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.