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Molecular Pharmacology, Vol 18, 65-71, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Cytotoxic Effects of Two Novel 8-Substituted Cyclic Nucleotide Derivatives in Cultured Rat Hepatoma Cells

JOHN W. KOONTZ 1 and WESLEY D. WICKS 1

1 Department of Pharmacology, University of Colorado Medical School, Denver, Colorado 80262

The cytotoxic effects of two structurally related cyclic nucleotide analogs have been investigated in a cultured rat hepatoma cell line (H35). Both analogs, 8-H2NcAMP and 8-OH(CH2)2HNcAMP, were lethal to growing H35 cells, exhibiting LC50's of 5-10 and approximately 50-80 µM, respectively. The potency of both analogs was significantly reduced by the concomitant addition of the phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine. However, a number of differences in the effects of these two derivatives were observed. A variant H35 clone has been selected which is resistant to the lethal effects of 8-H2NcAMP. This variant retains its sensitivity to 8-OH(CH2)2HNcAMP, demonstrating quite clearly that the cytotoxic actions of these two analogs are probably exerted at different metabolic loci. Analysis of the effect of either analog on the rapidly turning-over enzyme, tyrosine aminotransferase, showed that after 6 h of exposure, the activity of this enzyme dropped to less than 50% of basal, in contrast to other cyclic nucleotide analogs which induce the enzyme activity severalfold. Neither RNA nor protein synthesis is inhibited by either analog to the degree required to cause a 50% loss in enzyme activity, suggesting that other mechanisms may be operative.

Submitted on December 3, 1979
Accepted on February 25, 1980




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