Wakazono Y, Kubota M, Furusho K, Liu L, Gerson S L
Department of Pediatrics, Kyoto University, Japan.
Mutat Res. 1996 Jan 2;362(1):119-25. doi: 10.1016/0921-8777(95)00042-9.
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.
在早幼粒细胞性白血病HL - 60细胞系和T淋巴细胞性白血病Molt - 3细胞系中，研究了胸苷激酶（TK）突变缺失对烷化剂敏感性的影响。虽然这两种细胞系都表现出约1%的残余TK活性，但只有HL - 60 TK缺陷细胞的细胞内三磷酸胸苷（TTP）池减少，即仅为野生型细胞的20%。当用N - 甲基 - N'- 亚硝基胍或甲磺酸乙酯处理时，HL - 60 TK缺陷细胞在次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶（HGPRT）位点的杀伤频率和突变频率相对于野生型细胞显著增加。用O6 - 烷基鸟嘌呤 - DNA烷基转移酶抑制剂O6 - 苄基鸟嘌呤预处理细胞，可部分消除这些差异。用烷化剂处理后，Molt - 3野生型细胞和TK缺陷细胞具有相似的细胞存活率和HGPRT突变频率。这些结果表明，只有当检测到TTP池同时减少时，TK缺陷才在对烷化剂的细胞毒性和诱变作用的敏感性中起关键作用。
