guanosine-monophosphate and Leukemia-P388

Multinuclear Pt(II) complexes represent a novel class of antitumor agents. In this work, a dinuclear monofunctional Pt(II) complex {[cis-Pt(NH(3))(2)Cl](2)(4,4'-methylenedianiline)}(NO(3))(2) (1) was synthesized and characterized by (1)H NMR, electrospray mass spectrometry, and elemental analysis. The 2D [(1)H,(15)N] heteronuclear single quantum coherence NMR spectra of (15)N-labeled 1 revealed that the cationic core of this water-soluble complex hardly hydrolyzes in aqueous solution and reacts very slowly with glutathione. Hydrolysis appears not to be an essential step for the formation of Pt-guanosine-5'-monophosphate (5'-GMP) or Pt-DNA adducts because the complex can react readily with 5'-GMP and partially transform B-DNA into its Z form. Such properties are desired to achieve the goal of enhancing cytotoxicity and lowering side effects of Pt(II) complexes. In fact, complex 1 is highly cytotoxic against the murine leukemia (P-388) and the human non-small-cell lung cancer (A-549) cell lines, and it is more cytotoxic than cisplatin at most concentrations tested.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Circular Dichroism; DNA; Glutathione; Guanosine Monophosphate; Humans; Hydrolysis; Indicators and Reagents; Leukemia P388; Lung Neoplasms; Magnetic Resonance Spectroscopy; Mice; Organoplatinum Compounds; Spectrometry, Mass, Electrospray Ionization

The effect of inosine, guanosine, and guanosine 5'-monophosphate (GMP) on the antitumor activity of 5'-deoxy-5-fluorouridine (5'-DFUR) was investigated using P388 leukemia and P815 mastocytoma. The antitumor activity of 5'-DFUR was markedly enhanced by coadministration of inosine or guanosine. The increase in lifespan (ILS) of mice treated with 5'-DFUR was augmented by the combination with guanosine or inosine in a dose-dependent fashion, and the maximum ILS was about 160% with the combination, while that in the case of 5'-DFUR alone was only 48% in the P388 leukemia system. The therapeutic ratio (dose at ILSmax/dose at ILS30) of the combination with guanosine or inosine was 333 and 136, respectively, whereas that of 5'-DFUR alone was 3.6. GMP also markedly potentiated the antitumor activity of 5'-DFUR in both P388 leukemia and P815 mastocytoma systems, just as it potentiated the activity of 5-fluorouracil in the latter system. The uric acid level in the serum was elevated after IP injection of guanosine or inosine but the value was much lower in the case of guanosine than in inosine.

Topics: Animals; Drug Synergism; Floxuridine; Guanine Nucleotides; Guanosine; Guanosine Monophosphate; Inosine; Leukemia P388; Leukemia, Experimental; Male; Mast-Cell Sarcoma; Mice; Mice, Inbred Strains; Uric Acid

To obtain more effective treatment with the combination of 5-fluorouracil (FUra) and guanosine 5'-monophosphate (GMP), the influence of the time interval between FUra and GMP administration and of the molar ratio of GMP to FUra on the effect on P388 murine leukemia were investigated. The antitumor activity of FUra was significantly potentiated when GMP was administered either 0-60 min before or 5 min after FUra. The potentiated increase in lifespan (ILS) was almost the same as after simultaneous injection of the two agents. Coadministration of FUra and GMP increased the antitumor activity as compared with the respective dose of FUra alone in a treatment schedule of either day 1 only or days 1-9. The multiple-dose regimen (days 1-9) was more effective than a single high-dose regimen, and a GMP/FUra molar ratio of 4 seems to achieve the best therapeutic results against P388 leukemia. Daily simultaneous administration of FUra and GMP on days 1-9 also resulted in a significant increase in the antitumor activity against L1210 Leukemia as compared with FUra alone.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Fluorouracil; Guanosine Monophosphate; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Male; Mice; Mice, Inbred Strains; Time Factors

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

Two new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250) and 4-carbamoylimidazolium 5-olate (SM-108), were investigated for their antitumor activities against 6-mercaptopurine (6-MP)-resistant sublines of P388 and L1210 leukemia. It was found that both resistant sublines exhibited collateral sensitivity instead of cross-resistance to these new antipurine drugs. Since more potent cytotoxic activities of these drugs against 6-MP-resistant cells were observed even in vivo cell culture systems, this collateral sensitivity was proved on a cellular basis. Biochemical studies revealed that 6-MP-resistant sublines of both P388 and L1210 leukemia are deficient in hypoxanthine-guanine phosphoribosyltransferase activity. In these cells, not only the activation of 6-MP to its nucleotide but also the synthesis of guanosine 5'-monophosphate via the salvage pathway seems to be severely restricted. However, SL-1250 and SM-108 can be activated to their nucleotide even in these 6-MP-resistant cells because the activation of these compounds is proceeded by adenine phosphoribosyltransferase. In conclusion, suppression of de novo purine synthesis with SL-1250 and SM-108 seems to be a very efficient means of killing these 6-MP-resistant cells, which lack a salvage pathway for guanosine 5'-monophosphate.

Topics: Animals; Antineoplastic Agents; Biotransformation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Guanosine Monophosphate; Hypoxanthine Phosphoribosyltransferase; Imidazoles; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mercaptopurine; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Purines