The mechanism responsible for alterations in tumor growth following administration of somatostatin analogues is unknown. Somatostatin analogues, SMS 201-995 and RC-160, have demonstrated the potential to inhibit both tumor growth and vascularity, in vivo and in vitro. We hypothesized that SMS and RC-160 inhibit angiogenesis and this inhibition may alter tumor growth. To test this hypothesis, 2 mm methylcellulose disks containing concentrations of SMS 201-995 and RC-160 at 0, 0.5, 2.5, or 50 micrograms per disk, were implanted on the chorioallantoic membrane (CAM) of 6- to 7-day-old shell-less chick embryos. Inhibition of blood vessel growth in the region of the disk was visually assessed 24-36 hr following disk implantation and graded (0-4) based on the radius of the zone of inhibition from the center of the disk. The overall incidence of inhibition for the somatostatin analogues at concentrations of 0.5, 2.5, and 50 micrograms per disk was 13, 56, and 61% for SMS and 27, 49, and 68% for RC-160, respectively. Overall incidence of inhibition for the positive (inhibitory) control was 70.5% and those for buffer (negative) controls were 3-14%. Somatostatin analogues were associated in a dose-related fashion with both a greater percentage of inhibition of blood vessel growth and an increased grade of inhibition. Inhibition of angiogenesis may be a mechanism responsible for the tumor regression observed in vivo following SMS or RC-160 therapy.