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Factors determining cellular mechanisms of resistance to antimitotic drugs
1Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, TX, USA. fcabral@uth.tmc.edu
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.
Insights
Paclitaxel resistance in cancer treatment is a growing issue. Understanding how cancer cells become resistant, through mechanisms like altered drug accumulation or microtubule stability, is key to overcoming this challenge.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Paclitaxel and related taxanes are widely used in treating malignant diseases.
- The increasing clinical use of these agents necessitates understanding drug resistance mechanisms.
Purpose of the Study:
- To critically evaluate methods for generating drug-resistant mutants in tissue culture.
- To identify factors influencing the prevalence of specific resistance mechanisms.
Main Methods:
- Review of studies on drug-resistant mutant selection in tissue culture.
- Analysis of known mechanisms of taxane resistance.
Main Results:
- Drug resistance can arise from limited drug accumulation, altered microtubule stability, diminished tubulin binding, or variable tubulin gene expression.
- Tissue culture methods for generating resistant mutants are evaluated.
Conclusions:
- Underlying genetic mechanisms of clinical drug resistance are likely similar to those observed in culture.
- Pharmacokinetic factors and individual variability may complicate clinical drug resistance.