Angiogenesis and its inhibition represent one of the fasted growing areas of oncology. This therapeutic class remains very much experimental and although there has been a massive 7-fold increase in the number of angiogenesis inhibitors that have passed through preclinical stages of development into the clinic, market entry remains poor. This however is expected to change and indeed by 2006, the market for all products that play a role in angiogenesis is likely to reach $1.75 billion. Current trends are to identify pharmacological targets to allow selective and effective inhibition of angiogenesis. For example we recently reported on PlGF which is being developed by ThromboGenics as a target since it is over-expressed predominantly under pathological conditions (click here for more details). One area that is attracting rapidly increasing interest with respect to tumor angiogenesis and indeed tumor progression in general is the field of hemastasis. Plasminogen activation to plasmin under the control of enzymes including tPA and urokinase (u-PA) is crucial for the regulation of coagulation since plasmin plays a key role in the digestion of fibrin in blood clots. Plasminogen activation also plays critical roles in cell migration related to tumor growth and metastasis. For example, high u-PA levels are significantly associated with short overall survival in both premenopausal and postmenopausal breast cancer patients. The effect of plasminogen activation on tumor progression is related to proteolytic degradation of the matrix and resultant dissemination of tumor cells and facilitation of capillary tip advancement. Consequently inhibitors of plasminogen activation/u-PA have been shown to slow tumor progression. Much the same can be said of some members of the cathepsin family of lysosomal cysteine proteases and their inhibitors. For example, increased expression of the cathepsin B has been observed in many etiologically different tumors, including human brain, prostate, breast, and gastrointestinal cancers. Immunohistochemical and in situ histochemical studies have demonstrated expression of cathepsin B in neovessels induced during malignant progression of human suggesting a role in angiogenesis. With this background in mind, recent data reported by Japanese researchers are particularly exciting. Researchers at Kanazawa and Osaka Universities have developed a series of 13 ozonides. Representatives from this series inhibited in vitro u-PA production of HT-1080 cells and also exhibited strong anti-angiogenic activity. As well as blocking u-PA activity these molecules also inhibited cathepsin B activity. One molecule, 1-Phenyl-1, 4-epoxy-1H,4H-naphtho[1,8-de][1, 2]dioxepin (ANO-2) potently inhibited cathepsin B at sub-micromolar concentration as well as u-PA production, and was thus developed as a lead. ANO-2 inhibited tube formation by human umbilical vein endothelial cells cultured on Matrigel while exhibiting no cytotoxicity. Additionally, in vivo administration of ANO-2 inhibited angiogenesis induced by mouse Sarcoma-180 cells tested using the mouse dorsal air sac assay. Moreover, ANO-2 also suppressed primary tumor growth and reduced the number of pulmonary metastases caused by Lewis lung carcinoma cells in mice. These in vitro and in vivo activities indicate that ANO-2 has considerable potential as a new and potent anti-angiogenic drug that inhibits both u-PA production and enzymatic activity of cathepsins, indicating that ANO-2 may be a multifunctional inhibitor of angiogenesis.

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