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Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation
R Z Yusuf1, Z Duan, D E Lamendola
1Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.
Current Cancer Drug Targets
|February 7, 2003
Summary
Paclitaxel resistance in epithelial ovarian cancer is a significant challenge. This review details known resistance mechanisms and explores strategies to overcome them, focusing on MDR-1 inhibition.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Paclitaxel, approved by the FDA for platinum-resistant epithelial ovarian carcinoma, has broad applications in epithelial malignancies.
- Despite its novel mechanism, therapeutic resistance to paclitaxel is a common clinical challenge.
Purpose of the Study:
- To review in vitro data defining mechanisms of paclitaxel resistance.
- To evaluate the clinical relevance of these resistance mechanisms.
- To explore pharmacologic strategies for overcoming paclitaxel resistance.
Main Methods:
- Review of in vitro molecular data on paclitaxel resistance mechanisms.
- Critical evaluation of evidence for clinical participation of these mechanisms.
- Exploration of pharmacologic modulation strategies, including MDR-1 inhibition.
Main Results:
- Multiple resistance mechanisms identified: MDR-1 gene overexpression, betatubulin alterations, changes in apoptosis/mitosis proteins, lipid composition, and IL-6 overexpression.
- Evidence supporting the clinical role of these mechanisms in paclitaxel resistance is evaluated.
- Pharmacologic approaches, particularly targeting the MDR-1 efflux pump, are discussed.
Conclusions:
- Understanding diverse molecular mechanisms is crucial for addressing paclitaxel resistance.
- Targeting MDR-1 offers a promising strategy for modulating resistance.
- Further research into drug resistance and clinical manipulation is warranted.