Relationship between Beta-Tubulin Mutations and Taxol Resistance in Breast Cancer Cells
Abstract
Taxol has been approved by the FDA for the treatment of breast, ovarian and lung carcinomas, and has proven to be an important drug. Its antitumor activity is derived primarily from its ability to bind to beta-tubulin in the microtubule, thereby stabilizing the polymer and inhibiting cell division. However, development of Taxol resistance represents a major obstacle for the effective treatment of cancer. beta-tubulin gene mutations have been identified as a strong predictor of the response to Taxol in patients. Resistant cells isolated in the presence of Taxol, and other recently discovered microtubule-stabilizing agents such a epothilone, eleutherobin, and discodermolide, have been shown to carry specific mutations in beta-tubulin. However, isolation of spontaneous mutations can be a long and tedious process. In this study, I plan to identity resistant mutations in beta-tubulin by randomly mutating human beta-tubulin genes, and by selecting the mutant-expressing cells in the presence of Taxol. Taxol resistant cells will be tested for sensitivity to various tubulin drugs. My specific aim is to correlate each mutation with a specific drug response profile. A comprehensive database with mutation information and drug-sensitivity profile will be a valuable tool. It will help to rapidly locate the most effective drugs for cancer patients with specific tubulin mutations. In addition, structural information obtained from mutations at specific sites in beta-tubulin will benefit the rational design of new anti-tumor drugs.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2001
- Accession Number
- ADA405256
Entities
People
- Chen Jie-guang
Organizations
- Albert Einstein College of Medicine