Science et thérapie du cancer

The Chemopreventive Efficacy of Vandetanib, a Multikinase Inhibitor, in a Primary Respiratory Tract Epithelial Cell Transformation Model

Abstract

Sheela Sharma, Min-Xu Zou and Vernon E Steele

Targeted therapies by means of compounds that inhibit multiple target molecules represent a new perspective in the treatment and prevention of cancer. Vandetanib (Zactima ™ ) is an orally active, selective inhibitor of VEGFR-2 (vascular endothelial growth factor receptor-2) receptor tyrosine kinase that also demonstrates activity against EGFR (epidermal growth factor receptor) and RET (rearranged during transfection) tyrosine kinases. As there are indications of Vandetanib being effective in advanced NSLC patients for disease free survival, we have tested Vandetanib for efficacy in a primary rat tracheal epithelial (RTE) cell transformation model, which was originally developed for identifying potential chemopreventive agents belonging to different chemical classes/biological activity. RTE cells were treated with a tobacco-specific carcinogen, benzo[ a ]pyrene (B[ a ]P) alone or with five nontoxic concentrations of Vandetanib and the resulting transformed foci at the end of 30 days were scored for inhibition of transformation. In order to understand the mechanism(s) of this inhibition, the effect on biomarkers at different stages of RTE cell transformation was also tested. The results indicated that Vandetanib at half-log concentrations ranging from 0.003 – 0.3 μM, elicited an excellent dose-related inhibition of transformation (75- 93%) compared to B[ a ]P group (p = <0.0001). A significant dose-dependent inhibition (39- 93%) of phosphorylated tyrosine kinase activity was observed in Vandetanib-treated groups compared to B[ a ]P group. There was also an approximately 2-fold induction of apoptosis at 0.3 μM, and it inhibited survivin, a late stage biomarker, at all concentrations by 18-28%. In conclusion, the data shows that there is a very good correlation between the inhibition of B[ a ]P-induced transformation and corresponding inhibition of activated tyrosine kinase and other biomarkers. Based on this data, animal studies are planned to develop this drug for lung cancer prevention by administering it directly to the lungs as it was found to be very effective at lower doses compared to therapeutic doses.