Inhibition of colon tumor xenografts in nude mice by oral administration of SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases

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The nonreceptor protein tyrosine kinase Src is overexpressed in 70% of colon cancers. Src activity increases with disease progression, while modest increases in Src activity are associated with poor prognosis. Downregulation of Src by antisense RNA slows HT29 tumor growth in nude mice. We therefore examined whether a small molecule Src inhibitor could accomplish the same growth inhibition in HT29 and other colon tumor xenograft models. We report here that Src kinase inhibitor SKI-606 is orally active against HT29 and Colo205 colon tumor xenografts. In a dose response study, SKI-606 inhibited HT29 xenografts with once daily oral administration at 50 mg/kg, whereas twice daily administration at higher doses was required to inhibit the growth of Colo205 xenografts. The implications of this work will be discussed.