Angiogenesis inhibitors are administered to patients in an amount effective
to regulate normal, non-transformed vascularized tissue size and/or growth
by regulating its vascular compartment. Examples of tissues that can be
controlled include adipose tissue, intestinal polyps, muscle (including
cardiac) tissue, and endometrial tissue. The response of these tissues to
the angiogenesis inhibitors is dose-dependent, reversible, and common to a
variety of different angiogenesis inhibitors (examples use TNP-470,
angiostatin, and endostatin), based on studies in animal models of
obesity, intestinal polyps, cardiac hypertrophy, and endometriosis.
Initial studies conducted in an adipose tissue model (genetically obese
mice and normal control mice) showed that the growth and mass of adipose
tissue is under the control of microvascular endothelium. Expansion of
adipose tissue was associated with endothelial cell proliferation.
Inhibition of angiogenesis led to reduction in adipose tissue mass. Weight
gain in animals receiving angiogenesis inhibitors was significantly
restricted, in spite of increases in appetite sufficient to cause weight
gain in paired-fed mice. Discontinuation of the inhibitor resulted in
rapid expasion of the adipose tissue. The effect was dose-dependent,
repeatedly reversible, and occurred in response to all of the inhibitors
tested. Significant inhibition was also observed in both the intestinal
polyp and cardiac hypertrophy animal models, using dosages of two-thirds
or less than the dosages used to treat tumors. Preliminary results in an
endometriosis model also show a clear trend towards decreased development
of endometriosis in animals treated with angiogenesis inhibitors at a
dosage of one-third the dosage used to treat tumors. No effect on normal
tissue that was not proliferating, other than adipose tissue, was
observed.