Tiazofurin effects on IMP-dehydrogenase activity and expression in the leukemia cells of patients with CML blast crisis.
Tiazofurin effects on IMP-dehydrogenase activity and expression in the leukemia cells of patients with CML blast crisis.
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发表时间：
1996-11
影响因子：
2
通讯作者：
D. Wright;M. Boosalis;K. Waraska;L. Oshry;L. Weintraub;E. Vosburgh
中科院分区：
文献类型：
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作者：
D. Wright;M. Boosalis;K. Waraska;L. Oshry;L. Weintraub;E. Vosburgh
Tricot等人报道核苷类似物噻唑呋喃可以诱导慢性髓性白血病原细胞危象（CML-BC）患者的血液学缓解。这些报告促使我们开始在CML-BC中进行噻唑呋林的衍生II期试验，以确定这些研究者报告的有希望的发现是否可以复制。在我们正在进行的试验中，患者每24-48小时静脉输注一次噻唑呋林（2200- 4400mg /m2，持续1小时），持续10天。迄今为止，在该试验中接受治疗的3名患者中的每一位，在治疗的4-11天内，都经历了大量的血液学反应，白细胞计数正常化，血液中原细胞完全或部分清除。这些反应相对短暂，因为白血病细胞在治疗后4周内重新聚集在患者的骨髓和血液中，但在随后的治疗过程中再次被诱导。有趣的是，在连续的治疗过程中，胚细胞再积累的速率似乎逐渐增加。Tiazofurin抑制imp -脱氢酶（IMPDH）并阻断鸟嘌呤核糖核苷酸合成，已被证明在体外多种细胞系中增加IMPDH mRNA的表达，这显然是对鸟苷酸剥夺的代偿反应。对接受噻唑呋林治疗的CML-BC患者白血病母细胞中IMPDH mRNA表达的研究表明，体内也发生了同样的现象。由于IMPDH活性与肿瘤细胞的增殖活性有关，由噻唑呋喃诱导的IMPDH信息表达的扩增可能导致白血病克隆对循环活性剂的敏感性增加。
Tricot et al have reported that the nucleoside analog tiazofurin can induce hematologic remissions in patients with chronic myelogenous leukemia in blast crisis (CML-BC). These reports prompted us to begin a derivative, phase II trial of tiazofurin in CML-BC to determine if the promising findings reported by these investigators could be reproduced. In our ongoing trial patients receive tiazofurin by IV infusion (2200-4400 mg/m2 over 1 hr) once every 24-48 hrs for up to 10 days. Each of 3 patients, treated to date on this trial, experienced substantial hematologic responses with normalization of WBC counts and complete or partial clearance of blasts from the blood within 4-11 days of treatment. These responses were relatively brief, in that leukemic blasts reaccumulated in the marrow and blood of patients within 4 weeks following treatment, but were re-induced with subsequent courses of treatment. Of interest, the rates of blast cell reaccumulation appeared to increase progressively following sequential courses of treatment. Tiazofurin, which inhibits IMP-dehydrogenase (IMPDH) and blocks guanine ribonucleotide synthesis, has been shown to increase IMPDH mRNA expression in various cell lines in vitro, as an apparently compensatory response to guanylate deprivation. Studies of IMPDH mRNA expression in the leukemic blasts of CML-BC patients receiving tiazofurin treatment showed that this same phenomenon occurs in vivo. Since IMPDH activity is linked to the proliferative activity of neoplastic cells an amplification of IMPDH message expression induced by tiazofurin may lead to an increased sensitivity of the leukemic clone to cycle active agents.