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 lac tone 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 concentratio n, and exposure time was then explored. For all of the three cell lines, 9- AC cytotoxicity increased with both higher drug concentrations and longer e xposure times. However, when the duration of exposure was less than 24 h, c ytotoxicity 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 relatio nship between the survival fraction and the area under the drug concentrati on-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 expe riments were fitted very well to the pharmacodynamic model C(n)t = k (r(2), 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 co ncentrations can be achieved.