SEQUENTIAL IMPACT OF TIAZOFURIN AND RIBAVIRIN ON THE ENZYMATIC PROGRAM OF THE BONE-MARROW

Tiazofurin and ribavirin are clinically used inhibitors of IMP dehydro genase (DH), binding to the NAD and IMP sites, respectively, of the ta rget enzyme. In patients with chronic granulocytic leukemia in blast c risis, daily tiazofurin infusions decreased the high IMP DH activity i n blast cells and resulted in 77% response (G. Weber. In: R. A. Harkne ss et al. Purine and Pyrimidine Metabolism in Man, Vol. VII, Part B, p p. 287-292, 1991). However, patients relapsed in a few weeks with emer gence of high IMP DH activity (G. Tricot et al, Int. J. Cell Cloning, 8: 161-170, 1990). The present study showed that the tiazofurin-induce d depression of IMP DH activity in rat bone marrow can be maintained b y ribavirin injection. Tiazofurin (150 mg/kg, i.p., once a day for 2 d ays) decreased IMP DH activity to 10% and ribavirin (250 mg/kg, i.p., once a day for the subsequent 3 days) maintained the enzymic activity at 20 to 30% of control values. In control rats where no ribavirin was given, IMP DH activity of the tiazofurin-treated rats rapidly returne d to the range of untreated animals. The decrease of IMP DH activity ( t1/2 = 2.6 h) sharply preceded that of the bone marrow cellularity (t1 /2 = 17.4 h). In addition to the target enzyme, IMP DH, tiazofurin als o decreased activities of the guanylate metabolic enzymes, guanine pho sphoribosyltransferase and GMP reductase, and the pyrimidine salvage e nzymes, deoxycytidine and thymidine kinases with t1/2 of 2.6, 4.7, 6.0 , 3.4, and 6.5 h, respectively. In cycloheximide-treated rats, where m uch of protein biosynthesis was blocked, the t1/2s of these five enzym es in bone marrow were shorter, 1.6, 4.3, 3.0, 0.6, and 0.8 h, respect ively. Thus, the impact of tiazofurin in the bone marrow entails a dec rease in the activity of the target enzyme, IMP DH, and also of other enzymes in purine and pyrimidine biosynthesis as a result of the enzym e half-lives shortened by this drug. These novel observations should a ssist in achieving better protection and recovery of bone marrow durin g and after chemotherapy.