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Molecular Mechanisms of Patupilone Resistance

Molecular Mechanisms of Patupilone Resistance,Simona Mozzetti,Raffaella Iantomasi,Ilaria De Maria,Silvia Prislei,Marisa Mariani,Alessia Camperchioli,S

Molecular Mechanisms of Patupilone Resistance   (Citations: 9)
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Patupilone is an epothilone in advanced clinical development that has shown promising efficacy in heavily pretreated patients. This study aimed at characterizing the mechanisms of patupilone activity in resistant patients. To this end, we generated patupilone-resistant cells using two cellular models, the first characterized by high chemosensitivity and low class III B-tubulin (TUBB3) expression (A2780), and the second by low chemosensitivity and high TUBB3expression (OVCAR-3 ). The obtained cell lines were named EPO3and OVCAR-EPO, respectively. The same selection procedure was done in A2780 cells to generate a paclitaxel-resistant cell line (TAX50). Factors of resistance are expected to increase in the drug- resistant cell lines, whereas factors of drug sensitivity will be down-regulated. Using this approach, we found up-regulation of TUBB3in TAX50, but not EPO3 , cells, showing that TUBB3 mediates the resistance to paclitaxel but not to patupilone. Moreover, TUBB3was a factor of patupilone sensitivity because OVCAR-EPO cells exhibited a dramatic reduction of TUBB3and a concomitant sensitization to hypoxia and cisplatin-based chemotherapy. To identify the mechanisms underlying patupilone resistance, tubulin genes were se- quenced, thereby revealing that a prominent mechanism of drug resistance is represented by point mutations in class I B-tubulin. Overall, these results suggest that paclitaxel and patupilone have nonoverlapping mechanisms of resistance, thus allowing the use of patupilone for those patients relapsing after paclitaxel-based chemotherapy. Furthermore, patupilone represents a promising first-line option for the treatment of high-risk ovarian cancer patients, who exhibit high TUBB3levels and poor response to standard paclitaxel- platin chemotherapy. (Cancer Res 2008;68(24):10197-204)
Published in 2008.
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