No clinically effective
chemoprevention for
lung cancer has been found. Angiogenesis is an early feature of both
adenocarcinoma and squamous cell
lung cancer. We investigated the effects of
vascular endothelial growth factor (
VEGF) receptor-2 (VEGFR-2) inhibition on lung
carcinogenesis in a murine model of
adenocarcinoma. The
VEGFR-2 tyrosine kinase inhibitor,
vandetanib, was given to FVB/N mice in chow for 7 days at varying doses to show pharmacologic activity by inhibition of
VEGF-mediated VEFGR-2 and ERK phosphorylation. Plasma levels corroborated adequate dosage. For
chemoprevention experiments, mice were injected i.p. with 1 mg/g of
urethane, a
carcinogen found in tobacco
smoke. Chow containing
vandetanib, 75 mg/kg/d, or control chow was given to mice, starting 7 days after
urethane administration. Sixteen weeks after
urethane injection, mice were sacrificed,
tumors enumerated and measured.
Vandetanib resulted in reductions in
tumor multiplicity (6.5 +/- 0.86 versus 1.0 +/- 0.30, P = 0.001) and average
tumor volume (0.85 +/- 0.10 versus 0.15 +/- 0.09 mm(3), P = 0.001), but not incidence (71% versus 100%, P = ns), compared with control. As
vandetanib has other activities besides
VEGFR-2 tyrosine kinase inhibition, we gave the anti-VEGFR-2
monoclonal antibody, DC101, for weeks 11 to 15 of a
urethane carcinogenesis protocol with an arrest in
tumor volume increase, but no change in multiplicity or incidence. Further investigation of the chemopreventive effect of
vandetanib and other
VEGF signaling inhibitors is needed.