Genes Determining Taxol Sensitivity.
Abstract
Taxol is a chemotherapeutic compound that shows high response rate in metastatic breast carcinoma. However, some tumors are intrinsically resistant while others develop resistance to taxol in the course of treatment. We hypothesized that resistance may arise from deficiencies in cellular functions that normally potentiate cytotoxicity. To identify the genes involved in taxol response we are using the genetic suppressor element (GSE) approach. We performed GSE selection from a normalized library of randomly fragmented cDNA in a retroviral vector. Putative GSEs were identified after three rounds of infection, taxol treatment and insert recovery. Initial testing showed protective effect of these sequences, yet more extensive analysis produced variable results. A putative GSE derived from mitochondrial coxIII gene is nearly identical to an independently isolated GSE that confers aphidicolin resistance. To elucidate involvement of mitochondria in drug response, we established cell lines lacking mitochondrial DNA. These cell lines showed resistance to several anticancer drugs. To avoid the artifacts associated with selective markers used in prior selections, we developed novel retroviral vectors that use green fluorescent protein as a marker gene. A library in one of these vectors was used to initiate a new multistep taxol selection, which is currently in progress.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1998
- Accession Number
- ADA355425
Entities
People
- Eugene Kandel
Organizations
- University of Illinois at Chicago