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Apoptotic pathways of epothilone BMS 310705. Gynecol Oncol 2003 Oct;91(1):173-8

Date

10/08/2003

Pubmed ID

14529678

DOI

10.1016/s0090-8258(03)00481-5

Scopus ID

2-s2.0-0141757448 (requires institutional sign-in at Scopus site)   21 Citations

Abstract

OBJECTIVE: 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.

Author List

Uyar D, Takigawa N, Mekhail T, Grabowski D, Markman M, Lee F, Canetta R, Peck R, Bukowski R, Ganapathi R

Author

Denise S. Uyar MD Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Apoptosis
Camptothecin
Caspases
Cytochrome c Group
Drug Resistance, Neoplasm
Enzyme Activation
Epothilones
Female
Humans
Isoenzymes
Organoplatinum Compounds
Ovarian Neoplasms
Paclitaxel
Topotecan
Tumor Cells, Cultured