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Investigations into the mechanism of interaction between cisplatin and low-doses of x-irradiation in hypoxic cells Walter, Patrick


Cisplatin (cis-cuammmedichloroplatinum(II)) is a highly effective chemotherapeutic drug given either as a single agent or in combination with other drugs to treat several types of tumors. Radiation therapy is also a successful treatment used for many types of tumors. However, many tumors contain hypoxic regions, which are resistant to treatment by radiation and some forms of chemotherapy. Combining cisplatin with radiation may offer advantages to counteract hypoxic resistance. While enhancement of radiation cell killing by cisplatin has been observed, the mechanism of the interaction of these two anti-cancer agents is unknown. In most in vitro experiments on radiosensitizers in cultured hypoxic cells extrapolation from high radiation dose experiments is used to predict low dose responses. In this work, clinically relevant doses are used to irradiate both CHO and V79 hypoxic cells. Their survival was assessed by using the Cell Analyzer Imaging System. Three main approaches were used to investigate the mechanism of interaction. In the first approach, the delivery time of cisplatin relative to irradiation was varied. Results show that enhancement of radiation cell killing was independent of the timing between X-rays and cisplatin administration. In the second approach a series of cisplatin analogs which varied in their DNA cross-linking ability were investigated. None of these analogs produced as strong an enhancement of radiation effects as did cisplatin. The final approach involved depleting intracellular glutathionewhich has been implicated in the chemical repair of the cisplatin-DNA crosslink. The depletion of glutathione by buthionine sulfoximine sensitized hypoxic CHO cells to the cisplatin X-ray combination. Results suggest that the DNA cisplatin cross-link may be involved in the enhancement of the effects of low-doses of X-rays. Chromosome analysis of hypoxic and oxic cells shows that cisplatin modifies the radiation dose response of chromosome aberrations. Finally, the results from all experiments suggest that misrepair of damage caused by X-rays and cisplatin may be important in the mechanism of their interaction.

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