MECHANISM OF MULTIDRUG RESISTANCE IN HUMAN TUMOR-CELL LINES AND COMPLETE REVERSION OF CELLULAR-RESISTANCE

The biochemical basis of the multidrug-resistant (MDR) phenotype has been investigated in drug-resistant sublines derived from LoVo and SW984 human colon carcinoma cell lines by doxorubicin selection. Besides drug extrusion through the plasma membrane, two further observations, both ascribable to the drug transport property of the gp170 glycoprotein, were made. First drug deposition into cytoplasmic membranous structures which allows cells to tolerate a high intracellular drug concentration since it prevents drugs from reaching their cellular target site(s). Secondly drug removal from the complexes formed by interaction of drug with target cellular macromolecules, a phenomenon which extends its an effect that continues after treatment and appears to be the most important resistance mechanism in MDR cells. Treatments based on the gp170 inhibitory property of verapamil were developed that allowed abrogation of resistance in MDR cell lines, a strategy that may be applicable to therapy treatments.