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Resistance to paclitaxel mediated by P-glycoprotein can be modulated by changes in the schedule of administration
Purpose:
Increasing use of paclitaxel in clinical oncology has stimulated interest in its mechanisms of resistance and ways to overcome these. Studies were performed with paclitaxel to determine the role of P-glycoprotein in drug sensitivity, and the effect of schedule on relative resistance. We have previously reported that prolonged exposure to P-glycoprotein substrates decreases relative resistance in multidrug resistant cells.
Methods:
Using both unselected and drug-selected cell lines, cross-resistance and cytotoxicity reversal studies using cyclosporin A were performed. In multidrug-resistant cells, cross-resistance was evaluated after 3-, 24-, and 96-h exposures to paclitaxel.
Results:
Cross-resistance to paclitaxel in P-glycoprotein-expressing sublines was shown to be comparable to that of other drugs transported by P-glycoprotein. Sensitivity to paclitaxel could be modulated by cyclosporin A in unselected cell lines expressing P-glycoprotein and not in P-glycoprotein-negative cell lines. Resistance to paclitaxel was reduced tenfold by increasing the duration of exposure in P-glycoprotein-expressing cells. This effect was not observed in a paclitaxel-resistant cell line which does not express P-glycoprotein.
Conclusions:
These studies extend observations on the schedule dependence of paclitaxel cytotoxicity and the role of P-glycoprotein in mediating paclitaxel sensitivity. The schedule dependence of relative resistance suggests that infusional paclitaxel may help in overcoming P-glycoprotein-mediated resistance.
Insights
Prolonged exposure to paclitaxel (a chemotherapy drug) can reduce resistance mediated by P-glycoprotein. Infusional paclitaxel may overcome P-glycoprotein-related drug resistance in cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Paclitaxel is a widely used chemotherapy agent.
- Understanding and overcoming drug resistance is crucial in cancer therapy.
- P-glycoprotein (P-gp) is a key transporter involved in multidrug resistance.
Purpose of the Study:
- To investigate the role of P-glycoprotein in paclitaxel resistance.
- To determine how drug exposure schedule affects paclitaxel sensitivity.
- To explore strategies for overcoming P-gp-mediated paclitaxel resistance.
Main Methods:
- Utilized unselected and drug-selected cell lines for drug resistance studies.
- Performed cross-resistance and cytotoxicity reversal assays with cyclosporin A.
- Evaluated paclitaxel resistance after varying exposure durations (3, 24, 96 hours) in P-gp expressing cells.
Main Results:
- Paclitaxel exhibited cross-resistance in P-gp expressing cells, similar to other P-gp substrates.
- Cyclosporin A modulated paclitaxel sensitivity in P-gp positive cells but not in P-gp negative cells.
- Increasing paclitaxel exposure duration reduced resistance tenfold in P-gp expressing cells.
Conclusions:
- Paclitaxel cytotoxicity is schedule-dependent, influenced by P-glycoprotein.
- Infusional administration of paclitaxel shows potential for overcoming P-gp-mediated resistance.
- Findings contribute to strategies for enhancing chemotherapy efficacy in resistant cancers.