During malignant transformation qualitative and quantitative changes occur in protein synthesis and secretion. Some of these proteins are thought to modulate the transformed phenotype by affecting i) loss of cellular growth control, ii) invasion and metastasis, and iii) evasion of the host immune response. They include tumor-associated antigens, hormones, enzymes, oncogene products, growth factors, and angiogenic agents. The chemical and biological characterization of these molecules will likely provide insights into the regulatory events involved in malignancy which in turn might suggest procedures of practical utility in the detection, diagnosis, and treatment of neoplastic diseases. Angiogenesis -- the development of a hemovascular network -- is crucial to normal physiological processes and to pathological conditions including malignancy. New blood vessels must be elicited continuously from the host in order for tumors to grow and metastasize. Interfering with tumor-induced neovascularization, therefore, would be a promising therapeutic approach for the treatment of malignant diseases. We have isolated angiogenin, a blood vessel inducing protein, originally from medium conditioned by human colon adenocarcinoma cells (HT-29) in culture and later from human plasma. Two monoclonal antibodies directed against human angiogenin as well as a purified angiogenin binding protein have been shown to inhibit both the ribonucleolytic and angiogenic activities of this protein. Importantly, each of the three reagents when administered prophylactically delay or prevent growth of HT-29 xenografts in an athymic mouse model which approximates metastasis. Additionally, we have produced two site-specific mutants and a C-terminal synthetic peptide which also inhibit the activities of human angiogenin.
The aims of this proposal are to determine whether these non-immune angiogenin antagonists (ANGBP, mutants, synthetic peptides) have therapeutic efficacy in i) preventing the establishment and/or progressive growth of HT-29 and A549 human tumors in athymic mice and ii) inhibiting formation of experimental and spontaneous metastases in C57BL/6 mice induced by a series of syngeneic tumors known to secrete mouse angiogenin. Insights into mechanism(s) of inhibition will be gained through studies which include histopathology, in vitro and in vivo toxicity and correlations between tumor cell angiogenin secretory levels, receptor density and metastatic capability. It is anticipated that the data generated from these investigations will provide valuable insights into the use of anti-angiogenic agents, in general, and angiogenin antagonists, in particular, for the ultimate clinical treatment of malignancy.
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