Host toxicity of the dose regimen of
tubercidin (7-deazaadenosine) plus
nitrobenzylthioinosine 5'-monophosphate (
NBMPR-P) used in combination
therapy of
schistosomiasis (M. H. el Kouni, D. Diop, and S. Cha, Proc. Natl. Acad. Sci. USA 80:6667-6670, 1983; M. H. el Kouni, N. J. Messier, and S. Cha, Biochem. Pharmacol. 36:3815-3821, 1987) was examined in vivo in mice and in vitro with human bone marrow progenitor cells. Four successive daily
intraperitoneal injections of
tubercidin at 5 mg/kg per day produced 100% mortality in mice within 3 to 5 days following the first injection, with massive
peritonitis and
intestinal obstruction secondary to abdominal adhesions. Coadministration of
NBMPR-P (25 mg/kg per day) protected the mice from the lethality of
tubercidin and allowed the repetition of the regimen for a second time with 100% survival until the mice were sacrificed 22 days following the first injection. Blood chemistry, hematological studies, and histological examinations showed no evidence for injury to the liver, kidney, spleen, pancreas, mesentery, or peritoneal mesothelium. In vitro,
tubercidin alone had a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells, and consistent inhibition (50%) of granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E) occurred at 2 to 3 nM
tubercidin. At higher doses, BFU-E were more sensitive to
tubercidin toxicity than CFU-GM. Complete inhibition (99%) of BFU-E colonies occurred
at 10 nM
tubercidin, while complete inhibition of CFU-GM occurred at 100 nM.
NBMPR-P at 10 to 100 nM protected CFU-GM and BFU-E from
tubercidin toxicity in a dose-dependent matter.