Abstract:
Angiogenesis and metastasis are tumor-related processes that are interrelated. Angiogenesis is required for the growth of tumors beyond a certain size. The invasion of surrounding tissue by tumor and the establishment and growth of distant metastatic foci also requires angiogenesis. Certain critical events that are required for angiogenesis, such as breakdown of basement membrane and tissue matrix, are also integral in the physical process of tumor invasion and metastasis. Thus, agents that inhibit angiogenesis may also inhibit the process of tumor invasion and/or metastasis, and vice versa. Inhibition of angiogenesis may occur at one or more of 3 general steps: (1) the switch to the angiogenic phenotype by the tumor associated with release of angiogenic and other factors, (2) circulating angiogenic and other factors released by tumors, macrophages, and other cells, (3) the endothelial cell response to stimulation by angiogenic factors. An anti-angiogenic agent currently in clinical trials is TNP-470 (AGM-1470). TNP-470 is a fumagillin analog that is a potent inhibitor of angiogenesis in vitro (Ingber, et al Nature 348, 555, 1990). This agent has also been found to inhibit tumor growth as well as metastasis in a variety of animal model. Antitumor inhibitory activity in these animal models has been shown to be dose but not schedule-dependent. In addition, TNP-470 has been shown to inhibit in vitro Kaposi's sarcoma (KS)-derived spindle cell proliferation (Saville, et al J Cell Biochem Suppl 17E:22, 1993 abstr). At the present time, TNP-470 is undergoing Phase I clinical testing in patients with solid tumors as well as AIDS-associated KS. Means of inhibiting metastasis have to date been aimed at the inhibition of matrix metalloproteinases (MMP), a group of enzymes necessary for the breakdown of tissue matrix. These enzymes, exemplified by the type IV collagenase enzyme, are necessary for tumor cells to migrate beyond the original tumor site in order to invade surrounding tissue and gain access to the hematologic and lymphatic circulation. Interestingly, inhibitors of these enzymes also have anti-angiogenic activity. The tissue inhibitors of metalloproteinases (TIMPS) are naturally occurring agents that inhibit these enzymes and are antimetastatic agents. A cartilage-derived inhibitor of collagenase IV has also been described. These compounds have not, as yet, entered clinical trials. An agent that has been shown to inhibit several signal transduction pathways that are felt to be important in tumor-cell growth and metastasis is carboxyaminoimidazole (CAI). CAI has been shown to inhibit tumor growth and pulmonary metastasis in animal models (Kohn, et al Cancer Res 52, 3208, 1992), and may also possess anti-angiogenic properties. It currently is undergoing Phase I testing in patients with solid tumors. Thus, the processes of angiogenesis and metastasis appear intimately related, and new agents aimed at disrupting these processes may prove extremely useful in the treatment of cancer.
Keywords: Animals Antibiotics, Antineoplastic/*THERAPEUTIC USE Clinical Trials, Phase I Human Neoplasm Metastasis/*PREVENTION & CONTROL Neoplasms/BLOOD SUPPLY/*DRUG THERAPY/PATHOLOGY Neovascularization, Pathologic/*PREVENTION & CONTROL Sesquiterpenes/*THERAPEUTIC USE ABSTRACT 951030
M95A0966
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