Multidrug resistance in Yoshida rat ascites hepatoma cell lines

Rat ascites hepatoma (AH) cell lines that were induced by dimethylaminoazobenzene and established as transplantable tumors had different sensitivities to vinblastine (VBL). The most VBL-resistant cells, AH66, showed more cross-resistance to vincristine and anthracyclines than AH66F cells. The resistance of AH66 cells was significantly decreased by verapamil. VBL-resistance of AH66 cells was inhibited by other drugs reported as overcoming acquired multidrug resistance, while the sensitivity of AH66F cells was hardly influenced by these drugs. The lowered uptake and enhanced extrusion of the antitumor drug in AH66 cells were suppressed by verapamil. M(r) 160,000 protein in the plasma membrane from AH66 was labeled with a photoactive VBL analog and was immunopositive to a monoclonal antibody against P-glycoprotein, C219. The sensitive cells had barely detectable levels of the surface membrane components. Specific photo-labeling with a VBL analog of P-glycoprotein of AH66 cell membrane was inhibited by reserpine and verapamil which restored the VBL resistance. These results indicate that AH66 cells are a naturally acquired multidrug-resistant cell line overexpressing a P-glycoprotein, and AH cell lines are useful to study multidrug resistance of hepatic carcinomas and development of counteracting drugs.