CELLULAR-DRUG EFFLUX AND REVERSAL THERAPY OF CANCER

A prevalent form of multidrug resistance (MDR) in cancer cells is caus ed by an ATP-dependent drug efflux pump; this pump catalyzes the rapid exit of cytotoxic chemotherapy drugs from the cells. The Michaelis eq uation can be used to describe drug efflux through the MDR pump at a l ow drug substrate concentration [S]. The inhibition mechanism of an MD R reversal agent can be characterized when two different values of [S] are used to determine two values for the half-inhibition of efflux th rough the pump (I-50). The reaction is noncompetitive when the two val ues of I-50 are identical; the reaction is competitive when an increas e in [S] produces a significant increase in the value of I-50 The I-50 has been determined for several different reversal agents with the su bstrate rhodamine 123. The inhibition potency observed is: cyclosporin A > DMDP > amiodarone > verapamil > quinidine > quinine > propranolol . Chemotherapy drugs that are potent inhibitors of the MDR pump could be used for the treatment of MDR neoplasia.