title: Preclinical antitumor activity of water-soluble paclitaxel derivatives.
abstract: OBJECTIVE
  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 x 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 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, 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.
authors.affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Inc. Lawrenceville, New Jersey, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Rose
authors.forename: J L
authors.initials: JL
authors.lastname: Clark
authors.forename: F Y
authors.initials: FY
authors.lastname: Lee
authors.forename: A M
authors.initials: AM
authors.lastname: Casazza
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology*; D043823:Taxoids; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C105150:BMS 185660; D043823:Taxoids; D017239:Paclitaxel