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Nuclear Localization of ¹¹¹In After Intravenous Injection of [¹¹¹In-DTPA-D-Phe¹]-Octreotide in Patients with Neuroendocrine Tumors

Departments of Medical Sciences, Oncology, Radiology, and Clinical Immunology, Surgery, Genetics and Pathology, University Hospital, Uppsala, Sweden

Correspondence: For correspondence or reprints contact: Eva Tiensuu Janson, MD, PhD, Department of Medical Sciences, University Hospital, S-751 85 Uppsala, Sweden.

ABSTRACT

Treatment with tumor-targeting substances is currently being evaluated in clinical trials. For patients with neuroendocrine tumors expressing somatostatin receptors, the ¹¹¹In-labeled somatostatin analog [diethylenetriaminepentaacetic acid (DTPA)-D-Phe¹]-octreotide has been used with promising results. To further investigate the clinical effect of the injected conjugate, we analyzed the cellular distribution of ¹¹¹In by ultrastructural autora-diography. Methods: Seven patients with somatostatin receptor-expressing midgut carcinoid tumors scheduled for abdominal surgery were investigated by somatostatin receptor scintigraphy. During operation, tumor tissue samples and samples of normal intestine were collected, fixed, and processed for electron microscopy. A thin layer of film emulsion was applied on sections and after the exposure film was developed. The cellular distribution of silver precipitations indicating the presence of isotope was evaluated. Results: Cell surface receptor binding and internalization of [¹¹¹In-DTPA-D-Phe¹]-octreotide in the tumor cells was easily revealed by silver precipitations 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 the nucleus. For all patients, the silver precipitation patterns from ¹¹¹In decay were identical in all examined cells from removed tumors, and in most cells ¹¹¹In could be seen in the nucleus. The specificity of the silver reaction products is supported by the observation that enterocytes in intestinal tissue specimens from near the tumor did not show any silver grains and no background labeling was seen in the plastic. Conclusion: After intemalization through the somatostatin receptor system, ¹¹¹In 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 evaluated in this study. Despite the short irradiation range of ¹¹¹In, the nuclear localization can explain its clinical effectiveness. The results from this study suggest that [¹¹¹In-DTPA-D-Phe¹]-octreotide may act as a powerful tumor cell-targeting substance.

Key Words: autoradiography • carcinoid tumor • intemalization • octreotide • somatostatin analog • somatostatin receptor • treatment

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