Modified nucleotide polymers as inhibitors of DNA polymerases.
We have compared the relative inhibitory activity of poly (A) with its analogues poly N6-isopentenyl adenylic acid (poly(i6 A)) and poly N6-benzyl adenylic acid (poly(bzl6A)), and of poly (U) with its analogue poly 2'-fluoro-2'-deoxyuridylic acid (poly(dUfl)), against DNA polymerase, alpha, beta and gamma and terminal deoxynucleotidyl transferase from human cells and two oncorna virus DNA polymerases. Although poly (A) and its analogues were equally inhibitory against endogenous RNA-directed DNA polymerases of murine and feline leukemia viruses, the analogues in contrast to poly (A) were strongly inhibitory against all four cellular enzymes. Poly (dUfl), on the other hand, was up to 100-fold more potent than poly (U) against both viral and cellular enzymes. Since poly (U) at 100 mug/ml and poly (dUfl) at 1 mug/ml had no effect on terminal deoxynucleotidyl transferase while inhibiting other enzymes by 80--100 per cent these polymers could be useful in the characterization and assay of terminal deoxynucleotidyl transferase. In addition, the polymers such as poly (igA) and poly (bzl5A) which were strongly inhibitory to all cellular enzymes, could be useful in cancer chemotherapy if taken up preferentially by the malignant calls due to their high pinocytic activity. The results also demonstrate potential for large variation in inhibitory activity of polyribonucleotides as related to their chemical composition.
D002460:Cell Line; D004254:DNA Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D004261:DNA Replication / Q000187:drug effects; D007700:Kinetics; D011061:Poly A / Q000031:analogs & derivatives / Q000494:pharmacology; D011072:Poly U / Q000031:analogs & derivatives / Q000494:pharmacology; D011119:Polynucleotides / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011119:Polynucleotides; D011061:Poly A; D011072:Poly U; D004254:DNA Nucleotidyltransferases