THE EFFECT OF HYPERTHERMIA AND VERAPAMIL ON MELPHALAN CYTOTOXICITY AND TRANSPORT IN MULTIDRUG-RESISTANT CHINESE-HAMSTER OVARY CELLS

The effect of both hyperthermia and verapamil on cytotoxicity and tran sport of melphalan was studied in a pleiotropic drug-resistant Chinese hamster ovary cell line (CH(R)C5) and in the drug-sensitive parent li ne (AuxB1). The CH(R)C5 cell line was selected for resistance to colch icine but is also cross-resistant to other drugs including melphalan. Verapamil(10 mu M) increased melphalan cytotoxicity in drug-resistant cells but not in drug-sensitive cells. Hyperthermia (40 to 45 degrees C) increased melphalan cytotoxicity in both cell lines. In drug-resist ant but not drug-sensitive cells, melphalan cytotoxicity was increased further when verapamil was combined with hyperthermia (40 to 45 degre es C). The increased cytotoxicity caused by verapamil in drug-resistan t cells was accompanied by alterations in membrane permeability to mel phalan. The cellular uptake of melphalan after 15 min increased in the presence of verapamil (7 to 30 mu M) at 37 and 42 degrees C. When ver apamil (10 mu M) was present, the rate of efflux of melphalan from (CH CS)-C-R cells decreased by almost 40% at 37 degrees C, The rate of eff lux was increased at 42 degrees C relative to 37 degrees C, but with v erapamil the rate decreased to that obtained at 37 degrees C in CH(R)C 5 cells, In drug-sensitive cells, verapamil (less than or equal to 50 mu M) did not affect either uptake or efflux of melphalan. These findi ngs suggest that verapamil could be beneficial by increasing the effec tiveness of melphalan in the elimination of multidrug-resistant cells. The combination of hyperthermia and verapamil could be especially adv antageous by increasing melphalan cytotoxicity in a localized target r egion. (C) 1995 by Radiation Research Society