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Published on: July 21, 2018
Vascular endothelial growth factor receptor 2-targeted chemoprevention of murine lung tumors
Vijaya Karoor1, Mysan Le, Daniel Merrick
1Denver Veterans Affairs Medical Center, University of Colorado Cancer Center, Pulmonary 111A, 1055 Clermont Street, Denver, CO 80220, USA.
Abstract:
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.
Insights
Vandetanib, a vascular endothelial growth factor (VEGF) receptor-2 inhibitor, significantly reduced lung adenocarcinoma tumor size and number in mice. Further research into VEGF signaling inhibitors for lung cancer chemoprevention is warranted.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung cancer chemoprevention remains a significant clinical challenge.
- Angiogenesis, driven by vascular endothelial growth factor (VEGF), is crucial in lung adenocarcinoma and squamous cell carcinoma development.
- Targeting VEGF signaling pathways presents a potential strategy for lung cancer prevention.
Purpose of the Study:
- To investigate the chemopreventive efficacy of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) inhibition in a murine model of lung adenocarcinoma.
- To evaluate the impact of vandetanib, a VEGFR-2 tyrosine kinase inhibitor, on urethane-induced lung carcinogenesis.
- To assess the role of VEGF signaling in lung tumor development and progression.
Main Methods:
- FVB/N mice were administered urethane, a carcinogen, to induce lung adenocarcinoma.
- Vandetanib was administered orally to mice at a dose of 75 mg/kg/d, starting 7 days after urethane injection.
- Tumor multiplicity, incidence, and volume were measured 16 weeks post-urethane administration.
- A separate cohort received the anti-VEGFR-2 monoclonal antibody DC101 to differentiate between VEGFR-2 inhibition and other drug activities.
Main Results:
- Vandetanib treatment led to a significant reduction in tumor multiplicity (P = 0.001) and average tumor volume (P = 0.001) compared to controls.
- Vandetanib did not significantly affect tumor incidence (P = ns).
- The monoclonal antibody DC101 showed an arrest in tumor volume increase but no change in multiplicity or incidence, suggesting a specific role for VEGFR-2 inhibition.
Conclusions:
- Vandetanib demonstrates significant chemopreventive effects against lung adenocarcinoma in mice by reducing tumor burden.
- VEGFR-2 inhibition plays a critical role in suppressing lung carcinogenesis.
- Further investigation into vandetanib and other VEGF signaling inhibitors is necessary for developing effective lung cancer chemoprevention strategies.
