Protection against c/s-Diamminedichloroplatinum Cytotoxicity and Mutagenicity in V79 Cells by 2-[(Aminopropyl)amino]ethanethiol1

The effect(s) of the radioprotector 2-[(aminopropyl)amino]ethanethiol (WR1065) on c/s-diamminedichloroplatinum(ll) (cisDDP)-induced cytotoxicity and mutagenesis at the hypoxanthineguanine phosphoribosyl transferase locus in V79 Chinese ham ster cells was examined. With a standard exposure time of 30 min for both agents, WR1065, at a final working concentration of 4 mw, was added to cells either prior to, during, or immediately following treatment with selected doses of cis-DDP. With respect to cell survival, dose modification factors of 2.9, 1.4, and 1.4 were obtained for cells treated under each of these conditions, respectively. The induction of mutants under all conditions was linear as a function of cis-DDP concentration. Mutation frequen cies per ¿¿g of cis-DDP were 25 x 1(T7,1 x 10~7, 5 x 10~7, and 11 x 10~7 for protocols involving no protector present or WR1065 added before, during, or after cis-DDP treatment, re spectively. No WR1065-mediated cytotoxicity to cells derived from either wild-type or mutant colonies was observed. These data demonstrate that WR1065, the free thiol of S-2-(3-aminopropylamino)ethyl phosphorothioic acid (WR2721) which is cur rently being evaluated in clinical trials, affords substantial protec tion against the cytotoxic and mutagenic effects of cis-DDP, with the most effective protection occurring when the protector is administered prior to cis-DDP treatment. Due to their ability to better protect normal as compared to tumor tissue against acute effects, these protectors have generated considerable interest for use in improving the therapeutic gain of radiation therapy and chemotherapy. The ability of these compounds to also protect against the mutagenic effects of therapy agents may be an important additional benefit for consideration in their use in the treatment of human neoplasia.