National Cancer Institute Addresses Anti-Angiogenesis Issues

The National Cancer Institute (NCI), a division of the U.S. Department of Health and Human Services, responded this week to many of the questions raised by recent media coverage of anti-angiogenesis research.

An article in the New York Times, Sunday, May 3, 1998 discussed research on the effects of angiostatin and endostatin, two anti-angiogenic proteins that inhibit the formation of blood vessels that feed tumors. According to NCI, the Times article did not contain any new information. No public announcement regarding any new research finding about angiostatin and endostatin has been made by the NCI or any other research institution, NCI said.

On Nov. 27, 1997, Dr. Judah Folkman and colleagues at Children's Hospital in Boston reported data in the scientific journal Nature indicating that endostatin and angiostatin worked better in combination than either one alone in inducing the regression of tumors in mice. So far, these are the only published data from the Folkman laboratory on this subject. Several published articles have replicated Folkman's findings on angiostatin. See references

Folkman has presented other unpublished data on both angiostatin and endostatin at several meetings recently but according to NCI, it will be several more months before these results will appear in a scientific journal.

At least 11 compounds that may target angiogenesis are now in clinical trials, NCI said. Some of these are proteins; some are smaller molecules. While most are in early, Phase I or II trials, some are in later stage, or Phase III trials, potentially leading to the Food and Drug Administration's (FDA) approval and more widespread use. A number of other angiogenesis inhibitors, including angiostatin and endostatin, should enter clinical trials in about a year.

The table below lists the angiogenesis inhibitors now in clinical trials, and whether they are in Phase I, II, or III. NCI is involved in the evaluation of thalidomide and Col-3, and is negotiating with biotechnology companies to work on other compounds.

DRUG	PHASE OF TRIAL	SPONSOR
TNP-470	Phase II	TAP Pharmaceuticals, Deerfield, WI
Squalamine	Phase I	Magainin Pharmaceuticals, Plymouth Meeting, PA
Vitaxin	Phase I	Ixsys, Inc. San Diego, CA
Thalidomide	Phase II1	EntreMed, Inc. Rockville, MD
RhuMab, VEGF	Phase II	Genentech, Inc. South San Francisco, CA
SU5416	Phase I	Sugen, Inc. Redwood City, CA
Marimastat	Phase III2	British Biotech, Inc. Annapolis, MD
Bay 12-9566	Phase III3	Bayer Corp. West Haven, CT
AG3340	Phase III4	Agouron Pharmaceuticals La Jolla, CA
Col-3	Phase I	CollaGenex Pharmaceuticals Newton, PA
CM101	Phase I	Carbomed Brentwood, TN
1 Against Kaposi's sarcoma, breast, prostate, and primary brain cancers 2 Against pancreas, lung, gastric and breast cancers and glioma 3 Against lung and pancreas cancers 4 Against lung and prostate cancers

When the supply of nutrients from the blood is cut off, a tumor shrinks and dies. Angiostatin and endostatin have been shown to stop tumor growth in preclinical studies in mice. Unlike many other anti-angiogenesis drugs currently under investigation, angiostatin and endostatin are naturally occurring proteins found in the body.

In the published work with mice, scientists have been treating tumors that were transplanted into the mice, rather than tumors that developed naturally in mice, as they do in people. Tumors transplanted into mice have a different biology than naturally occurring tumors and are often not accurate predictors of what will happen in natural human cancers.

Neither angiostatin nor endostatin has entered any human studies yet, and researchers expect they will not begin such testing for at least a year. The compounds would not be available for compassionate use until after they had shown some activity against cancer in studies with cancer patients.

In the past, compounds with promising results in mice have proved less successful in treating human cancers. In the 1980s, interleukin-2 was very successful in treating tumors in mice. But subsequent studies in people showed that interleukin-2 caused significant side effects, such as severe drops in blood pressure and the leaking of fluid from blood vessels. These difficulties in people were not predicted based on the mouse studies. A large number of chemotherapy drugs have much greater effectiveness against mouse tumors than against human cancers.

The Cancer Information Service, NCI's national information and education network, provides a toll-free number (1-800-4-CANCER) for patients, the public, and health professionals to have access to the latest, most accurate, up-to-date cancer information.

NCI will also provide information at http://cancertrials.nci.nih.gov, its recently launched clinical trials site.

Edited by Beth Brindle

References for research replicating Folkman's findings (Folkman's journal citation is Nature 390: 404-407.)

Doug Z., Kumar R., Yang X., Fidler I.J. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 1997; 88:801-10.

Gately S., Twardowski P., Stack M.S., et al. Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin. Cancer Research 1996; 56:4887-90.

Gately S., Twardowski P.K., Stack M.S., et al. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA 1997; 94:10868-72.

Lannutti B.J., Gately S.T., Quevedo M.E., Soff G.A., Paller A.S. Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Research 1997; 57:5277-80.
Back to text