Pharmacological determinants of 9-aminocamptothecin cytotoxicity.
The camptothecins are a group of anticancer agents with a unique mechanism of action: poisoning of eukaryotic DNA topoisomerase I. 9-aminocamptothecin (9-AC), a potent water-insoluble derivative of camptothecin, is currently undergoing clinical testing. The kinetics of the active derivative 9-AC lactone in cell culture media was defined, and then 9-AC cytotoxicity against human breast (MCF-7), bladder (MGH-U1), and colon (HT-29) cancer cell lines was studied. The relationship between cytotoxic effects, drug concentration, and exposure time was then explored. For all of the three cell lines, 9-AC cytotoxicity increased with both higher drug concentrations and longer exposure times. However, when the duration of exposure was less than 24 h, cytotoxicity was limited and less than 1 log of cell killing occurred, even with very high drug concentrations. Minimal cell killing was also observed unless 9-AC concentrations exceeded a threshold of 2.7 nM. No fixed relationship between the survival fraction and the area under the drug concentration-time curve could be modeled that would fit all of the three cell lines. However, data for the three cell lines from the multiple exposure time experiments were fitted very well to the pharmacodynamic model C(n)t = k (r2, 0.90-0.99), where C is the drug concentration, n is the drug concentration coefficient, and t is the exposure time. For the three cell lines, to kill 1 log of cells, 0.30 < n < 0.85, which indicated that duration of exposure was more important than concentration. Our data support the use of 9-AC by infusion for 24 h or longer in clinical studies providing target plasma concentrations can be achieved.
Li
M L
ML
Faculty of Pharmacy University of Toronto, Ontario, Canada.
Horn
L
L
Firby
P S
PS
Moore
M J
MJ
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D002166:Camptothecin