潘生丁增强氨甲蝶呤的抗肿瘤作用

Potentiated Antitumor Effect of Methotrexate by Drpyridamole

外源性核苷能抵消抗代谢药对肿瘤细胞的杀伤作用;核苷转运抑制剂潘生丁则能阻断核苷的这种抵消作用,从而增强抗代谢药的细胞毒性。本研究证明,胸苷和次黄嘌呤可明显抵消氨甲蝶呤对L1210细胞的杀伤作用,潘生丁则能有效地阻断核苷的抵消作用;潘生丁和两性霉素B合用可明显增强氨甲蝶呤对小鼠S180肉瘤的抑制作用,但不增强氨甲蝶呤对动物的毒性。提示潘生丁有可能应用于肿瘤联合化疗。

Previous studies have shown that the cytotoxicity of antimetabolites to mammalian cells can be reversed by exogenous nucleosides. Dipyridamole (DP), a nucleoside transport inhibitor, can block the reversal effect, thus potentiating the cytotoxicity of antimetabolites to tumor cells. However, potentiation of antimetabolites by DP in vivo has not yet been reported. In this study we found that thymidine and hypoxanthine markedly reversed the cytotoxicity of methotrexate (MTX) to murine leukemia L1210 cells, and DP effectively blocked the reversal in vitro. In combination with amphote-ricin B (AmB), DP enhanced the inhibitory effect of MTX on sarcoma 180 in mice without a significant increase in toxicity. To our knowledge this is the first report that the combination of DP and AmB potentiates the antitumor effect of an antimetabolite in vivo. Results suggest that this combination may be potentially useful in cancer chemotherapy.