Preclinical antitumor activity of water-soluble paclitaxel derivatives

Abstract

 Purpose: Five water-soluble paclitaxel derivatives were extensively evaluated for their antitumor activities relative to the parent drug. Methods: Both subcutaneous (s.c.) murine (M109 lung) and human (A2780 ovarian, L2987 lung) tumor models were used for this purpose. Results: Consecutive daily intravenous (i.v.) paclitaxel therapy of mice bearing s.c. M109, beginning on day 4 or 5 posttumor implant and continuing for 5 days, resulted in a range of maximum gross log cell kill (LCK) values (reflective of delays in tumor growth) and maximum relative median survival time (%T/C) values (reflective of increases in lifespan) of 1.0–2.1 and 132–162% (and one outlying result of 235%), respectively. Against the same tumor model, using the same treatment schedule, each of the water-soluble derivatives was active, with maximum LCK of 1.3–2.5 and T/C of 124–254%. These LCK and %T/C values were always within 0.5 LCK and 15%, respectively, of the concomitantly obtained maximum effects of paclitaxel. When tested in several experiments against staged (50–100 mg) s.c. A2780 tumors, using various i.v. treatment schedules, the water-soluble derivatives achieved a maximum LCK of 1.4–3.8. Evaluated in parallel, paclitaxel achieved a maximum LCK of 2.1–4.5 following every other day×5 i.v. therapy. When paclitaxel was assayed in several experiments using the staged (50–100 mg) s.c. L2987 tumor model, maximum LCK of 0.9–>4.1 were produced following every other day×5 i.v. therapy. Concomitant testing of the water-soluble derivatives, using the same i.v. treatment schedule, resulted in maximum LCK of 0.2–>4.1. In each of the tumor models used, the consistently active, and usually the most active, water-soluble derivative was BMS-185660. The levels of activity observed were comparable (within 1 LCK) to those achieved concomitantly using paclitaxel, and its potency was only slightly inferior to the parent drug. Conclusions: Based on the evaluations performed in three distal site tumor models, we conclude that BMS-185660 is a water-soluble paclitaxel derivative with preclinical antitumor activity comparable to that of the parent drug.