Ducore J M, Rosenstein B S
Mutat Res. 1984 Oct;141(2):117-21. doi: 10.1016/0165-7992(84)90022-8.
The synergistic cytotoxic activity exhibited by bifunctional alkylating agents in the presence of methylxanthines has been associated with methylxanthine-induced reversal of alkylator-induced DNA replicon initiation inhibition. This has also been seen with methylxanthines and ionizing irradiation. Methylxanthines do not appear exacerbate drug or ionizing radiation-induced damage. We report here a situation in which methylxanthine-induced reversal of DNA replicon initiation inhibition is not associated with increased cytotoxicity of the alkylator. Murine L1210 leukemia cells were assayed for cytotoxicity following treatment with either L-PAM or cis-DDP in the presence or absence of theophylline. Theophylline increased the cytotoxicity seen after L-PAM treatment but failed to increase the cis-DDP induced cytotoxicity. Analysis of pulse-labeled DNA on alkaline sucrose gradients revealed the expected decrease in DNA replicon initiation in L1210 cells treated with either L-PAM or cis-DDP. Theophylline had no effect on replicon initiation in untreated cells. Theophylline reversed the replicon initiation inhibition in cells treated with either L-PAM or cis-DDP. The reason for the apparent lack of added toxicity of the replicon initiation inhibition reversal in L1210 cells treated with theophylline and DDP is unknown.
双功能烷化剂在甲基黄嘌呤存在时所表现出的协同细胞毒性活性，与甲基黄嘌呤诱导的烷化剂诱导的DNA复制子起始抑制的逆转有关。在甲基黄嘌呤与电离辐射的作用中也观察到了这种情况。甲基黄嘌呤似乎不会加剧药物或电离辐射诱导的损伤。我们在此报告一种情况，即甲基黄嘌呤诱导的DNA复制子起始抑制的逆转与烷化剂细胞毒性的增加无关。在用左旋苯丙氨酸氮芥（L-PAM）或顺铂（cis-DDP）处理的情况下，无论有无茶碱，均对小鼠L1210白血病细胞的细胞毒性进行了测定。茶碱增加了L-PAM处理后可见的细胞毒性，但未能增加顺铂诱导的细胞毒性。在碱性蔗糖梯度上对脉冲标记的DNA进行分析显示，用L-PAM或顺铂处理的L1210细胞中DNA复制子起始出现预期的减少。茶碱对未处理细胞的复制子起始没有影响。茶碱逆转了用L-PAM或顺铂处理的细胞中的复制子起始抑制。在用茶碱和顺铂处理的L1210细胞中，复制子起始抑制逆转明显缺乏额外毒性的原因尚不清楚。
