The hypothesis guiding this proposal is that AT4 receptor (angiotensin IV receptor) antagonists, which are antiangiogenic, have antitumor activity. To test this hypothesis, two AT4 antagonists, one agonist (negative control), one modified angiostatin fragment (putative AT4 receptor ligand), and angiostatin (positive control), will be administered continuously, via intraperitoneally implanted osmotic minipumps, to mice that have been seeded subcutaneously with Lewis lung carcinoma (LLC) cells, which are then allowed to consolidate and metastasize to the lung. Following removal of the primary tumor, the lung metastases grow rapidly. Alternatively, mice will be injected with B16-BL6 melanoma or (+SA) WAZ-2T mammary cancer cells and pulmonary metastases again monitored. It is predicted that the AT4 antagonists will attenuate this process. Lung weight and the number of visible metastases will be determined. Additionally, vascularization of metastases will be monitored by immunocytochemical methods. Finally, the pharmacokinetic distribution of test compounds will be determined.
Peptide and peptoid AT4 antagonists are antiangiogenic and should be useful for the treatment of solid tumor cancers.
