Antiangiogenesis as a Mechanism for the Antitumor Effects of Octreotide

September 1, 2002

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) vein segments.

Octreotide acetate (Sandostatin), a somatostatin receptorsubtype 2 (sst 2)-preferring somatostatin analog, inhibits angiogenesis in adose-dependent fashion in the chicken chorioallantoic membrane model (CAM) andin the human placental vein angiogenesis model (HPVAM).[1,2] To explain theseantiangiogenic effects, sst 2 gene expression in normal (resting) full-thicknesshuman placental vein segments was compared to tissue-matched counterparts thatinitiated an angiogenic response in culture. Using polymerase chain reaction (PCR)techniques, the sst 2 gene was found to be uniquely up-regulated in theangiogenic vessels, but not present in the tissue-matched resting (nonproliferative)vein segments.

To determine if this unique gene up-regulation resulted insst 2 receptor expression, normal and proliferating vein segments were stainedwith an anti-sst 2 antibody. Immunohistochemical evaluation showed that normalblood vessels exhibit no antibody localization, while the proliferating portionsof the angiogenic disk exhibited universally intense staining.[3] To confirm that these receptors werefunctional, mouse xenografts of SKNSH (sst 2-negative) human neuroblastomacells were treated with a radiolabeled sst 2-preferring analog, the backgroundallowed to clear, and the mouse scanned for evidence of somatostatin analogbinding to the sst 2 receptors expressed on the angiogenic response to this sst2-negative tumor. Intense binding in the tumor confirmed the functional natureof these receptors.[3]

To examine the development of an angiogenic responsefollowing exposure to radiolabeled somatostatin analogs, placental vein diskswere exposed to an 111In-labeledsomatostatin analog. The treated vessels exhibited a reduction in the initiationof their angiogenic response and exhibited inhibition of subsequent vesselgrowth.[4] Using cultured human tumor xenografts or fresh human tumor fragments,111In-pentetreotidetreatment of tumors can be directed at either the sst 2-expressing angiogenicvessels, the sst 2-expressing tumor cells, or a combination of the tumor cellsand their angiogenic response.[5]

Based on these observations, the antitumor activity ofoctreotide is likely the result of combined antitumor and antiangiogeniceffects. Unlabeled somatostatin analogs such as octreotide acetate and theirradiolabeled counterparts can effectively block the human angiogenic response.

References:

1. Woltering EA, Barrie R, O’Dorisio TM, et al:Somatostatin analogues inhibit angiogenesis in the chick chorioallantoicmembrane. 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. InvestNew Drugs 15:77-86, 1997.

3. Watson JC, Balster DA, Gebhardt BM, et al: Growingvascular endothelial cells express somatostatin subtype 2 receptors. Br JCancer 85:266-272, 2001.

4. Gulec SA, Gaffga CM, Anthony CT, et al: Antiangiogenictherapy with somatostatin receptor-mediated in situ radiation. Am Surg 67:1068-1071,2001.

5. Gulec SA, Drouant GJ, Fuselier J, et al: Antitumor and antiangiogeniceffects of somatostatin receptor-targeted in situ radiation with 111In-DTPA-JIC2DL. J Surg Res 97:131-137, 2001.