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Doxorubicin and multidrug resistance
1Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Abstract:
The circumvention of P-glycoprotein function by pharmacologic agents is a major focus of clinical trials aimed at increasing the cytotoxicity of multidrug resistance-associated drugs, including doxorubicin. The success of this approach will likely depend on the clinical significance of P-glycoprotein expression, which has not yet been elucidated for the common solid tumors, and the ability to achieve effective levels of circumventing agents without dose-limiting toxicities. Initial clinical studies suggested that biologically relevant concentrations of multidrug resistance modulators, eg, cyclosporine, can be achieved. Because pharmacologic agents that inhibit drug efflux by P-glycoprotein are themselves pumped out of cells by the transporter, this approach may have an inherent barrier to success. Laboratory studies have suggested alternative strategies for circumventing P-glycoprotein action, eg, the use of monoclonal antibodies directed against P-glycoprotein and liposome-encapsulated drugs.
Insights
Circumventing P-glycoprotein (P-gp) function is key to improving chemotherapy for multidrug resistance. New strategies are needed as P-gp efflux inhibitors face inherent barriers.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) limits chemotherapy efficacy.
- Clinical trials focus on circumventing P-gp to enhance cytotoxicity of drugs like doxorubicin.
- The clinical significance of P-gp expression in solid tumors remains unclear.
Purpose of the Study:
- To evaluate strategies for overcoming P-glycoprotein-mediated multidrug resistance.
- To assess the feasibility of achieving effective concentrations of P-gp inhibitors.
- To explore alternative approaches to circumvent P-gp action in cancer therapy.
Main Methods:
- Review of clinical trials and laboratory studies on P-gp circumvention agents.
- Analysis of P-glycoprotein expression and its clinical significance.
- Investigation of pharmacologic agents, monoclonal antibodies, and liposome-encapsulated drugs.
Main Results:
- Initial studies show achievable concentrations of multidrug resistance modulators like cyclosporine.
- Pharmacologic P-gp inhibitors face an inherent barrier as they are substrates for P-gp.
- Alternative strategies like monoclonal antibodies and liposomal drug delivery show promise.
Conclusions:
- Overcoming P-glycoprotein-mediated multidrug resistance is crucial for improving cancer treatment.
- Achieving effective P-gp inhibitor levels without toxicity is a significant challenge.
- Alternative strategies offer potential solutions for circumventing P-gp in clinical settings.