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Class III ß-Tubulin Overexpression Is a Prominent Mechanism of Paclitaxel Resistance in Ovarian Cancer Patients

¹ Laboratory of Antineoplastic Pharmacology and ² Gynecologic Oncology Unit, Università Cattolica Sacro Cuore, Rome, Italy and Departments of ³ Pathology and Histology and ⁴ Oncology, Università Cattolica Sacro Cuore, Campobasso, Italy

Requests for reprints: Giovanni Scambia, Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynaecology Università Cattolica Sacro Cuore, L.go Agostino Gemelli 8 00168 Rome, Italy. Phone: 635-502-407; Fax: 635-508-736; E-mail: cferlini{at}rm.unicatt.it.

The vast majority of women with advanced ovarian cancer will ultimately relapse and develop a drug-resistant disease with an overall 5-year survival of <50%. Unfortunately, the mechanisms of drug resistance actually operating in patients are still unknown. To address this issue, in 41 patients affected by advanced ovarian cancer the three main mechanisms of paclitaxel resistance were investigated: overexpression of MDR-1 gene, point mutations at prominently expressed -tubulin and ß-tubulin genes and selective alterations in the expression of ß-tubulin isotypes. MDR-1 and the ß-tubulin isotypes expression were evaluated by semiquantitative and real-time PCR. On the same specimens, quantitative immunohistochemistry was also done in the tumor area. No statistically significant changes of MDR-1 expression were noticed between the sensitive and resistant patients either at the mRNA or protein level. The tubulin mutations for the ubiquitous -tubulin and ß-tubulin genes were evaluated by automated DNA sequencing, and in all patients, no mutations were detected in both resistant and sensitive cases. With regard to the expression of tubulin isoforms, a statistically significant up-regulation of class III ß-tubulin was found in the resistant subset. It is worth noting that this statistically significant increase of the expression of class III ß-tubulin was detectable at the mRNA and protein level. By a direct comparison of the three main known mechanisms of paclitaxel resistance, this study indicates that overexpression of class III ß-tubulin is the most prominent mechanism of paclitaxel resistance in ovarian cancer.

Key Words: Drug Resistance • Paclitaxel • Ovarian Cancer

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