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Abstract
Objectives
Clear
cell carcinoma of the ovary (OCCC) is a distinct subtype of epithelial
cancer associated with chemoresistance and poor outcome compared to
serous papillary carcinomas (OSPC). Resistance to paclitaxel has been
linked to overexpression of class III β-tubulin in several human cancers
but inadequately characterized among OCCC. Chemoresistance has also
been variably linked to the drug efflux pump p-glycoprotein. Epothilones
are microtubule-stabilizing agents with putative activity in
paclitaxel-resistant malignancies. In this study, we clarify the
relationship between class III β-tubulin and p-glycoprotein expression
in OCCC, clinical outcome, and in vitro responsiveness to patupilone and paclitaxel.
Study Design
Class
III β-tubulin and p-glycoprotein were quantified by real time
polymerase chain reaction (qRT-PCR) in 61 fresh-frozen tissue samples
and 11 cell lines. Expression by PCR was correlated with
immunohistochemistry and overall survival. IC50 was determined using viability/metabolic assays. Impact of class III β-tubulin downregulation on IC50 was assessed with siRNAs.
Results
OCCC
overexpressed class III β-tubulin and p-glycoprotein relative to OSPC
in fresh-frozen tissues and cell lines. Class III β-tubulin
immunohistochemistry reflected qRT-PCR results and overexpression
stratified patients by overall survival. P-glycoprotein correlated with in vitro
paclitaxel resistance, but not clinical outcome. OCCC were exquisitely
sensitive to patupilone in a manner that correlated with class III
β-tubulin expression.
Conclusions
Class
III β-tubulin overexpression in OCCC discriminates poor prognosis,
serves as a marker for sensitivity to patupilone, and may contribute to
paclitaxel resistance. Immunohistochemistry reliably identifies tumors
with overexpression of class III β-tubulin, and accordingly a subset of
individuals likely to respond to patupilone.
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