10,11-Methylenedioxycamptothecin, a topoisomerase I inhibitor of increased potency: DNA damage and correlation to cytotoxicity in human colon carcinoma (HT-29) cells.
We had previously shown that 10,11-methylenedioxy-20-(RS)-camptothecin (MDO-CPT) is a more potent inhibitor of purified DNA topoisomerase I than 20-(S)-camptothecin (CPT). The current studies compared the cytotoxicity and DNA damage induced by MDO-CPT and CPT in the human colon carcinoma cell line, HT-29. MDO-CPT was 7- to 10-fold more potent than CPT both for cytotoxicity (ID50 = 25 vs. 180 nM) and production of DNA single-strand breaks (SSB). Kinetics of SSB formation and reversal were similar for MDO-CPT and CPT. DNA-protein crosslinks (DPC) were also produced by both drugs with a SSB/DPC ratio of 1/1. Moreover, no SSB were detected under non-deproteinizing conditions, indicating that both CPT and MDO-CPT produced protein-linked DNA single-strand breaks. A good correlation between cytotoxic potency and protein-linked DNA single-strand break production was observed for CPT and MDO-CPT, implying a causal relationship between drug-induced cytotoxicity and topoisomerase I inhibition. The sensitivity of human colon HT-29 cancer cells to camptothecins may be a selective phenomenon since these cells normally express natural resistance to current chemotherapeutic drugs, including topoisomerase II inhibitors.
O'Connor
P M
PM
Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Kerrigan
D
D
Bertrand
R
R
Kohn
K W
KW
Pommier
Y
Y
D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003114:Colony-Forming Units Assay; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D059004:Topoisomerase I Inhibitors
D059004:Topoisomerase I Inhibitors; C066731:10,11-methylenedioxy-20-camptothecin; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin