Selective reduction of intracellular guanosine 5'-triphosphate pool by 4-carbamoylimidazolium 5-olate in murine tumor cells.
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| Abstract |
Ehrlich carcinoma and P388 leukemia cells were rendered resistant to 4-carbamoylimidazolium 5-olate (SM-108), and assessments were made of biochemical and pharmacological determinants for the sensitivity to SM-108 using both sensitive and resistant sublines. We observed that the treatment of cells with SM-108 in vitro caused a remarkable decrease in the intracellular guanosine 5'-triphosphate pool level in sensitive but not in resistant sublines. There was no difference in the ability to take up SM-108 between sensitive and resistant sublines, but the cellular conversion of SM-108 to its nucleotide, which is the putative active anabolite of SM-108, proceeded only in sensitive sublines. Enzymological studies revealed that the activity of adenine phosphoribosyltransferase (EC 2.4.2.7), which is believed to conjugate SM-108 with 5-phospho-alpha-D-ribose 1-diphosphate, was very low in the resistant sublines. These results strongly support our previous hypothesis that SM-108 is activated by adenine phosphoribosyltransferase to SM-108-nucleotide which then inhibits hypoxanthine-5'-monophosphate dehydrogenase (EC 1.2.1.14), a key enzyme for the de novo synthesis of guanosine 5'-monophosphate.
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| Authors | M Fukui, M Inaba, S Tsukagoshi, Y Sakurai |
| Journal | Cancer research (Cancer Res) Vol. 46 Issue 1 Pg. 43-6 (Jan 1986) ISSN: 0008-5472 [Print] United States |
| PMID | 2866032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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