Prajda N, Hata Y, Abonyi M, Singhal R L, Weber G
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
Cancer Res. 1993 Dec 15;53(24):5982-6.
Tiazofurin and ribavirin are clinically used inhibitors of IMP dehydrogenase (DH), binding to the NAD and IMP sites, respectively, of the target enzyme. In patients with chronic granulocytic leukemia in blast crisis, daily tiazofurin infusions decreased the high IMP DH activity in blast cells and resulted in 77% response (G. Weber. In: R. A. Harkness et al., Purine and Pyrimidine Metabolism in Man, Vol. VII, Part B, pp. 287-292, 1991). However, patients relapsed in a few weeks with emergence of high IMP DH activity (G. Tricot et al., Int. J. Cell Cloning, 8: 161-170, 1990). The present study showed that the tiazofurin-induced depression of IMP DH activity in rat bone marrow can be maintained by ribavirin injection. Tiazofurin (150 mg/kg, i.p., once a day for 2 days) 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 returned 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 also decreased activities of the guanylate metabolic enzymes, guanine phosphoribosyltransferase and GMP reductase, and the pyrimidine salvage enzymes, 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 much of protein biosynthesis was blocked, the t1/2(8) of these five enzymes in bone marrow were shorter, 1.6, 4.3, 3.0, 0.6, and 0.8 h, respectively. Thus, the impact of tiazofurin in the bone marrow entails a decrease in the activity of the target enzyme, IMP DH, and also of other enzymes in purine and pyrimidine biosynthesis as a result of the enzyme half-lives shortened by this drug. These novel observations should assist in achieving better protection and recovery of bone marrow during and after chemotherapy.
替唑呋林和利巴韦林是临床上使用的肌苷酸脱氢酶（IMP DH）抑制剂，分别与靶酶的NAD和IMP位点结合。在急变期慢性粒细胞白血病患者中，每日输注替唑呋林可降低原始细胞中较高的IMP DH活性，并产生77%的缓解率（G. 韦伯。见：R. A. 哈克尼斯等人，《人类嘌呤和嘧啶代谢》，第七卷，B部分，第287 - 292页，1991年）。然而，患者在几周内复发，出现了较高的IMP DH活性（G. 特里科特等人，《国际细胞克隆杂志》，8: 161 - 170，1990年）。本研究表明，利巴韦林注射可维持替唑呋林诱导的大鼠骨髓中IMP DH活性的降低。替唑呋林（150 mg/kg，腹腔注射，每天1次，共2天）将IMP DH活性降至10%，利巴韦林（250 mg/kg，腹腔注射，随后3天每天1次）将酶活性维持在对照值的20%至30%。在未给予利巴韦林的对照大鼠中，经替唑呋林处理的大鼠的IMP DH活性迅速恢复到未处理动物的水平。IMP DH活性的降低（t1/2 = 2.6小时）比骨髓细胞数量的降低（t1/2 = 17.4小时）早得多。除了靶酶IMP DH外，替唑呋林还降低了鸟苷酸代谢酶鸟嘌呤磷酸核糖转移酶和GMP还原酶以及嘧啶补救酶脱氧胞苷激酶和胸苷激酶的活性，其t1/2分别为2.6、4.7、6.0、3.4和6.5小时。在环己酰亚胺处理的大鼠中，大部分蛋白质生物合成被阻断，这五种酶在骨髓中的t1/2（8）更短，分别为1.6、4.3、3.0、0.6和0.8小时。因此，并产生77%的缓解率（G. 韦伯。见：R. A. 哈克尼斯等人，《人类嘌呤和嘧啶代谢》，第七卷，B部分，第287 - 292页，1991年）。然而，患者在几周内复发，出现了较高的IMP DH活性（G. 特里科特等人，《国际细胞克隆杂志》，8: 161 - 170，1990年）。本研究表明，利巴韦林注射可维持替唑呋林诱导的大鼠骨髓中IMP DH活性的降低。替唑呋林（150 mg/kg，腹腔注射，每天1次，共2天）将IMP DH活性降至10%，利巴韦林（250 mg/kg，腹腔注射，随后3天每天1次）将酶活性维持在对照值的20%至30%。在未给予利巴韦林的对照大鼠中，经替唑呋林处理的大鼠的IMP DH活性迅速恢复到未处理动物的水平。IMP DH活性的降低（t1/2 = 2.6小时）比骨髓细胞数量的降低（t1/2 = 17.4小时）早得多。除了靶酶IMP DH外，替唑呋林还降低了鸟苷酸代谢酶鸟嘌呤磷酸核糖转移酶和GMP还原酶以及嘧啶补救酶脱氧胞苷激酶和胸苷激酶的活性，其t1/2分别为2.6、4.7、6.0、3.4和6.5小时。在环己酰亚胺处理的大鼠中，大部分蛋白质生物合成被阻断，这五种酶在骨髓中的t1/2（8）更短，分别为替唑呋林对骨髓的影响包括靶酶IMP DH活性的降低，以及由于该药物缩短了酶的半衰期，嘌呤和嘧啶生物合成中的其他酶活性也降低。这些新发现应有助于在化疗期间和化疗后更好地保护骨髓并促进其恢复。
