Mechanism of potentiation of antitumor activity of 5-fluorouracil by guanine ribonucleotides against adenocarcinoma 755.
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.
Iigo
M
M
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Yamaizumi
Z
Z
Nishimura
S
S
Hoshi
A
A
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004357:Drug Synergism; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use*; D006150:Guanine Nucleotides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D012265:Ribonucleotides / Q000032:analysis
D004273:DNA, Neoplasm; D006150:Guanine Nucleotides; D012334:RNA, Neoplasm; D012265:Ribonucleotides; D005472:Fluorouracil