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

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Clin Cancer Res. 2009 Aug 1;15(15):4867-74. Epub 2009 Jul 21.

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

Cruz-Munoz W, Man S, Kerbel RS.
Sunnybrook Health Sciences Centre, Molecular and Cellular Biology Research, Toronto, Ontario, Canada.
 
PURPOSE:
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.
EXPERIMENTAL DESIGN:
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).
RESULTS: 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.
CONCLUSIONS: 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.