Preclinical oral antitumor activity of BMS-185660, a paclitaxel derivative.
OBJECTIVE
A water soluble paclitaxel derivative, BMS-185660, identified previously as having parenteral activity comparable with that of the parent drug, was evaluated for antitumor activity when given orally.


METHODS
Staged subcutaneous (s.c.) tumor models of both murine and human origin were used for this purpose.


RESULTS
BMS-185660 achieved levels of activity following oral administration which were comparable with those maximum effects obtained using intravenous (i.v.) paclitaxel. Consecutive daily oral administrations of BMS-185660 resulted in maximum gross log cell kill (LCK) values of 1.7-2.0 in two experiments involving the s.c. Madison 109 murine lung tumor model, which were comparable with the best effects of the derivative injected intravenously, and 0.3 to 0.9 LCK greater than the maximum effects obtained with i.v. paclitaxel; paclitaxel given orally was inactive. Against a human ovarian tumor model with developed resistance to cisplatin (A2780/ cDDP), oral BMS-185660 achieved a maximum LCK of 1.8 compared with i.v. paclitaxel, which produced a maximum 2.4 LCK. Also, in the human HCT-116 colon carcinoma model, oral BMS-185660 cured a maximum of seven of eight mice compared with six of seven mice cured with i.v. paclitaxel. The loss in potency between comparably effective intravenously and orally administered doses of BMS-185660 was about four- to five-fold, but since no drug-associated lethality was ever observed following the oral administration of the highest doses of BMS-185660, further dose escalation may have been tolerated. The intermediate metabolite between BMS-185660 and paclitaxel is BMS-181681. This compound was also evaluated orally and found not to be active versus s.c. M109, despite demonstrating good activity by the i.v. route.


CONCLUSIONS
The comparable activities of both intravenously and orally administered BMS-185660 to intravenously administered paclitaxel, combined with the attribute of improved water solubility, provides a good basis for further derivative development.
Rose
W C
WC
Pharmaceutical Research Institute, Bristol-Myers Squibb, Lawrenceville, New Jersey, USA. rosew@bms.com
Lee
F Y
FY
Golik
J
J
Kadow
J
J
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; C105150:BMS 185660; D043823:Taxoids; D017239:Paclitaxel