Inactivation of Hypoxic Cells by Cisplatin and Radiation at Clinically Relevant Doses

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Abstract
We have examined the effects of exposure to cisplatin (cis-diamminedichloroplatinum(II)) on the response of exponentially growing V79 cells to low (0-4 Gy) and high (up to 30 Gy) doses of X rays under hypoxic and aerobic conditions. Survival in both dose regions was assessed by clonogenic assays; the low-dose studies were facilitated by a Cell Analyser (B. Palcic and B. Jaggi, Int. J. Radiat. Biol. 50, 345-352 (1986)). The results show that cisplatin, like its isomer trans-DDP, exhibits greater interaction with low than with high radiation doses in hypoxic cells. This increased interaction could be seen even with subtoxic exposures to cisplatin as low as 1 .mu.mol dm-3. In contrast, with cells irradiated in air in the presence of either complex, the interaction seen with high doses of radiation is completely lost or greatly diminished in the low radiation dose region. Further experiments showed that enhanced interaction of hypoxic cells with low doses of radiation could be equally effective with cisplatin pretreatments in air or in hypoxia, even if the cells are exposed to cisplatin only after irradiation. In experiments with nonproliferating plateau-phase cultures, the same enhanced interaction was observed in the low-dose region. These results, for example enhancement ratios of 2.3 and 1.2 at low- and high-dose regions, respectively, for 5 .mu.mol dm-3 cisplatin, are contrasted with those for nitroimidazoles which are better sensitizers in the high-dose region.