Mechanisms of potentiation of antitumor activity of 5-fluoro-2'-deoxyuridine in the adenocarcinoma 755 system by guanosine 5'-monophosphate.
The effect of guanosine 5'-monophosphate (GMP) on the antitumor activity of 5-fluoro-2'-deoxyuridine (FdUrd) was investigated by using a solid tumor, adenocarcinoma 755. FdUrd only slightly inhibited the tumor growth even at the maximum tolerated dos (ILS,6%). GMP at 300 mg/kg/day markedly potentiated the inhibition of tumor growth by FdUrd (ILS, 61%). When tumor-bearing mice were treated with the combination of 3H-FdUrd and GMP, 3H-FdUrd was significantly incorporated into tumor RNA as compared to the mice not given GMP, although the 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) level in the tumor in the combination with GMP was decreased. The increased incorporation of 3H-FdUrd into RNA ([FUra]RNA) of the tumor was due to an increased level of FUra in plasma and tumor. On the other hand, incorporation of 3H-FdUrd into the RNA of the small intestine, which is one of main target tissues of FUra toxicity, was not increased. Thus, the potentiating effect of GMP on the antitumor activity of FdUrd is apparently due to the specifically increased FdUrd and FUra levels in the tumor. The combination with GMP caused marked incorporation of 3H-FdUrd into RNA in the tumor but uptake of 3H-FdUrd into RNA in the small intestine was not increased. These results suggest that GMP can potentiate the antitumor activity of FdUrd without increasing gastro-intestinal toxicity.
Iigo
M
M
Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan.
Yamaizumi
Z
Z
Nakajima
Y
Y
Nishimura
S
S
Hoshi
A
A
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004357:Drug Synergism; D005467:Floxuridine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006150:Guanine Nucleotides / Q000494:pharmacology*; D006157:Guanosine Monophosphate / Q000494:pharmacology*; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012313:RNA / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014407:Tumor Cells, Cultured
D006150:Guanine Nucleotides; D005467:Floxuridine; D012313:RNA; D006157:Guanosine Monophosphate