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 their modulation by various compounds. The mechanisms of resistance to anthracyclines are multifactorial and can be summarized as follows: (i) decreased cellular drug concentration, mainly due to drug extrusion from the cell by the plasma membrane P-170 glycoprotein: (ii) defective metabolism of drug active compounds, (iii) increased drug detoxification: (iv) alteration of target proteins such as glutathione and topoisemerase II, (v) increase in the efficiency of DNA repair mechanisms. The activity of various chemosensitizers able to circumvent drug resistance acting on different resistance mechanisms has been described. Verapamil and nifedipine. active as calcium channel blockers. modulate adriamycin resistance by affecting membrane activity. Aphidicolin and novobiocin influence entracellular target sites, whereas calmodulin inhibitors and tamoxifen affect both membrane activity and intracellular structures. Since the clinical utility of any modulator depends not only on its ability to reverse drug resistance but also on its low toxicity in vivo, the selection of combinations of chemosensitizers with an acceptable toxicity would permit new approaches in cancer treatment.