Nuclear localization of In-111 after intravenous injection of [In-111-DTPA-D-Phe(1)]-octreotide in patients with neuroendocrine tumors

Treatment with tumor-targeting substances is currently being evaluated in c linical trials. For patients with neuroendocrine tumors expressing somatost atin receptors, the In-111-labeled somatostatin analog [diethylenetriaminep entaacetic acid (DTPA)-D-Phe(1)]-octreotide has been used with promising re sults. To further investigate the clinical effect of the injected conjugate , we analyzed the cellular distribution of (111)ln by ultrastructural autor adiography. Methods: Seven patients with somatostatin receptor-expressing m idgut carcinoid tumors scheduled for abdominal surgery were investigated by somatostatin receptor scintigraphy. During operation, tumor tissue samples and samples of normal intestine were collected, tired, and processed for e lectron microscopy. A thin layer of film emulsion was applied on sections a nd after the exposure film was developed. The cellular distribution of silv er precipitations indicating the presence of isotope was evaluated. Results : Cell surface receptor binding and internalization of [In-111-DTPA-D-Phe(1 )]-octreotide in the tumor cells was easily revealed by silver precipitatio ns in the film. Multiple silver grains were seen at the plasma membrane, in the cytoplasmic area among secretory granules and vesicular compartments. and in the perinuclear area. Silver grains were also regularly located in t he nucleus. For ail patients, the silver precipitation patterns from In-111 decay were identical in all examined cells from removed tumors, and in mos t cells In-111 could be seen in the nucleus. The specificity of the sliver reaction products is supported by the observation that enterocytes in intes tinal tissue specimens from near the tumor did not show any silver grains a nd no background labeling was seen in the plastic. Conclusion: After intern alization through the somatostatin receptor system, In-111 is translocated to the perinuclear area and into the nucleus. Whether the nuclide is still conjugated to the intact somatostatin analog or to part of it cannot be eva luated in this study. Despite the short irradiation range of In-111, the nu clear localization can explain its clinical effectiveness. The results from this study suggest that [In-111-DTPA-D-Phe(1)]-octreotide may act as a pow erful tumor cell-targeting substance.