Melanomas respond poorly to
chemotherapy. In this study, we investigated the sensitization of B16 mouse
melanoma tumors to
paclitaxel by a combination of two
tyrosine kinase inhibitors:
vatalanib, targeting
vascular endothelial growth factor receptors, and
imatinib, an inhibitor targeting for example, Abl/BCR-ABL, the
platelet-derived growth factor receptor, and
stem cell factor receptor c-Kit. C57Bl6/J mice carrying B16/
PDGF-BB mouse
melanoma tumors were treated daily with
vatalanib (25 mg/kg),
imatinib (100 mg/kg), or a combination of these drugs.
Paclitaxel was given subcutaneously twice during the study. The effects of the drugs on
tumor cell proliferation in vitro were determined by counting cells. B16/
PDGF-BB mouse
melanoma tumors were not sensitive to
paclitaxel at doses of either 5 or 20 mg/kg. However, the
tumor growth was significantly reduced by 58%, in response to
paclitaxel (5 mg/kg) when administered with daily doses of both
vatalanib and
imatinib.
Paclitaxel only inhibited the in-vitro growth of B16/
PDGF-BB tumor cells when given in combination with
imatinib.
Imatinib presumably targets c-Kit, as the cells do not express
platelet-derived growth factor receptor and as another c-Abl inhibitor was without effect. This was supported by data from three c-Kit-expressing human
melanoma cell lines showing varying sensitization to
paclitaxel by the
kinase inhibitors. In addition,
small interfering RNA knockdown of c-Kit sensitized the cells to
paclitaxel. These data show that combination of two
tyrosine kinase inhibitors,
imatinib and
vatalanib, increases the effects of
paclitaxel on B16/
PDGF-BB tumors, thus suggesting a novel strategy for the treatment of
melanomas expressing c-Kit.