Mechanism of inhibition of DNA polymerases by 4'-epiadriamycin and 4'-O-tetrahydropyranyladriamycin.
4'-Epiadriamycin and 4'-O-tetrahydropyranyladriamycin (THP-adriamycin), derivatives of adriamycin, strongly inhibited in vitro reactions of DNA polymerases alpha and beta from calf thymus by competing with activated DNA (template-primer). Preincubation of DNA polymerases with 4'-epiadriamycin or THP-adriamycin strongly inhibited the DNA polymerase, but the inhibition was reversed by adding excess amounts of template-primer. These results indicate that 4'-epiadriamycin and THP-adriamycin inhibit the in vitro reactions of DNA polymerases by direct interaction of the drugs with the enzymes as well as by impairing the template activity through intercalation into DNA, in agreement with results obtained for other anthracycline antitumor agents, daunomycin and adriamycin. The activity of DNA polymerase alpha may be more sensitive to both 4'-epiadriamycin (Ki, 9 microM) and THP-adriamycin (Ki, 5.5 microM) than that of DNA polymerase beta (Ki 30 microM for 4'-epiadriamycin and 22 microM for THP-adriamycin). DNA polymerase I from Escherichia coli was inhibited by these drugs in the same manner as DNA polymerase alpha. On the other hand, the inhibition of RNA polymerase from E. coli was more marked when the drug was preincubated with template DNA than with the enzyme.
D000818:Animals; D002417:Cattle; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015251:Epirubicin; D004926:Escherichia coli / Q000201:enzymology; D066298:In Vitro Techniques; D007700:Kinetics; D013698:Templates, Genetic; D013950:Thymus Gland / Q000201:enzymology
D015251:Epirubicin; D004317:Doxorubicin; C027260:pirarubicin; D012321:DNA-Directed RNA Polymerases; D004256:DNA Polymerase I; D004257:DNA Polymerase II