9-AMINOCAMPTOTHECIN - A TOPOISOMERASE-I INHIBITOR WITH PRECLINICAL ACTIVITY IN PROSTATE-CANCER

9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor currently be ing developed as an antineoplastic agent, The aim of these preclinical studies was to assess the activity of 9-AC against prostate cancer, a malignancy notoriously insensitive to most cytotoxic agents in the cl inic, The activity of 9-AC was first tested in vitro against one hormo ne-sensitive (LNCaP) and three hormone-resistant (PC-3, PC-3M, and DU1 45) human prostate cancer cell lines, After 96 h of drug exposure, con centrations required to inhibit cell viability to 50% of control value s (IC(50)s) were 34.1, 10, 6.5, and 8.9 nhr for PC-3, PC-3M, DU145, an d LNCaP, respectively. Because 9-AC is known to undergo rapid hydrolys is, we assayed lactone levels in tissue culture medium over 24 h and f ound that the half-life was 20 min, with only 15% of the drug remainin g as lactone at steady state, Consequently, the IC(50)s calculated fro m a single dose of the drug may represent overestimates, Subsequently, we tested the activity of a colloidal dispersion formulation of 9-AC against PC-3 implanted into flanks of nude mice, 9-AC was given for a total of 3 weeks by daily oral gavage (excluding weekends) or by twice weekly s.c. injections. 9-AC inhibited tumor growth at the lowest ora l dose (0.35 mg/kg/day), whereas higher oral doses (0.75 and 1 mg/kg/d ay) and s.c. administration (4 mg/kg/week) caused tumor regression, 9- AC was well tolerated at all doses, with no toxic death or weight loss of more than 10% observed in any group. Finally, we considered that t he activity of 9-AC seen in the mouse xenograft model might he explain ed, in part, by the relatively acidic tumor microenvironment, which wo uld favor the formation of the more potent lactone, Simultaneous deter mination of plasma and tumor 9-AC lactone concentrations confirmed thi s hypothesis. Taken together, these studies suggest that 9-AC should b e submitted for clinical trials in patients with prostate cancer.