For OA to be considered an effective anti-angiogenic agent, it must possess certain attributes; these include: (1) The ability to inhibit endothelial cell proliferation and migration in in vitro systems such as monolayer culture. We have shown that OA not only inhibits endothelial cell growth in monolayer culture but also inhibits angiogenesis in the human placental vein angiogenesis model (HPVAM); (2) The ability to inhibit angiogenesis in in vivo models such as the rabbit cornea or CAM models. We were the first group to demonstrate that OA inhibits angiogenesis using the CAM model. Using this system, we defined the somatostatin receptor subtype responsible for and defined the specific post-receptor signal transduction mechanisms involved in octreotide's inhibition of angiogenesis; (3) The ability to inhibit primary tumor growth in vitrolin vivo. Evidence for OA's ability to inhibit breast cancer (MCF-7, T-47-D) growth has been demonstrated in vitro by our group and others. Evidence of OA's ability to inhibit primary tumor growth in vivo has been provided by Weber et al., who demonstrated that octreotide therapy on MCF-7 and BT-20 implants in nude mice resulted in reduced tumor growth and increased tumor doubling time; (4) The ability to alter the initiation of primary tumors induced by carcinogens in vivo. Evidence of octreotide's ability to block or limit the development of carcinogen-induced tumors comes from the work of Weckbecker et al., who demonstrated that OA could block the development of and subsequent growth of DMBA-induced breast cancer in an in vivo (rat) model; and (5) The ability to alter the initiation/promotion of metastasis in an in vivo model. Weckbecker et al. demonstrated that oophorectomy induced only temporary remissions in DMBA-induced breast metastasis growth. Animals treated by oophorectomy (or oophorectomy combined with OA) had equivalent initial tumor growth response rates. Animals maintained on OA after oophorectomy regrew significantly fewer (number) and smaller (volume) metastatic sites. No data currently exist that demonstrates that OA can block the development of metastasis de novo. Inhibition of angiogenesis in the CAM model, the HPVAM, and in the in vivo systems cited above appears to be optimal at octreotide concentrations of 10-8 M (10,000 pg/ml). This level can be achieved in patients treated with higher doses of octreotide (2 mg/day or greater). Doses of lanreotide up to 18 mg/day and doses of octreotide up to 8 mg/day have been used clinically with few side effects. The biphasic dose response curves for endothelial cell growth and breast cancer growth observed in our laboratory predicts that the optimum circulating drug level must be tightly regulated for maximal drug effect. We feel that continuous subcutaneous administration of OA by an insulin pump provides the most consistent circulating drug levels. We currently measure octreotide acetate levels weekly or bi-weekly in patients beginning octreotide therapy and adjust daily drug dose to maintain octreotide levels at 10,000-15,000 pg/ml ≃ (10-8 M). Further studies are needed to conclude that OA is an effective inhibitor of angiogenesis in humans. Furthermore, in women with breast cancer, it will be critical to determine the role of hormones on angiogenesis induction or promotion as well as to determine the effect of OA in combination with hormones on angiogenesis. A proposed clinical trial (NSABP, B-29) which uses tamoxifen or tamoxifen plus octreotide in women with ER/PR+ breast cancers may help answer some of these questions. In summary, angiogenesis is under complex, multifactorial regulation, however, a more detailed understanding is needed of tumor-induced angiogenesis. Determination of the specific growth factor responsible for the induction and promotion of tumor-induced angiogenesis should ultimately enable the development of more effective anti-angiogenic somatostatin analogs, more effective tumor vessel targeting, and more efficient, non-toxic, anti-angiogenic therapies. We believe that our studies and the other studies outlined above have shown that SST-2-preferring somatostatin analogs such as octreotide acetate have significant anti-angiogenic activity in in vitro models and in in vivo models and should be used in clinical trials that test their angiogenic inhibitory effects on human tumors.
