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 sensitivity to alkylating agents was investigated in promyelocytic, HL-60, and T-lymphoblastoid, Molt-3, human leukemia cell lines. Although both cell lines exhibited approx. 1% residual TK activity, only HL-60 TK deficient 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 significantly increased killing and mutation frequencies at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus relative than did wild-type. Pretreatment of cells with O6-benzylguanine, an inhibitor of O6-alkylguanine-DNA alkyltransferase, partially abolished those differences. Molt-3 wild-type and TK deficient cells had similar cell survivals and HGPRT mutation frequencies following treatment with alkylating agents. These results indicate that TK deficiency, only when a concomitant decrease of TTP pool is detected, plays a pivotal role in the sensitivity to the cytotoxic and mutagenic effects of alkylating agents.
Department of Pediatrics, Kyoto University, Japan.
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Wakazono
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Kubota
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Furusho
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Liu
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Gerson
D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D005020:Ethyl Methanesulfonate / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000201:enzymology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016296:Mutagenesis / Q000187:drug effects*; D009153:Mutagens / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013937:Thymidine Kinase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013942:Thymine Nucleotides / Q000032:analysis / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D009153:Mutagens; D013942:Thymine Nucleotides; C064976:O(6)-benzylguanine; D008769:Methylnitronitrosoguanidine; D006147:Guanine; D005020:Ethyl Methanesulfonate; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase; C024157:thymidine 5'-triphosphate