Angiogenesis, the formation of new blood vessels, is crucial to a number of physiological processes such as reproduction, development and tissue repair, as well as in disease states including cancer, rheumatoid arthritis and other inflammatory diseases. Consequently angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. Angiogenesis is a well-programmed cascade of events, which contains a number of distinct steps. One such step involves the migration and adhesion of endothelial cells to areas that are destined to become hyper-vascularized.

Beta integrins, including beta(1), beta(3) and beta(5) subtypes, are present on endothelial cells and mediate endothelial cell-extracellular matrix interactions. Of particular interest to cancer progression is integrin alpha(5)beta(1) which is expressed on activated endothelial cells and plays a critical role in tumor angiogenesis. Likewise alpha(5)beta(1) integrin is also present on many tumor cells where is plays a key role in adhesion and migration and hence blocking this integrin can affect tumor progression both directly and also indirectly through the prevention of angiogenesis. Consequently researchers at the M. D. Anderson Cancer Center in collaboration with the San Diego-based pharmaceutical company, Attenuon investigated the possibility that the novel integrin alpha(5)beta(1) antagonist, ATN-161, would inhibit angiogenesis and the growth of liver metastases in a murine model. It was further hypothesized that combining ATN-161 with 5-fluorouracil (5-FU) chemotherapy would enhance the antineoplastic effect of 5-FU.

Liver metastases of murine colon cancer cells were diminished both with respect to tumor burden and the number of metastases following the treatment with a combination of ATN-161+5-FU. Liver tumors in the ATN-161 and ATN-161+5-FU groups had significantly fewer microvessels than tumors in the control or 5-FU-treated groups. Unlike treatment with either agent alone, ATN-161+5-FU significantly increased tumor cell apoptosis and decreased tumor cell proliferation and improved overall survival. Hence ATN-161 effectively reduced tumor angiogenesis and furthermore it also enhanced the antineoplastic activity of 5-FU. The mechanism of this synergistic activity is unclear however it should be noted that a number of "vascular targeting" agents act by rapidly shutting down the tumor vasculature and as a result increase the efficacy of chemotherapeutic agents delivered to the tumor milieu. Studies investigating whether ATN-161 has acute effects on the tumor vasculature as well as more long term effects on angiogenesis are eagerly awaited. Irrespective of the exact mechanism of action, the addition of non-cytotoxic cancer therapeutics such as ATN-161 that target both the tumor vasculature and the cancer cells themselves to commonly employed chemotherapeutic strategies may be a promising approach for treating metastatic colorectal cancer. Since the expression of alpha(5)beta(1) integrin by cancer cells and the role of this molecule in tumor angiogenesis extends across a range of different cancers, the therapeutic benefit of ATN-161 is expected to extend past colorectal cancer.

An alpha(v)beta(3) antagonists has been used with considerable success in an animal model of rheumatoid arthritis. Despite the fact that beta(1) integrins are highly expressed on RA synovial fluid lymphocytes, as well as synovial tissue lining cells, leukocytes, fibroblasts and endothelia the effects of an alpha(5)beta(1) have yet to be reported. ATN-161 therefore deserves further study in models of arthritis as well as cancer.

Entry date March, 2003

Adapted from Stoeltzing et al, Int J Cancer 2003 Apr 10;104(4):496-503.

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