pentostatin and formycin

The toxicology and pharmacology of formycin both as a single agent and combined with the adenosine deaminase inhibitor 2'-deoxycoformycin (dCF) were examined in outbred Swiss mice heterozygous for the nude gene (nu/+). The LD10 for formycin alone given on a daily x 5 schedule was 21 mg/kg. When the animals were pretreated with 1 mg/kg of dCF 1 hour prior to each dose of formycin, toxicity was approximately doubled, ie, LD10 was reduced to 10 mg/kg. Death was associated with hepatic toxicity in both treatment regimens; suppression of leukocyte counts was mild except at doses greater than the LD10. Formycin nucleotides were detected by high-performance liquid chromatography in the livers of mice treated with formycin either alone or combined with dCF. When isolated rat hepatocytes were incubated for 2 hours with either formycin or dCF plus formycin, analog nucleotides accumulated in the cells. Cellular ATP decreased to below the limits of detection, whereas a large peak corresponding to formycin-5'-triphosphate was present. This replacement of cellular ATP by formycin-5'-triphosphate may help explain the hepatic toxicity observed.

Topics: Adenosine Deaminase Inhibitors; Animals; Antibiotics, Antineoplastic; Aspartate Aminotransferases; Bilirubin; Blood Glucose; Blood Urea Nitrogen; Coformycin; Creatine; Drug Synergism; Female; Formycins; Lethal Dose 50; Liver; Male; Mice; Mice, Mutant Strains; Mice, Nude; Pentostatin; Rats; Ribonucleosides