Background: Human renal adenocarcinomas do not adequately respond to cancer chemotherapy. Their multidrug resistance is mainly conferred by the P-glycoprotein (P-gp). In this study, we analyzed effects of P-gp modulators on enhancement of anticancer activities against human renal cell carcinomas.
Methods: ACHN/ADM human renal adenocarcinoma cells with a high level expression of P-gp and 28 surgical specimens of renal cell adenocarcinomas were recruited. Adriamycin (ADM) and vinblastin (VLB) were used as anticancer drugs, and verapamil (Ver) and cyclosporin A (CsA) were as P-gp modulators. The chemosensitivity was determined by the ATP-assay.
Results: Ver and CsA exhibited 1.5-fold and 6-fold increase, respectively, in the anticancer activities of ADM against ACHN/ADM cells. The anticancer activities of VLB were also enhanced by the modulators; 7-fold for Ver and 11-fold for CsA. In the chemosensitivity test of clinical specimens, the cancer for which the viability of the cells assessed by the ATP-assay was 50% or less than 50% after exposure to the anticancer drug with or without a P-gp modulator was defined as sensitive to the drug. Of the 14 clinical specimens exposed to anticancer drugs without Ver, only 3 tumors and 1 tumor were sensitive to ADM and VLB, respectively, whereas with Ver, 6 tumors and 4 tumors were sensitive to ADM and VLB, respectively. Of the other 14 clinical specimens exposed to anticancer drugs without CsA, only 3 tumors and no tumor were sensitive to ADM and VLB, respectively, whereas, with CsA, 9 tumors and 6 tumors were sensitive to ADM and VLB, respectively.
Conclusion: This study indicate that Ver and CsA have effects on enhancement of the anticancer activities of ADM and VLB against human renal adenocarcinomas. The addition of Ver or CsA to chemotherapy will be a potential circumvention of P-gp-mediated multidrug resistance of renal cell adenocarcinomas.