Kwok J B, Tattersall M H
Department of Cancer Medicine, University of Sydney, N.S.W., Australia.
Biochem Pharmacol. 1991 Jul 15;42(3):507-13. doi: 10.1016/0006-2952(91)90312-s.
5,10-Dideazatetrahydrofolate (DDATHF) is an antifolate drug, the cytotoxic effects of which can be fully reversed by hypoxanthine, suggesting that DDATHF exerts its effects by inhibiting de novo purine biosynthesis. ICI198583 is a quinazoline based inhibitor of thymidylate synthase. In this study we examine the interaction between treatment of mouse leukaemic L1210 cells with these drugs. The addition of DDATHF with ICI198583 was correlated with a decrease in ICI198583 cytotoxicity in a dose dependent manner. This protection was associated with a decrease in DNA fragmentation, and a drop in intracellular dATP pools. These results support the hypothesis that inhibitory effects on de novo purine biosynthesis by inhibitors of dihydrofolate reductase may limit cytotoxicity, and indicate that a rise in dATP pools may be an important cytotoxic signal.
5,10-二去氮四氢叶酸（DDATHF）是一种抗叶酸药物，其细胞毒性作用可被次黄嘌呤完全逆转，这表明DDATHF通过抑制嘌呤从头合成发挥作用。ICI198583是一种基于喹唑啉的胸苷酸合成酶抑制剂。在本研究中，我们检测了用这些药物处理小鼠白血病L1210细胞之间的相互作用。DDATHF与ICI198583联合使用与ICI198583细胞毒性呈剂量依赖性降低相关。这种保护作用与DNA片段化减少以及细胞内dATP池水平下降有关。这些结果支持以下假说：二氢叶酸还原酶抑制剂对嘌呤从头合成的抑制作用可能会限制细胞毒性，并表明dATP池水平升高可能是一个重要的细胞毒性信号。
