BIOCHEMICAL BASIS OF THE PREVENTION OF 6-THIOPURINE TOXICITY BY THE NUCLEOBASES, HYPOXANTHINE AND ADENINE

被引:9
作者
HASHIMOTO, H [1 ]
KUBOTA, M [1 ]
SHIMIZU, T [1 ]
TAKIMOTO, T [1 ]
KITOH, T [1 ]
AKIYAMA, Y [1 ]
MIKAWA, H [1 ]
机构
[1] KYOTO UNIV, DEPT PEDIAT, SHOGOIN 54, SAKYO KU, KYOTO 606, JAPAN
关键词
6-THIOPURINE; HYPOXANTHINE; ADENINE; TRANSPORT; PHOSPHORIBOSYLATION;
D O I
10.1016/0145-2126(90)90120-X
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Co-incubation of human leukemia cell lines with naturally occurring nucleobases (hypoxanthine or adenine) significantly prevented the cytotoxic activity of 6-thiopurines. Extracellular hypoxanthine decreased the transport of 6-mercaptopurine into cells, but adenine had no significant effect. However, intracellular thioinosine monophosphate accumulation in the presence of 10-mu-M, 6-mercaptopurine was reduced to below 1% or 10% of that of the controls when 50-mu-M hypoxanthine or adenine was added, respectively. Finally, in adenine phosphoribosyl transferase deficient mutants, adenine provided no protective effect against 6-thiopurines, whereas hypoxanthine retained its modulating activity. These data suggest that the nucleobases compete with 6-thiopurines for the ribose-phosphate donor, 5'-phosphoribosyl-1-pyrophosphate, thus preventing the formation of active metabolites of 6-thiopurines.
引用
收藏
页码:1061 / 1066
页数:6
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