Antitumor Antibiotics in Cancer Chemotherapy: Mechanisms, Clinical Use, Resistance and New Approaches to Selectivity

Abstract

Antitumor antibiotics are anticancer drugs of microbial origin that kill cells mainly by damaging DNA or by stopping it from being used as a template. They are antibiotics by pedigree only; none is used to treat infection. The clinically important members are the anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin), dactinomycin, bleomycin and mitomycin C. The enediynes, which are too toxic to give as free drugs, have found a clinical role as payloads on antibodies. This review follows these agents from mechanism to bedside. Anthracyclines intercalate into DNA, poison topoisomerase II and generate oxidative stress. Dactinomycin intercalates and blocks transcription. Bleomycin cuts DNA through an iron-dependent oxygen chemistry, mitomycin C has to be reduced inside the cell before it can cross-link DNA, and the enediynes cause double-strand breaks through a diradical intermediate. What limits all of them is a narrow margin between tumor kill and normal-tissue injury: cardiomyopathy with anthracyclines, pulmonary fibrosis with bleomycin, and marrow suppression across most of the group. Resistance adds a second limit and arises through drug efflux, altered targets, faster repair, defective apoptosis and tumor heterogeneity. Current development is aimed less at making these drugs stronger than at controlling where and when they act. We discuss liposomal and nanoparticle carriers, antibody–drug conjugates, hypoxia-activated chemistry, DNA-repair inhibitors, biomarker-guided selection and cardioprotection with dexrazoxane. We conclude that the older members of this family remain clinically useful, and that their greatest remaining value may lie in the chemistry they offer for building targeted agents.