Anthracycline resistance: the problem and its current definition.

Anthracyclines were introduced for the treatment of breast cancer in the 1970s and were considered the most active single agents until the recent introduction of the taxoids. Although incorporation of anthracyclines into combination regimens has been shown to improve clinical outcomes, the duration of response and survival in women with metastatic disease is still modest, and 50% of women treated with adjuvant chemotherapy eventually relapse. Intrinsic and acquired drug resistance, leading to untreatable disease, are fundamental reasons for clinical failure in breast cancer, but the clinical relevance of the various known mechanisms of drug resistance is not clear. P-glycoprotein (Pgp)-mediated multidrug resistance, the most studied form of anthracycline resistance, can be inhibited by a variety of chemicals. While in vitro studies have demonstrated the efficacy of some Pgp inhibitors, and led to the development of more clinically acceptable agents, clinical studies have not shown a consistent advantage in using Pgp inhibitors. Since Pgp is a physiologic efflux mechanism, consideration also should be given to the possible consequences of its inhibition. Studies with Pgp knock-out transgenic mice suggest that Pgp is not essential for life, but that Pgp inhibition may make some tissues, such as the brain, more vulnerable to cytotoxic drugs. Correlating overexpression of the MDR1 gene in human tumor samples with treatment failure has not proved straightforward, and further studies are needed to clarify the contribution of multidrug resistance mechanisms to clinical anthracycline resistance. Mechanisms other than drug efflux pumps, which may contribute to anthracycline resistance, include changes in topoisomerase II, the major cellular target of anthracyclines. There remains a gulf between the laboratory definitions of drug resistance, which can be elucidated in great detail, and the clinical definition, which is based on the time to treatment failure. New drugs still need to be assessed empirically in the clinic, and these results may then be correlated with laboratory findings. We cannot yet reliably predict clinical efficacy, cross-resistance, or the mechanisms responsible for treatment failure from laboratory studies.