Growth Factor Receptor-Directed Therapy in Human Breast Cancer
Annual rept. 1 Nov 97-31 Oct 98
CALIFORNIA UNIV LOS ANGELES
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HER-2 growth factor receptor pathways are strongly implicated in the clinical progression of breast cancer. We have targeted these receptors for therapeutic intervention, using humanized monoclonal antibody to HER-2 receptor Herceptin. To assess how best to use Herceptin alone and in combination with chemotherapeutic agents, studies were designed to evaluate its inhibitory effects on cancer growth. The nature of interactions between Herceptin and cytotoxic drugs was evaluated by multiple drug analysis, with in vitro results showing that Herceptin has synergy with cisplatin and thiotepa and additive cytotoxicity with doxorubicin and paclitaxel. Herceptin combined with paclitaxel, doxorubicin or cyclophosphamide in vivo resulted in significant reductions in breast cancer volumes as compared to chemotherapy alone controls. The additive or synergistic interaction of Herceptin with alkylating agents, cisplatin, taxanes, and anthra-cyclines in HER-2-expressing breast cancer cells suggests that these are rational combinations to take to human trials. Preclinical studies also suggest that Herceptin, by targeting an alternative growth or survival pathway, may provide a new therapeutic option for some patients for whom antiestrogen therapy is not effective. Evaluation of biologic mechanisms underlying cisplatin- antibody synergy suggest that p21, a critical modulator of cell cycle arrest prior to the onset of DNA repair, is altered by Herceptin treatment in breast cancer cells with HER-2-overexpression.
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