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P-glycoprotein expression in bladder cancer
J Park1, N Shinohara, M Liebert
1Department of Pathology, University of Michigan, Ann Arbor.
Abstract:
Multi-drug resistance is a phenomenon by which tumor cells express resistance to a variety of chemically unrelated chemotherapeutic drugs. The classical form of multi-drug resistance is mediated through the expression of P-glycoprotein, which acts as an energy dependent drug efflux pump. P-glycoprotein expression was evaluated in 29 cystectomy specimens from patients with bladder cancer with no prior exposure to chemotherapeutic drugs, and in bladder biopsies from 9 subjects before treatment with intravesical doxorubicin. Furthermore, the strategy of circumvention of P-glycoprotein-mediated resistance using the combination of doxorubicin and verapamil intravesically was tested in 5 patients. P-glycoprotein was expressed in 75% of the cystectomy specimens. In the doxorubicin treated patients no correlation was noted between P-glycoprotein expression on the initial tumors and subsequent response to doxorubicin. The pilot trial of verapamil and doxorubicin was well tolerated but did not suggest increased efficacy of this combination. P-glycoprotein can be expressed on bladder cancer cells without prior chemotherapy. The role of P-glycoprotein mediated multi-drug resistance in bladder cancer treatment failure remains to be defined.
Insights
P-glycoprotein, a cause of multi-drug resistance in cancer, is present in most bladder tumors even without prior chemotherapy. Combining doxorubicin with verapamil showed no improved efficacy in a small trial.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multi-drug resistance (MDR) is a major challenge in cancer chemotherapy.
- P-glycoprotein (P-gp) is a key mediator of MDR, acting as an efflux pump.
- Understanding P-gp expression in bladder cancer is crucial for treatment strategies.
Purpose of the Study:
- To evaluate P-glycoprotein expression in bladder cancer specimens.
- To assess the correlation between P-gp expression and response to doxorubicin.
- To investigate the efficacy of intravesical doxorubicin combined with verapamil to overcome P-gp-mediated resistance.
Main Methods:
- P-glycoprotein expression analysis in 29 cystectomy specimens and 9 bladder biopsies.
- Evaluation of patient response to intravesical doxorubicin.
- Pilot trial of intravesical doxorubicin and verapamil in 5 patients.
Main Results:
- P-glycoprotein was expressed in 75% of cystectomy specimens.
- No correlation found between baseline P-gp expression and doxorubicin response.
- The doxorubicin-verapamil combination was well-tolerated but did not demonstrate increased efficacy.
Conclusions:
- P-glycoprotein can be expressed in bladder cancer cells prior to chemotherapy exposure.
- The clinical significance of P-gp-mediated MDR in bladder cancer treatment failure requires further investigation.
- Novel strategies may be needed to effectively overcome P-gp-mediated resistance in bladder cancer.