Potentiation of taxol efficacy and by discodermolide in ovarian carcinoma xenograft-bearing mice.
OBJECTIVE
To evaluate the drug combination of discodermolide and Taxol in human ovarian cancer cells and in an in vivo model of ovarian carcinoma.


METHODS
The combination index method was used to evaluate the interaction of Taxol and discodermolide in human ovarian SKOV-3 carcinoma cells. Data were correlated with alterations in cell cycle distribution and caspase activation. In addition, SKOV-3 xenograft-bearing mice were treated with either Taxol, discodermolide, or a combination of both drugs given concurrently to evaluate the antitumor efficacy and toxicity of this combination. The Matrigel plug assay and CD31 immunohistochemistry were done to assess antiangiogenic effects.


RESULTS
Taxol and discodermolide interact synergistically over a range of concentrations and molar ratios that cause drug-induced aneuploidy in ovarian carcinoma cells. In SKOV-3 xenograft-bearing mice, the combination is significantly superior to either single agent, and induces tumor regressions without notable toxicities. Immunohistochemical analysis of CD31 and Matrigel plug analysis show decreased vessel formation in mice treated with the combination relative to either drug alone.


CONCLUSIONS
The synergistic activity of Taxol and discodermolide in cells is most potent at drug concentrations that result in drug-induced aneuploidy rather than mitotic arrest. Moreover, in an animal model of ovarian carcinoma, this is a well-tolerated combination that induces tumor regressions and suppresses angiogenesis. These data confirm the potency of this combination and support the use of concurrent low doses of Taxol and discodermolide for potential use in cancer therapeutics.
Huang
Gloria S
GS
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Lopez-Barcons
Lluis
L
Freeze
B Scott
BS
Smith
Amos B
AB
Goldberg
Gary L
GL
Horwitz
Susan Band
SB
McDaid
Hayley M
HM
D000473:Alkanes / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002219:Carbamates / Q000008:administration & dosage; D020169:Caspases / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007783:Lactones / Q000008:administration & dosage; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects; D011753:Pyrones / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000473:Alkanes; D002219:Carbamates; D007783:Lactones; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011753:Pyrones; C071229:discodermolide; D020169:Caspases; D017239:Paclitaxel