一种有前景的抗白血病胸苷类似物5-羟甲基-2'-脱氧尿苷的体外和体内研究。

In vitro and in vivo studies of a promising antileukemic thymidine analogue, 5-hydroxymethyl-2' deoxyuridine.

作者信息

Kahilainen L, Bergstrom D, Kangas L, Vilpo J A

出版信息

Biochem Pharmacol. 1986 Dec 1;35(23):4211-5. doi: 10.1016/0006-2952(86)90697-0.

Abstract

The toxicity and metabolism of a thymidine analogue, 5-hydroxymethyl-2'-deoxyuridine (5HmdUrd) were studied with human leukemia cells (HL-60) and with human platelets. 3 X 10(-5) M 5HmdUrd caused a 50% inhibition in the proliferation of HL-60 cells. The compound was hydrolyzed to 5-hydroxymethyluracil (5HmUra) by the enzyme thymidine phosphorylase (EC 2.4.2.4) present in leukemia cells; this catabolic product was non-toxic. The catabolism of 5HmdUrd by human platelet thymidine phosphorylase could be inhibited by 6-aminothymine. The toxicity of 5HmdUrd was effectively reversed by deoxycytidine and 5HmdUrd increased the incorporation of deoxycytidine into dCTP and DNA several fold. The two latter phenomena are explicable in terms of a feedback action to ribonucleotide reductase, resulting in deoxycytidylate starvation, which is a known effect of excess thymidine. We report here also our preliminary observations that 5HmdUrd is active against mouse leukemia in vivo.

摘要

利用人白血病细胞（HL - 60）和人血小板研究了胸苷类似物5 - 羟甲基 - 2'-脱氧尿苷（5HmdUrd）的毒性和代谢。3×10⁻⁵M的5HmdUrd对HL - 60细胞的增殖产生50%的抑制作用。该化合物被白血病细胞中存在的胸苷磷酸化酶（EC 2.4.2.4）水解为5 - 羟甲基尿嘧啶（5HmUra）；这种分解代谢产物无毒。人血小板胸苷磷酸化酶对5HmdUrd的分解代谢可被6 - 氨基胸腺嘧啶抑制。脱氧胞苷可有效逆转5HmdUrd的毒性，且5HmdUrd使脱氧胞苷掺入dCTP和DNA的量增加了几倍。后两种现象可以用对核糖核苷酸还原酶的反馈作用来解释，导致脱氧胞苷酸饥饿，这是过量胸苷的已知效应。我们在此还报告了我们的初步观察结果，即5HmdUrd在体内对小鼠白血病有活性。