Factors determining cellular mechanisms of resistance to antimitotic drugs

Abstract

With the rapidly expanding use of paclitaxel and related taxanes to treat malignant diseases, comes the realization that development of resistance to this class of agents will become an increasingly significant clinical problem. Studies have indicated that acquisition of resistance to the cytotoxic action of these drugs can occur by limiting the drug's ability to accumulate in cells, altering the stability of cellular microtubules, diminishing the drug's ability to bind tubulin, or varying the expression of specific tubulin genes. This review will critically evaluate the selection methods used to generate drug resistant mutants in tissue culture and focus on the various factors that determine which resistance mechanisms are most likely to be encountered. It is anticipated that clinical drug resistance will be complicated by pharmacokinetic considerations and variability among individuals, but that underlying genetic mechanisms will be similar to those found in culture.