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Molecular Pharmacology, Vol 7, 375-380, Copyright © 1971 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Guanine Metabolism of Mammalian Tumor Cells by the Carbocyclic Analogue of Adenosine

DONALD L. HILL 1, SUZANNE STRAIGHT 1, PAULA W. ALLAN 1, and L. LEE BENNETT JR. 1

1 Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205

To tumor cells in culture, the carbocyclic analogue of adenosine {9-[beta-DL-2agr,3agr-dihydroxy-4-beta-(hydroxymethyl)cyclopentyl] adenine, C-Ado} has a potent toxicity which is increased in the presence of guanine. C-Ado strongly inhibits guanine utilization by intact cells, causes small amounts of xanthosine to accumulate in the cells, and reduces the ratio of AMP to IMP. The effect on guanine metabolism is reflected by a decreased incorporation of guanine into nucleic acids and by a decreased accumulation of guanine metabolites in the alcohol-soluble fraction of cells. Assays of enzymes involved in guanine metabolism show that C-Ado monophosphate is a potent, competitive inhibitor of GMP kinase (ATP:GMP phosphotransferase, EC 2.7.4.8). The inhibition constant for C-Ado monophosphate is 12 µM, compared to a Michaelis constant for GMP of 41 µM. C-Ado monophosphate does not inhibit either hypoxanthine (guanine) phosphoribosyltransferase (IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) on GDP kinase (ATP:nucleoside diphosphate phosphotransferase, EC 2.7.4.6). Inhibition of GMP kinase may be responsible for tue growth-inhibitory properties of C-Ado and may be involved in the increased toxicity of the analogue in the presence of guanine.

Note:
ACKNOWLEDGMENTS We are indebted to Miss D. Adamson and Mrs. M. H. Vail for provision of cell cultures, and to Mr. T. C. Herren and Mr. H. E. Finch for assays of radioisotopes.

Submitted on February 11, 1971




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