Anthracyclines - Pharmacology and Resistance, A Review

Anthracyclines are anti-tumor drugs with a wide spectrum of activity in human cancers. Th.ey were introduced in clinical practice in the early 1960's and have been extensively used in the adJuvant, curative and palltatlve settmg for both soltd tumors and hematologic malignancies. Their mechanisms of action have not yet been fully clarified. The best known cellular mechanisms are prevention of replication and transcription by intercalation of DNA , formation of DNA breaks possibly due to formation of tox1c topmsomerase complexes, and generation of free radicals. Pharmacokinetic studies revealed that anthracyclines dissappear fast from the plasma into tissues. Cellular uptake takes place b_Y d1ffuswn; efflux can take place by ener y-dependent membrane pumps. The intracellular concentration seems a major determmant for the cytotox1c effect. Anthracychnes are reduced to more hydrophilic glycide metabolites and aglycones. The drug .Js excreted vw the b1le and for a mmor degree v1a the unne. The cltmcal value of anthracyclines is limited by intrinsic or acqmred tumor cell resistance to anthracycltnes. D1fferent ways of resistance seem to play a role in multidrug resistance (MDR) such as the overexpression. of the membrane efflux pump P-glycoprotein , as well as th e overexpression of the multidrug res1stance associated protem (MRP) or probably other efflux pumps , a decrease in the activity of the target enzyme topoisomerase II and an .increase in cellular detoxifyin,g. capacity. Resistance against anthracyclines as well as early (myelosuppressiOn , mucosil!S) and late tox1c!ly (cardJOtOXJCity) have directed the search for analogs with higher antitumor efficacy and lower toxicity. This search delivered variants of the original daunorubicin such as epirubicin and idarubicin with a more favorable therapeutic index , and morpholino anthracyclines, drugs designed to circumvent P-glycoprotein and non P­ glycoprotem MDR. These last compounds recently enrolled phase IIII clinical trials . Results of these trials are of even more interest because up t now, results of clinical studies in solid tumors with modulators (resistance modifiers) of MDR , such as amwdarone, verapmml , cyclosponn A and PSC 833 are not very encouraging. In vivo studies with e.g. PET scanning to analyse the mtratumor kmellc behavior of anthracycltnes and modulators of drug resistance, are ongoing .