Reversal of multidrug resistance in hematologic malignancies with chemosensitizers: laboratory and clinical studies

Abstract

There has been much recent progress in the understanding of molecular mechanisms of resistance of cancer cells to chemotherapeutic agents. Knowledge of these mechanisms has provided the basis for rational approaches to overcoming or reversing drug resistance and thereby making cancer chemotherapy more effective. In vitro studies with tumor cell lines carried out by Ling in the mid-1970’s suggested that prolonged exposure of the cells to one compound (e.g. Colchicine) could give rise to a multidrug resistant phenotype, with cross resistance to a series of structurally quite different compounds (Ling, 1975). Importantly, Ling’s group established that cell lines exhibiting this form of multidrug resistance (MDR), overexpressed a 170kd Glycoprotein termed the «P- glycoprotein»(P-gp) on tumor cell membranes. Mechanistic studies have established that P-gp functions as a drug-efflux pump, capable of actively transporting a variety of structurally diverse anticancer drugs out of the tumor cell (Beck et al 1979; Gerlach et al 1986; Ling, 1975; Riordan and Ling, 1979). Included in this heterogeneous group of heterocyclic compounds effluxed by P-gp are antitumor antibiotics such as the anthracyclines, mitomycins and actinomycins, and plant alkaloids such as the vincas and the podophyllotoxins. The mechanism of drug resistance associated with MDR expression is considered related to the inability to achieve adequate intracellular cytotoxic drug concentrations.