MECHANISMS AND MODULATION OF RESISTANCE TO ANTHRACYCLINES

This review summarizes the main mechanisms of action of anthracyclines , the mechanisms of anthracycline resistance and the possibility of th eir modulation by various compounds. The mechanisms of resistance to a nthracyclines are multifactorial and can be summarized as follows: (i) decreased cellular drug concentration, mainly due to drug extrusion f rom the cell by the plasma membrane P-170 glycoprotein: (ii) defective metabolism of drug active compounds, (iii) increased drug detoxificat ion: (iv) alteration of target proteins such as glutathione and topois emerase II, (v) increase in the efficiency of DNA repair mechanisms. T he activity of various chemosensitizers able to circumvent drug resist ance acting on different resistance mechanisms has been described. Ver apamil and nifedipine. active as calcium channel blockers. modulate ad riamycin resistance by affecting membrane activity. Aphidicolin and no vobiocin influence entracellular target sites, whereas calmodulin inhi bitors and tamoxifen affect both membrane activity and intracellular s tructures. Since the clinical utility of any modulator depends not onl y on its ability to reverse drug resistance but also on its low toxici ty in vivo, the selection of combinations of chemosensitizers with an acceptable toxicity would permit new approaches in cancer treatment.