mercaptopurine and 6-mercapto-9-(tetrahydro-2-furyl)purine

Rimantadine, ribavirin, and 6-mercapto-9-(tetrahydro-2-furyl)purine, administered intraperitoneally every 8 h for 7 days starting minutes after virus challenge, had no effect on survival and mean survival time of BALB/c mice inoculated intracranially with dengue virus type 2. In contrast, intraperitoneal treatment with ribavirin 2',3',5'-triacetate, a lipophilic analog of ribavirin, effected significant increases in both mean survival time and survival rate, suggesting that ribavirin 2',3',5'-triacetate may be superior to rabavirin for treatment of viral diseases of the brain.

Topics: Adamantane; Animals; Brain Diseases; Dengue; Female; Mercaptopurine; Mice; Mice, Inbred BALB C; Ribavirin; Ribonucleosides; Rimantadine

The mechanisms of action of 9-(tetrahydro-2-furyl)-6-mercaptopurine (THFMP) have been studied in Chinese hamster ovary (CHO) cells in tissue culture. THFMP is relatively unstable in physiological buffers, being facilely converted to 6-mercaptopurine (6-MP) even in the absence of cells. Consequently, THFMP undergoes metabolic conversions characteristic of 6-MP, namely formation of 6-thioIMP and incorporation into DNA as 6-thio-guanine (6-TG) nucleotide. A number of purines are capable of preventing the toxicity of THFMP in wild-type cells in a manner similar to that of 6-MP. However, exogenous purines and pyrimidines did not prevent the toxicity of THFMP to cells deficient in the enzyme, hypoxanthine-guanine phosphoribosyltransferase (EF 2.4.2.8; HGPRTase). Cells lacking HGPRTase were 20--40-fold resistant to 6-TC and 6-MP but were only 2--4-fold resistant to THFMP. Furthermore, the time-course for killing CHO cells deficient in HGPRTase was different from that in wild-type cells containing the enzyme. There was no apparent effect of THFMP on the utilization of precursors for DNA, RNA or protein synthesis in the enzyme-deficient mutant cell line. The results suggest that THFMP is converted non-enzymatically to 6-MP and shares its mechanisms of action in wild-type cells containing HGPRTase, i.e., inhibition of de novo purine biosynthesis and incorporation into DNA as 6-TC nucleotide. However, the mechanism of action of THFMP in cells lacking HGPRTase is probably unique and is presently unknown.

Topics: Animals; Cell Division; Cell Line; Cell Survival; Cricetinae; Cricetulus; Female; Hypoxanthine Phosphoribosyltransferase; Mercaptopurine; Ovary; Pentosyltransferases; Time Factors

The antiviral effects of ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) and 6-mercapto-9-tetrahydro-2-furylpurine (6-MPTF) against dengue viruses were examined in vitro. Ribavirin significantly reduced the growth of dengue virus types 1-4 in LLC-MK2 cells at concentrations well below cytotoxic levels (cell viability was determined by trypan blue dye exclusion) Addition of guanosine to ribavirin-treated dengue virus-infected cell cultures completely reversed the antiviral effect of the drug. In contrast, ribavirin had no effect on dengue virus replication in human peripheral blood leukocytes (PBL). 6-MPIF, a specific inhibitor of hypoxanthine-guanine phosphoribosyltransferase, did not significantly reduce the growth of dengue viruses in either LIC-MK2 cells or human PBL. However, synergistic effects of 6-MPTF and ribavirin were observed, as combined treatment of the drugs markedly suppressed the replication of dengue viruses in human PBL. The successful demonstration that dengue virus replication in mononuclear leukocytes is markedly suppressed by the combined treatment of ribavirin and 6-MPTF signals a need to evaluate the efficacy of this treatment against dengue virus infections in vivo.

Topics: Animals; Cells, Cultured; Dengue Virus; Drug Synergism; Fibroblasts; Humans; Leukocytes; Macaca mulatta; Mercaptopurine; Nucleosides; Ribavirin; Ribonucleosides