Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes.
Doxorubicin is known to cause cardiomyopathy and congestive heart failure (CHF) upon chronic administration. A major obstacle to doxorubicin-containing multiagent therapies pertains to the possible development of cardiomyopathy and CHF at lower than expected cumulative doses of doxorubicin. For example, the cardiac toxicity of doxorubicin is aggravated by the anti-HER2 antibody Trastuzumab or by the tubulin-active taxane paclitaxel; however, the mechanisms by which Trastuzumab and paclitaxel aggravate doxorubicin-induced cardiotoxicity are mechanistically distinct: Trastuzumab interferes with cardiac-specific survival factors that help the heart to withstand stressor agents like anthracyclines, while paclitaxel acts by stimulating the formation of anthracycline metabolites that play a key role in the mechanism of cardiac failure. Here, we briefly review the molecular mechanisms of the cardiotoxic synergism of Trastuzumab or paclitaxel with doxorubicin, and we attempt to briefly outline how the mechanistic know-how translates into the clinical strategies for improving the safety of anthracycline-based multiagent therapies.
Gianni
Luca
L
Division of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, ViaVenezian 1, Milan 20133, Italy. luca.gianni@istitutotumori.mi.it
Salvatorelli
Emanuela
E
Minotti
Giorgio
G
D018943:Anthracyclines / Q000009:adverse effects* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects; D004357:Drug Synergism; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D043823:Taxoids / Q000009:adverse effects* / Q000378:metabolism; D000068878:Trastuzumab
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D004317:Doxorubicin; D000068878:Trastuzumab