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FEED A PROTEIN, STARVE A TUMOR


LA JOLLA- Two novel compounds that selectively inhibit tumor induced blood vessel proliferation while leaving other tissues alone could offer a new approach to inhibiting the spread of cancer, according to a new study by researchers at the Scripps Research Institute.

Angiogenesis, the creation of new blood vessels, is an essential component of numerous physiological processes including embryonic development, menstruation and wound repair. However, cancer cells in the body are known to secrete a number of angiogenesis factors which cause blood vessels to grow around them, providing a rich source of nutrients. This is a key element in how a very small mass of cancer cells can grow into a tumor and eventually metastasize (spread) throughout the body.

Researchers at the Scripps Research institute have identified a biochemical switch, called adhesion receptor integrin alpha-n-beta-3, that triggers blood vessel proliferation in many tumor types. The researchers tested two proteins, one a monoclonal antibody, the other a synthetic peptide antagonist, in an attempt to block the integrin.

The team conducted a series of experiments in chick embryos. The protocol involved transplanting pieces of human tumors onto chick chorioallantoic membranes. The tumors induced angiogenesis within a few hours. After 24 hours the experimental compounds, as well as control compounds were injected into the vasculature of the chick embryo membranes.

A single injection of the monoclonal antibody or the synthetic peptide succeeded in inducing rapid regression of the tumor growth. Positive results were seen against various solid tumors including cancers of the lung, colon, breast and brain, as well as melanoma. Subsequent experiments involving mice and rabbits produced similar results.

The compounds appear to selectively promote apoptosis, or programmed cell death, of those vascular cells which were interacting with the tumors. No effects were seen on adjacent vessels within the same embryos. Remarkably, the compounds not only halted the growth of the tumors, they appeared to starve the tumors, leading to regression and sometimes disappearance of the malignant tissues. While a number of other compounds are under study to inhibit tumor angiogenesis, this is he first report of tumor regression with any compound.

"Many angiogenic inhibitors have been directed towards blocking initial cytokine-dependent induction of new vessel growth. However, these approaches are problematic owing to the fact that tumors and inflammatory cells can secrete multiple activators of angiogenesis. Therefore, our findings that the alpha-N-beta-3 antagonists inhibit angiogenesis induced by tumors of distinct histologic origin indicate a potentially powerful antiangiogenic therapeutic approach," the researchers reported in Cell.

The researchers note that considerable work lies ahead before the compounds can be tried in humans, and that the safety concerns will have to be addressed. However, it all goes well, the compounds could be in clinical trials by 1996. If the compounds fulfill their early promise, they could provide a relatively simple way both to eliminate solid tumors and prevent the metastatic spread of tumor cells by eliminating their access to the blood supply.

The research is presented in depth in Brooks et al, in Cell,12/30/94, v. 79, Brooks et al., pp 1-20.


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