THYMIDINE KINASE DEFICIENT CELLS WITH DECREASED TTP POOLS ARE HYPERSENSITIVE TO DNA ALKYLATING-AGENTS

The effect of mutational loss of thymidine kinase (TK) on the sensitiv ity to alkylating agents was investigated in promyelocytic, HL-60, and T-lymphoblastoid, Molt-3, human leukemia cell lines, Although both ce ll lines exhibited approx. 1% residual TK activity, only HL-60 TK defi cient cells had a decreased intracellular TTP pool, i.e,, 20% of that of the wild-type. When treated with N-methyl-N'-nitronitrosoguanidine or ethyl methanesulfonate, HL-60 TK deficient cells showed significant ly increased killing and mutation frequencies at the hypoxanthine-guan ine phosphoribosyl transferase (HGPRT) locus relative than did the wil d-type. Pretreatment of cells with O-6-benzylguanine, an inhibitor of O-6-alkylguanine-DNA alkyltransferase, partially abolished those diffe rences. Molt-3 wild-type and TK deficient cells had similar cell survi vals and HGPRT mutation frequencies following treatment with alkylatin g agents. These results indicate that TK deficiency, only when a conco mitant decrease of TTP pool is detected, plays a pivotal role in the s ensitivity to the cytotoxic and mutagenic effects of alkylating agents .