Fighting ANs with Drugs:
the option of the future?
1. Proteins proven to dissolve tumors in mice
(from a patient, Feb. 1999)
I read reports last week that the FDA in conjunction with the National Cancer Institute have completed animal trials on angiostatin and endostatin which have proved to dissolve large tumors in mice, and they are beginning human trials in the next month. By the end of the year there may be some information regarding the action of endostatin and angiostatin on the growth of tumors. These products are two proteins which are extremely effective in preventing the growth of blood vessels that tumors need to obtain nutrients - a concept known as anti-angiogenisis. I am not sure how this will relate to benign tumors such as ANs, but even if they work on malignant tumors the results of the trials will be phenomenal. AN patients who have not been treated as yet, can only hope that if these tumor-shrinking drugs prove to work with maliganant tumors that they may also work for ANs!
2. Clues are discovered how these proteins work in humans
A Boston area newspaper, The Patriot Ledger, printed a piece in 3/99 entitled "Enzyme Discovery May Help Fight the Growth of Tumors". It is based on a recent article by Dr. Salvatore V. Pizzo (Duke University) in the Proceedings of the National Academy of Sciences, reporting that an enzyme ATP synthase was discovered to promote the growth of blood vessels which feed tumors in humans.
If tumors could not develop the blood vessels needed to receive nutrients, they would not grow beyond the size of a pinhead. Earlier, Dr. Judah Folkman (Children's Hospital, Boston) showed that he was able to stop tumor growth in mice by blocking the formation of blood vessels with compounds angiostatin and endostatin. Since then, a number of compounds that can block blood vessel formation in humans have been discovered, including angiostatin.
The Duke discovery may provide an answer to why these compounds work, putting researchers on track to isolate the component of angiostatin that works directly to block blood vessel formation in tumors. It is hoped that this will lead to new drugs to fight cancer; we hope it will also provide a new alternative to surgery for AN patients!
3. Many biomed start-ups are already hard at work
More than a dozen companies and laboratories are working on ways to starve cancer by cutting off a tumor's blood supply. Some seek to block the tiny new capillaries grown by tumors. Others work to stop the little blood vessels from ever forming. They include:
Canadian biotech company AEterna Laboratories is in Phase III clinical trials with a shark-based compound Neovastat. It is not clear how Neovastat stops vessel growth.
Agouron is in Phase III trials with its drug AG3340 for patients with advanced lung or prostate cancer. It works against an enzyme known as matrix metalloprotease (or metalloproteinase, also called MMP), which is involved in angiogenesis, or the growth of new blood vessels. AG3340 has been shown to starve tumors in animals, and initial human tests show it can shrink tumors.
British Biotech Plc., has a drug Marimastat that works against MMP. Marimastat is in Phase III clinical trials against several cancers, the final stage before the U.S. Food and Drug Administration (FDA) considers approval of a drug. So far, it has not done well against ovarian and pancreatic cancer.
Bayer Corporation has an MMP drug, 12-9566, in Phase III trials against lung and pancreatic cancer.
Carbomed, a firm put together by Vanderbilt University scientists in Tennessee, has a drug, CM101, in Phase I safety trials. It not only blocks the growth of new blood vessels but may also help regenerate severed nerves. It is licensed to Zeneca Plc.
Chiroscience Group Plc has an MMP inhibitor called D2163 about to go into its first human trials. The company, based in Britain, has an agreement with Bristol Myers Squibb to develop the drug.
Collagenex has yet another MMP inhibitor called Metastat, also known as COL-3. It is in Phase I safety trials in people under NCI auspices.
Cytran, a privately held company in Kirkland, Washington, is in Phase III trials of its IM862 against Kaposi's sarcoma, one of the defining diseases of AIDS.
EntreMed has three compounds that affect angiogenesis -- endostatin and angiostatin as well as thalidomide, the once-banned tranquilizer that has been found to help some cancers. Thalidomide is in Phase II trials.
The Genetics Institute of Cambridge, Massachusetts, is in Phase II trials of Interleukin-12, a natural immune signaling chemical that stops the growth of endothelial cells that line blood vessels.
Genentech of South San Francisco has a monoclonal antibody -- a kind
of self-targeting bullet -- that attacks
vascular endothelial growth factor (VEGF), the main protein responsible for starting blood vessel development. Known as RhuMab, it is in Phase II clinical trials against lung, breast, prostate and colorectal cancer.
ImClone Systems Incorporated of New York is working to develop antibodies to VEGF as well.
Ixsys Inc., a small La Jolla, California, company, has a drug called Vitaxin in Phase II trials of patients with leiomyosarcoma, a kind of muscle cancer. This monoclonal antibody homes in specifically against integrin, a protein needed for the development of new blood vessels.
Novartis has an MMP inhibitor called MMI270 in Phase I/II clinical trials.
The NCI is testing a compound known as CAI against ovarian, fallopian tube and primary peritoneal cancers and is in Phase II studies with this. It is not clear how it works.
Magainin Pharmaceuticals is in Phase I safety tests of squalamine, a compound derived from shark cartilage, which stops blood vessel growth by inhibiting the sodium-hydrogen exchanger in cells.
Sugen Inc has three anti-angiogenesis compounds in trials including SU5416, which blocks VEGF signaling, SU101, which blocks platelet-derived growth factor and is in Phase II clinical trials, and SU6668, about to enter Phase I trials.
TAP Pharmaceuticals, Inc. has a product called TNP-470, a chemical version of a fungus that acts against endothelial cells, in Phase II trials.
Then there are vascular targeting agents. Techniclone is developing drugs that would cause blood clots to choke off blood vessels that tumors grow. Vascular targeting agents induce coagulation, and can actually kill the tumor.
Swedish-based Oxigene is developing Combretastatin, derived from the African bush willow, for use against tumors.©
Last Edited: Wednesday, October 30, 2002