P.O. Box 7057, Amsterdam (Netherlands); Hendrikse, N.H. [VU University Medical Center, Department of Nuclear Medicine and PET Research, P.O. Box 7057, Amsterdam (Netherlands); VU University Medical Center, Department of Clinical Pharmacology and Pharmacy, Amsterdam (Netherlands); Smit, Egbert F. [VU University Medical Center, Department of Pulmonology, Amsterdam (Netherlands); Gerritsen, Winald R. [VU University Medical Center, Department of Medical Oncology, Amsterdam (Netherlands); Hoeven, Jacobus J.M. van der [Medical Center Alkmaar, Department of Internal Medicine, Alkmaar (Netherlands)

2010-10-15

Docetaxel is an important chemotherapeutic agent used for the treatment of several cancer types. As radiolabelled anticancer agents provide a potential means for personalized treatment planning, docetaxel was labelled with the positron emitter {sup 11}C. Non-invasive measurements of [{sup 11}C]docetaxel uptake in organs and tumours may provide additional information on pharmacokinetics and pharmacodynamics of the drug docetaxel. The purpose of the present study was to determine the biodistribution and radiation absorbed dose of [{sup 11}C]docetaxel in humans. Biodistribution of [{sup 11}C]docetaxel was measured in seven patients (five men and two women) with solid tumours using PET/CT. Venous blood samples were collected to measure activity in blood and plasma. Regions of interest (ROI) for various source organs were defined on PET (high [{sup 11}C]docetaxel uptake) or CT (low [{sup 11}C]docetaxel uptake). ROI data were used to generate time-activity curves and to calculate percentage injected dose and residence times. Radiation absorbed doses were calculated according to the MIRD method using OLINDA/EXM 1.0 software. Gall bladder and liver demonstrated high [{sup 11}C]docetaxel uptake, whilst uptake in brain and normal lung was low. The percentage injected dose at 1 h in the liver was 47 {+-} 9%. [{sup 11}C]docetaxel was rapidly cleared from plasma and no radiolabelled metabolites were detected. [{sup 11}C]docetaxel uptake in tumours was moderate and highly variable between tumours. The effective dose of [{sup 11}C]docetaxel was 4.7 {mu}Sv/MBq. As uptake in normal lung is low, [{sup 11}C]docetaxel may be a promising tracer for tumours in the thoracic region. (orig.)

Increased Toxicity of Chemotherapeutic Drugs by All-Trans Retinoic Acid in Cd44 Cells

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A Abbasi

2016-03-01

Full Text Available BACKGROUND AND OBJECTIVE: In recent studies, undifferentiated CD44 cells have been introduced as the major cause of chemotherapeutic drug resistance in esophageal cancer. In this study, we aimed to evaluate the effects of all-trans retinoic acid on reducing chemotherapeutic drug resistance and improving the associated toxic effects. METHODS: In this clinical study, CD44+ and CD44- cells were separated from KYSE-30 cell line, using magnetic-activated cell sorting (MACS method. The cytotoxic effects of retinoic acid treatment, combined with cisplatin and 5-fluorouracil, were separately evaluated in two cell groups, i.e., CD44+ and CD44-. Cytotoxicity was determined by identifying cellular metabolic activity, acridine orange/ethidium bromide staining, and flow cytometry. FINDINGS: In this study, CD44 marker was expressed in 6.25% of the cell population in KYSE-30 cell line. The results of flow cytometry revealed that treatment with a combination of retinoic acid and chemotherapeutic drugs could improve cell cycle arrest in CD44+ cells (p<0.05, unlike CD44- cells. Determination of cellular metabolic activity, increased cell apoptosis along with decreased half maximal inhibitory concentration (IC50, and acridine orange/ethidium bromide staining were indicative of the increased percentage of primary and secondary apoptotic CD44+ cells. However, in CD44- cells, these effects were only observed by using a combination of retinoic acid and cisplatin (p<0.05. CONCLUSION: The present results showed that all-trans retinoic acid could increase the toxicity of cisplatin and 5-fluorouracil in CD44+ cells.

Injury by ionizing radiations

International Nuclear Information System (INIS)

Upton, A.C.

1985-01-01

In view of the vast amount of effort devoted to the study of radiation injury during the past century, it may be concluded that the effects of radiation are better understood than those of any other physical or chemical agent. To this extent, it is useful to review our experience with radiation in addressing health problems associated with other environmental agents

A review of topotecan in combination chemotherapy for advanced cervical cancer

Directory of Open Access Journals (Sweden)

Minoo Robati

2008-03-01

Full Text Available Minoo Robati, David Holtz, Charles J DuntonDepartment of Obstetrics and Gynecology, Main Line Gynecologic Oncology, Lankenau Hospital, Wynnewood, PA, USAAbstract: Treatment of advanced, recurrent or persistent cervical cancer includes radiotherapy and chemotherapy. Radiation has been the primary treatment modality for locoregionally advanced cervical cancer. Concomitant systemic cisplatin chemotherapy and radiation have shown high response rates with improvements in durable remissions and overall survival. Cisplatin has been the standard medication for the treatment of advanced cervical cancer. Combinations with other chemotherapeutic agents have been the subject of clinical trials with varying results. The toxicity of combination chemotherapy and tolerability of patients are other factors that should be considered in the management of patients with advanced disease. Recently topotecan, in combination with cisplatin, achieved increased response and overall survival rates without further compromising the patients’ quality of life. This review focuses on the mechanism of action and toxicities of topotecan, as well as its role as a radio-sensitizer and chemotherapeutic agent in the management of advanced, recurrent, or persistent cervical cancer. Other combination modalities and dosages are also discussed.Keywords: topotecan, combination chemotherapy, advanced cervical cancer

Nivolumab-Induced Encephalitis in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

Directory of Open Access Journals (Sweden)

Benjamin Chaucer

2018-01-01

Full Text Available The treatment of cancer is a rapidly evolving field. As more chemotherapeutic agents become available, reporting the side effects of these agents in clinical practice becomes increasingly important. Nivolumab is one of the chemotherapeutic agents commonly used for treatment of renal cell carcinoma, metastatic melanoma, and metastatic non-small cell lung cancer. While common side effects are known and well documented, encephalitis is documented as an extremely rare side effect. We present the case of an extremely rare side effect to a common chemotherapeutic agent.

The combination of reduced MCL-1 and standard chemotherapeutics is tolerable in mice.

Science.gov (United States)

Brinkmann, Kerstin; Grabow, Stephanie; Hyland, Craig D; Teh, Charis E; Alexander, Warren S; Herold, Marco J; Strasser, Andreas

2017-12-01

A common therapeutic strategy to combat human cancer is the use of combinations of drugs, each targeting different cellular processes or vulnerabilities. Recent studies suggest that addition of an MCL-1 inhibitor to such anticancer drug treatments could be an attractive therapeutic strategy. Thus, it is of great interest to understand whether combinations of conventional anticancer drugs with an MCL-1 inhibitor will be tolerable and efficacious. In order to mimic the combination of MCL-1 inhibition with other cancer therapeutics, we treated Mcl-1 +/- heterozygous mice, which have a ~50% reduction in MCL-1 protein in their cells, with a broad range of chemotherapeutic drugs. Careful monitoring of treated mice revealed that a wide range of chemotherapeutic drugs had no significant effect on the general well-being of Mcl-1 +/- mice with no overt damage to a broad range of tissues, including the haematopoietic compartment, heart, liver and kidney. These results indicate that MCL-1 inhibition may represent a tolerable strategy in cancer therapy, even when combined with select cytotoxic drugs.

Schiff base-Poloxamer P85 combination demonstrates chemotherapeutic effect on prostate cancer cells in vitro.

Science.gov (United States)

Demirci, Selami; Doğan, Ayşegül; Türkmen, Neşe Başak; Telci, Dilek; Rizvanov, Albert A; Şahin, Fikrettin

2017-02-01

Prostate cancer is a multistep and complicated cancer type that is regulated by androgens at the cellular level and remains the second commonest cause of death among men. Discovery and development of novel chemotherapeutic agents enabling rapid tumor cell death with minimal toxic effects to healthy tissues might greatly improve the safety of chemotherapy. The present study evaluates the anti-cancer activity of a novel heterodinuclear copper(II)Mn(II) complex (Schiff base) in combination with poly(ethylene oxide) and poly(propylene oxide) block copolymer (Pluronic) P85. We used assays for cell proliferation, apoptosis, cell migration and invasion, DNA binding and cleavage to elucidate the molecular mechanisms of action, in addition to the anti-inflammatory potency of the new combination. The combined treatment of Schiff base and P85 lead to a remarkable anti-cancer effect on prostate cancer cell lines. Cell proliferation was inhibited in Schiff base-P85 treatment. The activity of this formulation is on DNA binding and cleavage and prevents inflammation in in vitro conditions. This is the first study presenting the anti-cancer activity of the present Schiff base derivative and its combination with P85 to treat prostate cancer in vitro. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4

Directory of Open Access Journals (Sweden)

Bo Yoon Chang

2015-10-01

Full Text Available Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE. MFE stimulated the production of cytokines, nitric oxide (NO and tumor necrosis factor-α (TNF-α and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase and nuclear factor-κB (NF-κB signaling pathways downstream from toll-like receptor (TLR 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK cell activity, cytotoxic T lymphocyte (CTL activity and IFN-γ production. Immunoglobulin G (IgG antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent.

Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4.

Science.gov (United States)

Chang, Bo Yoon; Kim, Seon Beom; Lee, Mi Kyeong; Park, Hyun; Kim, Sung Yeon

2015-10-13

Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE). MFE stimulated the production of cytokines, nitric oxide (NO) and tumor necrosis factor-α (TNF-α) and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase) and nuclear factor-κB (NF-κB) signaling pathways downstream from toll-like receptor (TLR) 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) activity and IFN-γ production. Immunoglobulin G (IgG) antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent.

Impact of Drug Therapy, Radiation Dose, and Dose Rate on Renal Toxicity Following Bone Marrow Transplantation

International Nuclear Information System (INIS)

Cheng, Jonathan C.; Schultheiss, Timothy E.; Wong, Jeffrey Y.C.

2008-01-01

Purpose: To demonstrate a radiation dose response and to determine the dosimetric and chemotherapeutic factors that influence the incidence of late renal toxicity following total body irradiation (TBI). Methods and Materials: A comprehensive retrospective review was performed of articles reporting late renal toxicity, along with renal dose, fractionation, dose rate, chemotherapy regimens, and potential nephrotoxic agents. In the final analysis, 12 articles (n = 1,108 patients), consisting of 24 distinct TBI/chemotherapy conditioning regimens were included. Regimens were divided into three subgroups: adults (age ≥18 years), children (age <18 years), and mixed population (both adults and children). Multivariate logistic regression was performed to identify dosimetric and chemotherapeutic factors significantly associated with late renal complications. Results: Individual analysis was performed on each population subgroup. For the purely adult population, the only significant variable was total dose. For the mixed population, the significant variables included total dose, dose rate, and the use of fludarabine. For the pediatric population, only the use of cyclosporin or teniposide was significant; no dose response was noted. A logistic model was generated with the exclusion of the pediatric population because of its lack of dose response. This model yielded the following significant variables: total dose, dose rate, and number of fractions. Conclusion: A dose response for renal damage after TBI was identified. Fractionation and low dose rates are factors to consider when delivering TBI to patients undergoing bone marrow transplantation. Drug therapy also has a major impact on kidney function and can modify the dose-response function

Propionyl-L-carnitine as a potential protective agent against radiation-induced cardiotoxicity

International Nuclear Information System (INIS)

Ramadan, L.A.

2003-01-01

In this study, propiony-L-carnitine (PLC); a natural short-chain derivative of L-carnitine, has been tested as a potential protective agent against radiation-induced cardio-toxicity. Cardiotoxicity was assessed in the homo-genate of the heart by measuring the plasma levels of creatine phosphokinase (CPK), lactic acid dehydrogenase (LDH), aspartate aminotransferase (AST), as well as malon-dialdehyde (MDA), glutathione content (GSH), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), adenosine triphosphate (ATP) and nitric oxide (NO) production, whole body gamma-irradiation (2 and 6Gy ) of rats significantly increased CPK, LDH, AST,MDA, and NO and significantly decreased GSH,GSH-PX, SOD and ATP. Daily administration (one week) of PLC before whole body irradiation caused significant recovery for the serum enzyme CPK, LDH, AST and MDA, GSH, GSH-PX, SOD, ATP and NO levels in cardiac tissue. The protective effect PLC was attributed to it's antioxidant properties. Radiation therapy, likewise, is a valuable method of treatment for a variety of intrathoracic neoplasms. During radiotherapy of thoracic tumorus, the heart is often included in the primary treatment volume and chronic impairment of myocadial function occurs (cilliers and lochner, 1993; benderitter et al., 1995). Irradiation causes numerous changes in different metabolic reactions within the cardiac cells with major adverse undersirable effects that involve cardiotoxicity

Study of occupational risk agents and its probable hazards to human health; Estudo dos agentes de risco ocupacional e seus provaveis agravos na saude humana

Energy Technology Data Exchange (ETDEWEB)

Carneiro, Janete Cristina G. Gaburo; Alves, Alice dos Santos; Sanches, Matias P., E-mail: janetegc@ipen.br, E-mail: alicesante@hotmail.com, E-mail: msanches@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

2013-07-01

Currently the workplaces become increasingly complex and a strategy evaluation and the control of occupational risks agents is needed. Workers may be exposed to environmental agents (chemical, physical and biological) and other unsuitable conditions by performing tasks that involve these agents directly. The main objective of this study is to approach conceptual aspects of risk conditions, physical in nature, with emphasis on ionizing radiation and its interaction with other agents in occupational and environmental situations. To meet this goal, it is performed a literature review and a summary of the main occupational agents known or suspected to cause any adverse health effects in humans. According to the available literature the reported studies on the effects of combined exposures to radiation and others agents are recognized and, as far as possible, should be taken into account in evaluating of the potential radiation risks at low levels of exposure. (author)

Quantal health effects of three toxic agents combined

International Nuclear Information System (INIS)

Seiler, F.A.

1988-01-01

Quantal health effects such as cancer, correlated with the combined action of three toxic agents, are considered. Data on the combined effects of two agents are scarce and no such data exist for three toxicants, yet concerns have arisen about simultaneous exposure of radiation workers to three different agents. Using models developed from the analysis of health effects involving two toxicants, equations for the combined effects of three agents are derived from a more general formalism. An application of practical interest is the incidence of cancer of the esophagus and its correlation with concurrent exposures to alcohol, tobacco, and either low- or high-LET radiation. (author)

Radiation as agents of somatic and genetic alterations

International Nuclear Information System (INIS)

de Eston, V.R.

1975-01-01

According to the report on ''The Effects on Population of Exposure to Low Levels of Ionizing Radiation,'' whether we regard a risk as acceptable or not depends on how avoidable it is, and, if not avoidable, how it compares with the risks of alternative options and those usually accepted by society. Regarding the use of ionizing radiation: No exposure should be permitted without the expectation of a commensurable benefit. The public must be protected from radiation, but not to the extent that the degree of protection provided results in the substitution of a worse hazard than that of the radiation avoided. Medical radiation exposure can and should be reduced considerably by limiting its use to clinically indicated procedures, utilizing efficient exposure techniques and optimal operation of radiation equipment. Consideration should be given to the following: (a) Restriction of the use of radiation for public health purposes, unless there is reasonable probability of significant detection of disease. (b) Inspection and licensing of radiation and ancillary equipment. (c) Appropriate training and certification of involved personnel. (d) Gonad shielding, especially shielding of the testis, is strongly recommended as a simple and highly efficient way to reduce the genetic significant dose. In a poignant phrase, Morgan has stated ''Radiation doesn't have to be feared, but should be respected.''

The analysis of the survey results for the current 'business agent'

International Nuclear Information System (INIS)

Kim, I. H.; Shim, H. S.; Jeon, I. Y.; Kang, W. S.; Yun, K. H.; Na, S. H.; Park, T. J.; Kim, I. S.

2004-01-01

Our survey is conducted about the current systems in the 'Business Agents' regulations which prescribes running business such as the safe control of radiation on behalf of any permitted users. The radiation safety staffs who are engaged in the handling of radioisotope respond our quaternaries. They are as follows: 1. the radiation safety staffs' attitude to the need of 'Business Agent' regulations, 2. the satisfaction level of 'Business Agent' service, 3. the propriety of the manpower. The survey results are that the 68.4% of the respondents are in favor of the need of 'Business Agent' regulations and the 63.6% of the respondents expressed satisfactions for the service of 'Business Agent'. For the one manpower managing 'Business Agent', 32.3% of the respondents expressed as 'overburdened' and 37.5% as 'appropriate.' Our results give the feedback to develop the system of 'Business Agent' regulations as making feedback effect

Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents

International Nuclear Information System (INIS)

Kim, Jae Ho; Kim, Sang Hie; Kolozsvary, A.

1995-01-01

The purpose of this investigation was to demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents. Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses or irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation. The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 μg/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 ± 0.1 and 1.3 ± 0.1, respectively. Exposure of cells to 10 μg/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 ± 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone. An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors. 25 refs., 6 figs

Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents

Energy Technology Data Exchange (ETDEWEB)

Kim, Jae Ho; Kim, Sang Hie; Kolozsvary, A. [Henry Ford Hospital, Detroit, MI (United States)] [and others

1995-11-01

The purpose of this investigation was to demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents. Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses or irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation. The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 {mu}g/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 {plus_minus} 0.1 and 1.3 {plus_minus} 0.1, respectively. Exposure of cells to 10 {mu}g/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 {plus_minus} 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone. An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors. 25 refs., 6 figs.

Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents

International Nuclear Information System (INIS)

Jae, Ho Kim; Sang, Hie Kim; Kolozsvary, Andrew; Brown, Stephen L.; Ok, Bae Kim; Freytag, Svend O.

1995-01-01

Purpose: To demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents. Methods and Materials: Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses of irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation. Results: The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 μg/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 ± 0.1 and 1.3 ± 0.1, respectively. Exposure of cells to 10 μg/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 ± 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone. Conclusion: An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors

Effects of combinations of chemotherapy and radiation on the emergence of drug resistant cells in 9L rat brain tumor spheroids

International Nuclear Information System (INIS)

Tofilon, P.J.; Arundel, C.; Vines, C.M.

1987-01-01

Repeated administration of antineoplastic chemotherapeutic agents is generally considered to induce and/or select for drug resistant cells. The authors recently begun to investigate whether chemotherapy interdigitated with radiation can minimize or eliminate the emergence of drug resiistent cells in 9L rat brain tumor spheroids grown from defined mixtures of cells sensitive (9L) and resistant (R/sub 3/) to BCNU. In this experimental system, the sister chromatid exchange (SCE) assay is used to quantitate the proportions of sensitive and resistant cells within the spheroids. While 9L and R/sub 3/ cell have different sensitivities to BCNU, they are equally sensitive to radiation. Mixed-cell spheroids consisting of 1% R/sub 3/ cells were treated with three doses of BCNU (10 μM) every 72 hr resulting in a shift in the 9L to R/sub 3/ ratio to greater than 50% R/sub 3/ cells. The combined protocols to be investigated will involve γ rays administered either 36 hr before or after each BCNU treatment. By initiating these combined protocols on spheroids of different sizes, the effectiveness of each protocol is evaluated with respect to the number of resistant cells present

Multi-Agent Software Engineering

International Nuclear Information System (INIS)

Mohamed, A.H.

2014-01-01

This paper proposed an alarm-monitoring system for people based on multi-agent using maps. The system monitors the users physical context using their mobile phone. The agents on the mobile phones are responsible for collecting, processing and sending data to the server. They can determine the parameters of their environment by sensors. The data are processed and sent to the server. On the other side, a set of agents on server can store this data and check the preconditions of the restrictions associated with the user, in order to trigger the appropriate alarms. These alarms are sent not only to the user who is alarmed to avoid the appeared restriction, but also to his supervisor. The proposed system is a general purpose alarm system that can be used in different critical application areas. It has been applied for monitoring the workers of radiation sites. However, these workers can do their activity tasks in the radiation environments safely

Clinical developments of chemotherapeutic nanomedicines: Polymers and liposomes for delivery of camptothecins and platinum (II) drugs

KAUST Repository

Kieler-Ferguson, Heidi M.; Frechet, Jean; Szoka, Francis C.

2013-01-01

For the past 40 years, liposomal and polymeric delivery vehicles have been studied as systems capable of modulating the cytotoxicity of small molecule chemotherapeutics, increasing tumor bearing animal survival times, and improving drug targeting

Early stage detection of chemotherapeutic effect on 203 GL glioma in mice as studied by P-31 NMR and flow cytometry

Energy Technology Data Exchange (ETDEWEB)

Itoh, Masamitsu; Yoshikawa, Koki; Nishikawa, Junichi; Iio, Masahiro; Shibui, Soichiro; Nomura, Kazuhiro; Saito, Hazime; Kodama, Masahiko

1988-08-01

The effect of chemotherapy against glioma in mouse was evaluated by /sup 31/P NMR spectroscopy and flow cytometry. We found that administration of ACNU or tegafur at a dose less than LD/sub 50/ resulted in the partial suppression of the ratio of inorganic phosphate (Pi)/phosphocreatine (PCr) and phosphomonoester (PME)/creatine phosphate (PCr) after 24 or 48 hr, although these ratios are usually increased together with growth of tumors. Flow cytometric analysis of glioma in vivo showed an accumulation in cells containing tetraploid DNA by G/sub 2/M block 24 - 48 hr after treatment. However, the change occurred at a period slightly later than that of the Pi/PCr ratio. In contrast, histological change was noted at eight days after administration. Hence, it is concluded that in vivo /sup 31/P NMR spectroscopy can detect a change in metabolic pathways in tumors as early as 24 - 48 hr after the administration of chemotherapeutic agents.

[Experimental study of the relationships between activation of erythropoiesis and hematotoxicity of some antitumoral agents (author's transl)].

Science.gov (United States)

Pannacciulli, I; Bogliolo, G; Massa, G; Ronco, D; Fresco, G; Saviane, A; Dolcino, G; Celle, G

1975-01-01

The changes in the blood toxicity of some antitumoral chemotherapeutic agents in the presence of erythropoiesis activation by bleeding are evaluated. The general toxicity seems to be unaffected but the damage to erythropoiesis proved, in absolute terms, to be more severe in the bled animals. The recovery of hematopoiesis was slower after some drug than others. These results are discussed in the light of present knowledge of hematopoietic kinetics and of the relationships between antiblastic drugs and staminal hematopoietic compartments.

Prospects of topical protection from ultraviolet radiation exposure: a critical review on the juxtaposition of the benefits and risks involved with the use of chemoprotective agents.

Science.gov (United States)

Bora, Nilutpal Sharma; Mazumder, Bhaskar; Chattopadhyay, Pronobesh

2018-05-01

Solar ultraviolet (UV) radiation exposure is known to cause inevitable damage to human skin via different mechanisms which include disruption of genetic material and generation of free radicals. In the ever emerging field of photoprotective agents, there have been constant endeavors to uphold the standards for optimum protection from solar UV-induced damages which include alarming conditions ranging from severe keratosis to malignant transformation of skin cells. Out of the various methods available for photoprotection, chemical photoprotective agents are most popular due to its ease of applicability, availability, and efficacy. However, the benevolences of chemophotoprotective agents are not excluded from the fact that all chemical agents are bound to suffer predestined consequences of toxicity and unwanted side effects. The present article focuses on the basic knowledge pertaining to achieve adequate sun protection and also on the beneficial and risk factors of using chemical agents as photoprotective formulations. The article highlights the US Food and Drug Administration (FDA) approved and unapproved UV filters; and also sheds light on the overall measures to protect an individual from UV radiation exposure, dispel misconceptions and present the newer technologies that are available in the market to accomplish ideal sun protection.

Radiation protection - quality and metrology

International Nuclear Information System (INIS)

Broutin, J.P.

2002-01-01

The radiation protection gathers three occupations: radiation protection agents; environment agents ( control and monitoring); metrology agents ( activities measurement and calibration). The quality and the metrology constitute a contribution in the technique competence and the guarantee of the service quality. This article, after a historical aspect of quality and metrology in France explains the advantages of such a policy. (N.C.)

Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells.

Directory of Open Access Journals (Sweden)

Heather E Wheeler

Full Text Available There are no effective agents to prevent or treat chemotherapy-induced peripheral neuropathy (CIPN, the most common non-hematologic toxicity of chemotherapy. Therefore, we sought to evaluate the utility of human neuron-like cells derived from induced pluripotent stem cells (iPSCs as a means to study CIPN. We used high content imaging measurements of neurite outgrowth phenotypes to compare the changes that occur to iPSC-derived neuronal cells among drugs and among individuals in response to several classes of chemotherapeutics. Upon treatment of these neuronal cells with the neurotoxic drug paclitaxel, vincristine or cisplatin, we identified significant differences in five morphological phenotypes among drugs, including total outgrowth, mean/median/maximum process length, and mean outgrowth intensity (P < 0.05. The differences in damage among drugs reflect differences in their mechanisms of action and clinical CIPN manifestations. We show the potential of the model for gene perturbation studies by demonstrating decreased expression of TUBB2A results in significantly increased sensitivity of neurons to paclitaxel (0.23 ± 0.06 decrease in total neurite outgrowth, P = 0.011. The variance in several neurite outgrowth and apoptotic phenotypes upon treatment with one of the neurotoxic drugs is significantly greater between than within neurons derived from four different individuals (P < 0.05, demonstrating the potential of iPSC-derived neurons as a genetically diverse model for CIPN. The human neuron model will allow both for mechanistic studies of specific genes and genetic variants discovered in clinical studies and for screening of new drugs to prevent or treat CIPN.

Comparison of the dose-effect relationship for UV radiation and ionizing radiation

International Nuclear Information System (INIS)

Leenhouts, H.P.; Sijsma, M.J.; Chadwick, K.H.

1990-06-01

Ionizing radiation and ultraviolet radiation (UV) are both physical agents with mutagenic and carcinogenic properties. However, there are some basic differences in the fundamental mechanism of their interaction with biological material that may have consequences for risk assessment. In this paper the dose-effect relationships for gamma radiation and UV at cellular level will be used to demonstrate the different radio-biological effectiveness of both agents. The results will be discussed in the framework of a biophysical model, based on the assumption that DNA doublestranded lesions are crucial for the cytotoxic action. After exposure to ionizing radiation, the lesions are fixed immediately following irradiation, but after UV exposure the lethal lesions are recognized only in the next DNA synthesis phase. The combination of this concept with the mechanism of lesion induction and the possibility of repair, leads to different dose and time relationships for the radiation effects of both agents. The possible consequences for risk assessment at low levels will be discussed. (author). 9 refs.; 5 figs

Lipoprotein Nanoplatform for Targeted Delivery of Diagnostic and Therapeutic Agents

Directory of Open Access Journals (Sweden)

Jerry D. Glickson

2008-03-01

Full Text Available Low-density lipoprotein (LDL provides a highly versatile natural nanoplatform for delivery of visible or near-infrared fluorescent optical and magnetic resonance imaging (MRI contrast agents and photodynamic therapy and chemotherapeutic agents to normal and neoplastic cells that overexpress low-density lipoprotein receptors (LDLRs. Extension to other lipoproteins ranging in diameter from about 10 nm (high-density lipoprotein [HDL] to over a micron (chylomicrons is feasible. Loading of contrast or therapeutic agents onto or into these particles has been achieved by protein loading (covalent attachment to protein side chains, surface loading (intercalation into the phospholipid monolayer, and core loading (extraction and reconstitution of the triglyceride/cholesterol ester core. Core and surface loading of LDL have been used for delivery of optical imaging agents to tumor cells in vivo and in culture. Surface loading was used for delivery of gadolinium-bis-stearylamide contrast agents for in vivo MRI detection in tumor-bearing mice. Chlorin and phthalocyanine near-infrared photodynamic therapy agents (≤ 400/LDL have been attached by core loading. Protein loading was used to reroute the LDL from its natural receptor (LDLR to folate receptors and could be used to target other receptors. A semisynthetic nanoparticle has been constructed by coating magnetite iron oxide nanoparticles with carboxylated cholesterol and overlaying a monolayer of phospholipid to which apolipoprotein A1 or E was adsorbed for targeting HDL or adsorbing synthetic amphipathic helical peptides ltargeting LDL or folate receptors. These particles can be used for in situ loading of magnetite into cells for MRI-monitored cell tracking or gene expression.

Environmental Agents Service (EAS) Registry System of Records

Data.gov (United States)

Department of Veterans Affairs — The Environmental Agent Service (EAS) Registries is the information system encompassing the Ionizing Radiation Registry (IRR), the Agent Orange Registry (AOR), and...

Use of virtual simulator for agent training in radiation protection actions in major events

International Nuclear Information System (INIS)

Passos, Claudio Azevedo; Mol, Antonio Carlos A.; Carvalho, Paulo V.R.; Lima, Fabio Almeida; Rocha, Tiago Lima

2015-01-01

With the proximity of the events of the Olympic Games, Brazil can become a great place of visibility for running dirty bombs or any other radiation mode proliferation by terrorists. Aware of these problems, the government and the organizations created managements of emergencies to ensure that these events elapse in an orderly and safe manner. The management of emergency situations at an event is a complex problem, which involves dynamic, unforeseen and unintended situations, emphasizing the potential complexity of the contexts in which organizations operate and, as a consequence, the people involved in the execution of multiple tasks from activities that require intense cognitive effort, are often challenged to adapt dynamically to maintain the productivity of the organization at satisfactory levels of performance usually impedes these people reflect on the results of their actions and learn from them. Therefore, it is extremely important to create tools that address the methods and techniques of Cognitive Task Analysis (CTA) to assist in the previous training of the security agents, for example, detection and approaches of people who carry radioactive elements. One of the possible ways to accomplish this training is through the use of virtual reality. Virtual environments bring some advantages like reducing costs and risks. The aim of this paper is to present a virtual simulator to evaluate the use in training agents in major events. As a case study, the Maracana and the agents of the National Nuclear Energy Commission (CNEN) was chosen. (author)

Use of virtual simulator for agent training in radiation protection actions in major events

Energy Technology Data Exchange (ETDEWEB)

Passos, Claudio Azevedo, E-mail: cpassos.cp2@gmail.com [Universidade Federal do Rio de Janeiro (CCMN/NCE/UFRJ), Rio de Janeiro, RJ (Brazil); Mol, Antonio Carlos A.; Carvalho, Paulo V.R., E-mail: mol@ien.gov.br, E-mail: paulov@ien.gov.br [nstituto de Engenharia Nuclear (IEN/CNEN-RJ), Rio de Janeiro, RJ (Brazil); Lima, Fabio Almeida; Rocha, Tiago Lima, E-mail: profantoniocarlosmol@gmail.com, E-mail: falmeida@unicarioca.edu.br, E-mail: tlrtiago@gmail.com [Centro Universitario Carioca (Unicarioca), Rio de Janeiro, RJ (Brazil)

2015-07-01

With the proximity of the events of the Olympic Games, Brazil can become a great place of visibility for running dirty bombs or any other radiation mode proliferation by terrorists. Aware of these problems, the government and the organizations created managements of emergencies to ensure that these events elapse in an orderly and safe manner. The management of emergency situations at an event is a complex problem, which involves dynamic, unforeseen and unintended situations, emphasizing the potential complexity of the contexts in which organizations operate and, as a consequence, the people involved in the execution of multiple tasks from activities that require intense cognitive effort, are often challenged to adapt dynamically to maintain the productivity of the organization at satisfactory levels of performance usually impedes these people reflect on the results of their actions and learn from them. Therefore, it is extremely important to create tools that address the methods and techniques of Cognitive Task Analysis (CTA) to assist in the previous training of the security agents, for example, detection and approaches of people who carry radioactive elements. One of the possible ways to accomplish this training is through the use of virtual reality. Virtual environments bring some advantages like reducing costs and risks. The aim of this paper is to present a virtual simulator to evaluate the use in training agents in major events. As a case study, the Maracana and the agents of the National Nuclear Energy Commission (CNEN) was chosen. (author)

Radiation-Force Assisted Targeting Facilitates Ultrasonic Molecular Imaging

Directory of Open Access Journals (Sweden)

Shukui Zhao

2004-07-01

Full Text Available Ultrasonic molecular imaging employs contrast agents, such as microbubbles, nanoparticles, or liposomes, coated with ligands specific for receptors expressed on cells at sites of angiogenesis, inflammation, or thrombus. Concentration of these highly echogenic contrast agents at a target site enhances the ultrasound signal received from that site, promoting ultrasonic detection and analysis of disease states. In this article, we show that acoustic radiation force can be used to displace targeted contrast agents to a vessel wall, greatly increasing the number of agents binding to available surface receptors. We provide a theoretical evaluation of the magnitude of acoustic radiation force and show that it is possible to displace micron-sized agents physiologically relevant distances. Following this, we show in a series of experiments that acoustic radiation force can enhance the binding of targeted agents: The number of biotinylated microbubbles adherent to a synthetic vessel coated with avidin increases as much as 20-fold when acoustic radiation force is applied; the adhesion of contrast agents targeted to αvβ3 expressed on human umbilical vein endothelial cells increases 27-fold within a mimetic vessel when radiation force is applied; and finally, the image signal-to-noise ratio in a phantom vessel increases up to 25 dB using a combination of radiation force and a targeted contrast agent, over use of a targeted contrast agent alone.

New therapeutic agent for radiation synovectomy - preparation of {sup 166}Ho-EDTMP-HA particle

Energy Technology Data Exchange (ETDEWEB)

Bai, H.; Jin, X.; Du, J.; Wang, F.; Chen, D.; Fan, H.; Cheng, Z.; Zhang, J. [China Institute of Atomic Energy, Beijing (Switzerland). Isotope Department

1997-10-01

In order to prepare new therapeutical agent for radiation synovectomy, Hydroxyapatite (HA) was labelled with {sup 166}Ho by EDTMP that had high affinity to HA particles. Radiolabelling of HA particles was divided into two steps, {sup 166}Ho-EDTMP was prepared first; then mixed with HA particles completely and vibrated for 15 minutes on the micromixer at room temperature, washed 3 times with deionized water. Radiolabelling particle was separated from free {sup 166}Ho via centrifugation to determine its radiolabelling efficiency. {sup 166}Ho-EDTMP-HA and {sup 166}Ho-EDTMP were injected into knee joint of normal rabbits respectively, every group was killed at different time postinjection, took out major organ and collected urine and blood, then weighted and determined their radio counts. HA particles, as a natural component of bone was known to have good compatibility with soft tissue and biodegrade into calcium and phosphate in vivo. It was readily prepared from common chemical and formed into particles of desired size range in a controlled process, it had high stability in vitro and vivo. Radiolabelling of HA particle with {sup 166}Ho by EDTMP was simple to perform and provides an excellent labelling yield that was more than 95% under the optimal labelling condition. The optimal labelling condition at room temperature was pH 6.0-8.0 and vibration time 15 minutes. The absorbed capacity of HA particle was 5 mg Ho/g HA particle and size of radiolabelling particle was at range of 2-5,{mu}m that is suitable for therapy of radiation synovectomy. {sup 166}Ho-EDTMP-HA particle demonstrated high in vitro stability in either normal saline or 1% BSA solution, but instability under extremely acidic condition (pH 1-2). The control studies performed with {sup 166}Ho-EDTMP not bound to HA particle provided information on the distribution of radioactivity that would occur upon leakage of the radiochemical compound from joint. Its short half-life, its extremely low leakage from the

Animal venoms as antimicrobial agents.

Science.gov (United States)

Perumal Samy, Ramar; Stiles, Bradley G; Franco, Octavio L; Sethi, Gautam; Lim, Lina H K

2017-06-15

Hospitals are breeding grounds for many life-threatening bacteria worldwide. Clinically associated gram-positive bacteria such as Staphylococcus aureus/methicillin-resistant S. aureus and many others increase the risk of severe mortality and morbidity. The failure of antibiotics to kill various pathogens due to bacterial resistance highlights the urgent need to develop novel, potent, and less toxic agents from natural sources against various infectious agents. Currently, several promising classes of natural molecules from snake (terrestrial and sea), scorpion, spider, honey bee and wasp venoms hold promise as rich sources of chemotherapeutics against infectious pathogens. Interestingly, snake venom-derived synthetic peptide/snake cathelicidin not only has potent antimicrobial and wound-repair activity but is highly stable and safe. Such molecules are promising candidates for novel venom-based drugs against S. aureus infections. The structure of animal venom proteins/peptides (cysteine rich) consists of hydrophobic α-helices or β-sheets that produce lethal pores and membrane-damaging effects on bacteria. All these antimicrobial peptides are under early experimental or pre-clinical stages of development. It is therefore important to employ novel tools for the design and the development of new antibiotics from the untapped animal venoms of snake, scorpion, and spider for treating resistant pathogens. To date, snail venom toxins have shown little antibiotic potency against human pathogens. Copyright © 2017 Elsevier Inc. All rights reserved.

Reactivating p53 and Inducing Tumor Apoptosis (RITA Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin

Directory of Open Access Journals (Sweden)

Armin Wiegering

2017-04-01

of RITA-sensitive CRC cells within both panels of established CRC cell lines and primary patient-derived CRC cell lines (6/14 that provide a rationale for combining RITA with 5FU or oxaliplatin to enhance the antiproliferative response to both chemotherapeutic agents.

Is There an Opportunity for Current Chemotherapeutics to Up-regulate MIC-A/B Ligands?

Directory of Open Access Journals (Sweden)

Kendel Quirk

2017-10-01

Full Text Available Natural killer (NK cells are critical effectors of the immune system. NK cells recognize unhealthy cells by specific ligands [e.g., MHC- class I chain related protein A or B (MIC-A/B] for further elimination by cytotoxicity. Paradoxically, cancer cells down-regulate MIC-A/B and evade NK cell’s anticancer activity. Recent data indicate that cellular-stress induces MIC-A/B, leading to enhanced sensitivity of cancer cells to NK cell-mediated cytotoxicity. In this Perspective article, we hypothesize that current chemotherapeutics at sub-lethal, non-toxic dose may promote cellular-stress and up-regulate the expression of MIC-A/B ligands to augment cancer’s sensitivity to NK cell-mediated cytotoxicity. Preliminary data from two human breast cancer cell lines, MDA-MB-231 and T47D treated with clinically relevant therapeutics such as doxorubicin, paclitaxel and methotrexate support the hypothesis. The goal of this Perspective is to underscore the prospects of current chemotherapeutics in NK cell immunotherapy, and discuss potential challenges and opportunities to improve cancer therapy.

Analysis by Fourier Transform Infrared (FTIR) of the gamma radiation effect on epoxy resin, used as solidification agent of radioactive wastes

International Nuclear Information System (INIS)

Liu, C.H.; Riella, H.G.; Guedes, S.M.L.

1995-01-01

The effects of gamma radiation on Epoxy resin, used as solidification agent of radioactive wastes, were studied by Fourier Transform Infrared (FTIR). The spectra showed no significant modifications on Epoxy resin functional groups (irradiated with dose from 0 to 1 MGy). Up to 1 MGy Epoxy resin did not oxidize, confirming the Epoxy good radiation strength. The presence of aromatic chain and amine group, mainly tertiary amine, give good radiolytic stability to the Epoxy, increasing the interest to use this material in nuclear facilities. (author). 3 refs, 2 figs

Low-dose radiation enhances therapeutic HPV DNA vaccination in tumor-bearing hosts.

Science.gov (United States)

Tseng, Chih-Wen; Trimble, Cornelia; Zeng, Qi; Monie, Archana; Alvarez, Ronald D; Huh, Warner K; Hoory, Talia; Wang, Mei-Cheng; Hung, Chien-Fu; Wu, T-C

2009-05-01

Current therapeutic approaches to treatment of patients with bulky cervical cancer are based on conventional in situ ablative modalities including cisplatin-based chemotherapy and radiation therapy. The 5-year survival of patients with nonresectable disease is dismal. Because over 99% of squamous cervical cancer is caused by persistent infection with an oncogenic strain of human papillomavirus (HPV), particularly type 16 and viral oncoproteins E6 and E7 are functionally required for disease initiation and persistence, HPV-targeted immune strategies present a compelling opportunity in which to demonstrate proof of principle. Sublethal doses of radiation and chemotherapeutic agents have been shown to have synergistic effect in combination with either vaccination against cancer-specific antigens, or with passive transfer of tumor-specific cytotoxic T lymphocytes (CTLs). Here, we explored the combination of low-dose radiation therapy with DNA vaccination with calreticulin (CRT) linked to the mutated form of HPV-16 E7 antigen (E7(detox)), CRT/E7(detox) in the treatment of E7-expressing TC-1 tumors. We observed that TC-1 tumor-bearing mice treated with radiotherapy combined with CRT/E7(detox) DNA vaccination generated significant therapeutic antitumor effects and the highest frequency of E7-specific CD8(+) T cells in the tumors and spleens of treated mice. Furthermore, treatment with radiotherapy was shown to render the TC-1 tumor cells more susceptible to lysis by E7-specific CTLs. In addition, we observed that treatment with radiotherapy during the second DNA vaccination generated the highest frequency of E7-specific CD8(+) T cells in the tumors and spleens of TC-1 tumor-bearing mice. Finally, TC-1 tumor-bearing mice treated with the chemotherapy in combination with radiation and CRT/E7(detox) DNA vaccination generate significantly enhanced therapeutic antitumor effects. The clinical implications of the study are discussed.

Laboratory determination of chemotherapeutic drug resistance in tumor cells from patients with leukemia, using a fluorometric microculture cytotoxicity assay (FMCA).

Science.gov (United States)

Larsson, R; Kristensen, J; Sandberg, C; Nygren, P

1992-01-21

An automated fluorometric microculture cytotoxicity assay (FMCA) based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) to fluorescein was employed for chemotherapeutic-drug-sensitivity testing of tumor-cell suspensions from patients with leukemia. Fluorescence was linearly related to cell number, and reproducible measurements of drug sensitivity could be performed using fresh or cryopreserved leukemia cells. A marked heterogeneity with respect to chemotherapeutic drug sensitivity was observed for a panel of cytotoxic drugs tested in 43 samples from 35 patients with treated or untreated acute and chronic leukemia. For samples obtained from patients with chronic lymphocytic and acute myelocytic leukemia, sensitivity profiles for standard drugs corresponded to known clinical activity and the assay detected primary and acquired drug resistance. Individual in vitro/in vivo correlations indicated high specificity with respect to the identification of drug resistance. The results suggest that the FMCA may be a simple and rapid method for in vivo-representative determinations of chemotherapeutic drug resistance in tumor cells obtained from patients with leukemia.

Report of National Cancer Institute symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. I. Common molecular mechanisms

International Nuclear Information System (INIS)

Borg, D.C.

1984-01-01

Some aspects of molecular mechanisms common to radiation and chemical carcinogenesis are discussed, particularly the DNA damage done by these agents. Emphasis is placed on epidemiological considerations and on dose-response models used in risk assessment to extrapolate from experimental data obtained at high doses to the effects from long-term, low-level exposures. 3 references, 6 figures

Report of National Cancer Institute symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. I. Common molecular mechanisms

Energy Technology Data Exchange (ETDEWEB)

Borg, D.C.

1984-01-01

Some aspects of molecular mechanisms common to radiation and chemical carcinogenesis are discussed, particularly the DNA damage done by these agents. Emphasis is placed on epidemiological considerations and on dose-response models used in risk assessment to extrapolate from experimental data obtained at high doses to the effects from long-term, low-level exposures. 3 references, 6 figures. (ACR)

The molecular basis for cell cycle delays following ionizing radiation. A review

International Nuclear Information System (INIS)

Maity, A.; McKenna, W.G.; Muschel, R.J.

1994-01-01

Exposure of a wide variety of cells to ionizing (X- or γ-) irradiation results in a division delay which may have several components including a G 1 block, a G 2 arrest or an S phase delay. The G 1 arrest is absent in many cells lines, and the S phase delay is typically seen following relatively high doses (>5 Gy). In contrast, the G 2 arrest is seen in virtually all eukaryotic cells and occurs following high and low doses, even under 1 Gy. The mechanism underlying the G 2 arrest may involve suppression of cyclin B1 mRNA and/or protein in some cell lines and tyrosine phosphorylation of p34 cdc2 in others. Similar mechanisms are likely to be operative in the G 2 arrest induced by various chemotherapeutic agents including nitrogen mustard and etoposide. The upstream signal transduction pathways involved in the G 2 arrest following ionizing radiation remain obscure in mammalian cells; however, in the budding yeast the rad9 gene and in the fission yeast the chk1/rad27 gene are involved. There is evidence indicating that shortening of the G 2 arrest results in decreased survival which has led to the hypothesis that during this block, cells repair damaged DNA following exposure to genotoxic agents. In cell lines examined to date, wildtype p53 is required for the G 1 arrest following ionizing radiation. The gadd45 gene may also have a role in this arrest. Elimination of the G 1 arrest leads to no change in survival following radiation in some cell lines and increased radioresistance in others. It has been suggested that this induction of radioresistance in certain cell lines is due to loss of the ability to undergo apoptosis. Relatively little is known about the mechanism underlying the S phase delay. This delay is due to a depression in the rate of DNA synthesis and has both a slow and a fast component. In some cells the S phase delay can be abolished by staurosporine, suggesting involvement of a protein kinase. Understanding the molecular mechanisms behind these delays

[Decorporation agents for internal radioactive contamination].

Science.gov (United States)

Ohmachi, Yasushi

2015-01-01

When radionuclides are accidentally ingested or inhaled, blood circulation or tissue/organ deposition of the radionuclides causes systemic or local radiation effects. In such cases, decorporation therapy is used to reduce the health risks due to their intake. Decorporation therapy includes reduction and/or inhibition of absorption from the gastrointestinal tract, isotopic dilution, and the use of diuretics, adsorbents, and chelating agents. For example, penicillamine is recommended as a chelating agent for copper contamination, and diethylene triamine pentaacetic acid is approved for the treatment of internal contamination with plutonium. During chelation therapy, the removal effect of the drugs should be monitored using a whole-body counter and/or bioassay. Some authorities, such as the National Council on Radiation Protection and Measurements and International Atomic Energy Agency, have reported recommended decorporation agents for each radionuclide. However, few drugs are approved by the US Food and Drug Administration, and many are off-label-use agents. Because many decontamination agents are drugs that have been available for a long time and have limited efficacy, the development of new, higher-efficacy drugs has been carried out mainly in the USA and France. In this article, in addition to an outline of decorporation agents for internal radioactive contamination, an outline of our research on decorporation agents for actinide (uranium and plutonium) contamination and for radio-cesium contamination is also presented.

Homologous tracheal transplantation with grafts previously exposed to high doses of gamma radiation in dogs without immunosuppressive agents

International Nuclear Information System (INIS)

Yokomise, Hiroyasu; Inui, Kenji; Kure, Toshio; Wada, Hiromi; Itomi, Shigeki

1993-01-01

The study was designed to determine whether previous high doses irradiation of gamma radiation would contribute to tracheal transplantation with no use of immunosuppressive agents. Twenty mongrel dogs were used as experimental animals. Five rings of thoracic tracheas, which were extracted from recipients, were exposed to 20000, 50000, or 100000 cGy in each 5 dogs. Five other non-irradiated dogs served as controls. Irradiated tracheal grafts were transplanted and covered with pedicled omentum. After transplantation, no immunosuppressive agents were given to dogs. All dogs in the control group died of tracheal stenosis due to graft-host rejection within one month. All but one long-term survivor died of tracheal stenosis, as well, in both the 20000 cGy and 50000 cGy groups. In the 100000 cGy group, grafts became viable in 4 dogs, and three of these survived one year or more. In conclusion, previous irradiation with high doses of 100000 cGy allowed homologous tracheal transplantation even when no immunosuppressive agents are given. (N.K.)

Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

Science.gov (United States)

Comish, Paul B; Drumond, Ana Luiza; Kinnell, Hazel L; Anderson, Richard A; Matin, Angabin; Meistrich, Marvin L; Shetty, Gunapala

2014-01-01

Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼ 70% of control and induced atrophic seminiferous tubules in ∼ 30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.

Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

Directory of Open Access Journals (Sweden)

Paul B Comish

Full Text Available Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1 mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2% and to 80% in the male offspring of L1 (control value 33%. These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼ 70% of control and induced atrophic seminiferous tubules in ∼ 30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i DNA damage is a common mechanism leading to induction of testicular cancer, ii increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.

A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia

International Nuclear Information System (INIS)

Saland, E; Boutzen, H; Castellano, R; Pouyet, L; Griessinger, E; Larrue, C; Toni, F de; Scotland, S; David, M; Danet-Desnoyers, G; Vergez, F; Barreira, Y; Collette, Y; Récher, C; Sarry, J-E

2015-01-01

Relevant preclinical mouse models are crucial to screen new therapeutic agents for acute myeloid leukemia (AML). Current in vivo models based on the use of patient samples are not easy to establish and manipulate in the laboratory. Our objective was to develop robust xenograft models of human AML using well-characterized cell lines as a more accessible and faster alternative to those incorporating the use of patient-derived AML cells. Five widely used AML cell lines representing various AML subtypes were transplanted and expanded into highly immunodeficient non-obese diabetic/LtSz-severe combined immunodeficiency IL2Rγ c null mice (for example, cell line-derived xenografts). We show here that bone marrow sublethal conditioning with busulfan or irradiation has equal efficiency for the xenotransplantation of AML cell lines. Although higher number of injected AML cells did not change tumor engraftment in bone marrow and spleen, it significantly reduced the overall survival in mice for all tested AML cell lines. On the basis of AML cell characteristics, these models also exhibited a broad range of overall mouse survival, engraftment, tissue infiltration and aggressiveness. Thus, we have established a robust, rapid and straightforward in vivo model based on engraftment behavior of AML cell lines, all vital prerequisites for testing new therapeutic agents in preclinical studies

Study of occupational risk agents and its probable hazards to human health

International Nuclear Information System (INIS)

Carneiro, Janete Cristina G. Gaburo; Alves, Alice dos Santos; Sanches, Matias P.

2013-01-01

Currently the workplaces become increasingly complex and a strategy evaluation and the control of occupational risks agents is needed. Workers may be exposed to environmental agents (chemical, physical and biological) and other unsuitable conditions by performing tasks that involve these agents directly. The main objective of this study is to approach conceptual aspects of risk conditions, physical in nature, with emphasis on ionizing radiation and its interaction with other agents in occupational and environmental situations. To meet this goal, it is performed a literature review and a summary of the main occupational agents known or suspected to cause any adverse health effects in humans. According to the available literature the reported studies on the effects of combined exposures to radiation and others agents are recognized and, as far as possible, should be taken into account in evaluating of the potential radiation risks at low levels of exposure. (author)

Correlation between radioactivity and chemotherapeutics of the 111In-VNB-liposome in pharmacokinetics and biodistribution in rats

Directory of Open Access Journals (Sweden)

Tsai TH

2012-02-01

Full Text Available Wen-Chuan Lee1,*, Chih-Hsien Chang2,3,*, Chih-Min Huang1, Yu-Tse Wu1, Liang-Cheng Chen2, Chung-Li Ho2, Tsui-Jung Chang2, Te-Wei Lee2, Tung-Hu Tsai1,41Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, 2Division of Isotope Application, Institute of Nuclear Energy Research, Taoyuan, 3Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 4Department of Education and Research, Taipei City Hospital, Taipei, Taiwan*These authors contributed equally to this workBackground: The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [111In-VNB-liposome] has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the 111In-VNB-liposome.Methods: The VNB-liposome and 111In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the 111In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111.Results: High uptake of the 111In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation (r = 0.97 between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the 111In-VNB-liposome.Conclusion: A significant positive correlation between the pharmacokinetics and biodistribution of 111Indium radioactivity and vinorelbine in blood, spleen

Perspectives on Phytochemicals as Antibacterial Agents: An Outstanding Contribution to Modern Therapeutics.

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Khatri, Savita; Kumar, Manish; Phougat, Neetu; Chaudhary, Renu; Chhillar, Anil Kumar

2016-01-01

Despite the considerable advancements in the development of antimicrobial agents, incidents of epidemics due to multi drug resistance in microorganisms have created a massive hazard to mankind. Due to increased resistance against conventional antibiotics, researchers and pharmaceutical industries are more concerned about novel therapeutic agents for the prevention of bacterial infections. Enormous wealth of traditional system of medicine gains importance in health therapies over again. With ancient credentials of potent medicinal plants, various herbal remedies came forward for the management of bacterial infections. The Ayurvedic approach facilitates the development of new therapeutic agents due to structural and functional diversity among phytochemicals. The abundance and diversity is responsible for the characterization of new lead structures from medicinal plants. Industrial interest has increased due to recent research advancements viz. synergistic and high-throughput screening approach for the evaluation of vast variety of phytochemicals. The review certainly emphasizes on the traditional medicines as alternatives to conventional chemotherapeutic drugs. The review briefly describes mode of action of various antibiotics and resistance mechanisms. This review focuses on the chemical diversity and various mechanisms of action of phytochemicals against bacterial pathogens.

Correlation of chromosome patterns in human leukemic cells with exposure to chemicals and/or radiation. Progress report, January 1, 1981-December 31, 1981

International Nuclear Information System (INIS)

Rowley, J.D.

1981-08-01

The overall aim is to determine whether there is a relationship between exposure to radiation, environmental pollutants, and/or genetic background and the development of ANLL or other hematologic malignancies. I will try to define the factors that influence the development of ANLL as a second malignancy in patients who have been exposed to large doses of radiotherapy and/or chemotherapeutic agents. Two long-term goals are (1) to identify the genes that are located at the sites of consistent translocations, and then to determine the alterations in gene function that are associated with these translocations and (2) to establish the baseline frequency of various chromosome changes (mutations) in myeloid cells and then to analyze the influence of various types of environmental exposure or medical treatment on this baseline mutation rate. Ultimately, it may be possible to determine the extent of mutagenic exposure in various populations through an analysis of the leukemic cells of that populations

[Ebola hemorrhagic fever: Properties of the pathogen and development of vaccines and chemotherapeutic agents].

Science.gov (United States)

Kiselev, O I; Vasin, A V; Shevyryova, M P; Deeva, E G; Sivak, K V; Egorov, V V; Tsvetkov, V B; Egorov, A Yu; Romanovskaya-Romanko, E A; Stepanova, L A; Komissarov, A B; Tsybalova, L M; Ignatjev, G M

2015-01-01

Ebola hemorrhagic fever (EHF) epidemic currently ongoing in West Africa is not the first among numerous epidemics in the continent. Yet it seems to be the worst EHF epidemic outbreak caused by Ebola virus Zaire since 1976 as regards its extremely large scale and rapid spread in the population. Experiments to study the agent have continued for more than 20 years. The EHF virus has a relatively simple genome with seven genes and additional reading frame resulting from RNA editing. While being of a relatively low genetic capacity, the virus can be ranked as a standard for pathogenicity with the ability to evade the host immune response in uttermost perfection. The EHF virus has similarities with retroviruses, but belongs to (-)RNA viruses of a nonretroviral origin. Genetic elements of the virus, NIRV, were detected in animal and human genomes. EHF virus glycoprotein (GP) is a class I fusion protein and shows more similarities than distinctions in tertiary structure with SIV and HIV gp41 proteins and even influenza virus hemagglutinin. EHF is an unusual infectious disease, and studying the molecular basis of its pathogenesis may contribute to new findings in therapy of severe conditions leading to a fatal outcome.

Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy: a novel strategy in drug development

Directory of Open Access Journals (Sweden)

Jan eStenvang

2013-12-01

Full Text Available Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and, unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I inhibitors and topoisomerase I as a potential predictive biomarker as case in point.

The ROS/SUMO Axis Contributes to the Response of Acute Myeloid Leukemia Cells to Chemotherapeutic Drugs

Directory of Open Access Journals (Sweden)

Guillaume Bossis

2014-06-01

Full Text Available Chemotherapeutic drugs used in the treatment of acute myeloid leukemias (AMLs are thought to induce cancer cell death through the generation of DNA double-strand breaks. Here, we report that one of their early effects is the loss of conjugation of the ubiquitin-like protein SUMO from its targets via reactive oxygen species (ROS-dependent inhibition of the SUMO-conjugating enzymes. Desumoylation regulates the expression of specific genes, such as the proapoptotic gene DDIT3, and helps induce apoptosis in chemosensitive AMLs. In contrast, chemotherapeutics do not activate the ROS/SUMO axis in chemoresistant cells. However, pro-oxidants or inhibition of the SUMO pathway by anacardic acid restores DDIT3 expression and apoptosis in chemoresistant cell lines and patient samples, including leukemic stem cells. Finally, inhibition of the SUMO pathway decreases tumor growth in mice xenografted with AML cells. Thus, targeting the ROS/SUMO axis might constitute a therapeutic strategy for AML patients resistant to conventional chemotherapies.

Preparation of 99mTc-Ancitabine as a Possible Tumor Imaging Agent

International Nuclear Information System (INIS)

Ibrahim, I.T.; Attallah, K.M.

2010-01-01

Ancitabine is one of the potent chemotherapeutic anticancer drugs. Tc-Ancitabine ( 99m Tc-ANC) was prepared using stannous chloride as reducing agent, which produced yield above 90% at ph 4 at room temperature within 1-5 min as reaction time. The labeled drug was stable for more than 8 h post labeling. Biodistribution study of 99m Tc-ANC in normal mice reflected that its uptake was increased in organ of high proliferation like stomach. In solid tumor bearing mice 99m Tc-ANC was incorporated rapidly in tumor site and declined slowly, while it was declined rapidly from other tissues. Biodistribution of 99m Tc-ANC in solid tumor presented a possible model for imaging of tumors.

Report on NCI symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. II. Cellular and animal models

International Nuclear Information System (INIS)

Fry, R.J.M.

1984-01-01

The point at which the common final pathway for induction of cancer by chemical carcinogens and ionizing radiation has not been identified. Although common molecular targets are suggested by recent findings about the role of oncogenes, the mechanism by which the deposition of radiation energy and the formation of adducts or other DNA lesions induced by chemicals affects the changes in the relevant targets may be quite different. The damage to DNA that plays no part in the transformation events, but that influences the stability of the genome, and therefore, the probability of subsequent changes that influence tumorigenesis may be more readily induced by some agents than others. Similarly, the degree of cytotoxic effects that disrupt tissue integrity and increase the probability of expression of initiated cells may be dependent on the type of carcinogen. Also, evidence was presented that repair of the initial lesions could be demonstrated after exposure to low-LET radiation but not after exposure to chemical carcinogens

Report on NCI symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. II. Cellular and animal models

Energy Technology Data Exchange (ETDEWEB)

Fry, R.J.M.

1984-01-01

The point at which the common final pathway for induction of cancer by chemical carcinogens and ionizing radiation has not been identified. Although common molecular targets are suggested by recent findings about the role of oncogenes, the mechanism by which the deposition of radiation energy and the formation of adducts or other DNA lesions induced by chemicals affects the changes in the relevant targets may be quite different. The damage to DNA that plays no part in the transformation events, but that influences the stability of the genome, and therefore, the probability of subsequent changes that influence tumorigenesis may be more readily induced by some agents than others. Similarly, the degree of cytotoxic effects that disrupt tissue integrity and increase the probability of expression of initiated cells may be dependent on the type of carcinogen. Also, evidence was presented that repair of the initial lesions could be demonstrated after exposure to low-LET radiation but not after exposure to chemical carcinogens.

Radiation-induced molecular imprinting of D-glucose onto poly(2-hydroxyethyl methacrylate) matrices using various crosslinking agents

International Nuclear Information System (INIS)

Ates, Zeliha; Gueven, Olgun

2010-01-01

Radiation-induced molecular imprinting of D-glucose onto poly(2-hydroxyethyl methacrylate) matrix was achieved to create three-dimensional cavities to recognize and bind D-glucose. The optimization of imprinting capability of matrices was achieved by investigating the effects of various parameters such as the type and amount of crosslinking agent, type of solvent, template to monomer ratio and total absorbed dose. Crosslinking agents with increasing chain lengths and different flexibilities were used in an attempt to elucidate the impact of relevant imprint parameters on the effectiveness of imprinting technique. The absorbed dose varied from 1 to 15 kGy. Cavity sizes of MIPs were measured by positron annihilation lifetime (PAL) experiments. Control matrices were synthesized with exactly the same composition in the absence of D-glucose. Separation of D-glucose has been shown to be successfully achieved in HPLC columns filled with MIPs whereas no separation was observed for non-imprint matrices.

Ways of improvement of treatment of esophageal cancer

International Nuclear Information System (INIS)

Kochegarov, A.A.

1984-01-01

An analysis of the results of treatment of 344 patients with cancer of the thoracic part of the esophagus was performed. Out of those, 104 received surgical and combined treatment and 240 (inoperable cancer) were given radiotherapy alone or in cOmbination with local hyperthermia, general chemotherapy or intratumoral iontophoresis of chemotherapeutic agents. The operation after Dobromyslov-Torek proved to be insufficient in most of surgical cases because there were metastatic lesions below the diaphragm. Local hyperthermia potentiated the effect of radiation treatment. The early results of treatment improved after intratumoral sarcolysin ionophoresis was used in conjunction with radiation therapy

Decontamination method and device for radiation contaminated product

International Nuclear Information System (INIS)

Morikawa, Kenji; Ohinata, Hiroshi; Omata, Kazuo; Sato, Toshihiko; Nakajima, Yoshihiko; Ichikawa, Seigo.

1996-01-01

In the present invention, radiation contaminated products generated during shot peening are decontaminated by a chelating agent, and the chelating agent is removed from the radiation contaminated products. Then the temperature of the radiation contaminated products is elevated by hot blowing at a temperature higher than a boiling point of the solvent. Then, a solvent is added to the radiation contaminated products and the solvent is evaporated abruptly. The solution of the chelating agent remained while being deposited thereto is removed by evaporation to remove it from the radiation contaminated products together with the solvent. With such procedures, all of the decontamination steps can be completed in one device without requiring a large space or not moving the radiation contaminated products on every step. (T.M.)

Synthesis and evaluation of new protecting agents against ionizing radiations

International Nuclear Information System (INIS)

Nadal, B.

2009-10-01

This thesis is devoted to the synthesis of new pulvinic acid derivatives and the evaluation of their antioxidant and radioprotective properties. This study has been conducted with the aim to develop new protecting agents against ionizing radiations. A new access to pulvinic acid derivatives was developed starting from L-dimethyl tartrate. It is based on a Dieckmann cyclization a dehydration and a Suzuki-Miyaura coupling. It allows a short effective preparation of various pulvinic acid derivatives: tetronic acid derivatives, mono-substituted pulvinic acid derivatives and methyl pulvinates. A modified method has been used to prepare pulvinones. This strategy gave access in four steps to the desired pulvinones. The rapidity of this method is provided by a tandem process, carried out in the final step, involving a Dieckmann cyclization and a β-elimination. A synthesis of 3-aryltetramic acids has also been developed in order to prepare nitrogen derivatives of pulvinic acid. The antioxidant activity of the prepared compounds was then evaluated using various tests: DPPH, ABTS, protection of thymidine and DNA study of lipid peroxidation. These evaluations allowed to define interesting structure-activity relationships of pulvinic derivatives. They have shown that several derivatives have very good antioxidant activities. Finally, radioprotective tests on TK6 cells and mice have have been performed on selected compounds. (author)

Natural agents: cellular and molecular mechanisms of photoprotection.

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Afaq, Farrukh

2011-04-15

The skin is the largest organ of the body that produces a flexible and self-repairing barrier and protects the body from most common potentially harmful physical, environmental, and biological insults. Solar ultraviolet (UV) radiation is one of the major environmental insults to the skin and causes multi-tiered cellular and molecular events eventually leading to skin cancer. The past decade has seen a surge in the incidence of skin cancer due to changes in life style patterns that have led to a significant increase in the amount of UV radiation that people receive. Reducing excessive exposure to UV radiation is desirable; nevertheless this approach is not easy to implement. Therefore, there is an urgent need to develop novel strategies to reduce the adverse biological effects of UV radiation on the skin. A wide variety of natural agents have been reported to possess substantial skin photoprotective effects. Numerous preclinical and clinical studies have elucidated that natural agents act by several cellular and molecular mechanisms to delay or prevent skin cancer. In this review article, we have summarized and discussed some of the selected natural agents for skin photoprotection. Copyright © 2010 Elsevier Inc. All rights reserved.

Quantitative risk in radiation protection standards

International Nuclear Information System (INIS)

Bond, V.P.

1978-01-01

The bases for developing quantitative assessment of exposure risks in the human being, and the several problems that accompany the assessment and introduction of the risk of exposure to high and low LET radiation into radiation protection, will be evaluated. The extension of the pioneering radiation protection philosophies to the control of other hazardous agents that cannot be eliminated from the environment will be discussed, as will the serious misunderstandings and misuse of concepts and facts that have inevitably surrounded the application to one agent alone, of the protection philosophy that must in time be applied to a broad spectrum of potentially hazardous agents. (orig.) [de

Genotoxic Effects of Low- and High-LET Radiation on Human Epithelial Cells Grown in 2-D Versus 3-D Culture

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Patel, Z. S.; Cucinotta, F. A.; Huff, J. L.

2011-01-01

Risk estimation for radiation-induced cancer relies heavily on human epidemiology data obtained from terrestrial irradiation incidents from sources such as medical and occupational exposures as well as from the atomic bomb survivors. No such data exists for exposures to the types and doses of high-LET radiation that will be encountered during space travel; therefore, risk assessment for space radiation requires the use of data derived from cell culture and animal models. The use of experimental models that most accurately replicate the response of human tissues is critical for precision in risk projections. This work compares the genotoxic effects of radiation on normal human epithelial cells grown in standard 2-D monolayer culture compared to 3-D organotypic co-culture conditions. These 3-D organotypic models mimic the morphological features, differentiation markers, and growth characteristics of fully-differentiated normal human tissue and are reproducible using defined components. Cultures were irradiated with 2 Gy low-LET gamma rays or varying doses of high-LET particle radiation and genotoxic damage was measured using a modified cytokinesis block micronucleus assay. Our results revealed a 2-fold increase in residual damage in 2 Gy gamma irradiated cells grown under organotypic culture conditions compared to monolayer culture. Irradiation with high-LET particle radiation gave similar results, while background levels of damage were comparable under both scenarios. These observations may be related to the phenomenon of "multicellular resistance" where cancer cells grown as 3-D spheroids or in vivo exhibit an increased resistance to killing by chemotherapeutic agents compared to the same cells grown in 2-D culture. A variety of factors are likely involved in mediating this process, including increased cell-cell communication, microenvironment influences, and changes in cell cycle kinetics that may promote survival of damaged cells in 3-D culture that would

Radiation, hypoxia and genetic stimulation: implications for future therapies

International Nuclear Information System (INIS)

Adams, Gerald E.; Hasan, Na'il M.; Joiner, Michael C.

1997-01-01

The cellular stress response, whereby very low doses of cytotoxic agents induce resistance to much higher doses, is an evolutionary defence mechanism and is stimulated following challenges by numerous chemical, biological and physical agents including particularly radiation, drugs, heat and hypoxia. There is much homology in the effects of these agents which are manifest through the up-regulation of various genetic pathways. Low-dose radiation stress influences processes involved in cell-cycle control, signal transduction pathways, radiation sensitivity, changes in cell adhesion and cell growth. There is also homology between radiation and other cellular stress agents, particularly hypoxia. Whereas traditionally, hypoxia was regarded mainly as an agent conferring resistance to radiation, there is now much evidence illustrating the cytokine-like properties of hypoxia as well as radiation. Stress phenomena are likely to be important in risks arising from low doses of radiation. Conversely, exploitation of the stress response in settings appropriate to therapy can be particularly beneficial not only in regard to radiation alone but in combinations of radiation and drugs. Similarly, tissue hypoxia can be exploited in novel ways of enhancing therapeutic efficacy. Bioreductive drugs, which are cytotoxically activated in hypoxic regions of tissue, can be rendered even more effective by hypoxia-induced increased expression of enzyme reductases. Nitric oxide pathways are influenced by hypoxia thereby offering possibilities for novel vascular based therapies. Other approaches are discussed

All-in-one theranostic nanoagent for head and neck cancer treatment

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Dreifuss, Tamar; Davidi, Erez Shmuel; Motiei, Menachem; Barnoy, Eran; Bragilovski, Dimitri; Lubimov, Leon; Kindler, Marc Jose Jonathan; Popovtzer, Aron; Popovtzer, Rachela

2018-02-01

Despite the significant improvement in the treatment paradigm of head and neck cancer, owing to advanced radiation techniques in combination with chemotherapy, resistance of tumors remains a critical problem, leading to poor outcomes and negative prognosis. In addition, chemotherapeutic agents result in severe systemic toxicity due to nonselective damaging of normal cells. Recently, nanoparticle-based approaches have gained broad attention for improving both radiation therapy and chemotherapy. In this study, we present a dual effect nanoplatform, consists of gold nanoparticles coated with glucose and cisplatin (CG-GNPs), which simultaneously acts as a radiosensitizer and as a carrier which specifically deliver cisplatin to head and neck tumor. Our CG-GNPs showed significant penetration into tumor cells and similar cellular toxicity as cisplatin alone. Moreover, in combination with radiation treatment, CG-GNPs led to greater tumor reduction than that of free cisplatin with radiation. Furthermore, our CG-GNPs also demonstrated highly efficient imaging capabilities, as they act as ideal tumor-targeted CT contrast agent. Therefore, this single nano-formulation is a promising theranostic agent that has the potential to increase the antitumor effect and allow imaging guided therapy.

Epigenetics of oropharyngeal squamous cell carcinoma: opportunities for novel chemotherapeutic targets.

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Lindsay, Cameron; Seikaly, Hadi; Biron, Vincent L

2017-01-31

Epigenetic modifications are heritable changes in gene expression that do not directly alter DNA sequence. These modifications include DNA methylation, histone post-translational modifications, small and non-coding RNAs. Alterations in epigenetic profiles cause deregulation of fundamental gene expression pathways associated with carcinogenesis. The role of epigenetics in oropharyngeal squamous cell carcinoma (OPSCC) has recently been recognized, with implications for novel biomarkers, molecular diagnostics and chemotherapeutics. In this review, important epigenetic pathways in human papillomavirus (HPV) positive and negative OPSCC are summarized, as well as the potential clinical utility of this knowledge.This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair.

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Löser, Dana A; Shibata, Atsushi; Shibata, Akiko K; Woodbine, Lisa J; Jeggo, Penny A; Chalmers, Anthony J

2010-06-01

As single agents, chemical inhibitors of poly(ADP-ribose) polymerase (PARP) are nontoxic and have clinical efficacy against BRCA1- and BRCA2-deficient tumors. PARP inhibitors also enhance the cytotoxicity of ionizing radiation and alkylating agents but will only improve clinical outcomes if tumor sensitization exceeds effects on normal tissues. It is unclear how tumor DNA repair proficiency affects the degree of sensitization. We have previously shown that the radiosensitizing effect of PARP inhibition requires DNA replication and will therefore affect rapidly proliferating tumors more than normal tissues. Because many tumors exhibit defective DNA repair, we investigated the impact of double-strand break (DSB) repair integrity on the sensitizing effects of the PARP inhibitor olaparib. Sensitization to ionizing radiation and the alkylating agent methylmethane sulfonate was enhanced in DSB repair-deficient cells. In Artemis(-/-) and ATM(-/-) mouse embryo fibroblasts, sensitization was replication dependent and associated with defective repair of replication-associated damage. Radiosensitization of Ligase IV(-/-) mouse embryo fibroblasts was independent of DNA replication and is explained by inhibition of "alternative" end joining. After methylmethane sulfonate treatment, PARP inhibition promoted replication-independent accumulation of DSB, repair of which required Ligase IV. Our findings predict that the sensitizing effects of PARP inhibitors will be more pronounced in rapidly dividing and/or DNA repair defective tumors than normal tissues and show their potential to enhance the therapeutic ratio achieved by conventional DNA-damaging agents.

Antimicrobial efficacy of oral topical agents on microorganisms associated with radiated head and neck cancer patients: an in vitro study.

Science.gov (United States)

Bidra, Avinash S; Tarrand, Jeffery J; Roberts, Dianna B; Rolston, Kenneth V; Chambers, Mark S

2011-04-01

A variety of oral topical agents have been used for prevention and management of radiotherapy-induced adverse effects. The antimicrobial nature of some of the commonly used agents is unknown. The purpose of this study was to evaluate antimicrobial efficacies of various oral topical agents on common microorganisms associated with radiated head and neck cancer patients. Seven commonly used topical oral agents-0.12% chlorhexidine with alcohol, 0.12% chlorhexidine without alcohol, baking soda-salt rinse, 0.4% stannous fluoride gel, 0.63% stannous fluoride rinse, calcium phosphate mouthrinse, and acemannan hydrogel (aloe vera) rinse-were evaluated in vitro for their antimicrobial efficacies against four common microorganisms. A combination of baking soda-salt rinse and 0.4% stannous fluoride gel was evaluated as the eighth agent. The microorganisms used were Staphylococcus aureus, group B Streptococcus, Escherichia coli, and Candida albicans. An ELISA reader was used to measure the turbidity of microbial culture wells and optical density (OD) values for each of the 960 wells recorded. Mean OD values were rank ordered based on their turbidity. One-way ANOVA with Tukey HSD post hoc analysis was used to study differences in OD values (P baking soda- salt, calcium phosphate rinse, and the combination of baking soda-salt and stannous fluoride gel. Mean OD values classified for microorganisms from lowest to highest were Escherichia coli, Staphylococcus aureus, group B Streptococcus, and Candida albicans. A significant difference among the antimicrobial efficacies of topical agents was evident for each of four microorganisms (P < .05). There was also a significant difference among the antimicrobial efficacies of the same topical agent on the four microorganisms tested (P < .05).

New strategies to interfere with radiation response: bio-modulation of radiation therapy

International Nuclear Information System (INIS)

Deutsch, E.; Kaliski, A.; Maggiorella, L.; Bourhis, J.

2005-01-01

The development of several new anti cancer agents has been made possible because of recent significant achievements in our global understanding of cancer biology. These new 'targeted' agents selectively inhibit targets necessary for tumor cell growth and viability with little toxicity to normal cells compared to conventional cytotoxic agents. So far, the efficacy of many of these new promising agents when used alone treatment remains limited, it is likely that the optimal use of these agents could be obtained in combination with conventional agents such as radiation therapy. The potential benefit of these targeted therapies combined with irradiation seems important. They might offer the advantage of increasing the tumor response to radiation with no or little increase in normal tissue damage. Therefore, these new types of chemo-radiation approaches might respect the normal tissue versus tumor cell 'therapeutic ratio'. These approaches can be sub divided in three sub groups: 1) Therapeutics targeting selectively one tumor related biochemical activity such as EGFR inhibitors. These approaches are efficient but one mutation of the target might render them inefficient. 2) Therapeutics directed against a widely expressed target. This is the case for anti insulin Growth Factor-1 (IGFIR) interventions: IGFIR inhibition seems to specifically alter tumor cell viability with a minimal effect on normal cells viability. 3) Strategies which are not targeted against the tumor but the microenvironment, especially angiogenesis. This type of approaches seems to be applicable independently of tumor intrinsic biologic related factors. (author)

Strategies for protection against exposure to ionizing radiation

International Nuclear Information System (INIS)

Goel, H.C.

2005-01-01

Radiations are known to be mutagenic, carcinogenic and cyto-lethal depending on the total dose, dose rate, quality of radiation and many other factors related to the person exposed. Therefore strategies for protection against exposure to ionizing radiations have to be accordingly planned. Radioprotection, though remains prophylactic in principle, includes mitigating and therapeutic modalities also. Initially, the central theme of biological radioprotection has been to protect against radiation-induced lethality and to optimize radiotherapy of tumours; the emphasis has now extended to cover many more situations of planned and unplanned nature. The central dogma of radioprotection work has been antioxidant action, which is relevant indeed against low LET radiation. The increasing understanding of the mechanism of radiation damage, however, permitted the advent of newer agents of both synthetic and natural origin. Sulfhydryl compounds like cysteamine, AET, Amifostine and endogenous molecules like GSH, SOD etc have been very important agents. Molecules like cytokines, immunomodulators, anti-inflammatory agents, angiotensin converting enzymes, metallo-elements and metallothionins, DNA ligands and Calcium antagonists have also been investigated recently. Unfortunately, no single agent could yield desired results especially due to toxicity at their radioprotective concentration. This led to the emergence of combinational modality where two or more agents working with different mechanisms could synergistically complement radioprotective action.. Recently, herbal extracts and dietary agents, which are the natural combinations of a large number of compounds that have important attributes to counter the damaging effects of ionizing radiations, have gained world-wide interest.. These agents have been found to be less toxic. Decorporation of radionuclei and protection against low dose chronic exposures like space flights and long haul inter-continental flights need to be

In-vivo models for radiation mitigator agents

International Nuclear Information System (INIS)

Macchiarini, Francesca

2014-01-01

The US Department of Health and Human Services assigned the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH), with the responsibility to identify, characterize and develop new medical countermeasure (MCM) products against radiological and nuclear attacks that may cause-a public health emergency. MCMs must be developed within the criteria of the U.S. Food and Drug Administration's (FDA) 'animal rule' (AR) which requires the design and conduct of validated animal models to define the major sequelae of the Acute Radiation Syndrome (ARS) and Delayed Effects of Acute Radiation Exposure (DEARE). To this end, the NIAID-funded Product Development Support Services Program has established an ARS/DEARE animal model research platform which includes several basic animal models for hematopoietic and gastrointestinal ARS in the mouse and nonhuman primate (NHP) using total-body irradiation (TBI), whole-thorax lung irradiation (WTLI), or a multi-organ dysfunction model defined by partial-body irradiation with 5% bone marrow sparing (PBI/ BM5). These specific models will be discussed as well as ongoing observational studies NIAID is funding to assess the long-term effects of radiation in NHPs and A-Bomb survivors. (author)

Radiation and contrast agent doses reductions by using 80-kV tube voltage in coronary computed tomographic angiography: A comparative study

Energy Technology Data Exchange (ETDEWEB)

Cao, Jian-xin [Department of Radiology, Wuhan 161th Hospital, Wuhan (China); Wang, Yi-min, E-mail: wym6669@yahoo.com.cn [Department of Radiology, Wuhan 161th Hospital, Wuhan (China); Lu, Jin-guo [Department of Cardiology, Asia Heart Hospital, Wuhan (China); Zhang, Yu; Wang, Peng; Yang, Cheng [Department of Radiology, Wuhan 161th Hospital, Wuhan (China)

2014-02-15

Objective: To investigate the effects of 80-kilovoltage (kV) tube voltage coronary computed tomographic angiography (CCTA) with a reduced amount of contrast agent on qualitative and quantitative image quality parameters and on radiation dose in patients with a body mass index (BMI) <23.0 kg/m{sup 2}. Methods: One hundred and twenty consecutive patients with a BMI <23.0 kg/m{sup 2} and a low calcium load undergoing retrospective electrocardiogram (ECG)-gated dual-source CCTA were randomized into two groups [standard-tube voltage (120-kV) vs. low-tube voltage (80-kV)]. The injection flow rate of contrast agent (350 mg I/mL) was adjusted to body weight of each patient (4.5–5.5 mL/s in the 120-kV group and 2.8–3.8 mL/s in the 80-kV group). Radiation and contrast agent doses were evaluated. Quantitative image quality parameters and figure of merit (FOM) of coronary artery were evaluated. Each coronary segment was evaluated for image quality on a 4-point scale. Results: Compared with the 120-kV group, effective dose and amount of contrast agent in the 80-kV group were decreased by 57.8% and 30.5% (effective dose:2.7 ± 0.5vs. 6.4 ± 1.3 mSv; amount of contrast agent:57.1 ± 3.2 vs. 82.1 ± 6.1 mL; both p < 0.0001), respectively. Image noise was 22.7 ± 2.1 HU for 120-kV images and 33.2 ± 5.2 HU for 80-kV images (p < 0.0001). Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in the proximal right coronary artery (RCA) and left main coronary artery (LMA) were all lower in 80-kV than 120-kV images (SNR in the proximal RCA: 16.5 ± 1.8 vs. 19.4 ± 2.8; SNR in the LMA: 16.3 ± 2.0 vs.19.6 ± 2.7; CNR in the proximal RCA: 19.4 ± 2.3 vs.22.9 ± 3.0; CNR in the LMA: 18.8 ± 2.4 vs. 22.7 ± 2.9; all p < 0.0001). FOM were all significantly higher in 80-kV than 120-kV images (proximal RCA: 146.7 ± 45.1 vs. 93.4 ± 32.0; LMA: 139.1 ± 47.2 vs. 91.6 ± 31.1; all p < 0.0001). There was no significant difference in image quality score between the two groups (3.3 ± 0

Radiation and contrast agent doses reductions by using 80-kV tube voltage in coronary computed tomographic angiography: A comparative study

International Nuclear Information System (INIS)

Cao, Jian-xin; Wang, Yi-min; Lu, Jin-guo; Zhang, Yu; Wang, Peng; Yang, Cheng

2014-01-01

Objective: To investigate the effects of 80-kilovoltage (kV) tube voltage coronary computed tomographic angiography (CCTA) with a reduced amount of contrast agent on qualitative and quantitative image quality parameters and on radiation dose in patients with a body mass index (BMI) <23.0 kg/m 2 . Methods: One hundred and twenty consecutive patients with a BMI <23.0 kg/m 2 and a low calcium load undergoing retrospective electrocardiogram (ECG)-gated dual-source CCTA were randomized into two groups [standard-tube voltage (120-kV) vs. low-tube voltage (80-kV)]. The injection flow rate of contrast agent (350 mg I/mL) was adjusted to body weight of each patient (4.5–5.5 mL/s in the 120-kV group and 2.8–3.8 mL/s in the 80-kV group). Radiation and contrast agent doses were evaluated. Quantitative image quality parameters and figure of merit (FOM) of coronary artery were evaluated. Each coronary segment was evaluated for image quality on a 4-point scale. Results: Compared with the 120-kV group, effective dose and amount of contrast agent in the 80-kV group were decreased by 57.8% and 30.5% (effective dose:2.7 ± 0.5vs. 6.4 ± 1.3 mSv; amount of contrast agent:57.1 ± 3.2 vs. 82.1 ± 6.1 mL; both p < 0.0001), respectively. Image noise was 22.7 ± 2.1 HU for 120-kV images and 33.2 ± 5.2 HU for 80-kV images (p < 0.0001). Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in the proximal right coronary artery (RCA) and left main coronary artery (LMA) were all lower in 80-kV than 120-kV images (SNR in the proximal RCA: 16.5 ± 1.8 vs. 19.4 ± 2.8; SNR in the LMA: 16.3 ± 2.0 vs.19.6 ± 2.7; CNR in the proximal RCA: 19.4 ± 2.3 vs.22.9 ± 3.0; CNR in the LMA: 18.8 ± 2.4 vs. 22.7 ± 2.9; all p < 0.0001). FOM were all significantly higher in 80-kV than 120-kV images (proximal RCA: 146.7 ± 45.1 vs. 93.4 ± 32.0; LMA: 139.1 ± 47.2 vs. 91.6 ± 31.1; all p < 0.0001). There was no significant difference in image quality score between the two groups (3.3 ± 0.8 vs. 3

Cycloxygenase-2(cox-2) - a potential target for screening of small molecules as radiation countermeasure agents: an in silico study

International Nuclear Information System (INIS)

Joshi, Jayadev; Shrivastava, Nitisha; Dimri, Manali; Ghosh, Subhajit; Mandal, Rahul Shubhra; Prem Kumar, I.; Barik, Tapan Kumar

2012-01-01

COX-2 is well established for its role in inflammation and cancer, and has also been reported to play a significant role in radiation induced inflammation and by standard effect. It's already reported to have a role in protection against radiation induced damage suggesting it to be an important target for identifying novel radiation countermeasure agents. Present study aims at identifying novel small molecules from pharmacopoeia using COX-2 as target in-silico. Systematic search of the reported molecules exhibiting radiation protection revealed lat around 29 % (40 in 138) of them have a role in inflammation and a small percentage of these molecules (20 %; 8 in 40) are reported to as non steroidal anti-inflammatory drugs (NSAIDS). Docking studies performed further clarified that all these 8 radioprotective molecules shows high binding affinity and inhibit COX-2. Further Johns Hopkins clinical compound library (JHCCL), a collection of small molecule clinical compounds, were screened virtually for COX-2 inhibition by docking approach. Docking of around 1400 small molecules against COX-2 lead to identification of a number of previously unreported molecules which are likely to act as radioprotectors. (author)

Cycloxygenase-2(cox-2) - a potential target for screening of small molecules as radiation countermeasure agents: an in silico study

Energy Technology Data Exchange (ETDEWEB)

Joshi, Jayadev; Shrivastava, Nitisha; Dimri, Manali; Ghosh, Subhajit; Mandal, Rahul Shubhra; Prem Kumar, I., E-mail: prem_indra@yahoo.co.in [Radiation Biosciences Division, Institute of Nuclear Medicine and Allied Sciences, Delhi (India); Barik, Tapan Kumar [P.G. Department of Zoology, Berhampur University, Berhampur (India)

2012-07-01

COX-2 is well established for its role in inflammation and cancer, and has also been reported to play a significant role in radiation induced inflammation and by standard effect. It's already reported to have a role in protection against radiation induced damage suggesting it to be an important target for identifying novel radiation countermeasure agents. Present study aims at identifying novel small molecules from pharmacopoeia using COX-2 as target in-silico. Systematic search of the reported molecules exhibiting radiation protection revealed lat around 29 % (40 in 138) of them have a role in inflammation and a small percentage of these molecules (20 %; 8 in 40) are reported to as non steroidal anti-inflammatory drugs (NSAIDS). Docking studies performed further clarified that all these 8 radioprotective molecules shows high binding affinity and inhibit COX-2. Further Johns Hopkins clinical compound library (JHCCL), a collection of small molecule clinical compounds, were screened virtually for COX-2 inhibition by docking approach. Docking of around 1400 small molecules against COX-2 lead to identification of a number of previously unreported molecules which are likely to act as radioprotectors. (author)

Dose-Effect Relationship of Alkylating Agents on Testicular Function in Male Survivors of Childhood Lymphoma.

Science.gov (United States)

Servitzoglou, Marina; De Vathaire, Florent; Oberlin, Odile; Patte, Catherine; Thomas-Teinturier, Cécile

2015-01-01

The purpose of our study was to assess the gonadal function in male survivors of childhood lymphoma. We studied 171 male survivors of childhood lymphoma (83 with B-cell non-Hodgkin lymphoma [B-NHL], 32 with T-cell non-Hodgkin lymphoma [T-NHL], 50 with Hodgkin lymphoma [HL], and 6 with anaplastic large-cell lymphoma [ALCL]), measuring follicle-stimulating hormone [FSH] and luteinizing hormone [LH] levels at a median age of 21.1 (17-30.4) years after a median delay of 9.3 (2-22.4) years from treatment. FSH levels were above normal range (≥10 IU/L) in 42.1% and LH levels ≥8 IU/L in only 8.9% of survivors. In multivariate analysis, only the following chemotherapeutic agents were associated with higher FSH or LH levels: cyclophosphamide (P alkylating agents on childhood lymphoma survivors is dose dependent and not correlated to diagnosis, age, or pubertal status at diagnosis.

Radioprotective Agents

Directory of Open Access Journals (Sweden)

Ilker Kelle

2008-01-01

Full Text Available Since1949, a great deal of research has been carried out on the radioprotective activity of various chemical substances. Thiol compounds, compounds which contain –SH radical, different classes of pharmacological agents and other compounds such as vitamine C and WR-2721 have been shown to reduce mortality when administered prior to exposure to a lethal dose of radiation. Recently, honey bee venom as well as that of its components melittin and histamine have shown to be valuable in reduction of radiation-induced damage and also provide prophylactic alternative treatment for serious side effects related with radiotherapy. It has been suggested that the radioprotective activity of bee venom components is related with the stimulation of the hematopoetic system.

A molecular targeting against nuclear factor-κB, as a chemotherapeutic approach for human malignant mesothelioma

International Nuclear Information System (INIS)

Nishikawa, Sho; Tanaka, Akane; Matsuda, Akira; Oida, Kumiko; Jang, Hyosun; Jung, Kyungsook; Amagai, Yosuke; Ahn, Ginae; Okamoto, Noriko; Ishizaka, Saori; Matsuda, Hiroshi

2014-01-01

Chronic inflammation due to the absorption of asbestos is an important cause of mesothelioma. Although the increased prevalence of mesothelioma is a serious problem, the development of effective chemotherapeutic agents remains incomplete. As the nuclear factor-κB (NF-κB) pathway contributes to malignant transformation of various types of cells, we explored NF-κB activity in three different pathological types of malignant mesothelioma cells, and evaluated the therapeutic potential of a recently reported NF-κB inhibitor, IMD-0354. NF-κB was constantly activated in MSTO-211H, NCI-H28, and NCI-H2052 cells, and the proliferation of these cell lines was inhibited by IMD-0354. D-type cyclins were effectively suppressed in mixed tissue type MSTO-211H, leading to cell cycle arrest at sub G 1 /G 1 phase. IMD-0354 reduced cyclin D3 in both epithelial tissue type NCI-H28 and sarcomatoid tissue type NCI-H2052. In a sphere formation assay, IMD-0354 effectively decreased the number and diameter of MSTO-211H spheres. Preincubation of MSTO-211H cells with IMD-0354 delayed tumor formation in transplanted immunodeficient mice. Furthermore, administration of IMD-0354 markedly rescued the survival rate of mice that received intrathoracic injections of MSTO-211H cells. These results indicate that a targeted drug against NF-κB might have therapeutic efficacy in the treatment of human malignant mesothelioma

Mitochondrial targeting of human O6-methylguanine DNA methyltransferase protects against cell killing by chemotherapeutic alkylating agents.

Science.gov (United States)

Cai, Shanbao; Xu, Yi; Cooper, Ryan J; Ferkowicz, Michael J; Hartwell, Jennifer R; Pollok, Karen E; Kelley, Mark R

2005-04-15

DNA repair capacity of eukaryotic cells has been studied extensively in recent years. Mammalian cells have been engineered to overexpress recombinant nuclear DNA repair proteins from ectopic genes to assess the impact of increased DNA repair capacity on genome stability. This approach has been used in this study to specifically target O(6)-methylguanine DNA methyltransferase (MGMT) to the mitochondria and examine its impact on cell survival after exposure to DNA alkylating agents. Survival of human hematopoietic cell lines and primary hematopoietic CD34(+) committed progenitor cells was monitored because the baseline repair capacity for alkylation-induced DNA damage is typically low due to insufficient expression of MGMT. Increased DNA repair capacity was observed when K562 cells were transfected with nuclear-targeted MGMT (nucl-MGMT) or mitochondrial-targeted MGMT (mito-MGMT). Furthermore, overexpression of mito-MGMT provided greater resistance to cell killing by 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) than overexpression of nucl-MGMT. Simultaneous overexpression of mito-MGMT and nucl-MGMT did not enhance the resistance provided by mito-MGMT alone. Overexpression of either mito-MGMT or nucl-MGMT also conferred a similar level of resistance to methyl methanesulfonate (MMS) and temozolomide (TMZ) but simultaneous overexpression in both cellular compartments was neither additive nor synergistic. When human CD34(+) cells were infected with oncoretroviral vectors that targeted O(6)-benzylguanine (6BG)-resistant MGMT (MGMT(P140K)) to the nucleus or the mitochondria, committed progenitors derived from infected cells were resistant to 6BG/BCNU or 6BG/TMZ. These studies indicate that mitochondrial or nuclear targeting of MGMT protects hematopoietic cells against cell killing by BCNU, TMZ, and MMS, which is consistent with the possibility that mitochondrial DNA damage and nuclear DNA damage contribute equally to alkylating agent-induced cell killing during chemotherapy.

Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property [v1; ref status: indexed, http://f1000r.es/15s

Directory of Open Access Journals (Sweden)

Asfar S Azmi

2013-06-01

Full Text Available “Let food be thy medicine and medicine be thy food” was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents.

Radiation recall dermatitis induced by Amol during tamoxifen therapy - case report

International Nuclear Information System (INIS)

Obtulowicz, A.; Pirowska, M.; Kosiniak-Kamysz, A.

2011-01-01

In the course of radiation therapy different types of adverse reactions of the skin are observed in approximately 95% of patients. Among the various complications encountered after radiotherapy, radiation recall dermatitis (RRD) deserves special attention. Radiation dermatitis is a form of delayed hypersensitivity of irradiated skin, and the direct trigger factors are medicines - most chemotherapeutics. The reaction is an inflammatory dermatosis. It is limited to previously irradiated skin and appears a number of months after radiotherapy. The aetiology of RRD is still unclear. Its clinical presentation may vary from mild erythema to necrosis and ulceration. The article presents the case of a 50-year-old patient, who after radiotherapy for breast cancer, during the hormonal therapy (tamoxifen), developed RRD type skin reactions after skin application of Amol. The article presents a detailed differential diagnosis of skin changes of RRD type, and discusses the principles of treatment and prevention. (authors)

The vascular disrupting agent ZD6126 shows increased antitumor efficacy and enhanced radiation response in large, advanced tumors

International Nuclear Information System (INIS)

Siemann, Dietmar W.; Rojiani, Amyn M.

2005-01-01

Purpose: ZD6126 is a vascular-targeting agent that induces selective effects on the morphology of proliferating and immature endothelial cells by disrupting the tubulin cytoskeleton. The efficacy of ZD6126 was investigated in large vs. small tumors in a variety of animal models. Methods and Materials: Three rodent tumor models (KHT, SCCVII, RIF-1) and three human tumor xenografts (Caki-1, KSY-1, SKBR3) were used. Mice bearing leg tumors ranging in size from 0.1-2.0 g were injected intraperitoneally with a single 150 mg/kg dose of ZD6126. The response was assessed by morphologic and morphometric means as well as an in vivo to in vitro clonogenic cell survival assay. To examine the impact of tumor size on the extent of enhancement of radiation efficacy by ZD6126, KHT sarcomas of three different sizes were irradiated locally with a range of radiation doses, and cell survival was determined. Results: All rodent tumors and human tumor xenografts evaluated showed a strong correlation between increasing tumor size and treatment effect as determined by clonogenic cell survival. Detailed evaluation of KHT sarcomas treated with ZD6126 showed a reduction in patent tumor blood vessels that was ∼20% in small ( 90% in large (>1.0 g) tumors. Histologic assessment revealed that the extent of tumor necrosis after ZD6126 treatment, although minimal in small KHT sarcomas, became more extensive with increasing tumor size. Clonogenic cell survival after ZD6126 exposure showed a decrease in tumor surviving fraction from approximately 3 x 10 -1 to 1 x 10 -4 with increasing tumor size. When combined with radiotherapy, ZD6126 treatment resulted in little enhancement of the antitumor effect of radiation in small (<0.3 g) tumors but marked increases in cell kill in tumors larger than 1.0 g. Conclusions: Because bulky neoplastic disease is typically the most difficult to manage, the present findings provide further support for the continued development of vascular disrupting agents such as

Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria.

Science.gov (United States)

Lehouritis, Panos; Stanton, Michael; McCarthy, Florence O; Jeavons, Matthieu; Tangney, Mark

2016-01-28

Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action. Copyright © 2015 Elsevier B.V. All rights reserved.

Characterization of the microDNA through the response to chemotherapeutics in lymphoblastoid cell lines.

Directory of Open Access Journals (Sweden)

Pamela Mehanna

Full Text Available Recently, a new class of extrachromosomal circular DNA, called microDNA, was identified. They are on average 100 to 400 bp long and are derived from unique non-repetitive genomic regions with high gene density. MicroDNAs are thought to arise from DNA breaks associated with RNA metabolism or replication slippage. Given the paucity of information on this entirely novel phenomenon, we aimed to get an additional insight into microDNA features by performing the microDNA analysis in 20 independent human lymphoblastoid cell lines (LCLs prior and after treatment with chemotherapeutic drugs. The results showed non-random genesis of microDNA clusters from the active regions of the genome. The size periodicity of 190 bp was observed, which matches DNA fragmentation typical for apoptotic cells. The chemotherapeutic drug-induced apoptosis of LCLs increased both number and size of clusters further suggesting that part of microDNAs could result from the programmed cell death. Interestingly, proportion of identified microDNA sequences has common loci of origin when compared between cell line experiments. While compatible with the original observation that microDNAs originate from a normal physiological process, obtained results imply complementary source of its production. Furthermore, non-random genesis of microDNAs depicted by redundancy between samples makes these entities possible candidates for new biomarker generation.

Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent.

Science.gov (United States)

Unger, E C; McCreery, T P; Sweitzer, R H; Caldwell, V E; Wu, Y

1998-12-01

Paclitaxel-carrying lipospheres (MRX-552) were developed and evaluated as a new ultrasound contrast agent for chemotherapeutic drug delivery. Paclitaxel was suspended in soybean oil and added to an aqueous suspension of phospholipids in vials. The headspace of the vials was replaced with perfluorobutane gas; the vials were sealed, and they were agitated at 4200 rpm on a shaking device. The resulting lipospheres containing paclitaxel were studied for concentration, size, acute toxicity in mice, and acoustic activity and drug release with ultrasound. Lipospheres containing sudan black dye were produced to demonstrate the acoustically active liposphere (AAL)-ultrasound release concept. Acoustically active lipospheres containing paclitaxel had a mean particle count of approximately 1 x 10(9) particles per mL and a mean size of 2.9 microns. Acute toxicity studies in mice showed a 10-fold reduction in toxicity for paclitaxel in AALs compared with free paclitaxel. The AALs reflected ultrasound as a contrast agent. Increasing amounts of ultrasound energy selectively ruptured the AALs and released the paclitaxel. Acoustically active lipospheres represent a new class of acoustically active drug delivery vehicles. Future studies will assess efficacy of AALs for ultrasound-mediated drug delivery.

Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast.

Directory of Open Access Journals (Sweden)

Zoey Tay

Full Text Available Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance.

Antitumor activity of ZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiates the effects of radiation in a human non-small cell lung cancer xenograft model.

Science.gov (United States)

Raben, David; Bianco, Cataldo; Damiano, Vincenzo; Bianco, Roberto; Melisi, Davide; Mignogna, Chiara; D'Armiento, Francesco Paolo; Cionini, Luca; Bianco, A Raffaele; Tortora, Giampaolo; Ciardiello, Fortunato; Bunn, Paul

2004-08-01

Targeting the tumor vasculature may offer an alternative or complementary therapeutic approach to targeting growth factor signaling in lung cancer. The aim of these studies was to evaluate the antitumor effects in vivo of the combination of ZD6126, a tumor-selective vascular-targeting agent; ZD1839 (gefitinib, Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor; and ionizing radiation in the treatment of non-small cell lung cancer xenograft model. Athymic nude mice with established flank A549 human non-small cell lung cancer xenograft model xenografts were treated with fractionated radiation therapy, ZD6126, ZD1839, or combinations of each treatment. ZD6126 (150 mg/kg) was given i.p. the day after each course of radiation. Animals treated with ZD1839 received 100 mg/kg per dose per animal, 5 or 7 days/wk for 2 weeks. Immunohistochemistry was done to evaluate the effects on tumor growth using an anti-Ki67 monoclonal antibody. Effects on tumor-induced vascularization were quantified using an anti-factor VIII-related antigen monoclonal antibody. ZD6126 attenuated the growth of human A549 flank xenografts compared with untreated animals. Marked antitumor effects were observed when animals were treated with a combination of ZD6126 and fractionated radiation therapy with protracted tumor regression. ZD6126 + ZD1839 resulted in a greater tumor growth delay than either agent alone. Similar additive effects were seen with ZD1839 + fractionated radiation. Finally, the addition of ZD6126 to ZD1839 and radiation therapy seemed to further improve tumor growth control, with a significant tumor growth delay compared with animals treated with single agent or with double combinations. Immunohistochemistry showed that ZD1839 induced a marked reduction in A549 tumor cell proliferation. Both ZD1839 and ZD6126 treatment substantially reduced tumor-induced angiogenesis. ZD6126 caused marked vessel destruction through loss of endothelial cells and thrombosis

Effect of acyclovir on radiation- and chemotherapy-induced mouth lesions

International Nuclear Information System (INIS)

Bubley, G.J.; Chapman, B.; Chapman, S.K.; Crumpacker, C.S.; Schnipper, L.E.

1989-01-01

Several chemotherapeutic regimens and radiation therapy, if delivered to the oral mucosa, are associated with a high frequency of mouth lesions. The cause of this side effect is not known for certain, but in past studies it has sometimes been associated with the ability to culture herpes simplex virus type 1 from the mouth. In a double-blind prospective trial, patients with head and neck tumors treated with chemotherapy or radiation therapy were treated with either acyclovir or placebo. Although the frequency of culture-positive herpes simplex virus was low in the untreated group, it was significantly lower, zero, in the acyclovir-treated group. However, there were no differences in the frequency or type of mouth lesions experienced by patients receiving either radiation or chemotherapy who were taking acyclovir or placebo. These results suggest that herpes simplex virus is not a frequent cause or complication of oral lesions afflicting this patient population

Exposure of hospital operating room personnel to potentially harmful environmental agents

International Nuclear Information System (INIS)

Sass-Kortsak, A.M.; Purdham, J.T.; Bozek, P.R.; Murphy, J.H.

1992-01-01

Epidemiologic studies of risk to reproductive health arising from the operating room environment have been inconclusive and lack quantitative exposure information. This study was undertaken to quantify exposure of operating room (OR) personnel to anesthetic agents, x-radiation, methyl methacrylate, and ethylene oxide and to determine how exposure varies with different operating room factors. Exposures of anesthetists and nurses to these agents were determined in selected operating rooms over three consecutive days. Each subject was asked to wear an x-radiation dosimeter for 1 month. Exposure to anesthetic agents was found to be influenced by the age of the OR facility, type of surgical service, number of procedures carried out during the day, type of anesthetic circuitry, and method of anesthesia delivery. Anesthetists were found to have significantly greater exposures than OR nurses. Exposure of OR personnel to ethylene oxide, methyl methacrylate, and x-radiation were well within existing standards. Exposure of anesthetists and nurses to anesthetic agents, at times, was in excess of Ontario exposure guidelines, despite improvements in the control of anesthetic pollution

The Clone Wars – Revenge of the Metastatic Rogue State: The Sarcoma Paradigm

International Nuclear Information System (INIS)

Spraker, Holly L.; Price, Shawn L.; Chaturvedi, Aashi; Schiffman, Joshua D.; Jones, Kevin B.; Lessnick, Stephen L.; Beckerle, Mary; Randall, R. Lor

2012-01-01

Ewing sarcoma (ES) is the second most common bone tumor affecting primarily adolescents and young adults. Despite recent advances in biological understanding, intensification of chemotherapeutic treatments, and progress in local control with surgery and/or radiation therapy, patients with metastatic or recurrent ES continue to have a dismal prognosis with less than 20% overall survival. All ES is likely metastatic at diagnosis although our methods of detection and classification may not account for this. Progressive disease may arise via a combination of: (1) selection of chemotherapy-resistant clones in primary tumor, (2) signaling from bone or lung microenvironments that may attract tumor cells to distant locations, and/or (3) genetic changes within the ES cells themselves due to DNA-damaging chemotherapeutic agents or other “hits.” These possibilities and the evidence base to support them are explored.

Synthesis of Taxol-Like Prostate Cancer Chemotherapeutic Agents

National Research Council Canada - National Science Library

Jo, Hyunil

2008-01-01

This report describes the synthetic approaches toward a potent microtubule stabilizing natural product, eleutherobin, utilizing tandem Diels-Alder reaction/Grob-type fragmentation reaction as key steps...

Investigation of X-ray permeability of surgical gloves coated with different contrast agents

Science.gov (United States)

Kayan, Mustafa; Yaşar, Selçuk; Saygın, Mustafa; Yılmaz, Ömer; Aktaş, Aykut Recep; Kayan, Fatmanur; Türker, Yasin; Çetinkaya, Gürsel

2016-01-01

Objective: We aimed to investigate the effectiveness and radiation protection capability of latex gloves coated with various contrast agents as an alternative to lead gloves. Methods: The following six groups were created to evaluate the permeability of X-ray in this experimental study: lead gloves, two different non-ionic contrast media (iopromide 370/100 mg I/mL and iomeprol 400/100 mg I/mL), 10% povidone–iodine (PV–I), 240/240 g/mL barium sulphate and a mixture of equal amounts of all contrast agents. A radiation dose detector was placed in coated latex gloves for each one. The absorption values of radiation from latex gloves coated with various contrast agents were measured and compared with the absorption of radiation from lead gloves. This study was designed as an ‘experimental study’. Results: The mean absorption value of X-ray from lead gloves was 3.0±0.08 µG/s. The mean absorption values of X-ray from latex gloves coated with various contrast agents were 3.7±0.09 µG/s (iopromide 370/100 mg I/mL), 3.6±0.09 µG/s (iomeprol 400/100 mg I/mL), 3.7±0.04 µG/s (PV–I), 3.1±0.07 µG/s (barium sulphate) and 3.8±0.05 µG/s (mixture of all contrast agents). Latex gloves coated with barium sulphate provided the best radiation absorption compared with latex gloves coated with other radiodense contrast agents. Conclusion: Latex gloves coated with barium sulphate may provide protection equivalent to lead gloves. PMID:26680548

Comparative risk assessment of radiation and other mutagenic agents

International Nuclear Information System (INIS)

Leenhouts, H.P.; Pruppers, M.J.M.; Wijngaard, E.; Sijsma, M.J.; Bouwens, B.T.; Chadwick, K.H.

1990-04-01

This is the final report of a contract of RIVM in the framework of the Radiation Protection Programme of the Commission of the European Communities. The aim of the project was to investigate the nature of the dose-effect relationship for radiobiological effects after different types of ionizing radiation and UV. The results support the idea that the linear-quadratic dose relationship for radiobiological effects does reflect a 2-hit or 2-event type of radiation effect. The track structure calculations of the linear term indicate that the DNA double-strand break could be the crucial lesion and that the 2 simultaneous events should occur close to each strand of the DNA molecule in a single track. The experimental data indicate that the quadratic term arises from the combination of 2 time independently induced events the role of which can be modified by repair but these data do not provide any information on the nature of the radiation induced lesions. (author). 8 refs.; 7 figs

SU-E-QI-13: Predictable Models for Radio-Sensitizing Agent Kinetics: Application to Stereotactic Synchrotron Radiation Therapy

Energy Technology Data Exchange (ETDEWEB)

Obeid, L; Schmitt, M; Esteve, F; Adam, J [Grenoble Institut des Neurosciences, La Tronche, RHONE-ALPES (France)

2014-06-15

Purpose: Iodine-enhanced radiotherapy is an innovative treatment combining the selective accumulation of an iodinated contrast agent in brain tumors with irradiations using monochromatic medium energy x-rays. The radiation dose enhancement depends on the time course of iodine in the tumors. A prolonged CT scanning (∼30 min) is required to follow-up iodine kinetics for recruited patients. This protocol could lead to substantial radiation dose to the patient. A novel method is proposed to reduce the acquisition time. Methods: 12 patients received an intravenous bolus of iodinated contrast agent, followed by a steady-state infusion to ensure stable intra-tumoral amounts of iodine during the treatment. Absolute iodine concentrations (IC) were derived from 40 multi-slice dynamic conventional CT images of the brain. The impulse response function (IRF) to the bolus was estimated using the adiabatic approximation of the Johnson and Wilson's model. The arterial input function (AIF) of the steady-state infusion was fitted with several models: Gamma, Gamma with recirculation and hybrid. Estimated IC were calculated by convolving the IRF with the modeled AIF and were compared to the measured data. Results: The gamma variate function was not relevant to model the AIF due to high differences with the measured AIF. The hybrid and the gamma with recirculation models provided differences below 8% during the whole acquisition time. The absolute difference between the measured and the estimated IC was lower than 0.5 mg/ml, which corresponds to 5% of dose enhancement error. Conclusion: The proposed method allows a good estimation of the iodine time course with reduced scanning delays (3 instead of 30 min) and dose to the patient. The results suggest that the dose errors may stay within the radiotherapy standards.

Anticancer chemotherapy

Energy Technology Data Exchange (ETDEWEB)

Weller, R.E.

1991-10-01

This document examines chemotherapeutic agents for use in veterinary oncology. It lists some of the most common categories of chemotherapeutic drugs, such as alkylating agents and corticosteroids. For each category, the paper lists some example drugs, gives their mode of action, tumors usually susceptible to the drug, and common side effects. A brief discussion of mechanisms of drug resistance is also provided. (MHB)

Novel approaches to development and characterization of radiomodifying agents

International Nuclear Information System (INIS)

Tenchova, V.

1993-01-01

A review of Bulgarian experience in developing radiomodifying agents, methods for selection and comprehensive assessment of their properties, as well as the experimental results obtained is presented. Discussed are the principles underlying development of 'molecular combinations' of radioprotective agents through: modification of the structure of well-established radioprotective substances by introducing moieties that themselves have a radioprotective effect; linking into one molecule of two or more radioprotective agents by covalent or hetero-polar bond; linking into one molecule a chemical radioprotective agents with biogenic or biologically active components; linking radioprotective agents with polymers to obtain sustained action products; optimizing the effect of clinically tested radiosensitizers by combination with biologically active components or polymer carriers. Among the molecular combinations original in idea and implementation, the best effect was observed for ATP-salts with MEA (Citriphos) and AET (Adeturone), and these preparations have undergone extended studies in Bulgaria and abroad. Results are also presented on the effect of agents for biological protection, the efficiency of antiradiation agents encapsulated into cell membranes, the possibilities for using adaptogens and immunomodulators to raise radioresistance and enhance the effect of anti radiation agents. A methodology developed for experimental assessment of radiomodifying preparations is described, which includes synthesis, physical chemistry and identification procedures, as well as radiobiological studies with the aid of a set of biometric parameters, biophysical, hematologic, biochemical, radioisotope and other techniques. The investigations have been performed with a variety of biological materials using ionizing radiations of varying characteristics. (author)

A review on the study of bioreductive drugs

International Nuclear Information System (INIS)

Chen Xiaojing; Jin Yizun

2003-01-01

Hypoxia is a feature that exists in most solid tumors. Bio-reductive drugs are pro-drugs that can selectively target the hypoxia cells in tumors. In reductive environment, they are reductively metabolized to generate toxic species. There are 3 main classes of bio-reductive drugs: the nitro-aromatics, N-oxides and quinones. Recently, bio-reductive drugs were combined with GDEPT for the treatment of cancer, in addition to radiation and the chemotherapeutic agents. Bio-reductive drugs will play a significant role in future cancer therapy

Degree and therapy of acute radiation syndromes. Introduction of a suggestion on acute radiation sickness therapy made by strategic national stockpile radiation working group of USA. part 2

International Nuclear Information System (INIS)

Min Rui; Pan Zhen; Li Yu

2005-01-01

Recommendations based on radiation dose and physiologic response are made for treatment of the hematopoietic syndrome. Therapy includes treatment with hematopoietic cytokines, blood transfusion, and stem-cell transplantation in selected cases. Additional medical management based on the evolution of clinical signs and symptoms includes the use of antimicrobial agents (quinolones, antiviral therapy, and antifungal agents), antiemetic agents, and analgesic agents. Because of the strong psychological impact of a possible radiation exposure, psychosocial support will be required for those exposed, regardless of the dose, as well as for family and friends. Treatment of pregnant women must account for risk to the fetus. For terrorist or accidental events involving exposure to radioiodines, prophylaxis against malignant disease of the thyroid is also recommended, particularly for children and adolescents. (authors)

Interaction of hyperthermia and radiation: radiation quality

International Nuclear Information System (INIS)

Loshek, D.D.; Orr, J.S.; Solomonidis, E.

1981-01-01

Cell-survival data were collected to determine the survival response of asynchronous CHO cells subject to radiation and hyperthermia. The irradiation was at room temperature 100 minutes before exposure to hyperthermia at 42 0 C. The survival response to the combination of these two agents is expressed by means of a survival surface, a three-dimensional concept relating cell survival to heat dose and radiation dose. The survival surface could be approximately described by a survival model comprising three components of cell killing: the unperturbed radiation component, the unperturbed hyperthermia component and the interaction component. The dependence of the radiation component and the interaction component on radiation quality were investigated by irradiating with either 60 Co γ rays, 250 kV X rays or 14.7 MeV neutrons. An analysis suggests that the interaction component and the radiation component exhibit similar dependencies on radiation quality both for the deposition of damage and the repair or accumulation of that damage. (U.K.)

MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents.

Science.gov (United States)

Kaina, Bernd; Christmann, Markus; Naumann, Steffen; Roos, Wynand P

2007-08-01

O(6)-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in the defense against alkylating agents that generate, among other lesions, O(6)-alkylguanine in DNA (collectively termed O(6)-alkylating agents [O(6)AA]). The defense is highly important, since O(6)AA are common environmental carcinogens, are formed endogenously during normal cellular metabolism and possibly inflammation, and are being used in cancer therapy. O(6)AA induced DNA damage is subject to repair, which is executed by MGMT, AlkB homologous proteins (ABH) and base excision repair (BER). Although this review focuses on MGMT, the mechanism of repair by ABH and BER will also be discussed. Experimental systems, in which MGMT has been modulated, revealed that O(6)-methylguanine (O(6)MeG) and O(6)-chloroethylguanine are major mutagenic, carcinogenic, recombinogenic, clastogenic and killing lesions. O(6)MeG-induced clastogenicity and cell death require MutS alpha-dependent mismatch repair (MMR), whereas O(6)-chloroethylguanine-induced killing occurs independently of MMR. Extensive DNA replication is required for O(6)MeG to provoke cytotoxicity. In MGMT depleted cells, O(6)MeG induces apoptosis almost exclusively, barely any necrosis, which is presumably due to the remarkable ability of secondarily formed DNA double-strand breaks (DSBs) to trigger apoptosis via ATM/ATR, Chk1, Chk2, p53 and p73. Depending on the cellular background, O(6)MeG activates both the death receptor and the mitochondrial apoptotic pathway. The inter-individual expression of MGMT in human lymphocytes is highly variable. Given the key role of MGMT in cellular defense, determination of MGMT activity could be useful for assessing a patient's drug sensitivity. MGMT is expressed at highly variable amounts in human tumors. In gliomas, a correlation was found between MGMT activity, MGMT promoter methylation and response to O(6)AA. Although the human MGMT gene is inducible by glucocorticoids and genotoxins such as radiation and

Cytogenetic evaluation of hospital workers occupationally exposed to low levels of ionizing radiation. Assessment of two cytogenetic procedures: accumulated dosimetry versus radiosensitivity

International Nuclear Information System (INIS)

Garcia-Sagredo, J. M.; Villalon, C.; Lopez-Abente, G.; Arranz, L.; Ferro, M. T.; Ferrando, P.; Pollan, M.; Aragones, N.; Ferrer, N.; Sastre, J. M.

2004-01-01

We try to establish a cumulative ionising radiation (IR) biologicla dosimetry in occupationally exposed workers as a routine health tes, analysing chromosome translocations. 100 hospital workers occupationally exposed to low levels of X-ray, g-ray and radioactive isotopes are included in this study. Blood samples were cultured for cytogenetic analysis. Chromosome translocatiosn were scored using whole chromosome paint probes cocktail (Vysis) for chromosomes 1, 2, 3, 4, 5 and 6. Furthermore, a personal detailed interview about confounding factors, as tobacco smoking X-ray examination, occupational exposure to chemotherapeutics agents and solvents, electromagnetic fields exposure, and others was done. Our results showed that there is no statistical association between cumulative doses of IRE, type of LET and chromosome translocation rate. For the contraty, we have found a translocation risk increase related with IR equivalent dose rate, independently of the time of exposure and age. Those workers receiving 1mSv/year or more vs<1mSv/year show a relative risk of 2.56 (95% confidence interval 1.10-5.95). A comparison of translocationrate and different confounding factors suggest a relative risk increase in intensive users of mobile phones. Other exposures as tobacco smoking solvents, UV radiation anaesthetic gases and any other confounding factors have not shown assocaition with translocation rate. At the same time, we try to analyse radiosensitivity through the CBMN-test (cytokinesis block micronucelus test). Results on CBMN are in progress. Finally we try to asses the two cytogentic procedures as the most suitable routine health test in radiation occupational protection. (Author)

Therapeutic applications of histone deacetylase inhibitors in sarcoma.

Science.gov (United States)

Tang, Fan; Choy, Edwin; Tu, Chongqi; Hornicek, Francis; Duan, Zhenfeng

2017-09-01

Sarcomas are a rare group of malignant tumors originating from mesenchymal stem cells. Surgery, radiation and chemotherapy are currently the only standard treatments for sarcoma. However, their response rates to chemotherapy are quite low. Toxic side effects and multi-drug chemoresistance make treatment even more challenging. Therefore, better drugs to treat sarcomas are needed. Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are epigenetic modifying agents that can inhibit sarcoma growth in vitro and in vivo through a variety of pathways, including inducing tumor cell apoptosis, causing cell cycle arrest, impairing tumor invasion and preventing metastasis. Importantly, preclinical studies have revealed that HDIs can not only sensitize sarcomas to chemotherapy and radiotherapy, but also increase treatment responses when combined with other chemotherapeutic drugs. Several phase I and II clinical trials have been conducted to assess the efficacy of HDIs either as monotherapy or in combination with standard chemotherapeutic agents or targeted therapeutic drugs for sarcomas. Combination regimen for sarcomas appear to be more promising than monotherapy when using HDIs. This review summarizes our current understanding and therapeutic applications of HDIs in sarcomas. Copyright © 2017 Elsevier Ltd. All rights reserved.

Association between Chemotherapy-Response Assays and Subsets of Tumor-Infiltrating Lymphocytes in Gastric Cancer: A Pilot Study.

Science.gov (United States)

Lee, Jee Youn; Son, Taeil; Cheong, Jae-Ho; Hyung, Woo Jin; Noh, Sung Hoon; Kim, Choong-Bai; Park, Chung-Gyu; Kim, Hyoung-Il

2015-12-01

The purpose of this pilot study was to evaluate the association between adenosine triphosphate-based chemotherapy response assays (ATP-CRAs) and subsets of tumor infiltrating lymphocytes (TILs) in gastric cancer. In total, 15 gastric cancer tissue samples were obtained from gastrectomies performed between February 2007 and January 2011. Chemotherapy response assays were performed on tumor cells from these samples using 11 chemotherapeutic agents, including etoposide, doxorubicin, epirubicin, mitomycin, 5-fluorouracil (5-FU), oxaliplatin, irinotecan, docetaxel, paclitaxel, methotrexate, and cisplatin. TILs in the tissue samples were evaluated using antibodies specific for CD3, CD4, CD8, Foxp3, and Granzyme B. The highest cancer cell death rates were induced by etoposide (44.8%), 5-FU (43.1%), and mitomycin (39.9%). Samples from 10 patients who were treated with 5-FU were divided into 5-FU-sensitive and -insensitive groups according to median cell death rate. No difference was observed in survival between the two groups (P=0.216). Only two patients were treated with a chemotherapeutic agent determined by an ATP-CRA and there was no significant difference in overall survival compared with that of patients treated with their physician's choice of chemotherapeutic agent (P=0.105). However, a high number of CD3 TILs was a favorable prognostic factor (P=0.008). Pearson's correlation analyses showed no association between cancer cell death rates in response to chemotherapeutic agents and subsets of TILs. Cancer cell death rates in response to specific chemotherapeutic agents were not significantly associated with the distribution of TIL subsets.

Combined effect of gamma radiation and some fungal control agents on the greasy cut- worm

International Nuclear Information System (INIS)

Abd EL- Wahed, A. G.

2011-01-01

The greasy cut worm, Agrotis ipsilon (Lepidoptera- Noctuidae) is widely distributed all over the world, particularly in moderate and subtropical countries of the northern and southern hemispheres (Kononenko ,2003). The greasy cut worm causes damage to vegetables, cucurbitaceous and industrial crops. The greatest damage is caused to cotton, essential-oil cultures, maize, tobacco, sunflower, tomatoes, sugar beet and potato. The pest can strongly harm vegetables, and also damage seedlings of tree species (pine, maple, and nut). This pest has solitary habits. They commonly feed on seedlings at ground level, cutting off the stem and sometimes dragging the plants into their burrows. The continuous use of chemical pesticides against pests, resistance to the action of pesticides had dramatically evolved. Also, the extensive use of these chemicals has given rise to problems such as residual toxicity (pollution) and harmful effects on beneficial insects, which are natural enemies of target or nontarget pest species. Such problems have become a cause of search for safety pesticides including microbial agents as fungi, bacteria and viruses (Rashed, 1993). The use of radiation to induce dominate lethal mutations in the sterile insect technique (SIT) is now as the major component of many large and successful programs for pest suppression and eradication. Adult insects, and their different developmental stages, differ in their sensitivity to the induction of dominate lethal mutation. Care has to be taken to identify the appropriate dose of radiation that produces the required level of sterility without impairing the overall fitness of the released insects.(Sawires, 2005). This technique would be successful control device for suppressing and combating many lepidopteraus insect pests, including A. Ipsilon has been studied (EL- kady et al., 1983, EL-Naggar et al., 1984, Abd El -Hamid 2004 and Gabarty, 2008). Entomopathogenic fungi that infect insects have received considerable

Radioprotective and radiotherapeutic properties of biotechnological agent MD2

International Nuclear Information System (INIS)

Sobol, C.V.; Komar, V.E.; Sobol, Y.T.

1996-01-01

In recent years as the result of nuclear testing and accidents at nuclear power plants such as Chernobyl, etc. radiation exposure has become a major issue in various parts of the world. Experience of recent nuclear accidents has shown there is no effective treatment for patients expose to doses of radiation that result in fatal hematopoietic failure and /or secondary infections. Therefore, agents that are effective when administered after irradiation, are of great interest. In this study, the possibility of using biotechnological agent MD2 after lethal total body irradiation (TBI) and radiotherapy has been demonstrated. In addition, the considerable radioprotection without toxic effect can be obtained. (author)

Radioprotection in E. coli by an agent from M. radiodurans

Energy Technology Data Exchange (ETDEWEB)

Goldstein, L S; Gersten, D M; Bruce, A K [State Univ. of New York, Buffalo (USA). Dept. of Biology

1978-10-01

An agent extracted from the radioresistant bacterium M. radiodurans was found to protect several strains of E. coli from X-radiation. Optimal radioprotection was observed when the repair-proficient B/r strain was irradiated in the presence of the agent under hypoxic conditions. It is proposed that this agent acts to modify damage incurred in the presence of reduced oxygen concentrations so that this damage might be subsequently repaired.

Biology panel: coming to a clinic near you. Translational research in radiation biology

International Nuclear Information System (INIS)

Travis, Elizabeth L.; Thames, Howard D.

1996-01-01

The explosion of knowledge in molecular biology coupled with the rapid and continuing development of molecular techniques allow a new level of research in radiation biology aimed at understanding the processes that govern radiation damage and response in both tumors and normal tissues. The challenge to radiation biologists and radiation oncologists is to use this knowledge to improve the therapeutic ratio in the management of human tumors by rapidly translating these new findings into clinical practice. This panel will focus on both sides of the therapeutic ratio coin, the manipulation of tumor control by manipulating the processes that control cell cycle regulation and apoptosis, and the reduction of normal tissue morbidity by applying the emerging information on the genetic basis of radiosensitivity. Apoptosis is a form of cell death believed to represent a minor component of the clinical effects of radiation. However, if apoptosis is regulated by anti-apoptotic mechanisms, then it may be possible to produce a pro-apoptotic phenotype in the tumor cell population by modulating the balance between pro- and anti-apoptotic mechanisms by pharmacological intervention. Thus signaling-based apoptosis therapy, designed to overcome the relative resistance to radiation-induced apoptosis, may improve the therapeutic ratio in the management of human tumors. The explosion of information concerning cell cycle regulation in both normal and tumor cells has provided the opportunity for insights into the mechanism of action of chemotherapeutic agents that can act as radiosensitizers. The second talk will explore the hypothesis that the dysregulation of cell cycle checkpoints in some cancers can be exploited to improve the therapeutic index of radiation sensitizers, specifically the fluoropyrimidines which appear to act at the G1/S transition. Finally, efforts to increase tumor control will be translated into clinical practice only if such treatments do not increase the complication

Protection policies for ionizing and UV radiation

International Nuclear Information System (INIS)

Bosnjakovic, B.F.M.

1987-01-01

Although ultraviolet radiation is generally considered as being part of non-ionizing radiation, the existing similarities with ionizing radiation are too striking to be overseen. A comparison of these two agents is becoming important in view of the increasing awareness of various environmental and health risks and the tendency to develop more uniform risk management policies with respect to the different physical and chemical agents. This paper explores the similarities and differences of UV and ionizing radiation from the point of view of policies either adopted or in development. Policy determinants include, among others, the following factors: biological effects, dosimetric quantities, relative contribution to exposure from different sources, hazard potential of different sources, quantification of detrimental consequences, public perception of the radiation hazards and regulation developments. These factors are discussed

CpG oligodeoxynucleotides are potent enhancers of radio- and chemoresponses of murine tumors

International Nuclear Information System (INIS)

Mason, Kathryn A.; Neal, Robert; Hunter, Nancy; Ariga, Hisanori; Ang, Kian; Milas, Luka

2006-01-01

Background and purpose: Synthetic oligodeoxynucleotides (ODNs) containing unmethylated cytosine-guanine (CpG) motifs bind to Toll-like receptor 9 (TLR9) and stimulate both innate and adaptive immune reactions and possess anti-tumor activity. We recently reported that CpG ODN 1826 strongly enhances radioresponse of both immunogenic [Milas L, Mason K, Ariga H, et al. CpG oligodeoxynucleotide enhances tumor response to radiation. Cancer Res 2004;64:5074-7] and non-immunogenic [Mason KA, Ariga H, Neal R, et al. Targeting toll-like receptor-9 with CpG oligodeoxynucleotides enhances tumor response to fractionated radiotherapy. Clin Cancer Res 2005;11:361-9] murine tumors. Using two immunogenic murine tumors, a fibrosarcoma (FSa) and a mammary carcinoma (MCa-K), the present study explored whether CpG ODN 1826 also improves the response of murine tumors to the chemotherapeutic agent docetaxel (DOC). Materials and methods: CpG ODN 1826 (100 μg) was given sc three times: when leg tumors were 6 mm, when they grew to 8 mm and again 1 week later. DOC (33 mg/kg iv) and local tumor radiation (10 Gy) were given when tumors were 8 mm. Effects of the treatments were assayed by tumor growth delay, defined as days for tumors to grow from 8 to 12 mm in diameter. Results: Treatment with CpG ODN 1826 resulted in strongly enhanced response of FSa tumors to radiation and MCa-K tumors to the chemotherapeutic agent DOC. Enhancement of tumor treatment response was demonstrated by a strong prolongation in the primary tumor treatment endpoint, tumor growth delay. Coincidentally, this treatment also resulted in a higher rate of tumor cure than that observed after tumor radiotherapy or chemotherapy alone. When all three agents were combined the effect was comparable to that of the combination of CpG ODN 1826 with radiation in the case of FSa or of the combination of CpG ODN 1826 with DOC in the case of MCa-K. Conclusion: Overall results show that CpG ODN 1826 can markedly improve tumor response

Enhanced vesicular stomatitis virus (VSVΔ51 targeting of head and neck cancer in combination with radiation therapy or ZD6126 vascular disrupting agent

Directory of Open Access Journals (Sweden)

Alajez Nehad M

2012-06-01

Full Text Available Abstract Background Head and neck squamous cell carcinoma (HNSCC is the 5th most common cancer worldwide. Locally advanced HNSCC are treated with either radiation or chemo-radiotherapy, but still associated with high mortality rate, underscoring the need to develop novel therapies. Oncolytic viruses have been garnering increasing interest as anti-cancer agents due to their preferential killing of transformed cells. In this study, we evaluated the therapeutic potential of mutant vesicular stomatitis virus (VSVΔ51 against the human hypopharyngeal FaDu tumour model in vitro and in vivo. Results Our data demonstrated high toxicity of the virus against FaDu cells in vitro, which was associated with induction of apoptosis. In vivo, systemic injection of 1 × 109 pfu had minimal effect on tumour growth; however, when combined with two doses of ionizing radiation (IR; 5 Gy each or a single injection of the vascular disrupting agent (ZD6126, the virus exhibited profound suppression of tumour growth, which translated to a prolonged survival in the treated mice. Concordantly, VSVΔ51 combined with ZD6126 led to a significant increase in viral replication in these tumours. Conclusions Our data suggest that the combinations of VSVΔ51 with either IR or ZD6126 are potentially novel therapeutic opportunities for HNSCC.

Interstitial shadow on chest CT is associated with the onset of interstitial lung disease caused by chemotherapeutic drugs

International Nuclear Information System (INIS)

Niho, Seiji; Goto, Koichi; Yoh, Kiyotaka; Kim, Y.H.; Ohmatsu, Hironobu; Kubota, Kaoru; Saijo, Nagahiro; Nishiwaki, Yutaka

2006-01-01

Pretreatment computerized tomography (CT) films of the chest was studied to clarify the influence of interstitial shadow on developing interstitial lung disease (ILD). Eligible patients were those lung cancer patients who started to receive first-line chemotherapy between October 2001 and March 2004. Patients who received thoracic radiotherapy to the primary lesion, mediastinum, spinal or rib metastases were excluded. We reviewed pretreatment conventional CT and plain X-ray films of the chest. Ground-glass opacity, consolidation or reticular shadow without segmental distribution was defined as interstitial shadow, with this event being graded as mild, moderate or severe. If interstitial shadow was detected on CT films of the chest, but not via plain chest X-ray, it was graded as mild. Patients developing ILD were identified from medial records. A total of 502 patients were eligible. Mild, moderate and severe interstitial shadow was identified in 7, 8 and 5% of patients, respectively. A total of 188 patients (37%) received tyrosine kinase inhibitor (TKI) treatment, namely gefitinib or erlotinib. Twenty-six patients (5.2%) developed ILD either during or after chemotherapy. Multivariate analyses revealed that interstitial shadow on CT films of the chest and treatment history with TKI were associated with the onset of ILD. It is recommended that patients with interstitial shadow on chest CT are excluded from future clinical trials until this issue is further clarified, as it is anticipated that use of chemotherapeutic agents frequently mediate onset of ILD in this context. (author)

Novel concepts in modification of radiation sensitivity

International Nuclear Information System (INIS)

Bump, E.A.; Palayoor, S.T.; Lai, L.L.; Cerce, B.A.; Langley, R.E.; Coleman, C.N.; Braunhut, S.J.

1994-01-01

The purpose of this study was to determine whether biological effects of radiation, such as apoptosis, that differ from classical clonogenic cell killing, can be modified with agents that would not be expected to modify classical clonogenic cell killing. This would expand the range of potential modifiers of radiation therapy. EL4 murine lymphoma cell apoptosis was determined by electrophoretic analysis of deoxyribonucleic acid (DNA) fragmentation. DNA was extracted 24 h after irradiation or addition of inducing agents. Modifiers of radiation-induced apoptosis were added immediately after irradiation. The effects of radiation on wounded endothelial monolayers were studied by scraping a line across the monolayer 30 min after irradiation. Cell detachment was used as an endpoint to determine the protective effect of prolonged exposure to retinol prior to irradiation. EL4 cell apoptosis can be induced by tert-butyl hydroperoxide or the glutathione oxidant SR-4077. Radiation-induced EL4 cell apoptosis can be inhibited with 3-aminobenzamide, an agent that sensitizes cells to classical clonogenic cell killing. Radiation-induced endothelial cell detachment from confluent monolayers can be modified by pretreatment with retinol. These results raise the possibility that radiation could induce apoptosis by an oxidative stress mechanism that is different from that involved in classical clonogenic cell killing. These and other recent findings encourage the notion that differential modification of classical clonogenic cell killing and other important endpoints of radiation action may be possible. 47 refs., 3 figs

Judgement in achieving protection against radiation

International Nuclear Information System (INIS)

Taylor, L.S.

1980-01-01

This article includes the following topics: Ionizing radiation as a toxic agent; value judgement in establishing protection standards; origin of radiation protection standards; numerical radiation protection standards; exposure of populations; the proportional dose-effect relationship; assumptions involved in the proportional dose-effect relationship and a continued need for value judgement

Pharmacological toxicological studies on certain drugs subjected to radiation or used radioprotective agents

Energy Technology Data Exchange (ETDEWEB)

Hassan, S H.M. [Durng Research Dept., National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, (Egypt)

1995-10-01

The present study represents two main subjects. The first encounters the effect of radiosterilization of certain pharmaceretical preparations such as antihistaminics (cimetidine), anticonvulsants (diazepam), beta and calcium channel blacker (propranolol and verapamil) on their pharmacological activity. Results of this study revealed that the previously mentioned drugs can be effectively and safely sterilized by gamma irradiation without deleterious effect on their pharmacological activity. The other subject presented in this study is essentially a pharmacological subject encountering toxicological problems. Data of this study demonstrated that chemical radiation protection has been successfully reported using single drug administration has been successfully reported using single drug administration such as imidazole, and Sh-bearing compounds. In the present work, the radioprotective effect of imidazole was demonstrated on the cardiovascular and respiratory systems. Furthermore, combined drug administration was found to exert more protective action with less toxicity and therefore minimize the side effects of the radioprotective drugs. Thus, combination of imidazole and serotonin showed potential protective effect on blood gases was also reported. In addition, combination of cysteine and vitamin E afforded a better protection on adrenocortical function in rats than either agent alone. 4 figs., 1 tab.

Pharmacological toxicological studies on certain drugs subjected to radiation or used radioprotective agents

International Nuclear Information System (INIS)

Hassan, S.H.M.

1995-01-01

The present study represents two main subjects. The first encounters the effect of radiosterilization of certain pharmaceretical preparations such as antihistaminics (cimetidine), anticonvulsants (diazepam), beta and calcium channel blacker (propranolol and verapamil) on their pharmacological activity. Results of this study revealed that the previously mentioned drugs can be effectively and safely sterilized by gamma irradiation without deleterious effect on their pharmacological activity. The other subject presented in this study is essentially a pharmacological subject encountering toxicological problems. Data of this study demonstrated that chemical radiation protection has been successfully reported using single drug administration has been successfully reported using single drug administration such as imidazole, and Sh-bearing compounds. In the present work, the radioprotective effect of imidazole was demonstrated on the cardiovascular and respiratory systems. Furthermore, combined drug administration was found to exert more protective action with less toxicity and therefore minimize the side effects of the radioprotective drugs. Thus, combination of imidazole and serotonin showed potential protective effect on blood gases was also reported. In addition, combination of cysteine and vitamin E afforded a better protection on adrenocortical function in rats than either agent alone. 4 figs., 1 tab

Review of actinide decorporation with chelating agents

Energy Technology Data Exchange (ETDEWEB)

Ansoborlo, E. [CEA Valrho, Dir. de l' Energie Nucleaire (DEN/DRCP/CETAMA), 30 - Marcoule (France); Amekraz, B.; Moulin, Ch. [CEA Saclay, Dept. de Physico-Chimie (DEN/DPC/SECR), 91 - Gif sur Yvette (France); Moulin, V. [CEA Saclay, Dir. du Developpement et de l' Innovation Nucleares (DEN/DDIN/MR), 91 - Gif Sur Yvette (France); Taran, F. [CEA Saclay (DSV/DBJC/SMMCB), 91 - Gif-sur-Yvette (France); Bailly, Th.; Burgada, R. [Centre National de la Recherche Scientifique (CNRS/LCSB/UMR 7033), 93 - Bobigny (France); Henge-Napoli, M.H. [CEA Valrho, Site de Marcoule (INSTN), 30 (France); Jeanson, A.; Den Auwer, Ch.; Bonin, L.; Moisy, Ph. [CEA Valrho, Dir. de l' Energie Nucleaire (DEN/DRCP/SCPS), 30 - Marcoule (France)

2007-10-15

In case of accidental release of radionuclides in a nuclear facility or in the environment, internal contamination (inhalation, ingestion or wound) with actinides represents a severe health risk to human beings. It is therefore important to provide effective chelation therapy or decorporation to reduce acute radiation damage, chemical toxicity, and late radiation effects. Speciation governs bioavailability and toxicity of elements and it is a prerequisite tool for the design and success of new ligands or chelating agents. The purpose of this review is to present the state-of-the-art of actinide decorporation within biological media, to recall briefly actinide metabolism, to list the basic constraints of actinide-ligand for development, to describe main tools developed and used for decorporation studies, to review mainly the chelating agents tested for actinides, and finally to conclude on the future trends in this field. (authors)

Electrocardiographic Changes After Granisetron Administration for Chemotherapy Induced Nausea and Vomiting

Directory of Open Access Journals (Sweden)

Alidoosti Asadolah

2009-10-01

Full Text Available Cancer patient receive various cytotoxic drugs in association with antiemetic drugs such as 5HT3 receptor antagonists as their chemotherapy regimen. 5HT3 receptor antagonists have been reported to produce changes in ECG parameter. There are only a few studies about cardiovascular events of these drugs in patient receiving potentially cardiotoxic chemotherapies. The subject of this study is to evaluate ECG changes after administration of chemotherapeutic agents and granisetron (the most commonly used 5HT3 antagonist in Iran in adults with cancer. For this clinical trial study, all cancer patients referred to department of radiation oncology of Imam Hossein Hospital since August 2005 to March 2006 were evaluated if they had inclusion criteria. Granisetron (3 mg was infused intravenously over 30 seconds just a few minutes before chemotherapeutic agent administration. The 12-lead ECG recording was obtained before and 90 minutes after infusion of granisetron. One cardiologist determined PR, QRS, QTc intervals and heart rate of all ECGs. During the study period 54 patients fulfilled our criteria. With paired t-test, the PR and QTc intervals, but not QRS interval showed statistically significant prolongation after drug infusion (P < 0.0001, and heart rate showed statistically significant decrease (P < 0.0001. The ECG findings of chemotherapeutic agents and granisetron administration were prolongation of PR and QTc intervals and decrease of heart rate (P < 0.0001. Although these changes did not cause clinical signs, with keeping in mind that there may be possible drug-drug interactions and preexisting cardiac comorbidities in cancer patient, it seems reasonable and necessary to consider physical condition specifically cardiac condition and drug usage of each patient, while designing chemotherapy regimen and supportive drugs.

Doxorubicin-loaded micelles of reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers as efficient "active" chemotherapeutic agents.

Science.gov (United States)

Cambón, A; Rey-Rico, A; Mistry, D; Brea, J; Loza, M I; Attwood, D; Barbosa, S; Alvarez-Lorenzo, C; Concheiro, A; Taboada, P; Mosquera, V

2013-03-10

Five reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers, BOnEOmBOn, with BO ranging from 8 to 21 units and EO from 90 to 411 were synthesized and evaluated as efficient chemotherapeutic drug delivery nanocarriers and inhibitors of the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line. The copolymers were obtained by reverse polymerization of poly(butylene oxide), which avoids transfer reaction and widening of the EO block distribution, commonly found in commercial poly(ethylene oxide)-poly(propylene oxide) block copolymers (poloxamers). BOnEOmBOn copolymers formed spherical micelles of 10-40 nm diameter at lower concentrations (one order of magnitude) than those of equivalent poloxamers. The influence of copolymer block lengths and BO/EO ratios on the solubilization capacity and protective environment for doxorubicin (DOXO) was investigated. Micelles showed drug loading capacity ranging from ca. 0.04% to 1.5%, more than 150 times the aqueous solubility of DOXO, and protected the cargo from hydrolysis for more than a month due to their greater colloidal stability in solution. Drug release profiles at various pHs, and the cytocompatibility and cytotoxicity of the DOXO-loaded micelles were assessed in vitro. DOXO loaded in the polymeric micelles accumulated more slowly inside the cells than free DOXO due to its sustained release. All copolymers were found to be cytocompatible, with viability extents larger than 95%. In addition, the cytotoxicity of DOXO-loaded micelles was higher than that observed for free drug solutions in a MDR ovarian NCI-ADR-RES cell line which overexpressed P-gp. The inhibition of the P-gp efflux pump by some BOnEOmBOn copolymers, similar to that measured for the common P-gp inhibitor verapamil, favored the retention of DOXO inside the cell increasing its cytotoxic activity. Therefore, poly(butylene oxide)-poly(ethylene oxide) block copolymers offer interesting features as cell

Radioprotection: mechanism and radioprotective agents including honeybee venom

Energy Technology Data Exchange (ETDEWEB)

Varanda, E.A.; Tavares, D.C. [UNESP, Araraquara, SP (Brazil). Escola de Ciencias Farmaceuticas. Dept. de Ciencias Biologicas

1998-07-01

Since 1949, a great deal of research has been carried on the radioprotective action of chemical substances. These substances have shown to reduce mortality when administered to animals prior to exposure to a lethal dose of radiation. This fact is of considerable importance since it permits reduction of radiation-induced damage and provides prophylactic treatment for the damaging effects produced by radiotherapy. The following radioprotection mechanisms were proposed: free radical scavenger, repair by hydrogen donation to target molecules formation of mixed disulfides, delay of cellular division and induction of hypoxia in the tissues. Radioprotective agents have been divided into four major groups: the thiol compounds, other sulfur compounds, pharmacological agents (anesthetic drugs, analgesics, tranquilizers, etc.) and other radioprotective agents (WR-1065, WR-2721, vitamins C and E, glutathione, etc.). Several studies revealed the radioprotective action of Apis mellifera honeybee venom as well as that of its components mellitin and histamine. Radioprotective activity of bee venom involves mainly the stimulation of the hematopoietic system. In addition, release of histamine and reduction in oxygen tension also contribute to the radioprotective action of bee venom. (author)

Radioprotection: mechanism and radioprotective agents including honeybee venom

International Nuclear Information System (INIS)

Varanda, E.A.; Tavares, D.C.

1998-01-01

Since 1949, a great deal of research has been carried on the radioprotective action of chemical substances. These substances have shown to reduce mortality when administered to animals prior to exposure to a lethal dose of radiation. This fact is of considerable importance since it permits reduction of radiation-induced damage and provides prophylactic treatment for the damaging effects produced by radiotherapy. The following radioprotection mechanisms were proposed: free radical scavenger, repair by hydrogen donation to target molecules formation of mixed disulfides, delay of cellular division and induction of hypoxia in the tissues. Radioprotective agents have been divided into four major groups: the thiol compounds, other sulfur compounds, pharmacological agents (anesthetic drugs, analgesics, tranquilizers, etc.) and other radioprotective agents (WR-1065, WR-2721, vitamins C and E, glutathione, etc.). Several studies revealed the radioprotective action of Apis mellifera honeybee venom as well as that of its components mellitin and histamine. Radioprotective activity of bee venom involves mainly the stimulation of the hematopoietic system. In addition, release of histamine and reduction in oxygen tension also contribute to the radioprotective action of bee venom. (author)

Radiation and chemically induced potentially lethal lesions in noncycling mammalian cells: recovery analysis in terms of x-ray- and ultraviolet-like-systems

International Nuclear Information System (INIS)

Hahn, G.M.

1975-01-01

Recovery from and fixation of potentially lethal damage after exposure of Chinese hamster cells to uv and to x irradiation were investigated, as was recovery after exposure to chemotherapeutic agents. Recovery after uv radiation has a T/sub 1 / 2 / of about 20 hr; the fraction of cells able to undergo recovery depends upon nutritional factors both before and after exposure. After x irradiation, recovery proceeds with a T/sub 1 / 2 / of approximately 2 hr and is much less influenced by nutritional factors. Fixation after serum stimulation has a T/sub 1 / 2 / of 3 to 4 hr in uv-irradiated cells, a T/sub 1 / 2 / of 30 min in x-irradiated cells. Recovery kinetics after nitrogen mustard and bleomycin exposures mimic those for x-ray exposure; after methyl methane sulfonate the kinetics are mainly uv-like, though with an x-ray-like component. Recovery by cells with BUdR-substituted DNA and irradiated with visible light is primarily x-ray-like, though with a uv-like component. There is no recovery by cells exposed to adriamycin or to 1,3-bis(2-chloroethyl)-1-nitrosourea

STTARR: a radiation treatment and multi-modal imaging facility for fast tracking novel agent development in small animal models

International Nuclear Information System (INIS)

Yeung, Ivan; McKee, Trevor; Jaffray, David; Hill, Richard

2014-01-01

Small animal models play a pivotal role in the pipeline development of novel agents and strategies in personalized cancer therapy. The Spatio-Temporal Targeting and Amplification of Radiation Response Program (STTARR) consists of an animal imaging and precision radiation facility designed to provide innovative biologic imaging and targeted radiation treatment strategies in small animals. The design is to mirror the imaging and radiation treatment facility in a modern cancer center. The STTARR features imaging equipment of small animal scale including CT, MRI, PET, SPECT, Optical devices as well as image guided irradiators. The fleet of imaging and irradiation equipment provides a platform for identification of biological targets of the specific molecular pathways that influence both tumor progression and a patient's response to radiation therapy. Examples will be given in the utilization of the imaging facilities for development in novel approaches in cancer therapy including a PET-FAZA study for hypoxia measurement in a pancreatic adenocarcinoma xenograft model. In addition, the cone-beam image guided small animal irradiator developed at our institute will also be described. The animal platform (couch) provides motion in 3 dimensions to position the animal to the isocentre of the beam. A pair of rotational arms supporting the X-ray/detector pair enables acquisition of cone-beam images of the animal which give rise to image guided precision of 0.5 mm. The irradiation energy ranges from 50 to 225 kVp at a dose rate from 10-400 cGy/min. The gantry is able to direct X-ray beam of different directions to give conformal radiation treatment to the animal. A dedicated treatment planning system is able to perform treatment planning and provide commonly used clinical metrics in the animal treatment plan. Examples will be given to highlight the use of the image guided irradiator for research of drug/irradiation regimen in animal models. (author)

Synthesis and characterization of Cu(II)-based anticancer chemotherapeutic agent targeting topoisomerase Iα: in vitro DNA binding, pBR322 cleavage, molecular docking studies and cytotoxicity against human cancer cell lines.

Science.gov (United States)

Tabassum, Sartaj; Zaki, Mehvash; Afzal, Mohd; Arjmand, Farukh

2014-03-03

New metal-based anticancer chemotherapeutic drug candidates [Cu(phen)L](NO₃)₂ (1) and [Zn(phen)L](NO₃)₂ (2) were synthesized from ligand L (derived from pharmacophore scaffold barbituric acid and pyrazole). In vitro DNA binding studies of the L, 1 and 2 were carried out by various biophysical techniques revealing electrostatic mode. Complex 1 cleaves pBR322 DNA via oxidative pathway and recognizes major groove of DNA double helix. The molecular docking study was carried out to ascertain the mode of action towards the molecular target DNA and enzymes. The complex 1 exhibited remarkably good anticancer activity on a panel of human cancer cell lines (GI₅₀ values < 10 μg/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Radiobiological research needed for the improvement of radiotherapy

International Nuclear Information System (INIS)

1977-01-01

. Hyperthermia appears to be a promising way of treating various types of cancer either alone or in combination with radiation. Although the mechanisms of action of hyperthermia on tumour and normal cells is obscure at the moment, it has increased the radiation sensitivity of many types of tumours. Hyperthermia also increases cytotoxic effects of conventional chemotherapeutic agents and may therefore prove useful in combination with chemotherapy. The chemotherapy drugs extensively used in cancer treatment can be classified as alkylating agents, antimetabolites, mitotic inhibitors, anti-tumour antibiotics, and miscellaneous other chemicals whose mechanism of action has not been understood. Combination of radiation therapy with chemotherapy has proved to be the best mode of cancer treatment. During the discussions it became evident that radiation effects on cells are understood to a greater extent than are the effects of chemotherapeutic agents. It was therefore emphasized that more basic research ought to be done on the mechanism of action of chemotherapeutic drugs. Use of heavily ionizing radiations, such as neutrons, rr-mesons and stripped nuclei, has been advocated for treatment of certain tumours. Intensive research is underway on the effects of such radiations in the USA, Canada and Western Europe. In a panel discussion on future radiobiological research needs for radiotherapy, it was pointed out that radiobiologists and radiotherapists have so far worked on different platforms. Whereas the radiotherapist has been overburdened with treatment of patients, radiobiologists have mainly concentrated their efforts on in vitro systems which may or may not be of use in patient treatment. It was therefore emphasized that radiotherapy clinics must have consultant radiobiologists, and that radiobiologists ought to be familiar with the clinical problems in hospitals. In the UK and USA such arrangements have been mutually profitable. (author)

Radiation dosimetry in radiotherapy with internal emitters

International Nuclear Information System (INIS)

Stabin, Michael G.

1997-01-01

Full text. Radiation dosimetry radionuclides are currently being labeled to various biological agents used in internal emitter radiotherapy. This talk will review the various technologies and types of radiolabel in current use, with focus on the characterization of the radiation dose to the various important tissues of the body. Methods for obtaining data, developing kinetic models, and calculating radiation doses will be reviewed. Monoclonal antibodies are currently being labeled with both alpha and beta emitting radionuclides in attempts to find effective agents against cancer. Several radionuclides are also being used as bone pain palliation agents. These agents must be studied in clinical trials to determine the biokinetics and radiation dosimetry prior to approval for general use. In such studies, it is important to ensure the collection of the appropriate kinds of data and to collect the data at appropriate time intervals. The uptake and retention of activity in all significant source organs and in excreta be measured periodically (with at least 2 data points phase of uptake or clearance). Then, correct dosimetry methods must be applied - the best available methods for characterizing the radionuclide kinetic and for estimating the dosimetry in the various organs of the body especially the marrow, should be used. Attempts are also under way to develop methods for estimating true patient-specific dosimetry. Cellular and animal studies are also. Valuable in evaluating the efficacy of the agents in shrinking or eliminating tumors; some results from such studies will also be discussed. The estimation of radiation doses to patients in therapy with internal emitters involves several complex phases of analysis. Careful attention to detail and the use of the best available methods are essential to the protection of the patient and a successful outcome

Pediatric malignancies and radiation therapy: What are the chronic treatment sequelae?

International Nuclear Information System (INIS)

Constine, Louis S.; Shelton, Dabney

1997-01-01

Most pediatric malignancies have proved to be vulnerable targets to cytotoxic therapy. The bleak outlook that historically accompanied these diseases has changed into an optimism for cure; 65% of affected children now survive. These gains are a direct consequence of the development of effective chemotherapeutic agents, radiotherapeutic and surgical techniques, and strategies to maximize their complementary actions in obtaining both local and systemic tumor control. In concert with the advances in tumor eradication has come an increased flexibility for devising approaches which reduce associated morbidities, including second malignancies. Children are particularly vulnerable for developing debilitating normal tissue effects, and are particularly complicated because in children a mosaic of different tissues are developing at different rates and in different temporal sequences. Understanding these biologic principles in the setting of progress in radiotherapeutic technique is critical to accomplishing the goal of appropriate and safe treatment delivery. Second malignancies result from the collision of cytotoxic therapy and the genetic constitution of the child. Since death is a frequent outcome, their importance is heightened. The objective of this course is to provide an understanding of organ-specific chronic effects of cancer therapy, and to offer a systematic guide to their evaluation and management. Since one of every 1000 young adults is now a childhood cancer survivor, the late sequelae of therapy, including second malignancies, become increasingly relevant for the radiation oncologist to appreciate, manage, and consider when formulating therapy

Pediatric malignancies and radiation therapy: what are the chronic treatment sequelae?

International Nuclear Information System (INIS)

Shelton, Dabney; Constine, Louis S.

1995-01-01

Most pediatric malignancies have proved to be vulnerable targets to cytotoxic therapy. The bleak outlook that historically accompanied these diseases has changed into an optimism for cure; 65% of affected children now survive. These gains are a direct consequence of the development of effective chemotherapeutic agents, radiotherapeutic and surgical techniques, and strategies to maximize their complementary actions in obtaining both local and systemic tumor control. In concert with the advances in tumor eradication has come an increased flexibility for devising approaches which reduce associated morbidities, including second malignancies. Children are particularly vulnerable for developing debilitating normal tissue effects, and are particularly complicated because in children a mosaic of different tissues are developing at different rates and in different temporal sequences. Understanding these biologic principles in the setting of progress in radiotherapeutic technique is critical to accomplishing the goal of appropriate and safe treatment delivery. Second malignancies result from the collision of cytotoxic therapy and the genetic constitution of the child. Since death is a frequent outcome, their importance is heightened. The objective of this course is to provide an understanding of organ-specific chronic effects of cancer therapy, and to offer a systematic guide to their evaluation and management. Since one of every 1000 young adults is now a childhood cancer survivor, the late sequelae of therapy, including second malignancies, become increasingly relevant for the radiation oncologist to appreciate, manage, and consider when formulating therapy

Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review.

Science.gov (United States)

Anjum, Komal; Shagufta, Bibi Ibtesam; Abbas, Syed Qamar; Patel, Seema; Khan, Ishrat; Shah, Sayed Asmat Ali; Akhter, Najeeb; Hassan, Syed Shams Ul

2017-08-01

Glioblastoma multiforme (GBM) is the deadliest form of heterogeneous brain cancer. It affects an enormous number of patients every year and the survival is approximately 8 to 15 months. GBM has driven by complex signaling pathways and considered as a most challenging to treat. Standard treatment of GBM includes surgery, radiation therapy, chemotherapy and also the combined treatment. This review article described inter and intra- tumor heterogeneity of GMB. In addition, recent chemotherapeutic agents, with their mechanism of action have been defined. FDA-approved drugs also been focused over here and most importantly highlighting some natural and synthetic and novel anti- glioma agents, that are the main focus of researchers nowadays. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Differences in practice patterns and costs between small cell and non-small cell lung cancer patients in Japan

International Nuclear Information System (INIS)

Kuwabara, Kazuaki; Matsuda, Shinya; Fushimi, Kiyohide; Anan, Makoto; Ishikawa, Koichi B.; Horiguchi, Hiromasa; Hayashida, Kenshi; Fujimori, Kenji

2009-01-01

Many reports exist regarding the economic evaluation of evolving chemotherapeutic regimens or diagnostic images for lung cancer (LC) patients. However, it is not clear whether clinical information, such as pathological diagnosis or cancer stage, should be considered as a risk adjustment in lung cancer. This study compared the cost and practice patterns between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) patients. 6,060 LC patients treated at 58 academic hospitals and 14,507 at 257 community hospitals were analyzed. Study variables included demographic variables, comorbid status, cancer stage, use of imaging and surgical procedures, type of adjuvant therapy (chemotherapy, radiation or chemoradiation), use of ten chemotherapeutic agents, length of stay (LOS), and total charges (TC; US$1=100 yen) in SCLC and NSCLC patients. The impact of pathological diagnosis on LOS and TC was investigated using multivariate analysis. We identified 3,571 SCLC and 16,996 NSCLC patients. The proportion of demographic and practice-process variables differed significantly between SCLC and NSCLC patients, including diagnostic imaging, adjuvant therapy and surgical procedures. Median LOS and TC were 20 days and US$6,015 for SCLC and 18 days and US$6,993 for NSCLC patients, respectively (p<0.001 for each variable). Regression analysis revealed that pathological diagnosis was not correlated with TC. Physicians should acknowledge that pathological diagnosis dose not accounts for any variation in cost of LC patients but that should remain as an indicator of appropriate care like selection of chemotherapeutic agents. (author)

Biochemical toxicology of environmental agents

International Nuclear Information System (INIS)

Bruin, A. de

1976-01-01

A thorough and up-to-date account of the molecular-biological aspects of harmful agents - both chemical and physical - is given. This current treatise is principally intended to serve as an informative reference work for researchers in various areas of the field. In the pursuit of this aim, a devision of the entire field into 42 chapters has been made. Each chapter starts with a short introductory account dealing with the biochemical essentials of the particular subject. Radiation effects are discussed briefly at the end of each treatise. In order to make the treatise useful as a source book, a substantial collection of pertinent literature references is provided which are numbered in order of citation in the text. Initial chapters are devoted to the metabolic fate of the major classes of xenobiotic compounds. Peripheral topics, closely related to metabolism and dealing with modification of xenobiotic-metabolizing ability, as well as interaction phenomena follow (chs. 5-8). Subjects that draw heavily on the practical field of occupational hygiene are dealt with in chapters 9 and 10. The systematic treatment of how chemical and physical agents interact with the various biochemical and enzymatic systems they encounter during their passage through the organism occupies quantitatively the main part of the book (chs. 11-36). Finally, radiation biochemistry is discussed from the viewpoint of its high degree of scientific advancement, and secondly because the type of biochemical changes produced in vivo by X-rays closely parallel those evoked by chemical agents

Risk equivalent of exposure versus dose of radiation

International Nuclear Information System (INIS)

Bond, V.P.

1986-01-01

Radiation is perhaps unique among all agents of interest in the Health Sciences in that it alone is both a therapeutic agent for the control of cancer and an essentially ubiquitous environmental agent with a potential for increasing the cancer rate in human populations. Therapy of tumors is accomplished with the high-level exposure (HLE) to radiation in order to effect control or a cure. Thus, it conforms to the concepts and approaches of pharmacology, toxicology, and therapeutic medicine. Only one function, that which relates the object-oriented and nonstochastic independent variable organ dose to its effect on a cancer or an organ, is needed to estimate the probability, P 2 , of a quantal response. Only P 2 is needed because P 1 , that the cancer slated for such treatment will receive some amount of the agent and be affected to some degree, is effectively unity. The health problem involving low-level exposure (LLE) to radiation, in contrast, is not at all analogous to those of pharmacology, toxicology, and medicine. Rather, it presents a public health problem in that it is a health population, albeit of cells, that is exposed in a radiation field composed of moving radiation particles with some attendant low-order carcinogenic or mutagenic risk. Thus, the concepts, quantities, and terminology applied to low-level radiation must be modified from their present orientation toward pharmacology, toxicology, medicine, and dose to conform to those of public health and accident statistics, in which both P 1 and P 2 for the exposed cells must be estimated

Investigation of the possibility of the reduction of chemotherapeutics by activation of PBMCs in tumor cell

International Nuclear Information System (INIS)

Schwanninger, M.

2009-01-01

The three big columns in the treatment of malignant tumour are chemotherapeutics, radiotherapy and surgical interventions. However, beside these three types of therapies the hormone therapy plays an extremely important role as well. In modern medicine chemotherapeutics are the main therapy for most malignant tumour diseases. This fact mainly follows from the absence of other, just as well working alternatives. Administration of these substances sometimes leads to strong undesirable side effects or to insufficient response. The mentioned lack of alternatives, neither in the form of chemotherapeutics nor in the form of other possibilities of treatment, can heavily endanger the desired therapy success. Today it is clear that there is a complicated teamwork between immune defence, inflammation and carcinoma. Up to twenty times more Macrophages are located in tumour surroundings than in healthy fabric. These so called tumour associated or M2 Macrophages (TAMs) differ from other Macrophages, the M1 Macrophages, by their non-inflammatory effects. They do not necessarily lead to immune defence. In 2008, Hunder et al described in a study that cloned CD4+ T cells injected in Melanoma lead to a remission of the tumour. An activation of PBMCs and subsequent administration could be helpful with the fight against malignant tumours. Using the Δ;NS virus PBMCs will be stimulated - more exactly, monocytes and as a result PBMCs - and initiate an immunological reaction against tumour cells. Furthermore it will be shown that PBMCs immunosuppressed earlier - as they appear in tumour surroundings - can be activated by means of Δ;NS virus again. The 'tumour friendly' environment may be altered in a 'tumour-unfriendly' environment, and, as a direct consequence, the growth of the tumour cells will decrease. It is clear that this activation of the immune system cannot substitute a chemotherapy as a whole, but an improved killing or reduction of the dose should lead to the reduction of the

Copper complexes as 'radiation recovery' agents

International Nuclear Information System (INIS)

Sorenson, J.R.J.

1989-01-01

Copper and its compounds have been used for their remedial effects since the beginning of recorded history. As early as 3000 BC the Egyptians used copper as an antiseptic for healing wounds and to sterilise drinking water; and later, ca 1550 BC, the Ebers Papyrus reports the use of copper acetate, copper sulphate and pulverised metallic copper for the treatment of eye infections. These historical uses of copper and its compounds are particularly interesting in the light of modern evidence concerning the use of certain copper complexes for the treatment of radiation sickness and more recently as an adjunct to radiotherapy for cancer patients. (author)

Combined genetic effects of chemicals and radiation

International Nuclear Information System (INIS)

Kada, T.; Inoue, T.; Yokoiyama, A.; Russel, L.B.

1979-01-01

Interactions of chemicals and radiation are complex and there may exist other unexpected patterns that are not mentioned. We show some examples. Photodynamic mutation induction by fluorescein dyes and Radiosensitization with iodine compounds are classified as Interactions of chemicals and radiation outside of the cell. On the other hand, the Antimutagenic effects of cobaltous chloride is concerned with events taking place in cells that had already been exposed to a mutagenic agent. It is likely that the action of a mutagenic agent is not direct and that cellular functions, such as mutators or repair systems, are involved in the mutagenesis initiated by the agent. Such cellular functions can be affected by a second agent. In sexually reproducing organisms, the two agents can also act on separate cells (male and female germcells) which subsequently fuse. Interaction effects of all types will be useful in future research in shedding light on the main pathways of mutagenesis

The role of the HCR system in the repair of lethal lesions of Bacillus subtilis phages and their transfecting DNA damaged by radiation and alkylating agents

International Nuclear Information System (INIS)

Vizdalova, M.; Janovska, E.; Zhestyanikov, V.D.

1980-01-01

The role of the HCR system in the repair of prelethal lesions induced by UV light, γ radiation and alkylating agents was studied in the Bacillus subtilis SPP1 phage, its heat sensitive mutants (N3, N73 nad ts 1 ) and corresponding infectious DNA. The survival of phages and their transfecting DNA after treatment with UV light is substantially higher in hcr + cells than in hcr cells, the differences being more striking in intact phages than in their transfecting DNA's. Repair inhibitors reduce survival in hcr + cells: caffeine lowers the survival of UV-irradiated phage SPP1 in exponentially growing hcr + cells but has no effect on its survival in competent hcr + cells; acriflavin and ethidium bromide decrease the survival of the UV-irradiated SPP1 phage in both exponentially growing and competent hcr + cells to the level of survival observed in hcr cells; moreover, ethidium bromide lowers the number of infective centres in hcr + cells of the UV-irradiated DNA of the SPP1 phage. Repair inhibitors do not lower the survival of the UV-irradiated phages or their DNA in hcr cells. The repair mechanism under study also effectively repairs lesions induced by polyfunctional alkylating agents in the transfecting DNA's of B. subtilis phages but is not functional with lesions induced by these agents in free phages and lesions caused in the phages and their DNA by ethyl methanesulphonate or γ radiation. (author)

Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas.

Science.gov (United States)

Yoon, C; Lee, H-J; Park, D J; Lee, Y-J; Tap, W D; Eisinger-Mathason, T S K; Hart, C P; Choy, E; Simon, M C; Yoon, S S

2015-06-30

Human sarcomas with a poor response to vascular endothelial growth factor-A (VEGF-A) inhibition and radiation therapy (RT) have upregulation of hypoxia-inducible factor 1α (HIF-1α) and HIF-1α target genes. This study examines the addition of the hypoxia-activated chemotherapy TH-302 to VEGF-A inhibition and RT (a.k.a. trimodality therapy). Trimodality therapy was examined in two xenograft models and in vitro in tumour endothelial cells and sarcoma cell lines. In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth. When TH-302 was added, this trimodality therapy completely blocked tumour growth with tumours remaining dormant for over 3 months after cessation of therapy. Trimodality therapy caused 2.6- to 6.2-fold more endothelial cell-specific apoptosis than bimodality therapies, and microvessel density and HIF-1α activity were reduced to 11-13% and 13-20% of control, respectively. When trimodality therapy was examined in vitro, increases in DNA damage and apoptosis were much more pronounced in tumour endothelial cells compared with that in sarcoma cells, especially under hypoxia. The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1α activity.

Feasibility and safety of electrochemotherapy (ECT in the pancreas: a pre-clinical investigation

Directory of Open Access Journals (Sweden)

Girelli Roberto

2015-06-01

Full Text Available Background. Pancreatic ductal adenocarcinoma (PDAC is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT, thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents.

The state of knowledge of astronaut radiation protection principles

International Nuclear Information System (INIS)

Boszkiewicz, T.

1986-01-01

Different noxious agents such as accelerations, vibration, weightlessness, emotional tention, microclimate of hermetic space-ship or orbital station and cosmic radiation act on organism during space flight. No health hazardous radioactive radiation intensity or harmful influence on astronaut organism are observed during the not-long-lasted flights on low ceilings. But scientific researches show the danger exists in case of longlasted flights on high ceilings particularly during interplanetary flights, so it is necessary to undertake suitable countermeasures. The problem is even more important because the parallel activity of radioactive radiation and some more noxious agents can be very harmfull even with the small radiation dose. 8 refs. (author)

A Systematic Overview of Radiation Therapy Effects in Head and Neck Cancer

International Nuclear Information System (INIS)

Zackrisson, Bjoern; Mercke, Claes; Strander, Hans; Wennerberg, Johan; Cavallin-Staahl, Eva

2003-01-01

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately. This synthesis of the literature on radiation therapy for head and neck cancer is based on data from 39 randomized trials and 1 meta-analysis. In total, 40 scientific articles are included, involving 20,893 patients. The results were compared with those of a similar overview from 1996 including 79,174 patients. The conclusions reached can be summarized as follows: General, non-nasopharynx: Substantial evidence indicates that the tumour effect of radiotherapy can be increased by the concomitant administration of chemotherapeutic agents, particularly cisplatin and 5-fluorouracil. There is moderate evidence of a survival benefit of radiation combined with concomitant chemotherapy compared to radiation alone. However, the results are equivocal. There is substantial evidence in published studies for an increased frequency of severe acute side effects as a result of concomitant chemotherapy and radiotherapy. There are very few studies that allow any estimates of the risk for serious late side effects. There is a weak indication of an increased risk for serious fibrosis. Comment: The general quality of studies and the lack of information on serious side effects indicate a need for large, well-designed clinical studies with a reasonable follow-up. Larynx preservation studies: There is strong evidence that larynx preservation is possible in 50% of the patients surviving for 5 years with hypopharyngeal cancers when treated with neoadjuvant chemotherapy and radical radiotherapy. There is a non-significant trend for the overall survival being lower in non-surgically treated patients than in those treated with primary surgery and postoperative radiotherapy. Nasopharynx There is moderate evidence that patients with nasopharyngeal carcinomas

Low-dose radiation as an environmental agent affecting intrauterine development

International Nuclear Information System (INIS)

Kameyama, Yoshiro

1982-01-01

The low-dose radiation effects which have been recognized in mammalian teratological studies are direct injuries to the particularly radiosensitive tissues of embryo and fetus, and increased incidences of spontaneous malformations and minor anomalies. The lowest radiation doses for manifestation of those effects in mice and rats are: 5 rad for resorption of preimplantation embryos; 5-10 rad for acute cytological changes such as pyknosis, cytoplasmic degeneration and mitotic delay; 5 rad for increasing frequency of spontaneous minor anomalies of the skeleton; 15-20 rad for malformations of the eye, brain and spinal cord; 20-25 rad for histogenetic and functional disorders of the central nervous system; and 20-25 rad for impaired fertility. Pregnant women who are subject to X-ray examination are much concerned about potential hazard of radiation to their offspring in utero. The above experimental findings suggest that the possibility of teratogenic effects of diagnostic radiation on human embryos and fetuses is extremely low, and probably negligible, given the proper dose control measures. (author)

Towards producing novel fish gelatin films by combination treatments of ultraviolet radiation and sugars (ribose and lactose) as cross-linking agents.

Science.gov (United States)

Bhat, Rajeev; Karim, A A

2014-07-01

Developing novel fish gelatin films with better mechanical properties than mammalian gelatin is a challenging but promising endeavor. Studies were undertaken to produce fish gelatin films by combining treatments with different sugars (ribose and lactose) followed 'by' 'and' ultraviolet (UV) radiation, as possible cross-linking agents. Increase in tensile strength and percent elongation at break was recorded, which was more significant in films without sugars that were exposed to UV radiation. Films with added ribose showed decreased solubility after UV treatment and exhibited higher swelling percentage than films with added lactose, which readily dissolved in water. FTIR spectra of all the films showed identical patterns, which indicated no major changes to have occurred in the functional groups as a result of interaction between gelatin, sugars and UV irradiation. The results of this study could be explored for commercial use, depending on industrial needs for either production of edible films or for food packaging purposes.

Transgenic Plants as Low-Cost Platform for Chemotherapeutic Drugs Screening

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Daniele Vergara

2015-01-01

Full Text Available In this work we explored the possibility of using genetically modified Arabidopsis thaliana plants as a rapid and low-cost screening tool for evaluating human anticancer drugs action and efficacy. Here, four different inhibitors with a validated anticancer effect in humans and distinct mechanism of action were screened in the plant model for their ability to interfere with the cytoskeletal and endomembrane networks. We used plants expressing a green fluorescent protein (GFP tagged microtubule-protein (TUA6-GFP, and three soluble GFPs differently sorted to reside in the endoplasmic reticulum (GFPKDEL or to accumulate in the vacuole through a COPII dependent (AleuGFP or independent (GFPChi mechanism. Our results demonstrated that drugs tested alone or in combination differentially influenced the monitored cellular processes including cytoskeletal organization and endomembrane trafficking. In conclusion, we demonstrated that A. thaliana plants are sensitive to the action of human chemotherapeutics and can be used for preliminary screening of drugs efficacy. The cost-effective subcellular imaging in plant cell may contribute to better clarify drugs subcellular targets and their anticancer effects.

Epidermal growth factor receptor (EGFR mutation status and Rad51 determine the response of glioblastoma (GBM to multimodality therapy with cetuximab, temozolomide and radiation

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Phyllis Rachelle Wachsberger

2013-02-01

Full Text Available Purpose: EGFR amplification and mutation (i.e., EGFRvIII are found in 40% of primary GBM tumors and are believed to contribute to tumor development and therapeutic resistance. This study was designed to investigate how EGFR mutational status modulates response to multimodality treatment with cetuximab, an anti-EGFR inhibitor, the chemotherapeutic agent, temozolamide (TMZ and radiation therapy (RT Methods and Materials: In vitro and in vivo experiments were performed on two isogenic U87 GBM cell lines: one overexpressing wildtype EGFR (U87wtEGFR and the other overexpressing EGFRvIII (U87EGFRvIII. Results: Xenografts harboring EGFRvIII were more sensitive to TMZ alone and TMZ in combination with RT and/or cetuximab than xenografts expressing wtEGFR. In vitro experiments demonstrated that U87EGFRvIII-expressing tumors appear to harbor defective DNA homologous recombination repair in the form of Rad51 processing, Conclusions: The difference in sensitivity between EGFR-expressing and EGFRvIII-expressing tumors to combined modality treatment may help in the future tailoring of GBM therapy to subsets of patients expressing more or less of the EGFR mutant.

Studies on the relationship between the cancer chemotherapeutic agent, hydroxyurea, and DNA repair in mammalian cells

International Nuclear Information System (INIS)

Katz, E.J.

1988-01-01

To examine the possibility that manipulating DNA repair might lessen drug resistance, we investigated whether depletion of the thymidine triphosphate (TTP) pool or administration of hydroxyurea could interfere with the ability of confluent normal human skin fibroblasts to repair ultraviolet irradiation-induced DNA damage. A method was developed for the quantitation of cellular TTP pools by labeling them with [ 3 H]thymidine. The addition of hydroxyurea, either simultaneously with [ 3 H]thymidine or two hours later, resulted in a dose- and time-dependent increase in the [ 3 H]TTP pool. The capacity of these cells to carry out DNA repair was quantitated by their ability to perform repair replication synthesis of DNA after exposure to ultraviolet irradiation. This radiation produces thymine dimers in DNA, which are repaired by the nucleotide excision repair pathway. The experimental protocol resulted in an 8-10-fold reduction in the [ 3 H]TTP pool. Saturating levels of DNA repair synthesis were observed under these conditions, with no further diminution of the already reduced [ 3 H]TTP pool. Repair replication and [ 3 H]TTP pool measurements were identical in cultures treated with 10 mM hydroxyurea and in those not exposed to the drug

Epidemiology and Radiation Protection

International Nuclear Information System (INIS)

1987-01-01

Epidemiology aims at providing direct evidence of the long term health effects in humans due to potentially dangerous exposures to various nuisance agents, including ionising radiation. Inappropriate interpretation and use of the results of epidemiological studies may result in inaccurate assessments of the risks associated with radiation exposure. This report presents the proceedings of a Workshop organised by the NEA to create an opportunity for epidemiologists and radiation protection specialists to exchange their experiences and views on the problems of methodology in epidemiological research and on the application of its results to the assessment of radiation risks

Immunotherapy of distant metastatic disease

DEFF Research Database (Denmark)

Schadendorf, D; Algarra, S M; Bastholt, L

2009-01-01

Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated with signif......Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated...

Infrared radiation

International Nuclear Information System (INIS)

Moss, C.E.; Ellis, R.J.; Murray, W.E.; Parr, W.H.

1989-01-01

All people are exposed to IR radiation from sunlight, artificial light and radiant heating. Exposures to IR are quantified by irradiance and radiant exposure to characterize biological effects on the skin and cornea. However, near-IR exposure to the retina requires knowledge of the radiance of the IR source. With most IR sources in everyday use the health risks are considered minimal; only in certain high radiant work environments are individuals exposed to excessive levels. The interaction of IR radiation with biological tissues is mainly thermal. IR radiation may augment the biological response to other agents. The major health hazards are thermal injury to the eye and skin, including corneal burns from far-IR, heat stress, and retinal and lenticular injury from near-IR radiation. 59 refs, 13 figs, 2 tabs

Combined genetic effects of chemicals and radiation

International Nuclear Information System (INIS)

Kada, T.; Inoue, T.; Yokoiyama, A.; Russell, L.B.

1979-01-01

The interactions of chemicals and radiation are complex, and there may exist other unexpected patterns. The photodynamic induction of mutation by fluorescein dyes, and the radiosensitization with iodine compounds are classified as the interactions of chemicals and radiation outside cells. On the other hand, the antimutagenic effects of cobaltous chloride is concerned with the events taking place in the cells that had already been exposed to mutagenic agents. It is likely that the action of mutagenic agents is not direct, and that cellular functions, such as mutators or repair systems, are involved in the mutagenesis initiated by the agents. Such cellular functions can be affected by a second agent. In sexually reproducing organisms, two agents can also act on separate cells (male and female germ cells) which subsequently fuse. In mice, the experiments combining the radiation applied to one sex with the chemicals given to the other sex are only in early stages. Males were irradiated with X-ray (spermatozoa and spermatids sampled) and females (mature oocytes) were treated with caffeine. When the endpoint was dominant lethal, the level of X-ray effect induced in the male genome was independent of the caffeine treatment of the female. However, when the endpoint was sex-chromosome-loss, and a different strain of female was used, the caffeine potentiation was statistically significant at 5% level. (Yamashita, S.)

Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system

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Han Ruolan

2008-04-01

Full Text Available Abstract Background Cancer treatment with a variety of chemotherapeutic agents often is associated with delayed adverse neurological consequences. Despite their clinical importance, almost nothing is known about the basis for such effects. It is not even known whether the occurrence of delayed adverse effects requires exposure to multiple chemotherapeutic agents, the presence of both chemotherapeutic agents and the body's own response to cancer, prolonged damage to the blood-brain barrier, inflammation or other such changes. Nor are there any animal models that could enable the study of this important problem. Results We found that clinically relevant concentrations of 5-fluorouracil (5-FU; a widely used chemotherapeutic agent were toxic for both central nervous system (CNS progenitor cells and non-dividing oligodendrocytes in vitro and in vivo. Short-term systemic administration of 5-FU caused both acute CNS damage and a syndrome of progressively worsening delayed damage to myelinated tracts of the CNS associated with altered transcriptional regulation in oligodendrocytes and extensive myelin pathology. Functional analysis also provided the first demonstration of delayed effects of chemotherapy on the latency of impulse conduction in the auditory system, offering the possibility of non-invasive analysis of myelin damage associated with cancer treatment. Conclusions Our studies demonstrate that systemic treatment with a single chemotherapeutic agent, 5-FU, is sufficient to cause a syndrome of delayed CNS damage and provide the first animal model of delayed damage to white-matter tracts of individuals treated with systemic chemotherapy. Unlike that caused by local irradiation, the degeneration caused by 5-FU treatment did not correlate with either chronic inflammation or extensive vascular damage and appears to represent a new class of delayed degenerative damage in the CNS.

Mixtures of toxic agents and attributable risk calculations

International Nuclear Information System (INIS)

Seiler, F.A.; Scott, B.R.

1987-01-01

Calculations of attributable risks have attracted increasing interest recently. However, these efforts have been limited to mostly one agent, radiation, and no interactions with effects of other toxic agents have been taken into account. This paper outlines a generic approach to the calculation of attributable risks for an exposure to several toxic agents and interaction effects associated with them. In this calculation, the partition of interaction terms between the agents responsible is of particular importance. At present, there are no rules on how to assign equitable shares, so one methodology will be proposed and others discussed briefly. For one example of an assignment, the standard errors of the attributable risks are determined in terms of the uncertainties of the input parameters, thus setting the stage for a comparison of the different shares of responsibility

Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo.

Science.gov (United States)

Zhao, Xiao-qin; Xie, Jing-dun; Chen, Xing-gui; Sim, Hong May; Zhang, Xu; Liang, Yong-ju; Singh, Satyakam; Talele, Tanaji T; Sun, Yueli; Ambudkar, Suresh V; Chen, Zhe-Sheng; Fu, Li-wu

2012-07-01

Neratinib, an irreversible inhibitor of epidermal growth factor receptor and human epidermal receptor 2, is in phase III clinical trials for patients with human epidermal receptor 2-positive, locally advanced or metastatic breast cancer. The objective of this study was to explore the ability of neratinib to reverse tumor multidrug resistance attributable to overexpression of ATP-binding cassette (ABC) transporters. Our results showed that neratinib remarkably enhanced the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates. It is noteworthy that neratinib augmented the effect of chemotherapeutic agents in inhibiting the growth of ABCB1-overexpressing primary leukemia blasts and KBv200 cell xenografts in nude mice. Furthermore, neratinib increased doxorubicin accumulation in ABCB1-overexpressing cell lines and Rhodamine 123 accumulation in ABCB1-overexpressing cell lines and primary leukemia blasts. Neratinib stimulated the ATPase activity of ABCB1 at low concentrations but inhibited it at high concentrations. Likewise, neratinib inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner (IC(50) = 0.24 μM). Neither the expression of ABCB1 at the mRNA and protein levels nor the phosphorylation of Akt was affected by neratinib at reversal concentrations. Docking simulation results were consistent with the binding conformation of neratinib within the large cavity of the transmembrane region of ABCB1, which provides computational support for the cross-reactivity of tyrosine kinase inhibitors with human ABCB1. In conclusion, neratinib can reverse ABCB1-mediated multidrug resistance in vitro, ex vivo, and in vivo by inhibiting its transport function.

Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea

Science.gov (United States)

Huber, S. E.; Śmiałek, M. A.; Tanzer, K.; Denifl, S.

2016-06-01

Dissociative electron attachment to hydroxyurea was studied in the gas phase for electron energies ranging from zero to 9 eV in order to probe its radiosensitizing capabilities. The experiments were carried out using a hemispherical electron monochromator coupled with a quadrupole mass spectrometer. Diversified fragmentation of hydroxyurea was observed upon low energy electron attachment and here we highlight the major dissociation channels. Moreover, thermodynamic thresholds for various fragmentation reactions are reported to support the discussion of the experimental findings. The dominant dissociation channel, which was observed over a broad range of energies, is associated with formation of NCO-, water, and the amidogen (NH2) radical. The second and third most dominant dissociation channels are associated with formation of NCNH- and NHCONH2-, respectively, which are both directly related to formation of the highly reactive hydroxyl radical. Other ions observed with significant abundance in the mass spectra were NH2-/O-, OH-, CN-, HNOH-, NCONH2-, and ONHCONH2-.

Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea

Energy Technology Data Exchange (ETDEWEB)

Huber, S. E.; Tanzer, K.; Denifl, S. [Institute for Ion Physics and Applied Physics and Center of Molecular Biosciences Innsbruck, Leopold Franzens University of Innsbruck, Technikerstr. 25, 6020 Innsbruck (Austria); Śmiałek, M. A., E-mail: smialek@pg.gda.pl [Department of Control and Power Engineering, Faculty of Ocean Engineering and Ship Technology, Gdańsk University of Technology, Gabriela Narutowicza 11/12, 80-233 Gdańsk (Poland)

2016-06-14

Dissociative electron attachment to hydroxyurea was studied in the gas phase for electron energies ranging from zero to 9 eV in order to probe its radiosensitizing capabilities. The experiments were carried out using a hemispherical electron monochromator coupled with a quadrupole mass spectrometer. Diversified fragmentation of hydroxyurea was observed upon low energy electron attachment and here we highlight the major dissociation channels. Moreover, thermodynamic thresholds for various fragmentation reactions are reported to support the discussion of the experimental findings. The dominant dissociation channel, which was observed over a broad range of energies, is associated with formation of NCO{sup −}, water, and the amidogen (NH{sub 2}) radical. The second and third most dominant dissociation channels are associated with formation of NCNH{sup −} and NHCONH{sub 2}{sup −}, respectively, which are both directly related to formation of the highly reactive hydroxyl radical. Other ions observed with significant abundance in the mass spectra were NH{sub 2}{sup −}/O{sup −}, OH{sup −}, CN{sup −}, HNOH{sup −}, NCONH{sub 2}{sup −}, and ONHCONH{sub 2}{sup −}.

Characteristics and overcome of the resistance to chemotherapeutic agents

International Nuclear Information System (INIS)

Hong, Weon Seon; Im, Young Hyuck; Kim, Young Sun

1993-01-01

Although the clinical use of colony-stimulating factor (CSF) improves the therapeutic results, there have been a lot of evidences that CSF may stimulate the growth of cancer cells. This study was conducted to investigate the effects of granulocytemacrophage(GM)-CSF and granulocyte(G)-CSF on the colony formations in eight human cancer cell lines. The stimulatory effects of GM-CSF and G-CSF on the colony formation were evaluated in human tumor colony assay against four human cancer cell lines, four sublines resistant to adriamycin or cisplatin : PC-9 and PC-14 (pulmonary adenoca), MKN-45 and KATO III (gastric adenoca), PC/ADM and PC/CDDP (sublines of PC-14 resistant to adriamycin and cisplatin, respectively), MKN/ADM and MKN/CDDP (sublines of MKN-45 resistant to adriamycin and cisplatin, respectively). Cancer cells were plated at concentrations of 1x10 3 and 1x10 5 cells/well in the upper layer. Two kinds of GM-CSF (LBD-005 and CSF 39-300) and two kinds of G-CSF (Grasin and Neutrogin) were tested by the addition of final concentrations of GM-CSF and G-CSF (0.01, 0.1 and 1.0 μg/ml) to the lower layer to allow continuous exposure for 14 days. The colony formations (%) of eight cell lines tested were 85-113% and 92-106% in wells plated at the concentrations (/well) of 1x10 3 and 1x10 5 plated, respectively, in all cell lines compared to those of control wells. These results suggest that GM-CSF and G-CSF dose not directly stimulate the growth of cancer cells in all cell lines tested. (Author)

Radiation exposure to patient and radiologist during transcatheter arterial embolization therapy for hepatocellular carcinoma. Multicenter study in Japan

International Nuclear Information System (INIS)

Ishiguchi, T.; Nakamura, H.; Okazaki, M.

2000-01-01

Transcatheter arterial embolization (TAE) is now most commonly used as a treatment of hepatocellular carcinoma. Present multicenter study was carried out to evaluate radiation exposure to patients and interventional radiologists during the procedure. Thirty-nine procedures of TAE for hepatocellular carcinoma in eight institutes were analyzed. Radiation exposure to the patients and the interventional radiologists were evaluated with LiF thermoluminescence dosimeters (TLDs) placed on the patient's skin at the posterior hepatic portion and the pelvis and the operator's forehead and abdomen (in front and back of the lead apron). A real-time dosimeter was also used to evaluate skin dose of the patient. TAE was performed by angiographic techniques, using a microcatheter advanced to the hepatic artery branch(es) under the guidance of X-ray fluoroscopy and digital subtraction angiography (DSA), and then injecting chemotherapeutic agents mixed with oily contrast material and followed by gelatin sponge particles. The mean fluoroscopic time was 21 minutes and the mean number of DSA acquisition was 6. TLD dosimetry showed that the mean entrance surface dose of the patient at the hepatic portion was 973±681 mSv (mean±SD), and the anterior skin dose at the pelvis was 0.98±0.69 mSv. The doses of the radiologist were 0.04±0.04 mSv at the forehead, 0.15±0.19 mSv at the abdomen in front of the lead apron, and 0.005±0.01 mSv behind it. The real-time dosimetry showed that 56% of the surface dose at the hepatic portion was from DSA and 44% was from fluoroscopy. The radiation exposure to the patients and the interventional radiologists during TAE for hepatocellular carcinoma was considered to be acceptable when proper techniques are used. Further effort to reduce radiation doses during the procedure will be directed toward both digital angiographic and fluoroscopic techniques. (author)

Vitamin C acts as radiation-protecting agent

International Nuclear Information System (INIS)

Platzer, Isabel; Getoff, Nikola

1998-01-01

It is well known that vitamin C (L-ascorbic acid) is a very efficient, water soluble antioxidant. Its multifunctional biological and biochemical activities are rather well established in the last few decades (e.g. Sies and Stahl, 1995; Meydani et al., 1995; NRC, 1989. In the present letter we are reporting briefly the pronounced radiation-protecting properties of ascorbate (AH - ) observed on bacteria (E. coli AB1157) as well as on cultured cells (SCC VII, eukaryotic cells)

Decreased expression of microRNA let-7i and its association with chemotherapeutic response in human gastric cancer

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Liu Kun

2012-10-01

Full Text Available Abstract Background MicroRNA let-7i has been proven to be down-regulated in many human malignancies and correlated with tumor progression and anticancer drug resistance. Our study aims to characterize the contribution of miRNA let-7i to the initiation and malignant progression of locally advanced gastric cancer (LAGC, and evaluate its possible value in neoadjuvant chemotherapeutic efficacy prediction. Methods Eighty-six previously untreated LAGC patients who underwent preoperative chemotherapy and radical resection were included in our study. Let-7i expression was examined for pairs of cancer tissues and corresponding normal adjacent tissues (NATs, using quantitative RT-PCR. The relationship of let-7i level to clinicopathological characteristics, pathologic tumor regression grades after chemotherapy, and overall survival (OS was also investigated. Results Let-7i was significantly down-regulated in most tumor tissues (78/86: 91% compared with paired NATs (P P =0.024 independently of other clinicopathological factors, including tumor node metastasis (TNM stage (HR = 3.226, P = 0.013, depth of infiltration (HR = 4.167, P P = 0.037. Conclusions These findings indicate that let-7i may be a good candidate for use a therapeutic target and a potential tissue marker for the prediction of chemotherapeutic sensitivity and prognosis in LAGC patients.

Bases for protection against radiation and conventional hazards

International Nuclear Information System (INIS)

Ganguly, A.K.

1977-01-01

The living and working environment of man is polluted by : (1) ionizing radiations, both natural and man-made, (2) man-made non-ionizing radiations e.g. microwaves, and (3) man-made chemicals. Many of these agents are carcinogenic and mutagenic. The basic radiation safety standards laid down by the ICRP have long-term objectives and take into account all aspects of radiation protection problem, but in the case of other agents the safety standards, whatever few are available, have short-term objectives and differ widely from country to country. If the paramountcy of man's health is accepted as the objective of all safety programmes i.e. either for radiation hazards or conventional hazards, the above disparity must be removed. In order to achieve this goal, just as assessment of damage to organs and tissues of man is available in the case of ionizing radiations, similar assessment in the case of conventional hazards must be made available by collecting relevant data. (M.G.B.)

Modification of radiation damage by naturally occurring substances

International Nuclear Information System (INIS)

Prasad, K.N.

1984-01-01

The major objectives of studying the modification of radiation sensitivity have been (1) to identify a compound that will produce a differential protection or sensitization of the effect of irradiation on normal and tumor tissue, and (2) to understand more about the mechanisms of radiation damage. In spite of massive research on this particular problem since World War II, the first objective remains elusive. During this period, numerous radioprotective and radiosensitizing agents have been identified. These agents have served as important biologic tools for increasing our understanding of radiation injuries. Most of these substances are synthetic compounds and are very toxic to humans. In addition, very few of the compounds provide differential modifications of the effect of radiation on tumor and normal cells. This chapter presents objectives for identifying naturally occurring substances that modify the effect of x-radiation on mammalian cells and discusses the role of physiologic substances in modifying radiation injuries on mammalian normal and tumor cells

Radiation hormesis in higher plants

Energy Technology Data Exchange (ETDEWEB)

Kim, Jae Sung [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

1996-03-01

The most remarkable aspect in the hormesis law is that low dose of harmful agents can produce effect that are diametrically opposite to the effect found with high doses of the same agent. Minute quantities of a harmful agent bring about very small change in the organism and control mechanisms appear to subjugate normal processes to place the organism in a state of alert and repair. The stimulated organism is more responsive to changes in environmental factors than it did before being alerted. Routine functions, including repair and defense, have priority for available energy and material. The alerted organism utilizes nutrients more efficiently, grows faster, shows improved defense reactions, matures faster, reproduces more effectively, has less disease, and lives longer. Accelerated germination, sprouting, growth, development, blooming and ripening, and increased crop yield and resistance to disease are found in plants. Another concept supported by the data is that low doses of ionizing radiation provide increased resistance to subsequent high doses of radiation. The hormesis varies with subject plant, variety, state of seed, environmental and cultural conditions, physiologic function measured, dose rate and total exposure. The results of hormesis are less consistently found, probably due to the great number of uncontrolled variables in the experiments. The general dosage for radiation hormesis in about 100 times ambient or 100 times less than a definitely harmful dose, but these must be modified to the occasion. Although little is known about most mechanisms of hormesis reaction, overcompensation of repair mechanism is offered as on mechanism. Radiation hormesis can provide more efficient use of resources, maximum production of foods, and increased health by the use of ionizing radiation as a useful tool in our technologic society. Efficient utilization of nature`s resources demands support to explore the practical application of radiation hormesis.

Radiation hormesis in higher plants

International Nuclear Information System (INIS)

Kim, Jae Sung

1996-03-01

The most remarkable aspect in the hormesis law is that low dose of harmful agents can produce effect that are diametrically opposite to the effect found with high doses of the same agent. Minute quantities of a harmful agent bring about very small change in the organism and control mechanisms appear to subjugate normal processes to place the organism in a state of alert and repair. The stimulated organism is more responsive to changes in environmental factors than it did before being alerted. Routine functions, including repair and defense, have priority for available energy and material. The alerted organism utilizes nutrients more efficiently, grows faster, shows improved defense reactions, matures faster, reproduces more effectively, has less disease, and lives longer. Accelerated germination, sprouting, growth, development, blooming and ripening, and increased crop yield and resistance to disease are found in plants. Another concept supported by the data is that low doses of ionizing radiation provide increased resistance to subsequent high doses of radiation. The hormesis varies with subject plant, variety, state of seed, environmental and cultural conditions, physiologic function measured, dose rate and total exposure. The results of hormesis are less consistently found, probably due to the great number of uncontrolled variables in the experiments. The general dosage for radiation hormesis in about 100 (10 to 1,000) times ambient or 100 (10 to 1,000) times less than a definitely harmful dose, but these must be modified to the occasion. Although little is known about most mechanisms of hormesis reaction, overcompensation of repair mechanism is offered as on mechanism. Radiation hormesis can provide more efficient use of resources, maximum production of foods, and increased health by the use of ionizing radiation as a useful tool in our technologic society. Efficient utilization of nature's resources demands support to explore the practical application of

Radiation resistant polypropylene blended with mobilizer,. antioxidants and nucleating agent

Science.gov (United States)

Shamshad, A.; Basfar, A. A.

2000-03-01

Post-irradiation storage of medical disposables prepared from isotactic polypropylene renders them brittle due to degradation. To avoid this, isotactic polypropylene [(is)PP] was blended with a mobilizer, dioctyl pthallate (DOP), three antioxidants (hindered amines and a secondary antioxidant) and benzoic acid to obtain radiation-resistant, thermally-stable and transparent material. Different formulations prepared were subjected to gamma radiation to doses of 25 and 50 kGy. Tests of breakage on bending after ageing in an oven at 70°C up to 12 months have shown that the addition of DOP and the antioxidants imparts improved radiation and thermal stability as compared to (is)PP alone or its blend with DOP. All the formulations irradiated or otherwise demonstrated excellent colour stability even after accelerated ageing at 70°C for prolonged periods.

Genetic effects of ionizing radiation and repair processes

International Nuclear Information System (INIS)

Tuschl, H.

1986-11-01

Since DNA (=desoxyribonucleic acid) is the largest molecule within the cell it is the most important target for direct and indirect radiation effects. Within DNA the total genetic information is stored, thus damage to DNA in germ cells causes genetic disorders and damage in somatic cells is implicated in cancer and immunodeficiences. Alterations of DNA structure are not only due to ionizing radiation effects, but also to spontaneous DNA modifications and damage from interactions with environmental ultraviolet light and chemical agents. To maintain its genetic integrity, each organism had to develop different repair systems able to recognize and remove DNA damage. Repeated exposure to a DNA damaging agent can even lead to adaptation processes and increased resistance to the same agent. At normal function of repair systems it can be assumed that the capacity of those systems is adequate to scope with the effects of low radiation doses. (Author)

The chemotherapeutic potential of glycol alkyl ethers: structure-activity studies of nine compounds in a Fischer-rat leukemia transplant model.

Science.gov (United States)

Dieter, M P; Jameson, C W; Maronpot, R R; Langenbach, R; Braun, A G

1990-01-01

further development as chemotherapeutic agents.

Chemical protection against ionizing radiation

International Nuclear Information System (INIS)

Livesey, J.C.; Reed, D.J.

1987-01-01

Over 40 years have passed since the research of the Manhattan Project suggested the possibility of chemical protection against ionizing radiation. During that time, much has been learned about the nature of radiation-induced injury and the factors governing the expression of that injury. Thousands of compounds have been tested for radioprotective efficacy, and numerous theories have been proposed to account for these actions. The literature on chemical radioprotection is large. In this article, the authors consider several of the mechanisms by which chemicals may protect against radiation injury. They have chosen to accent this view of radioprotector research as opposed to that research geared toward developing specific molecules as protective agents because they feel that such an approach is more beneficial in stimulating research of general applicability. This paper describes the matrix of biological factors upon which an exogenous radioprotector is superimposed, and examines evidence for and against various mechanisms by which these agents may protect biological systems against ionizing radiation. It concludes with a brief outlook for research in chemical radioprotection

18-F-FDG PET-CT in Monitoring of Chemotherapeutic Effect in a Case of Metastatic Hepatic Epithelioid Hemangioendothelioma.

Science.gov (United States)

Shamim, Shamim Ahmed; Tripathy, Sarthak; Mukherjee, Anirban; Bal, Chandrasekhar; Roy, Shambo Guha

2017-01-01

Hepatic epithelioid hemangioendothelioma is a rare variant of mesenchymal tumor. Surgical resection or partial hepatectomy is the treatment of choice in the case of localized disease. However, in metastatic cases, chemotherapeutic drugs targeting the tyrosine kinase are being used. We hereby present 18-F-fludeoxyglucose positron emission tomography-computed tomography findings in a case of a 35-year old woman with metastatic HEHE showing significant response to Sorafenib therapy after 6 months.

The experimental study on protective effects and mechanisms of chelating agents of catechols amino carboxylic acid for radiation injury induced by actimides(Th-234)

International Nuclear Information System (INIS)

Chen, H. H.; Luo, M. C.; Sun, M. Z.; Hu, Y. X.; Wang, Y. H.; Jin, M. Y.; Cheng, W. Y.

2002-01-01

The decorporative efficacy and antioxidative action of prompt and delayed consecutive administration of catecholicpolyaminopolycarboxylate ligands, 7601 and 9501 for radiothorium in mice were investigated. DTPA and Vitamin E were used as positive controls. The competitive abilities of 7601 and 9501 to mobilize the thorium with BSA were studied. Their inhibition effects on superoxide anionas radicals were measured with electron spin resonance. The results showed that 7601 and 9501 are able to effectively prevent the internal radiation injury induced radiothorium, attributing to their double functions of pronounced removal effectiveness and antioxidative action. Their protective effects were better than DTPA and Vitamin E. The mechanisms of protective effects of 7601 and 9501 for internal radiation injury was close related to competitive ability of chelating agent to chelate the thorium with BSA and oxygen free radical scavenging activities

Molecular cloning and characterization of taurocyamine kinase from Clonorchis sinensis: a candidate chemotherapeutic target.

Directory of Open Access Journals (Sweden)

Jing-Ying Xiao

2013-11-01

Full Text Available BACKGROUND: Adult Clonorchis sinensis lives in the bile duct and causes endemic clonorchiasis in East Asian countries. Phosphagen kinases (PK constitute a highly conserved family of enzymes, which play a role in ATP buffering in cells, and are potential targets for chemotherapeutic agents, since variants of PK are found only in invertebrate animals, including helminthic parasites. This work is conducted to characterize a PK from C. sinensis and to address further investigation for future drug development. METHODOLOGY/PRINCIPAL FINDINGS: [corrected] A cDNA clone encoding a putative polypeptide of 717 amino acids was retrieved from a C. sinensis transcriptome. This polypeptide was homologous to taurocyamine kinase (TK of the invertebrate animals and consisted of two contiguous domains. C. sinensis TK (CsTK gene was reported and found consist of 13 exons intercalated with 12 introns. This suggested an evolutionary pathway originating from an arginine kinase gene group, and distinguished annelid TK from the general CK phylogenetic group. CsTK was found not to have a homologous counterpart in sequences analysis of its mammalian hosts from public databases. Individual domains of CsTK, as well as the whole two-domain enzyme, showed enzymatic activity and specificity toward taurocyamine substrate. Of the CsTK residues, R58, I60 and Y84 of domain 1, and H60, I63 and Y87 of domain 2 were found to participate in binding taurocyamine. CsTK expression was distributed in locomotive and reproductive organs of adult C. sinensis. Developmentally, CsTK was stably expressed in both the adult and metacercariae stages. Recombinant CsTK protein was found to have low sensitivity and specificity toward C. sinensis and platyhelminth-infected human sera on ELISA. CONCLUSION: CsTK is a promising anti-C. sinensis drug target since the enzyme is found only in the C. sinensis and has a substrate specificity for taurocyamine, which is different from its mammalian counterpart

Overcoming Multidrug Resistance via Photodestruction of ABCG2-Rich Extracellular Vesicles Sequestering Photosensitive Chemotherapeutics

Science.gov (United States)

Goler-Baron, Vicky; Assaraf, Yehuda G.

2012-01-01

Multidrug resistance (MDR) remains a dominant impediment to curative cancer chemotherapy. Efflux transporters of the ATP-binding cassette (ABC) superfamily including ABCG2, ABCB1 and ABCC1 mediate MDR to multiple structurally and functionally distinct antitumor agents. Recently we identified a novel mechanism of MDR in which ABCG2-rich extracellular vesicles (EVs) form in between attached neighbor breast cancer cells and highly concentrate various chemotherapeutics in an ABCG2-dependent manner, thereby sequestering them away from their intracellular targets. Hence, development of novel strategies to overcome MDR modalities is a major goal of cancer research. Towards this end, we here developed a novel approach to selectively target and kill MDR cancer cells. We show that illumination of EVs that accumulated photosensitive cytotoxic drugs including imidazoacridinones (IAs) and topotecan resulted in intravesicular formation of reactive oxygen species (ROS) and severe damage to the EVs membrane that is shared by EVs-forming cells, thereby leading to tumor cell lysis and the overcoming of MDR. Furthermore, consistent with the weak base nature of IAs, MDR cells that are devoid of EVs but contained an increased number of lysosomes, highly accumulated IAs in lysosomes and upon photosensitization were efficiently killed via ROS-dependent lysosomal rupture. Combining targeted lysis of IAs-loaded EVs and lysosomes elicited a synergistic cytotoxic effect resulting in MDR reversal. In contrast, topotecan, a bona fide transport substrate of ABCG2, accumulated exclusively in EVs of MDR cells but was neither detected in lysosomes of normal breast epithelial cells nor in non-MDR breast cancer cells. This exclusive accumulation in EVs enhanced the selectivity of the cytotoxic effect exerted by photodynamic therapy to MDR cells without harming normal cells. Moreover, lysosomal alkalinization with bafilomycin A1 abrogated lysosomal accumulation of IAs, consequently preventing

Molecular Cloning and Characterization of Taurocyamine Kinase from Clonorchis sinensis: A Candidate Chemotherapeutic Target

Science.gov (United States)

Tokuhiro, Shinji; Nagataki, Mitsuru; Jarilla, Blanca R.; Nomura, Haruka; Kim, Tae Im; Hong, Sung-Jong; Agatsuma, Takeshi

2013-01-01

Background Adult Clonorchis sinensis lives in the bile duct and causes endemic clonorchiasis in East Asian countries. Phosphagen kinases (PK) constitute a highly conserved family of enzymes, which play a role in ATP buffering in cells, and are potential targets for chemotherapeutic agents, since variants of PK are found only in invertebrate animals, including helminthic parasites. This work is conducted to characterize a PK from C. sinensis and to address further investigation for future drug development. Methology/Principal findings A cDNA clone encoding a putative polypeptide of 717 amino acids was retrieved from a C. sinensis transcriptome. This polypeptide was homologous to taurocyamine kinase (TK) of the invertebrate animals and consisted of two contiguous domains. C. sinensis TK (CsTK) gene was reported and found consist of 13 exons intercalated with 12 introns. This suggested an evolutionary pathway originating from an arginine kinase gene group, and distinguished annelid TK from the general CK phylogenetic group. CsTK was found not to have a homologous counterpart in sequences analysis of its mammalian hosts from public databases. Individual domains of CsTK, as well as the whole two-domain enzyme, showed enzymatic activity and specificity toward taurocyamine substrate. Of the CsTK residues, R58, I60 and Y84 of domain 1, and H60, I63 and Y87 of domain 2 were found to participate in binding taurocyamine. CsTK expression was distributed in locomotive and reproductive organs of adult C. sinensis. Developmentally, CsTK was stably expressed in both the adult and metacercariae stages. Recombinant CsTK protein was found to have low sensitivity and specificity toward C. sinensis and platyhelminth-infected human sera on ELISA. Conclusion CsTK is a promising anti-C. sinensis drug target since the enzyme is found only in the C. sinensis and has a substrate specificity for taurocyamine, which is different from its mammalian counterpart, creatine. PMID:24278491

Investigation of leaching of an antifouling agent from marine paint formulations using radiotracer technique

International Nuclear Information System (INIS)

Pant, H.J.; Sharma, V.K.; Gursharan Singh; Kalgutkar, D.B.; Patil, S.P.; Jayachandran, N.; Unni, V.K.P.

2012-01-01

A radiotracer technique was used to investigate the leaching of an antifouling agent from different marine paint formulations with an objective to select the best paint formulation for bulk production. The antifouling agent (Diuron) itself was labeled with carbon-14 (half-life: 5,730 years, β-energy: 156 keV) and used as a radiotracer. The different paint formulations added with radiolabeled Diuron were applied onto suitably selected substrates and measured for initial intensity of β-radiation using a Geiger-Muller detector connected to a ratemeter. The painted substrates were subjected to shower tests for a pre-decided time and subsequently measured for β-radiations. The comparison of intensity of β-radiations in substrates prior and post shower tests provides information about leaching of antifouling agent Diuron from the paint formulation. The high leaching percentage of antifouling agent Diuron post shower tests indicates non-suitability of paint formulation for marine and civil structures. However, low leaching rate of Diuron will make a paint formulation more efficient and suitable. Based on the results of investigation, a paint formulation with minimum leaching rate was identified and selected for bulk production by a paint company. (author)

Bioterrorism and radiation. What to do? What research is needed?

International Nuclear Information System (INIS)

Coleman, C.N.; Tofilon, P.

2003-01-01

Radiological and nuclear terrorism has emerged as a major concern. Often included within the broad category of bioterrorism, the response to the intentional exposure of populations to radiation requires governmental agencies, law enforcement agencies, policy-makers, experts in radiation medicine and radiation biology and an educated citizenry. Emerging knowledge of normal tissue injury following radiation will provide important areas for research, as outlined in a recent Radiation Research Program (RRP) Workshop from the National Cancer Institute (NCI) (Stone HB, Rad Res 157:204- 223, 2002). Such research involves radiation biology and wound healing and may ultimately provide strategies for pre-exposure radioprotectors as well as post-exposure strategies to prevent serious normal tissue damage. Radiation in the Moderate Dose range, defined as 1-10 Gy, applies to radiological and nuclear terrorism and also to clinical radiation therapy. (RRP Moderate Dose Radiation Workshop, Coleman CN, Rad Res, in press 2003). New approaches such as Intensity Modulated Radiotherapy (IMRT) will expose more tissues to low doses of radiation. Strategies for developing agents for normal tissue targets (Tofilon). The successful application of radiotherapy as a cancer treatment modality is severely constrained by the risk for normal tissue injury. Because approximately half of all cancer patients receive radiation treatment, the ability to selectively protect normal tissue would be of obvious clinical benefit. In addition to cancer therapy, current geopolitical circumstances reinforce the need for generating agents that protect against the consequences of environmental radiation exposure, accidental or intentional. Currently, there are relatively few available agents with the potential to reduce or eliminate radiation-induced normal tissue injury after clinical and/or environmental exposure. A goal of the Radiation Research Program is to identify and develop novel radioprotectors

Enhanced tumor responses through therapies combining CCNU, MISO and radiation

International Nuclear Information System (INIS)

Siemann, D.W.; Hill, S.A.

1984-01-01

Studies were performed to determine whether the radiation sensitizer misonidazole (MISO) could enhance the tumor control probability in a treatment strategy combining radiation and the nitrosourea 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). In initial experiments KHT sarcoma-bearing mice were injected with 1.0 mg/g of MISO simultaneously with a 20 mg/kg dose of CCNU 30-40 min prior to irradiation (1500 rad). With this treatment protocol approximately 60% of the mice were found to be tumor-free 100 days post treatment. By comparison all 2 agent combinations led to 0% cures. To evaluate the relative importance of chemopotentiation versus radiosensitization in the 3 agent protocol, tumors were treated with MISO plus one anti-tumor agent (either radiation of CCNU) and then at times ranging from 0 to 24 hr later exposed to the other agent. When the time between treatments was 0 to 6 hr, a 60 to 80% tumor control rate was achieved for both MISO plus radiation followed by CCNU and MISO plus CCNU followed by radiation. However if the time interval was increased to 18 or 24 hr, the cure rate in the former treatment regimen dropped to 10% while that of the latter remained high at 40%. The data therefore indicate that (1) improved tumor responses may be achieved when MISO is added to a radiation-chemotherapy combination and (2) MISO may be more effective in such a protocol when utilized as a chemopotentiator