Octreotide acetate (Sandostatin), a somatostatin receptor
subtype 2 (sst 2)-preferring somatostatin analog, inhibits angiogenesis in a
dose-dependent fashion in the chicken chorioallantoic membrane model (CAM) and
in the human placental vein angiogenesis model (HPVAM).[1,2] To explain these
antiangiogenic effects, sst 2 gene expression in normal (resting) full-thickness
human placental vein segments was compared to tissue-matched counterparts that
initiated an angiogenic response in culture. Using polymerase chain reaction (PCR)
techniques, the sst 2 gene was found to be uniquely up-regulated in the
angiogenic vessels, but not present in the tissue-matched resting (nonproliferative)
To determine if this unique gene up-regulation resulted in
sst 2 receptor expression, normal and proliferating vein segments were stained
with an anti-sst 2 antibody. Immunohistochemical evaluation showed that normal
blood vessels exhibit no antibody localization, while the proliferating portions
of the angiogenic disk exhibited universally intense staining. To confirm that these receptors were
functional, mouse xenografts of SKNSH (sst 2-negative) human neuroblastoma
cells were treated with a radiolabeled sst 2-preferring analog, the background
allowed to clear, and the mouse scanned for evidence of somatostatin analog
binding to the sst 2 receptors expressed on the angiogenic response to this sst
2-negative tumor. Intense binding in the tumor confirmed the functional nature
of these receptors.
To examine the development of an angiogenic response
following exposure to radiolabeled somatostatin analogs, placental vein disks
were exposed to an 111In-labeled
somatostatin analog. The treated vessels exhibited a reduction in the initiation
of their angiogenic response and exhibited inhibition of subsequent vessel
growth. Using cultured human tumor xenografts or fresh human tumor fragments,
treatment of tumors can be directed at either the sst 2-expressing angiogenic
vessels, the sst 2-expressing tumor cells, or a combination of the tumor cells
and their angiogenic response.
Based on these observations, the antitumor activity of
octreotide is likely the result of combined antitumor and antiangiogenic
effects. Unlabeled somatostatin analogs such as octreotide acetate and their
radiolabeled counterparts can effectively block the human angiogenic response.
1. Woltering EA, Barrie R, O’Dorisio TM, et al:
Somatostatin analogues inhibit angiogenesis in the chick chorioallantoic
membrane. J Surg Res 50:245-251, 1991.
2. Woltering EA, Watson JC, Alperin-Lea RC, et al:
Somatostatin analogs: angiogenesis inhibitors with novel mechanisms of action. Invest
New Drugs 15:77-86, 1997.
3. Watson JC, Balster DA, Gebhardt BM, et al: Growing
vascular endothelial cells express somatostatin subtype 2 receptors. Br J
Cancer 85:266-272, 2001.
4. Gulec SA, Gaffga CM, Anthony CT, et al: Antiangiogenic
therapy with somatostatin receptor-mediated in situ radiation. Am Surg 67:1068-1071,
5. Gulec SA, Drouant GJ, Fuselier J, et al: Antitumor and antiangiogenic
effects of somatostatin receptor-targeted in situ radiation with 111In-DTPA-JIC
2DL. J Surg Res 97:131-137, 2001.