Abstract
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.
Highlights
Cancer is still the second-leading cause of death in the United States, with an estimated 1,529,560 people diagnosed with cancer in 2010 and nearly 36% of them succumbing to it [1]
Activated, mutated forms of RET receptor tyrosine kinase are responsible for multiple endocrine neoplasia type 2 (MEN2), and are considered vital for the growth and survival of medullary thyroid tumors and other types of cancers related to RET oncogene expression [6]
The colony-forming efficiency (CFE) data from the one week assay of treating rat tracheal epithelial (RTE) cells with five log concentrations of Vandetanib up to 100 μM indicated that Vandetanib has significant toxicity to the primary cells at concentrations of 3, 30 and 100 μM (Figure 2)
Summary
Cancer is still the second-leading cause of death in the United States, with an estimated 1,529,560 people diagnosed with cancer in 2010 and nearly 36% of them succumbing to it [1]. Since many of the human cancers have complex etiologies (e.g., lung, breast and colon cancer) with an extended dormant period, the most effective chemopreventive strategy would be to employ agents that will inhibit promotion/progression of existing mutated cells to malignancy. A class of compounds that control cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Vandetanib has been shown to exert anti-angiogenic, anti-tumourigenic activity against a broad range of histologically distinct human tumor xenografts, including those of the lung, prostate, breast, colon, liver, central nervous system, and RET-dependent thyroid tumor cell growth [2,7,8,9,10]. Enhanced antitumor efficacy has been reported with Vandetanib in combination with various chemotherapeutic drugs and radiotherapy in both in vitro and in vivo models including cancer cells with acquired resistance to anti-EGFR therapy (e.g., lung, colon, and ovary) [11,12,13,14]
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