CELLULAR-RESISTANCE TO ANTHRACYCLINES

The antracyclines induce multiple intracellular effects; however, inhi bition of the nuclear enzyme topoisomerase II (TOPO II) is the main me chanism of action. Resistance to anthracyclines in tumor cells is mult ifactorial. The main mechanisms are: (1) the classic multidrug resista nce (MDR) phenotype, which is due to the presence of P-glycoprotein (P GP) in plasma membrane, that is, a ''pump'' that can extrude a wide ra nge of anticancer drugs. Membrane active drugs (e.g., verapamil) have been found in vitro to reverse this phenotype. Most clinical studies i ncluding chemosensitizers have, however, been disappointing. (2) Non P GP-mediated MDR: this phenotype is characterized by expression of othe r proteins in the plasma membrane which are also able to extrude antic ancer drugs. (3) Changes in the intracellular distribution of drug: th is mechanism has been demonstrated in several cell lines, most often i n combination with PGP or non PGP-mediated resistance, (4) Glutathione transferases (GST) and detoxification mechanisms: these represent a m ultigene family of enzymes that conjugate glutathione to chemically re active groups. Direct evidence for a causative role of GST in anthracy cline resistance is missing. (5) Alterations in TOPO II (at MDR): DNA topoisomerases are involved in several aspects of DNA metabolism, in p articular genetic recombination, DNA transcription, and chromosome seg regation. Low levels of expression or alterations in TOPO II are assoc iated in vitro with resistance. (6) Increased DNA repair: in several c ell lines, an increase in the efficacy of DNA repair has been associat ed with resistance to doxorubicin (DOX). So far, only classic MDR has been shown to contribute to resistance in clinical conditions, whereas evidence for the other mechanisms of resistance is still missing.