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Increased Cell Death After Therapy with an Arg-Gly-Asp-Linked Somatostatin Analog

¹ Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
² Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

ABSTRACT

Receptor-targeted scintigraphy and radionuclide therapy with radiolabeled somatostatin analogs are successfully applied for somatostatin receptor-positive tumors. The synergistic effects of an apoptosis-inducing factor, for example, the Arg-Gly-Asp (RGD) motif, can increase the radiotherapeutic efficacy of these peptides. Hence, the tumoricidal effects of the hybrid peptide RGD-diethylaminetriaminepentaacetic acid (DTPA)-Tyr³-octreotate (cyclic[c](Arg-Gly-Asp-D-Tyr-Asp)-Lys(DTPA)-D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr), hereafter referred to as RGD-DTPA-octreotate, were evaluated in comparison with those of RGD (c(Arg-Gly-Asp-D-Tyr-Asp)) and Tyr³-octreotate (D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr). Methods: The therapeutic effects of RGD-¹¹¹In-DTPA-octreotate, ¹¹¹In-DTPA-RGD, and ¹¹¹In-DTPA-Tyr³-octreotate were investigated with various cell lines by use of a colony-forming assay, and caspase-3 activity was also determined. Results: Tumoricidal effects were found with ¹¹¹In-DTPA-RGD, ¹¹¹In-DTPA-Tyr³-octreotate, and RGD-¹¹¹In-DTPA-octreotate, in order from least effective to most effective. Also, the largest increase in caspase-3 levels was found with RGD-¹¹¹In-DTPA-octreotate. Conclusion: RGD-¹¹¹In-DTPA-octreotate has more pronounced tumoricidal effects than ¹¹¹In-DTPA-RGD and ¹¹¹In-DTPA-Tyr³-octreotate, because of increased apoptosis, as indicated by increased caspase-3 activity.

Key Words: apoptosis • caspase-3 • octreotate • radionuclide therapy • Arg-Gly-Asp

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