噻唑呋林及其硒类似物（2-β-D-呋喃核糖基-4-硒唑甲酰胺）的生化及抗肿瘤活性

Biochemical and antitumor activity of tiazofurin and its selenium analog (2-beta-D-ribofuranosyl-4-selenazolecarboxamide).

作者信息

Boritzki T J, Berry D A, Besserer J A, Cook P D, Fry D W, Leopold W R, Jackson R C

出版信息

Biochem Pharmacol. 1985 Apr 1;34(7):1109-14. doi: 10.1016/0006-2952(85)90617-3.

Abstract

2-beta-D-Ribofuranosyl-4-selenazolecarboxamide (selenazofurin, CI-935), the selenium analog of tiazofurin (CI-909), was 3- to 10-fold more cytotoxic to murine or human tumor cells in vitro than tiazofurin and was also more active against P388 mouse leukemia in vivo. In vitro cytotoxicity could be reversed by guanosine or guanine but not by other purine nucleosides or bases. Three human tumor cell lines selected for selenazofurin or tiazofurin resistance showed cross resistance between selenazofurin and tiazofurin. Treatment with tiazofurin, selenazofurin, or mycophenolic acid decreased guanylate pools and caused an accumulation of IMP in WIL2 human lymphoma cells. The decrease in guanylate pools was accompanied by inhibition of RNA and DNA synthesis. The NAD analogs of tiazofurin and selenazofurin were inhibitors of L1210 IMP dehydrogenase (IMP:NAD oxidoreductase, EC 1.2.1.14), and both showed uncompetitive inhibition with respect to NAD having Kii values of 5.7 X 10(-8)M and 3.3 X 10(-8)M respectively.

摘要

2-β-D-呋喃核糖基-4-硒唑甲酰胺（硒唑呋林，CI-935）是噻唑呋林（CI-909）的硒类似物，在体外对鼠类或人类肿瘤细胞的细胞毒性比噻唑呋林高3至10倍，并且在体内对P388小鼠白血病也更具活性。体外细胞毒性可被鸟苷或鸟嘌呤逆转，但不能被其他嘌呤核苷或碱基逆转。选择的三种对硒唑呋林或噻唑呋林耐药的人类肿瘤细胞系显示出硒唑呋林和噻唑呋林之间的交叉耐药性。用噻唑呋林、硒唑呋林或霉酚酸处理会降低WIL2人淋巴瘤细胞中的鸟苷酸池，并导致IMP积累。鸟苷酸池的降低伴随着RNA和DNA合成的抑制。噻唑呋林和硒唑呋林的NAD类似物是L1210 IMP脱氢酶（IMP：NAD氧化还原酶，EC 1.2.1.14）的抑制剂，并且两者对NAD均表现出非竞争性抑制，其Kii值分别为5.7×10^(-8)M和3.3×10^(-8)M。