BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy

Citation
Fyf. Lee et al., BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy, CLIN CANC R, 7(5), 2001, pp. 1429-1437
Citations number
22
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
1078-0432 → ACNP
Volume
7
Issue
5
Year of publication
2001
Pages
1429 - 1437
Database
ISI
SICI code
1078-0432(200105)7:5<1429:BANEAW>2.0.ZU;2-K
Abstract
BMS-247550, a novel epothilone derivative, is being developed by Bristol-My ers Squibb Company (BMS) as an anticancer agent for the treatment of patien ts with malignant tumors. BMS-247550 is a semisynthetic analogue of the nat ural product epothilone B and has a mode of action analogous to that of pac litaxel (i,e,, microtubule stabilization). bl vitro, it is twice as potent as paclitaxel in inducing tubulin polymerization. Like paclitaxel, BMS-2475 50 is a highly potent cytotoxic agent capable of killing cancer cells at lo w nanomolar concentrations. Importantly, BMS-247550 retains its antineoplas tic activity against human cancers that are naturally insensitive to paclit axel or that have developed resistance to paclitaxel, both in vitro and in vivo. Tumors for which BMS-247550 demonstrated significant antitumor activi ty encompass both paclitaxel-sensitive and -refractory categories, i,e,, (a ) paclitaxel-resistant: HCT116/VM46 colorectal (multidrug resistant), Pat-2 1 breast and Pat-7 ovarian carcinoma (clinical isolates; mechanisms of resi stance not fully known), and A2780Tax ovarian carcinoma (tubulin mutation); (b) paclitaxel-insensitive : Pat-26 human pancreatic carcinoma (clinical i solate) and M5076 murine fibrosarcoma; and (c) paclitaxel sensitive: A2780 ovarian, LS174T, and HCT116 human colon carcinoma. In addition, BMS-247550 is p,o, efficacious against preclinical human tumor xenografts grown in imm unocompromised mice or rats. Schedule optimization studies indicate that BM S-247550 is efficacious when administered frequently (every 2 days x 5) or intermittently (every 4 days x 3 or every 8 days x 2), These efficacy data demonstrate that BMS-247550 has the potential to surpass Taxol((R)) in both clinical efficacy and ease of use (i,e,, less frequent treatment schedule and/or oral administration).