o-(chloroacetylcarbamoyl)fumagillol and Endometriosis

Endometriosis is a debilitating disease characterized by the growth of ectopic endometrial tissue. It is widely accepted that angiogenesis plays an integral part in the establishment and growth of endometriotic lesions. Recent data from a variety of angiogenesis-dependent diseases suggest a critical role of bone marrow-derived endothelial progenitor cells (EPCs) in neovascularization. In this study we examined the blood levels of EPCs and mature circulating endothelial cells in a mouse model of surgically induced endometriosis. Fluorescence-activated cell sorting analysis revealed elevated levels of EPCs in the blood of mice with endometriosis compared with control subject that underwent a sham operation. EPC concentrations positively correlated with the amount of endometriotic tissue and peaked 1 to 4 days after induction of disease. In a green fluorescent protein bone marrow transplant experiment we found green fluorescent protein-positive endothelial cells incorporated into endometriotic lesions but not eutopic endometrium, as revealed by flow cytometry and immunohistochemistry. Finally, treatment of endometriosis-bearing mice with the angiogenesis inhibitor Lodamin, an oral nontoxic formulation of TNP-470, significantly decreased EPC levels while suppressing lesion growth. Taken together, our data indicate an important role for bone marrow-derived endothelial cells in the pathogenesis of endometriosis and support the potential clinical use of anti-angiogenic therapy as a novel treatment modality for this disease.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Bone Marrow Transplantation; Cell Separation; Cyclohexanes; Disease Models, Animal; Endometriosis; Endothelial Cells; Female; Flow Cytometry; Green Fluorescent Proteins; Immunohistochemistry; Mice; Mice, Inbred C57BL; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Stem Cells; Up-Regulation

Endometriosis, the presence of ectopic endometrial tissue, is a common disease associated with high morbidity and socioeconomic problems. Angiogenesis, the formation of new blood vessels, plays an important role in the formation and growth of endometriotic lesions. We have created a novel, noninvasive model to monitor the growth of these lesions and the associated angiogenesis in vivo. First, we generated luciferase-expressing transgenic mice by inserting the human ubiquitin C promoter coupled to the firefly luciferase reporter. Injection of luciferin in these mice causes full-body bioluminescence, which can be detected using a low-light CCD camera. Endometrial tissue from these transgenic mice was surgically implanted into nonluminescent recipients. Bioluminescence of lesions was noninvasively imaged after intravenous or intraperitoneal injection of luciferin. Transabdominal luminescence compared well with the location of the transgenic endometriotic lesions, and lesion size correlated with the intensity of luminescence. Systemic treatment with the angiogenesis inhibitors caplostatin and endostatin peptide mP-1 delayed and suppressed the onset and intensity of the luminescent signal. Caplostatin suppressed the growth of endometriotic lesions by 59% compared with controls. This novel, noninvasive model of endometriosis provides a means to study early angiogenesis in vivo and to monitor endometriotic growth and the efficacy of systemic antiangiogenic therapy.

Topics: Angiogenesis Inhibitors; Animals; Cyclohexanes; Disease Models, Animal; Endometriosis; Endometrium; Female; Humans; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes

A prospective study was performed to determine the effects of the angiostatic compounds anti-hVEGF antibody, TNP-470, endostatin, and anginex on the vascularization and on endometriosis-like lesion formation in the chicken chorioallantoic membrane model. Endometriosis-like lesion formation was significantly impaired after treatment with angiostatic agents, which was associated with decreased vessel densities in the surrounding chorioallantoic membrane and more necrosis in the endometriosis-like lesions.

Topics: Angiogenesis Inhibitors; Animals; Antibodies; Chick Embryo; Chickens; Chorioallantoic Membrane; Cyclohexanes; Endometriosis; Endostatins; Female; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Vascular Endothelial Growth Factor A

It is known that angiogenesis is of pivotal importance for the development of endometriosis. However, in the treatment of endometriosis patients, prevention of endometriosis lesion development only will not be sufficient as a therapy. Treatment options, aimed at interfering with established lesions, have to be developed. In this study we evaluated whether inhibition of angiogenesis by angiostatic therapy is also effective in antagonizing the sustentation of endometriosis. We evaluated the effect of the angiostatic compounds antihuman vascular endothelial growth factor, TNP-470, endostatin, and anginex on the growth of established endometriosis lesions in the nude mouse model. We show that human endometrium in the proliferative endometrium is highly angiogenic and that vascular endothelial growth factor-A is the most important angiogenesis promotory factor. The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions. In the remaining lesions, the number of pericyte-protected vessels is not different in control and treated mice; however, the number of unprotected vessels was significantly reduced in the groups treated with the angiostatic agents. Our data demonstrate that inhibitors of angiogenesis effectively interfere with the maintenance and growth of endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis.

Topics: Adult; Angiogenesis Inhibitors; Animals; Cyclohexanes; Endometriosis; Endometrium; Endostatins; Female; Humans; Mice; Mice, Nude; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peptides; Proteins; Sesquiterpenes