Iigo M, Yamaizumi Z, Nishimura S, Hoshi A
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Eur J Cancer Clin Oncol. 1987 Jul;23(7):1059-65. doi: 10.1016/0277-5379(87)90359-2.
The effect of various guanine ribonucleotides on the antitumor activity of 5-fluorouracil (FUra) was investigated by its action on adenocarcinoma 755. 5'-GDP and 5'-GMP were both equally effective in potentiating the antitumor activity of FUra without increasing toxicity. 5'-GTP and 5'-IMP also potentiated the activity but not as much as 5'-GMP. 2'-GMP and 3'-GMP did not enhance the antitumor activity. In contrast, cGMP antagonized the effects of FUra. The incorporation of 3H-labeled FUra into RNA or DNA showed there was no obvious association between the incorporation and antitumor activity after any treatment with guanine ribonucleotides. The combination of FUra and 5'-GMP produced the greatest inhibition of RNA synthesis. The combination of FUra and 2'-GMP had no effect on RNA synthesis. The inhibition of RNA synthesis may be the result of decreased pyrimidine pool size and increased incorporation of FUra into RNA. Potentiation of the antitumor activity of FUra by 5'-GMP was reversed by the injection of cytidine. Moreover, the combination of 5-fluorocytidine (FCyd) and 5'-GMP showed greater antitumor activity than FCyd alone. These results indicate that a decreased CTP pool potentiates the antitumor activity of FUra. Thus, 5'-GMP or 5'-GDP strongly enhanced the antitumor activity of FUra, and the potentiation resulted from the inhibition of RNA synthesis caused by reduction of the CTP and UTP pool sizes and increased incorporation of FUra into RNA.
通过观察各种鸟嘌呤核糖核苷酸对腺癌755的作用，研究了它们对5-氟尿嘧啶（FUra）抗肿瘤活性的影响。5'-GDP和5'-GMP在增强FUra的抗肿瘤活性方面同样有效，且不增加毒性。5'-GTP和5'-IMP也能增强其活性，但效果不如5'-GMP。2'-GMP和3'-GMP不能增强抗肿瘤活性。相反，cGMP拮抗FUra的作用。用3H标记的FUra掺入RNA或DNA的实验表明，在用鸟嘌呤核糖核苷酸处理后，掺入与抗肿瘤活性之间没有明显关联。FUra与5'-GMP联合使用对RNA合成的抑制作用最大。FUra与2'-GMP联合使用对RNA合成没有影响。RNA合成的抑制可能是嘧啶池大小减小以及FUra掺入RNA增加的结果。注射胞苷可逆转5'-GMP对FUra抗肿瘤活性的增强作用。此外，5-氟胞苷（FCyd）与5'-GMP联合使用比单独使用FCyd具有更强的抗肿瘤活性。这些结果表明，CTP池的减少可增强FUra的抗肿瘤活性。因此，5'-GMP或5'-GDP能强烈增强FUra的抗肿瘤活性，这种增强作用是由于CTP和UTP池大小减少导致RNA合成受到抑制以及FUra掺入RNA增加所致。
