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| Original article |
| Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers |
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| Mark Pegram1, Sheree Hsu1, Gail Lewis2, Richard Pietras1, Malgorzata Beryt1, Mark Sliwkowski2, Daniel Coombs2, Deborah Baly2, Fairooz Kabbinavar1 and Dennis Slamon1,a |
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1Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, California 90095, USA
2Genentech, Inc. One DNA Way, South San Francisco, California, USA
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aAuthor for correspondence: UCLA School of Medicine, Department of Medicine, Division of Hematology-Oncology, 11-934 Factor Building, Los Angeles, CA 90095, USA |
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| Abstract |
| Previous studies have demonstrated a synergistic interaction between rhuMAb HER2 and the cytotoxic drug cisplatin in human breast and ovarian cancer cells. To define the nature of the interaction between rhuMAb HER2 and other classes of cytotoxic drugs, we applied multiple drug effect/combination index (CI) isobologram analysis to a variety of chemotherapeutic drug/rhuMAb HER2 combinations in vitro. Synergistic interactions at clinically relevant drug concentrations were observed for rhuMAb HER2 in combination with cisplatin (CI=0.48, P=0.003), thiotepa (CI=0.67, P=0.0008), and etoposide (CI=0.54, P=0.0003). Additive cytotoxic effects were observed with rhuMAb HER2 plus doxorubicin (CI=1.16, P=0.13), paclitaxel (CI=0.91, P=0.21), methotrexate (CI=1.15, P=0.28), and vinblastine (CI=1.09, P=0.26). One drug, 5-fluorouracil, was found to be antagonistic with rhuMAb HER2 in vitro (CI=2.87, P=0.0001). In vivo drug/rhuMAb HER2 studies were conducted with HER-2/neu-transfected, MCF7 human breast cancer xenografts in athymic mice. Combinations of rhuMAb HER2 plus cyclophosphamide, doxorubicin, paclitaxel, methotrexate, etoposide, and vinblastine in vivo resulted in a significant reduction in xenograft volume compared to chemotherapy alone (P<0.05). Xenografts treated with rhuMAb HER2 plus 5-fluorouracil were not significantly different from 5-fluorouracil alone controls consistent with the subadditive effects observed with this combination in vitro. The synergistic interaction of rhuMAb HER2 with alkylating agents, platinum analogs and topoisomerase II inhibitors, as well as the additive interaction with taxanes, anthracyclines and some antimetabolites in HER-2/neu-overexpressing breast cancer cells demonstrates that these are rational combinations to test in human clinical trials. |
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| Keywords |
| HER-2/neu (c-erbB-2); chemotherapy; breast cancer; multiple drug effects analysis; synergy |
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| Received 13 May 1998; revised 27 October 1998; accepted 27 October 1998 |
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| 1 April 1999, Volume 18, Number 13, Pages 2241-2251 |
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