In vitro and in vivo histone deacetylase inhibitor therapy with vorinostat and paclitaxel in ovarian cancer models: does timing matter?
OBJECTIVE
To determine whether the combination of vorinostat (suberoylanilide hydroxamic acid, SAHA) and paclitaxel is more effective than either individual agent and to evaluate the effect of drug sequencing in ovarian cancer cell lines and in mouse models.


METHODS
For in vitro studies, three ovarian cancer cell lines (2774, SKOV-3 and OVCAR-3) were grown with either 10 nM paclitaxel, or vorinostat (0.3, 1, 3 or 10 μM), or vehicle (DMSO) and subsequently treated with 10 nM paclitaxel, or vorinostat (0.3, 1, 3, or 10 μM), or DMSO. Apoptosis was analyzed. In the mouse, treatments were given for a total of 5 weeks: vehicle control, paclitaxel, vorinostat, vorinostat followed by paclitaxel, paclitaxel followed by vorinostat, and simultaneous vorinostat and paclitaxel. Endpoints were survival, ascites and tumor weight. Protein expression was analyzed by Western blots.


RESULTS
In two cell lines (SKOV-3, OVCAR-3), the sequence of vorinostat and paclitaxel administration did not significantly alter the apoptosis percentages and the combination was not superior to individual agents. However, in one cell line (2774), the most effective combination in achieving apoptosis was paclitaxel followed by low dose vorinostat. In the mouse model, both control and vorinostat alone treatment groups were inferior to paclitaxel and the combination treatment groups, but no significant differences were observed between the groups receiving both paclitaxel and vorinostat based on the sequence of administration.


CONCLUSIONS
The efficacy of the combination and sequence of vorinostat and paclitaxel administration was cell line dependent and suggests that responses vary based on tumor specific characteristics.
Modesitt
Susan C
SC
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia Health System, Charlottesville, VA 22908-0172, USA. scm6h@virginia.edu
Parsons
Sarah J
SJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D019926:Cyclin B; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051028:bcl-2-Associated X Protein; D000077337:Vorinostat; D006655:Histone Deacetylases; D017239:Paclitaxel