Differential inhibition by an antitumoral drug 10-[gamma-diethylaminopropylamino]-6-methyl-5H-pyrido[3',4': 4,5]pyrrolo [2,3-G]isoquinoline (BD-40), a pyrido-pyrrolo-isoquinoline derivative, of in vitro DNA synthesis catalyzed by various DNA polymerases.
The effects of BD-40, a pyrido-pyrrolo-isoquinoline analogue of ellipticines, and its 2-acetylated derivative (BD-84) and in vitro DNA synthesis catalyzed by purified preparations of various DNA polymerases were examined. The major conclusions are: (1) Both BD-40 and BD-84 strongly inhibit the DNA synthesis by DNA polymerase or reverse transcriptase with poly(rA).oligo(dT) as the template.primer. (2) Both compounds moderately inhibit the DNA synthesis by DNA polymerase alpha or E. coli DNA polymerase I with activated DNA. However, the DNA synthesis by DNA polymerase beta is resistant to inhibition by BD-40 and slightly sensitive to that by BD-84. (3) BD-84 is more inhibitory than BD-40 in DNA syntheses by various DNA polymerases except in those by DNA polymerase alpha and terminal deoxyneuclotidyltransferase to which both compounds are similarly inhibitory. (4) Kinetic analyses revealed that the observed inhibitions are due to competition between the drug or the drug-bound template.primer and the free template.primer for the same binding site of the enzyme.
Ono
K
K
Laboratory of Viral Oncology, Aichi Cancer Center Research Institute, Nagova, Japan.
Nakane
H
H
Barre-Sinoussi
F
F
Chermann
J C
JC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004611:Ellipticines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004611:Ellipticines; D007211:Indoles; D007546:Isoquinolines; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; C024256:pazelliptine; D004256:DNA Polymerase I; C046349:retelliptine