Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers

Previous studies have demonstrated a synergistic interaction between rhuMAb HER2 and the cytotoxic drug cisplatin in human breast and ovarian cancer c ells. To define the nature of the interaction between rhuMAb HER2 and other classes of cytotoxic drugs, we applied multiple drug effect/combination in dex (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 cisp latin (CI = 0.48, P = 0.003), thiotepa (CI = 0.67, P = 0.0008), and etoposi de (CI = 0.54, P = 0.0003). Additive cytotoxic effects were observed with r huMAb 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 rhuMA b HER2 in vitro (CI = 2.87, P = 0.0001). In vivo drug/rhuMAb HER2 studies w ere conducted with HER-2/neu-transfected, MCF7 human breast cancer xenograf ts in athymic mice. Combinations of rhuMAb HER2 plus cyclophosphamide, doxo rubicin, paclitaxel, methotrexate, etoposide, and vinblastine in vivo resul ted 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 consist ent with the subadditive effects observed with this combination in vitro. T he synergistic interaction of rhuMAb HER2 with alkylating agents, platinum analogs and topoisomerase II inhibitors, as well as the additive interactio n with taxanes, anthracyclines and some antimetabolites in HER-2/neu-overex pressing breast cancer cells demonstrates that these are rational combinati ons to test in human clinical trials.