guanosine-monophosphate and Adenocarcinoma

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.

Topics: Adenocarcinoma; Animals; Chromatography, High Pressure Liquid; Drug Synergism; Floxuridine; Guanine Nucleotides; Guanosine Monophosphate; Injections, Intravenous; Intestine, Small; Liver; Male; Mice; Mice, Inbred Strains; RNA; Spleen; Tumor Cells, Cultured

The chemotherapeutic effect of the 5-fluorouracil (5-FU)-guanosine 5'-monophosphate (GMP) combination in various mouse tumor systems was compared with that of 5-FU monotherapy. Antitumor activity of 5-FU against L-1210 leukemia was potentiated without increasing its toxicity to the host when GMP at 30-100 mg/kg/day was injected simultaneously with 5-FU. Any time interval between the administrations of 5-FU and GMP diminished the increase in survival. Moreover, the combination of 5-FU and GMP at 100 mg/kg/day produced marked antitumor effects in the P-388 leukemia, ascites sarcoma 180, and Ehrlich ascites carcinoma systems. GMP also potentiated the antitumor activity of 5-FU in solid tumor systems (adenocarcinoma 755 and Lewis lung carcinoma) when given by intravenous injection, but not intraperitoneal injection. The therapeutic effect of 5-FU on various murine tumors was markedly potentiated by GMP at 100 mg/kg/day or less without increasing the toxicity to the host.

Topics: Adenocarcinoma; Animals; Drug Therapy, Combination; Fluorouracil; Guanine Nucleotides; Guanosine Monophosphate; Leukemia L1210; Leukemia P388; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Time Factors