The Effect of DNA Repair Inhibitors on the Response of Tumors Treated with X-Ray and Alkylating Agents 1
The Effect of DNA Repair Inhibitors on the Response of Tumors Treated with X-Ray and Alkylating Agents 1
复制标题
DNA 修复抑制剂对 X 射线和烷化剂治疗肿瘤反应的影响 1
DOI：
10.3181/00379727-137-35544
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发表时间：
1971
影响因子：
--
通讯作者：
J. Brown
中科院分区：
文献类型：
--
作者：
D. Gaudin;K. L. Yielding;A. Stabler;J. Brown
近年来，许多工作人员已经证明，细菌（1-4）和哺乳动物细胞（5-7）都有能力修复其细胞DNA的各种损伤事件。用于治疗恶性疾病的烷化剂和X射线被认为在细胞中发挥其细胞毒性作用，主要是由于受影响细胞中DNA的化学改变（8，9），确切地说是可以通过DNA修复机制修复的类型（8-12）。因此，DNA修复可能在许多肿瘤对这些药物表达的抗性中起重要作用。在体外实验中，该过程的抑制剂大大增强了烷基化和辐射损伤的细胞毒性作用（13-15）。由于这一事实，确定修复抑制剂对体内肿瘤对X射线和烷化剂治疗的反应的影响是非常有意义的。在本实验室进行的早期工作已经证明，在单独使用烷化剂或X射线无效的情况下，修复抑制剂咖啡因和氯喹与环磷酰胺或X射线联合使用时，可有效阻止环磷酰胺抗性浆细胞瘤的生长（16）。由于氯喹与黑色素结合（17），因此集中在色素细胞中，因此确定这种DNA修复抑制剂对植入金黄色叙利亚仓鼠的恶性黑色素瘤显示的对烷化剂和X射线的抗性的影响也很有意义。下面报告的实验证明，氯喹与苯丙氨酸氮芥或X射线联合使用，可以阻止植入仓鼠体内的恶性黑素瘤的生长;而在通常的治疗剂量下，单独使用药物或X射线都不能阻止这种生长。
In recent years, numerous workers have demonstrated that both bacterial (1-4) and mammalian cells (5-7) have the ability to repair a variety of damaging events to their cellular DNA. The alkylating agents and X-rays used in the therapy of malignant diseases are thought to exert their cytotoxic effect in cells principally as a result of chemical alteration of DNA in the affected cells (8, 9), of precisely the kinds which can be repaired by the DNA repair mechanism (8-12). DNA repair, therefore, may play an important role in the resistance expressed by many tumors towards these agents. Inhibitors of this process greatly enhance the cytotoxic effect of alkylation and radiation damage in in vitro experiments (13-15). Because of this fact, it was of great interest to determine the effect of the repair inhibitors on the response of tumors in vivo to treatment with X-rays and alkylating agents. Earlier work performed in this laboratory has demonstrated that the repair inhibitors, caffeine and chloro-quine, when used in conjunction with Cytoxan or X-rays, were effective in stopping the growth of Cytoxan-resistant plasmacytomas under conditions where the alkylating agents or X-rays alone were ineffective (16). Because chloroquine binds to melanin (17) and is therefore concentrated in pigmented cells, it was also of interest to determine the effect of this DNA repair inhibitor on the resistance to alkylating agents and X-rays shown by malignant melanomas implanted in golden Syrian hamsters. The experiments reported below demonstrate that the use of chloroquine, in combination with either phenylalanine mustard or X-rays, can stop the growth of malignant melanomas implanted in hamsters; whereas neither drug nor X-ray alone at the usual therapeutic doses, is able to stop such growth.