Tiazofurin: molecular and clinical action.
Tiazofurin: molecular and clinical action.
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发表时间：
1996-11
影响因子：
2
通讯作者：
G. Weber;N. Prajda;M. Abonyi;K. Look;G. Tricot
中科院分区：
文献类型：
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作者：
G. Weber;N. Prajda;M. Abonyi;K. Look;G. Tricot
未加标签的目的是提供对噻唑呋喃的分子和临床影响的概述。方法报告生化和临床技术(1、2)。结果IMP-水解酶活性在各种动物和人类肿瘤中均升高，尤其在白血病母细胞中活性最高。活性的增加是由于II型同工酶的mRNA浓度的增加。噻唑呋喃是一种C-核苷，在敏感细胞中被转化为活性代谢物TAD，它紧密结合在NADH位点上，抑制了IMP水解酶的活性。抑制作用可降低GTP浓度，下调ras和myc癌基因表达，并诱导原始细胞成熟。新的证据表明，由于PI和PIP激酶活性的降低，导致第二信使IP3的浓度下降，噻唑呋喃注射液下调了信号转导活性。在患者中，滴注噻唑呋喃和使用别嘌醇可导致IMP-水解酶活性和GTP浓度降低。别嘌醇抑制黄嘌呤氧化酶活性，导致次黄嘌呤浓度显着升高，从而抑制增加的鸟嘌呤挽救途径。在临床上，血次黄嘌呤浓度的升高是噻唑呋喃类药物治疗成功的关键。噻唑呋喃与利巴韦林、维甲酸、紫杉醇、槲皮素、吉西他滨、双嘧达莫、灯盏花素表现出相加或协同作用。利巴韦林通过抑制IMP位点上的IMP-Dh，延长了噻唑呋喃对大鼠骨髓细胞IMP的抑制作用。结论噻唑呋喃和别嘌醇通过抑制IMP、水解酶和GPRT活性，实现白血病细胞GTP浓度的降低。因此，诱导成熟伴随着ras和myc癌基因的下调，并可能降低信号转导能力。噻唑呋喃在白血病患者中的疗效超过75%，患者可以用这种联合治疗数月，并获得良好的生活质量。这些临床和生化结果最近被独立证实(3)。
UNLABELLED The purpose is to provide an overview of the molecular and clinical impact of tiazofurin. METHOD The biochemical and clinical techniques were reported (1, 2). RESULTS IMP DH activity increased in various animal and human tumors and was particularly high in leukemic blast cells. The increased activity was due to an elevation in the mRNA concentration of type II isozyme. Tiazofurin, a C-nucleoside, was converted in sensitive cells to the active metabolite, TAD, which tightly bound at the NADH site inhibited IMP DH activity. The inhibition led to decreased GTP concentration, down-regulation of ras and myc oncogenes and induced maturation of blast cells. New evidence shows that tiazofurin injection downregulated signal transduction activity due to a reduction of the activities of PI and PIP kinases leading to a decrease in the concentration of the second messenger, IP3. In patients; tiazofurin infusion and allopurinol administration led to reduction of IMP DH activity and GTP concentration. Allopurinol inhibited xanthine oxidase activity leading to a marked rise in hypoxanthine concentration which inhibited the increased guanine salvage pathway. In the clinic, the increase in serum hypoxanthine concentration is essential for the success of tiazofurin treatment. Tiazofurin showed additivity or synergism with ribavirin, retinoic acid, taxol, quercetin, gemcitabin, dipyridamole and brefeldin. Ribavirin which inhibits IMP DH at the IMP site has been shown to prolong the IMP depressing action of tiazofurin in rat bone marrow cells. CONCLUSION Tiazofurin and allopurinol achieve reduction of GTP concentration in leukemic blast cells through inhibition of IMP DH and GPRT activities. As a result, induced maturation occurs with down-regulation of ras and myc oncogenes and probably reduced signal transduction capacity. Tiazofurin in leukemic patients provides over 75% therapeutic responses and patients can be treated with this combination for many months with good quality of life. These clinical and biochemical results were recently confirmed independently (3).