The limits to radioprotection of Chinese hamster V79 cells by WR-1065 under aerobic conditions

Clonogenic survival and drug content for Chinese hamster V79-171 cells incubated in suspension with WR-1065 prior to gamma irradiation have been determined. Factors that might influence the radioprotection by WR-1065 were investigated in control studies. Intracellular drug levels studied ranged between 0-36 nmol per 10(6) cells. In control studies, it was established that extracellular drug toxicity was not significant for cells in suspension at 10(6) per milliliter over short periods but was important when residual drug was present above 2 microM in the final plating of cells. Accumulation of intracellular drug above 30 nmol per 10(6) cells produced significant cytotoxicity in unirradiated cells. Irradiation with doses as high as 150 Gy produced no significant change in the total drug level or the thiol/disulfide ratio, either for the drug in the cells or for the drug in the medium. Preirradiation with 8 Gy did not change the ability of cells to import the drug but did appear to increase the cytotoxicity of the intracellular drug at levels above 25 nmol per 10(6) cells. There was no qualitative difference in the ability of WR-1065 to protect viable cells preirradiated with 8 Gy compared with protection of unirradiated cells. For a given gamma-ray dose from 2 to 40 Gy, there is a limiting value for surviving fraction which cannot be increased by further elevation of the intracellular drug level in V79-171 cells. Such limiting radioprotection was demonstrated for HT-29/SP-ld, HeLa, Me-180-VCII and OV-2008-VI human tumor cells.