Effective treatment of advanced human melanoma metastasis in immunodeficient mice using combination metronomic chemotherapy regimens.

Abstract

The development of effective therapeutic approaches for treatment of metastatic melanoma remains an immense challenge. Present therapies offer minimal benefit. Although dacarbazine chemotherapy remains the standard therapy, it mediates only low response rates, usually of short duration, even when combined with other chemotherapeutic agents. Thus, new therapeutic strategies are urgently needed. Using a newly developed preclinical model, we evaluated the efficacy of various doublet metronomic combination chemotherapy against established advanced melanoma metastasis and compared these with the standard maximum tolerated dose dacarbazine (alone or in combination with chemotherapeutic agents or vascular endothelial growth factor receptor-blocking antibody). Whereas maximum tolerated dose dacarbazine therapy did not cause significant improvement in median survival, a doublet combination of low-dose metronomic vinblastine and low-dose metronomic cyclophosphamide induced a significant increase in survival with only minimal toxicity. Furthermore, we show that the incorporation of the low-dose metronomic vinblastine/low-dose metronomic cyclophosphamide combination with a low-dose metronomic dacarbazine regimen also results in a significant increase in survival, but not when combined with maximum tolerated dose dacarbazine therapy. We also show that a combination of metronomic vinblastine therapy and a vascular endothelial growth factor receptor 2-blocking antibody (DC101) results in significant control of metastatic disease and that the combination of low-dose metronomic vinblastine/DC101 and low-dose metronomic dacarbazine induced a significant improvement in median survival. The effective control of advanced metastatic melanoma achieved by these metronomic-based chemotherapeutic approaches warrants clinical consideration of this treatment concept, given the recent results of a number of metronomic-based chemotherapy clinical trials.