Cocktail modulator mixtures for overcoming multidrug resistance in renal cell carcinoma.
OBJECTIVE
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.
Yu
D S
DS
Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Sun
G H
GH
Ma
C P
CP
Chang
S Y
SY
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D004317:Doxorubicin / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004317:Doxorubicin