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Cocktail modulator mixtures for overcoming multidrug resistance in renal cell carcinoma
1Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Objectives:
To determine the effect of various modulators on intracellular drug accumulation in renal cell carcinoma (RCC) tumor cells and the modulation of cytotoxicity of various chemotherapeutic drugs on the native RCC cell line and acquired intrinsic multidrug resistance (MDR) sublines because MDR is a major obstacle to effective chemotherapy of RCC.
Methods:
The cytotoxicity of adriamycin to RCC 8701 and its MDR subline was analyzed. Fourteen MDR modulators, including calcium antagonists, protein kinase C inhibitor, glutathione transferase inhibitor, protein/peptide synthesis inhibitors, respiratory chain inhibitors, uncoupling reagent, adenosine triphosphate synthesis inhibitor, and ionophores, were examined for their MDR-reverse activity using the microplate tetrazolium test.
Results:
The intracellular adriamycin concentration significantly increased and reached maximum 4 hours after simultaneous treatment with calcium antagonists, tamoxifen, and oligomycin. The result demonstrated that verapamil, quinidine, tamoxifen, and oligomycin had an additive effect on the cytotoxicity of adriamycin and vinblastine against RCC8701 and RCC8701/ADR800 tumor cells. RCC8701/ADR800 tumor cells were more sensitive to modulator enhancement than native cells. The enhancement was related to the dosage and treatment duration of the modulators. Further trials on simultaneous additions to cocktail mixtures of the above four modulators showed no additive or synergistic effect on cytotoxicity against RCC8701/ADR800 tumor cells.
Conclusions:
Calcium antagonists and tamoxifen and oligomycin can individually be an effective chemotherapy adjunct for overcoming the native drug resistance or acquired MDR in RCC. Combination regimens, however, need more study regarding timing of administration, dosage, and frequency of modulators.
Insights
Certain modulators like calcium antagonists, tamoxifen, and oligomycin can enhance chemotherapy effectiveness against renal cell carcinoma (RCC) by reversing multidrug resistance (MDR). These agents increase intracellular drug levels and cytotoxicity in RCC cells, particularly those with acquired resistance.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Multidrug resistance (MDR) significantly hinders effective chemotherapy for renal cell carcinoma (RCC).
- Understanding modulators that can overcome MDR is crucial for improving RCC treatment outcomes.
Purpose of the Study:
- To evaluate the impact of various modulators on intracellular drug accumulation in RCC cells.
- To assess the ability of these modulators to reverse MDR and enhance the cytotoxicity of chemotherapeutic agents in both native and resistant RCC cell lines.
Main Methods:
- Cytotoxicity of adriamycin was assessed in RCC 8701 and its MDR subline.
- Fourteen MDR modulators, including calcium antagonists, were tested for their MDR-reversing activity using the microplate tetrazolium assay.
Main Results:
- Calcium antagonists, tamoxifen, and oligomycin increased intracellular adriamycin concentration, peaking at 4 hours.
- Verapamil, quinidine, tamoxifen, and oligomycin showed additive effects on adriamycin and vinblastine cytotoxicity in both native and MDR RCC cells.
- MDR RCC cells exhibited greater sensitivity to modulator-enhanced cytotoxicity compared to native cells, with effects dependent on modulator dosage and duration.
Conclusions:
- Calcium antagonists, tamoxifen, and oligomycin show promise as adjuncts to chemotherapy for overcoming drug resistance in RCC.
- Further research is needed to optimize combination regimens, including timing, dosage, and frequency, for these modulators in clinical settings.