PRECLINICAL ANTITUMOR-ACTIVITY OF WATER-SOLUBLE PACLITAXEL DERIVATIVES

Purpose: Five water-soluble paclitaxel derivatives were extensively ev aluated for their antitumor activities relative to the parent drug. Me thods: Both subcutaneous (s.c.) murine (M109 lung) and human (A2780 ov arian, L2987 lung) tumor models were used for this purpose. Results: C onsecutive daily intravenous (i.v.) paclitaxel therapy of mice bearing s.c. M109, beginning on day 4 or 5 posttumor implant and continuing f or 5 days, resulted in a range of maximum gross log cell kill (LCK) va lues (reflective of delays in tumor growth) and maximum relative media n 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 e ffects of paclitaxel. When tested in several experiments against stage d (50-100 mg) s.c. A2780 tumors, using various i.v. treatment schedule s, the water-soluble derivatives achieved a maximum LCK of 1.4-3.8. Ev aluated in parallel, paclitaxel achieved a maximum LCK of 2.1-4.5 foll owing every other day x 5 i.v. therapy. When paclitaxel was assayed in several experiments using the staged (50-100 mg) s.c. L2987 tumor mod el, maximum LCK of 0.9- >4.1 were produced following every other day x 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, an d usually the most active, water-soluble derivative was EMS-185660. Th e levels of activity observed were comparable (within 1 LCK) to those achieved concomitantly using paclitaxel, and its potency was only slig htly inferior to the parent drug. Conclusions: Based on the evaluation s performed in three distal site tumor models, we conclude that BMS-18 5660 is a water-soluble paclitaxel derivative with preclinical antitum or activity comparable to that of the parent drug.