At SRI International, we have developed a novel class of steroidal compounds aimed at blocking the angiogenic process in cancerous tissues. Tumor growth and metastasis is largely dependent on the angiogenic process to form new blood vessels to supply the tissues with nutrients and oxygen allowing the cancer cells to proliferate. The mechanisms tumors utilize for growth resemble those present in wound healing in that the response is generated by the host tissue when it senses injury by forming fibrin at the injured site. The formation of fibrin attracts the inflammatory and endothelial cells to invade the fibrin provisional matrix and transform it into granulation tissue, which represents a balanced mix of angiogenesis and matrix development. Normally, this process is self-limiting and results in scar tissue formation, but tumors take advantage of this process by limiting the remodeling phase of wound healing. Instead, tumors continue to form new blood vessels and matrix, by-passing the regulatory pathways. The lead compound, SR16388, potently inhibited the proliferation of human microvascular endothelial cells in vitro (IC50 = 80 nM). It reduced the angiogenesis response as measured by microvessel density during wound healing using a Fibrin Z-chamber rat model and at 3 mg/kg, the microvessel density was reduced by 30% as compared to control. The remodeling phase of the wound healing response as measured by granulation tissue thickness in the Fibrin Z-chamber rat model was also inhibited and at 3 mg/kg, the granulation tissue thickness was reduced by 25% of the control. In additional, SR16388 inhibited embryonic angiogenesis as measured in the chick chorioallantoic membrane (CAM) assay. At 3 μg/CAM, at Day 7 the blood vessel density was reduced by 70% of control by SR16388. SR16388 also inhibits proliferation of breast, ovarian, and prostate cancer cells in vitro in addition to being an angiogenesis inhibitor. It induces apoptosis of prostate cancer cells as measured by the TUNEL assay, and induces G1 phase arrest of prostate cancer cells as measured by flow cytometer. In vivo, a single daily oral dose of SR16388 inhibited tumor growth of PC-3 prostate cancer xenografts in nude mice in a dose dependent manner without observable side effect. In conclusion, we believe that SR16388 has great potential for the treatment of various cancers by attacking both the growth of tumor cells and their blood supply.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]