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Circumvention of multidrug resistance in genitourinary tumors
J P van Brussel1, G H Mickisch
1Department of Urology, Erasmus University Hospital, Rotterdam, The Netherlands.
Abstract:
Chemotherapy is the principal strategy to systemically challenge metastasized cancers of genitourinary origin. Unfortunately, the efficacy of chemotherapy is often hampered by multidrug resistance, the resistance to a variety of structurally and functionally distinct cytotoxic agents. Multidrug resistance can be either intrinsic or acquired, and can be caused by several mechanisms. The so-called classical multidrug resistance, mediated by the MDR1 gene product P-glycoprotein, has been held mainly responsible for inferring the multidrug resistance phenotype on urologic malignancies. However, several other multidrug resistance pathways have been identified. Multidrug resistance can be caused by the membrane-bound multidrug-resistance-associated protein, the detoxifying glutathione metabolism, the antiapoptotic protein BCL2, and changes in levels or activity of the topoisomerase enzymes. Strategies to overcome multidrug resistance of genitourinary tumors have arisen from the better understanding of the biologic and molecular mechanisms of multidrug resistance, and have been studied in experimental and clinical settings. However, attempts to modulate multidrug resistance in clinical renal cell, bladder, prostate, and testicular cancer have not been very rewarding so far, despite the optimism that had arisen from experimental data. Nevertheless, application of novel therapies to reverse multidrug resistance and to increase efficacy of chemotherapy for urologic cancers should be further pursued, within the setting of controlled clinical trials, to improve on current strategies.
Insights
Multidrug resistance significantly limits chemotherapy effectiveness in genitourinary cancers. Further research into novel therapies is crucial to overcome this challenge and improve treatment outcomes for urologic malignancies.
Area of Science:
- Oncology
- Pharmacology
- Genitourinary Cancer Research
Background:
- Chemotherapy is a primary treatment for metastasized genitourinary cancers.
- Multidrug resistance (MDR) significantly compromises chemotherapy efficacy.
- MDR can be intrinsic or acquired, involving various molecular mechanisms.
Purpose of the Study:
- To review the mechanisms of multidrug resistance in genitourinary cancers.
- To discuss strategies for overcoming MDR in urologic malignancies.
- To evaluate the clinical success of MDR-modulating therapies.
Main Methods:
- Literature review of MDR mechanisms in genitourinary cancers.
- Analysis of experimental and clinical studies on MDR reversal strategies.
- Examination of MDR-associated proteins like P-glycoprotein, MRP, BCL2, and topoisomerases.
Main Results:
- Classical MDR is often mediated by P-glycoprotein (MDR1 gene product).
- Other MDR pathways involve MRP, glutathione metabolism, BCL2, and topoisomerases.
- Clinical attempts to modulate MDR in renal cell, bladder, prostate, and testicular cancers have yielded limited success.
Conclusions:
- Understanding MDR mechanisms is key to developing new therapeutic strategies.
- Current clinical strategies to overcome MDR in urologic cancers require further development.
- Novel therapies targeting MDR should be pursued in controlled clinical trials to enhance chemotherapy efficacy.