Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone of the renin-angiotensin system with vasodilator and anti-proliferative properties. Epidemiological studies showed that treatment of patients with angiotensin converting enzyme (ACE) inhibitors which elevate Ang-(1-7) reduced the incidence of cancer, particularly lung cancer, suggesting that the heptapeptide may prevent lung cancer. In this study, we investigated whether Ang-(1-7) reduced the formation of lung tumors using a novel tetracycline-inducible, lung-specific bitransgenic Ki-rasG12C mouse model. Bi-transgenic mice were produced by crossing mono-transgenic Ki-rasG12C mice with Clara cell secretory protein-reverse tet trans-activator (CCSP-rtTA) transgenic mice. Doxycycline (500 µg /mL) was administered to the mice in their drinking water, beginning at 2 months of age and continuing throughout the study, to induce expression of the Ki-rasG12C transgene. Induction of the mutant Ki-rasG12C transgene resulted in the formation of proliferative pulmonary lesions morphologically diagnosed as bronchoalveolar hyperplasias and adenomas. Ang-(1-7) (24 µg/kg/h) or saline (6 µL/24 h) was administered into the jugular vein by osmotic minipumps beginning at 5 months of age and animals were sacrificed 3 months later. Infusion of Ang-(1-7) increased plasma concentrations of the heptapeptide approximately 3-fold over saline-treated animals (from 59.7 ± 12 pg/mL to 168 ± 36.6 pg/mL, p < 0.05), similar to the increase observed following ACE inhibitor administration. No adverse reactions or gross pathological abnormalities were observed in the mice treated with the heptapeptide, an important characteristic of a pharmacological agent and a primary requirement for a chemopreventive agent. Mice administered saline had a lung tumor multiplicity of 12.8 ± 1.0 tumors/mice (n = 8), whereas animals infused with Ang-(1-7) had a significant reduction in tumor multiplicity to 6.4 ± 0.9 tumors/mice (n = 7, p < 0.05), demonstrating that Ang-(1-7) reduced lung tumor formation. The decrease in tumor incidence was associated with a reduction in immunoreactive Ki-67, a proliferation marker. In addition, cyclooxygenase-2 (COX-2) was markedly decreased in tumors of Ang-(1-7)-infused mice as compared withsaline-treated animals (from 68.8 ± 10.2% immunoreactive cells to 29.3 ± 8.2%, p < 0.05). These results suggest that the heptapeptide reduces COX-2 activity with a subsequent decrease in proinflammatory prostaglandinsto prevent lung tumor growth. Since Ang-(1-7) mediates its biological effects by activation of a unique angiotensin receptor mas, the heptapeptide may be a novel targeted chemopreventive agent for treatment of patients at risk for lung cancer.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA