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
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.