Antitumor activity of combinations of anti-HER-2 antibody trastuzumab and oral fluoropyrimidines capecitabine/5′-dFUrd in human breast cancer models

Abstract.

The anti-HER-2 antibody, trastuzumab (Herceptin), and the oral fluoropyrimidine, capecitabine (Xeloda), are both effective in breast cancer with different modes of action and toxicity profiles. Therefore, the efficacy in combination therapy of these agents for the treatment of HER-2-overexpressing breast cancer was of interest. An antagonistic interaction in vitro between trastuzumab and 5-fluorouracil (5-FUra) in combination has previously been reported. In the same study, the in vivo antitumor activity of this combination was investigated. However, the results were inconclusive since 5-FUra at the dose used had sufficient antitumor efficacy as a single agent and therefore it was not possible to clarify the potential difference between 5-FUra alone and the combination. In the present study, we investigated the efficacy of trastuzumab in combination with capecitabine or its intermediate metabolite 5′-dFUrd in HER-2-overexpressing human breast cancer cell lines and xenograft models. In vivo antitumor activity of the combination was at least additive, in terms of tumor growth inhibition and tumor growth delay, in human breast cancer models KPL-4 and BT-474. The combination treatment in vivo was superior to the treatment with either single agent alone, even though in vitro treatment with trastuzumab and 5′-dFUrd/5-FUra showed antagonistic antiproliferative activity in these cell lines. The reason for the discrepancy between the in vivo and in vitro results was not clarified. However, observed additive in vivo antitumor activity clearly indicates that the clinical efficacy of the combination of trastuzumab and capecitabine/5′-dFUrd against HER-2-overexpressing breast cancer is worth investigating.