We have shown that solid tumors are angiogenesis-dependent. We have worked out the sequence of steps involved in capillary growth and have shown that the rate of capillary growth can be modulated by fragments of heparin which themselves do not have anticoagulant activity. A new class of corticosteroids which are potent angiogenesis inhibitors in the presence of heparin, but have no other activity, has recently been discovered, and their structure has been elucidated. Two of these compounds are natural metabolites of cortisone which have previously been thought to be biologically inactive. When administered with hexasaccharide fragments of heparin, they inhibit angiogenesis in several in vivo systems, and also act as inhibitors of tumor growth. It appears that these """"""""angiostatic"""""""" steroids contribute to the physiologic suppression of endothelial cell turnover and that tumors must continuously override this sytem to induce angiogenesis. In another set of experiments, the high binding affinity of heparin for endothelial growth factors has permitted us to purify a tumor-derived angiogenic factor. This factor has now been found in mouse tumors, rat tumors, and in the first five human tumors tested. Furthermore, a similar factor has been found in some normal tissues (hypothalamus and brain). It now appears that the major difference between normal and neoplastic tissues is that tumors express these angiogenesis factors continuously, whereas normal tissues rarely express them, and then only under a tightly regulated program. Current work is focused on: (1) animal studies necessary for preparing the angiostatic steroids for clinical trial; and (2) determination of the amino acid sequence of the pure tumor angiogenic factor and production of antibodies against it. (J)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037395-05
Application #
3175268
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1983-01-01
Project End
1987-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Folkman, Judah (2006) Angiogenesis. Annu Rev Med 57:1-18
Satchi-Fainaro, Ronit; Mamluk, Roni; Wang, Ling et al. (2005) Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell 7:251-61
Sternlicht, M D; Werb, Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463-516
O'Reilly, M S; Brem, H; Folkman, J (1995) Treatment of murine hemangioendotheliomas with the angiogenesis inhibitor AGM-1470. J Pediatr Surg 30:325-9;discussion 329-30
Nguyen, M; Watanabe, H; Budson, A E et al. (1994) Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 86:356-61
Li, V W; Folkerth, R D; Watanabe, H et al. (1994) Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumours. Lancet 344:82-6
Nguyen, M; Watanabe, H; Budson, A E et al. (1993) Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients. J Natl Cancer Inst 85:241-2
Brem, H; Gresser, I; Grosfeld, J et al. (1993) The combination of antiangiogenic agents to inhibit primary tumor growth and metastasis. J Pediatr Surg 28:1253-7
Folkman, J; Szabo, S; Stovroff, M et al. (1991) Duodenal ulcer. Discovery of a new mechanism and development of angiogenic therapy that accelerates healing. Ann Surg 214:414-25;discussion 426-7
Li, W W; Grayson, G; Folkman, J et al. (1991) Sustained-release endotoxin. A model for inducing corneal neovascularization. Invest Ophthalmol Vis Sci 32:2906-11

Showing the most recent 10 out of 25 publications