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Gemzar: Mechanisms of Cytotoxicity and Radiosensitization

Gemzar：细胞毒性和放射增敏机制

基本信息

批准号：
7216757
负责人：
DONNA S. SHEWACH
金额：
$ 25.18万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-08 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7216757
关键词：
Abbreviations Apoptotic Biological Assay Breast Sarcoma Cell Cycle Kinetics Cell Death Cell Line Cells Chromosomes Clinic Clinical Clinical Research Combination Chemotherapy Commit Complementary DNA Condition Cytarabine DNA DNA Damage DNA Double Strand Break Data Deoxyribonucleosides Diphosphates Drug Exposure Event Exhibits Exposure to Genes Grant H2AFX gene HCT116 Cells Human Ionizing radiation Lesion MLH1 gene Malignant neoplasm of lung Metabolism Microtubules Mismatch Repair Modality Mutation Nature Nucleotides Numbers Pathway interactions Patients Pharmaceutical Preparations Phase Plasmids Play Property Radiation Radiation Tolerance Radiation therapy Radiation-Sensitizing Agents Radiosensitization Range Reporting Ribonucleotide Reductase Role Shuttle Vectors Solid Neoplasm TP53 gene Testing Transfection Treatment Protocols base cancer cell chemotherapeutic agent clinical efficacy cytotoxic cytotoxicity design docetaxel drug metabolism gemcitabine gemzar human H2AX protein irradiation mutant nucleoside analog null mutation plasmid DNA prevent repaired response success tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): Previously we hypothesized and then proved that 2',2'-difluoro-2'-deoxycytidine (dFdCyd, gemcitabine) is a potent radiation sensitizer. During the current grant period we demonstrated that radiosensitization correlated strongly with inhibition of ribonucleotide reductase by the 5'-diphosphate of dFdCyd, resulting in greater than 80 percent depletion of dATP, whereas the 5'-triphosphate contributed primarily to the cytotoxic effect. Cells that were radiosensitized by dFdCyd accumulated in the less radiosensitive S-phase during drug exposure. Radiosensitization did not require apoptotic cell death, and it could occur in p53 wild-type as well as mutant p53 cell lines. Gemcitabine did not increase DNA double strand breaks prior to or following irradiation, nor did it inhibit their repair. Thus, the accumulated data suggest that radiosensitization with dFdCyd is determined by the nature of the DNA damage sustained prior to irradiation rather than the response to DNA damage after irradiation. We now hypothesize that the critical lesion for radiosensitization with dFdCyd is the incorporation in DNA of an incorrect nucleotide caused by the depleted dATP and, if this lesion is not repaired prior to S-phase, irradiation will prevent repair of the misincorporation events resulting in permanent mutation and enhanced cell death. This hypothesis would predict that cells defective in repairing misincorporated nucleotides, such as mismatch repair deficient cells, would be better radiosensitized than cells proficient in this pathway. Preliminary data indicate that mismatch repair deficient HCT-116 cells are radiosensitized by dFdCyd whereas the mismatch repair proficient counterpart was not, although it was more sensitive to cytotoxicity with dFdCyd. We propose to evaluate the factors that determine dFdCyd cytotoxicity and radiosensitivity in isogenic cell lines defective or proficient in mismatch repair. Using a shuttle vector assay, we will determine whether the hypothesized radiosensitizing lesions, misincorporated nucleotides, are more prevalent in cells that are radiosensitized by dFdCyd. In addition to defining the mechanism of radiosensitization for dFdCyd, we will also determine the mechanism of synergy when it is combined with docetaxel, based on high antitumor efficacy reported recently in patients. Preliminary data demonstrate that this synergy is not related to the ability of docetaxel to block cells in G2/M, but rather we hypothesize docetaxel commits dFdCyd-treated cells to S-phase specific cell death.

描述（由申请人提供）：