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Antiangiogenesis as a Mechanism for the Antitumor Effects of Octreotide

Antiangiogenesis as a Mechanism for the Antitumor Effects of Octreotide

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.

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.[3] 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.[3]

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.[4] Using cultured human tumor xenografts or fresh human tumor fragments, 111In-pentetreotide 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.[5]

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.

References

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, 2001.

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.

 
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