Drug Resistance in Breast Cancer: Characterization of Rationally Designed Paclitaxel Analogs in Model Systems.

摘要

Breast cancer is a leading cause of cancer related deaths among women in the developed world. Treatment options for breast cancer include taxanes, which mediate cytotoxic effects by inducing microtubule polymerization which impedes cell division. Taxane resistant breast cancer is a mounting clinical problem, and can in part be explained by differential expression of beta-III tubulin and/or multidrug efflux pumps. I hypothesized that drugs traverse to the taxane active site through interactions at 275 and 278 residues (intermediate binding sites) within microtubule nanopores. I developed paclitaxel resistant SKBR-3 cell sub-lines, used synthesized paclitaxel analogs designed to interact with the suggested residues and attempted to dissect the progression of resistance by monitoring global microRNA profiles. Data did not favour interpretations on the hypothesized interactions with amino acid residues; evidence suggested that expression of beta-III tubulin alone does not explain drug resistance and a combination of mechanisms likely mediates resistance.