Increased cell death after therapy with an Arg-Gly-Asp-linked somatostatin analog.
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.


CONCLUSIONS
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.
Capello
Astrid
A
Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. a.capello@erasmusmc.nl
Krenning
Eric P
EP
Bernard
Bert F
BF
Breeman
Wout A P
WA
van Hagen
Martin P
MP
de Jong
Marion
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical; D007205:Indium Radioisotopes / Q000008:administration & dosage*; D009842:Oligopeptides / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000532:radiotherapy*; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D016499:Radioimmunotherapy / Q000379:methods; D051381:Rats; D016896:Treatment Outcome
D007205:Indium Radioisotopes; D009842:Oligopeptides; D010456:Peptides, Cyclic; C470036:octreotate, Tyr(3)-; C047981:arginyl-glycyl-aspartic acid