Gemcitabine in combination with trastuzumab and/or platinum salts in breast cancer cells with HER2 overexpression.
Trastuzumab (Herceptin) is an effective treatment in patients with HER2-overexpressing metastatic breast cancer. Risk of trastuzumab-induced cardiotoxicity raises concerns regarding combined use with anthracyclines or other potentially cardiotoxic agents following anthracycline treatment. We characterized interactions between trastuzumab and gemcitabine (Gemzar) and the combination of gemcitabine and cisplatin or carboplatin (Paraplatin) as such combinations might help reduce the risk of cardiotoxicity. Multiple drug effect/combination index isobologram analysis was used to study the efficacy of chemotherapeutic drug plus trastuzumab combinations in HER2-overexpressing breast cancer cell lines. Combination index values were derived from parameters of the median effect plots, and statistical tests were used to determine whether the mean combination index at multiple effect levels significantly differed from a combination index value of 1.0 (values < 1.0 indicate synergy; values > 1.0, antagonism; values equal to 1.0, additivity). At a wide range of clinically achievable drug concentrations, interactions between trastuzumab and gemcitabine were synergistic at low concentrations of gemcitabine and antagonistic at high concentrations. A consistent synergistic interaction was observed with the three-drug combination of trastuzumab plus gemcitabine plus carboplatin or cisplatin. Available clinical data on the use of trastuzumab plus gemcitabine, and trastuzumab plus gemcitabine/paclitaxel, as well as clinical data on the use of gemcitabine/cisplatin in breast cancer, are discussed. These findings indicate that trastuzumab plus gemcitabine and trastuzumab plus gemcitabine plus cisplatin or carboplatin are rational combinations to evaluate in clinical trials.
Konecny
Gottfried E
GE
University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California 90095-1678, USA. gkonecny@ucla.edu
Pegram
Mark D
MD
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004336:Drug Antagonism; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2 / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced; D006801:Humans; D017671:Platinum Compounds / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D016190:Carboplatin; D002945:Cisplatin; D003841:Deoxycytidine; D017671:Platinum Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000093542:Gemcitabine