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Apoptotic pathways of epothilone BMS 310705.

AbstractOBJECTIVE:
BMS 310705 is a novel water-soluble analog of epothilone B currently in phase I clinical evaluation in the treatment of malignancies such as ovarian, renal, bladder, and lung carcinoma. Using an early passage cell culture model derived from the ascites of a patient clinically refractory to platinum/paclitaxel therapy, we evaluated the pathway of caspase-mediated apoptosis.
METHODS:
Cells were treated for 1 h and subsequently evaluated for apoptosis, survival, and caspase activity. Apoptosis was determined by fluorescent microscopy. Caspase-3, -8, and -9 activities were determined by fluorometry using target tetrapeptide substrates. Mitochondrial release of cytochrome c was determined by immunoblot analysis.
RESULTS:
After treatment with BMS 310705, apoptosis was confirmed in >25% of cells at 24 h. Survival was significantly lower (P < 0.02) in cells treated with 0.05 micro M BMS 310705 vs paclitaxel. Analysis revealed an increase of caspase-9 and -3 activity; no caspase -8 activity was observed. Release of cytochrome c was detected at 12 h following treatment. SN-38 and topotecan failed to induce apoptosis.
CONCLUSIONS:
BMS 310705 induces significant apoptosis, decreases survival, and utilizes the mitochondrial-mediated pathway for apoptosis in this model.
AuthorsDenise Uyar, Nagio Takigawa, Tarek Mekhail, Dale Grabowski, Maurie Markman, Francis Lee, Renzo Canetta, Ron Peck, Ronald Bukowski, Ram Ganapathi
JournalGynecologic oncology (Gynecol Oncol) Vol. 91 Issue 1 Pg. 173-8 (Oct 2003) ISSN: 0090-8258 [Print] United States
PMID14529678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • BMS 310705
  • Cytochrome c Group
  • Epothilones
  • Isoenzymes
  • Organoplatinum Compounds
  • Irinotecan
  • Topotecan
  • Caspases
  • Paclitaxel
  • Camptothecin
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Camptothecin (analogs & derivatives, pharmacology)
  • Caspases (metabolism)
  • Cytochrome c Group (metabolism)
  • Drug Resistance, Neoplasm
  • Enzyme Activation (drug effects)
  • Epothilones (pharmacology)
  • Female
  • Humans
  • Irinotecan
  • Isoenzymes (metabolism)
  • Organoplatinum Compounds (pharmacology)
  • Ovarian Neoplasms (drug therapy, enzymology, pathology)
  • Paclitaxel (pharmacology)
  • Topotecan (pharmacology)
  • Tumor Cells, Cultured

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