Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2′-deoxyribonucleosides
Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2′-deoxyribonucleosides
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DOI：
10.1016/s0006-2952(00)00253-7
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发表时间：
2000-05-15
影响因子：
5.8
通讯作者：
Asao, T
中科院分区：
文献类型：
--
作者：
Fukushima, M;Suzuki, N;Asao, T
一类新的取代在6位的5-卤化嘧啶类似物被评价为胸苷磷酸化酶（TPase）的竞争性抑制剂。其中最有效的是5-氯-6-（2-亚胺吡啶-1-酰基）甲基-2,4(1H,3H)-嘧啶二酮盐酸（TPI），其表观K-i值为1.7 × 10(-8) M. TPI有选择性地抑制TPase的活性，但对尿苷磷酸化酶、胸苷激酶、羊角酸磷酸核糖基转移酶和二氢嘧啶脱氢酶没有抑制作用。使用胸腺嘧啶类似物5-三氟甲基-2'-脱氧尿苷（F(3)dThd）作为底物对TPI进行的体外抑制研究表明，TPI （1 × 10(-6) M）在人体肝脏、小肠和肿瘤、食环猴的肝脏和小肠以及啮齿动物的肝脏提取物中显著抑制F(3)dThd的磷酸化活性，但在狗的肝脏或小肠或啮齿动物的小肠中没有抑制作用。提示人类和动物之间TPase的分布存在差异，TPI可能参与了人类TPase的调节。当F(3)dThd或5-碘-2'-脱氧尿苷（IdUrd）与TPI以1:1的摩尔比共给药时，血中F(3)dThd（或IdUrd）的水平比单独给药时高约2倍。在猴子体内，单独口服F(3)dThd后的最大浓度（C-max）和浓度-时间曲线下面积（AUC）分别为0.23 μ g/mL和0.28 μ g。分别达到15.18 μ g/mL（约70倍）和28.47 μ g。hr/mL（约100倍），当与等摩尔TPI联合使用时。联合口服TPI可显著增强F(3)dThd对裸鼠AZ-521人胃癌异种移植物的抗肿瘤活性。综上所述，TPI不仅可以抑制tpase介导的生物功能，还可以通过与各种2'-脱氧尿嘧啶和胸腺嘧啶衍生物的结合来增强它们的生物活性。(C) 2000 Elsevier Science Inc.；
A new class of 5-halogenated pyrimidine analogs substituted at the 6-position was evaluated as competitive inhibitors of thymidine phosphorylase (TPase). The most potent member of the series was 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride (TPI), which has an apparent K-i value of 1.7 x 10(-8) M. TPI selectively inhibited the activity of TPase, but not that of uridine phosphorylase, thymidine kinase, orotate phosphoribosyltransferase, or dihydropyrimidine dehydrogenase. In vitro inhibition studies of TPI using a thymidine analogue, 5-trifluoromethyl-2'-deoxyuridine (F(3)dThd), as the substrate demonstrated that F(3)dThd phosphorolytic activity was inhibited markedly by TPI (1 x 10(-6) M) in extracts from the liver, small intestine, and tumors of humans, from the liver and small intestine of cynomolgus monkeys, and from the liver of rodents, but not from the liver or small intestine of dogs or the small intestine of rodents, suggesting that the distribution of TPase differs between humans and animal species, and that TPI could contribute to the modulation of TPase in humans. When F(3)dThd or 5-iodo-2'-deoxyuridine (IdUrd) was coadministered to mice with TPI at a molar ratio of 1:1, the blood levels of F(3)dThd (or IdUrd) were about 2-fold higher than when F(3)dThd (or IdUrd) was administered alone. In monkeys, the maximum concentration (C-max) and the area under the concentration-time curve (AUC) after oral F(3)dThd alone were 0.23 mu g/mL and 0.28 mu g . hr/mL, respectively, lour markedly increased to 15.18 mu g/mL (approximately 70-fold) and 28.47 mu g . hr/mL (approximately 100-fold), respectively, when combined with equimolar TPI. Combined oral administration of TPI significantly potentiated the antitumor activity of F(3)dThd on AZ-521 human stomach cancer xenografts in nude mice. In conclusion, TPI may contribute not only to inhibition of TPase-mediated biological functions but also to potentiation of the biological activity of various 2'-deoxyuridine and thymidine derivatives by combining with them. (C) 2000 Elsevier Science Inc.