Sano H, Kubota M, Kasai Y, Hashimoto H, Shimizu T, Adachi S, Mikawa H
Department of Pediatrics, Kyoto University, Japan.
Int J Cancer. 1991 Apr 22;48(1):92-5. doi: 10.1002/ijc.2910480117.
The cytotoxicity and DNA lesions induced by methotrexate (MTX) were compared in wild-type, hypoxanthine-guanine phosphoribosyltransferase-deficient (HGPRT-) and thymidine-kinase-deficient (TK-) HL-60 cells. TK- and HGPRT- cells were approximately 10 and 3 times more sensitive to MTX than wild-type cells, respectively. Following incubation with 2 microM MTX for 16 hr, TK- cells showed a significantly higher number of DNA strand breaks. Concomitantly, DNA fragmentation at the nucleosomal linker region was detected more prominently in TK- cells. Although MTX tended to decrease TTP pools similarly in all 3 cells types, the initial TTP level in TK- cells was only about one-fifth of that found in the wild type. These results indicate that the thymidine salvage pathway has a pivotal role in mediating MTX-induced toxicity and DNA lesions.
在野生型、次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶缺陷型（HGPRT-）和胸苷激酶缺陷型（TK-）HL-60细胞中比较了甲氨蝶呤（MTX）诱导的细胞毒性和DNA损伤。TK-细胞和HGPRT-细胞对MTX的敏感性分别比野生型细胞高约10倍和3倍。用2微摩尔/升MTX孵育16小时后，TK-细胞显示出明显更多的DNA链断裂。同时，在TK-细胞中更显著地检测到核小体连接区的DNA片段化。尽管MTX在所有三种细胞类型中都倾向于类似地降低三磷酸胸苷（TTP）池，但TK-细胞中的初始TTP水平仅约为野生型细胞的五分之一。这些结果表明，胸苷补救途径在介导MTX诱导的毒性和DNA损伤中起关键作用。
