title: BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy.
abstract: BMS-247550, a novel epothilone derivative, is being developed by Bristol-Myers Squibb Company (BMS) as an anticancer agent for the treatment of patients with malignant tumors. BMS-247550 is a semisynthetic analogue of the natural product epothilone B and has a mode of action analogous to that of paclitaxel (i.e., microtubule stabilization). In vitro, it is twice as potent as paclitaxel in inducing tubulin polymerization. Like paclitaxel, BMS-247550 is a highly potent cytotoxic agent capable of killing cancer cells at low nanomolar concentrations. Importantly, BMS-247550 retains its antineoplastic activity against human cancers that are naturally insensitive to paclitaxel or that have developed resistance to paclitaxel, both in vitro and in vivo. Tumors for which BMS-247550 demonstrated significant antitumor activity encompass both paclitaxel-sensitive and -refractory categories, i.e., (a) paclitaxel-resistant: HCT116/VM46 colorectal (multidrug resistant), Pat-21 breast and Pat-7 ovarian carcinoma (clinical isolates; mechanisms of resistance not fully known), and A2780Tax ovarian carcinoma (tubulin mutation); (b) paclitaxel-insensitive: Pat-26 human pancreatic carcinoma (clinical isolate) 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 immunocompromised mice or rats. Schedule optimization studies indicate that BMS-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 in both clinical efficacy and ease of use (i.e., less frequent treatment schedule and/or oral administration).
authors.affiliation: Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.
authors.forename: F Y
authors.initials: FY
authors.lastname: Lee
authors.forename: R
authors.initials: R
authors.lastname: Borzilleri
authors.forename: C R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: B H
authors.initials: BH
authors.lastname: Long
authors.forename: C
authors.initials: C
authors.lastname: Reventos-Suarez
authors.forename: G D
authors.initials: GD
authors.lastname: Vite
authors.forename: W C
authors.initials: WC
authors.lastname: Rose
authors.forename: R A
authors.initials: RA
authors.lastname: Kramer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D034261:Epothilones; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D012509:Sarcoma / Q000188:drug therapy; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D004852:Epoxy Compounds; D013844:Thiazoles; D014404:Tubulin; C430592:ixabepilone; D017239:Paclitaxel; C093788:epothilone B