Inhomogeneous activity distribution of 177Lu-DOTA0-Tyr3-octreotate and effects on somatostatin receptor expression in human carcinoid GOT1 tumors in nude mice

Abstract

The aim of this study was to investigate the activity distribution in neouroendocrine tumors after diagnostic, or therapeutic, amounts of [(177)Lu-DOTA(0)-Tyr(3)]-octreotate and to investigate how the activity distribution influences the absorbed dose. Furthermore, the activity distribution of a second administration of radiolabeled octreotate was studied. Nude mice with subcutaneously grown human midgut carcinoid (GOT1) were injected intravenously with different amounts of (177)Lu-octreotate. At different time points thereafter (4 h to 13 days), a second injection of [(111)In-DOTA(0)-Tyr(3)]-octreotate was given to estimate the somatostatin receptor (sstr) expression. The activity distribution in the tumors was then determined. Monte Carlo simulations with PENELOPE were performed for dosimetry. Fifty-one out of 58 investigated tumors showed a lower activity concentration in the peripheral part than in the central part of the tumor. The amount of activity injected, or time after administration, did neither influence the relative activity nor the sstr distribution in the tumor. After an initial down-regulation (at 4-24 h), there was an up-regulation of sstr (1.5-2 times, at 7-14 days). Monte Carlo simulations demonstrated an inhomogeneous absorbed dose distribution in the tumor using (177)Lu, with twice as high absorbed dose centrally than peripherally. The high activity concentration centrally and the up-regulation of sstr demonstrated will facilitate fractionated therapy using radiolabeled somatostatin analogues if similar results will be obtained also in patients. The inhomogeneous activity distribution in the tumor has to be taken into account when the absorbed dose distribution in tumor is calculated.

Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1

“…These findings are not in accordance with previous results, which did not show any increased 177 Lu-octreotate uptake in normal tissues [12]. An additional explanation to the higher activity concentrations found in tumoral and non-tumoral SSTR-expressing tissues might be that the priming administration influences vascular perfusion.…”

“…The kinetics of SSTR expression are clearly time dependent, and further studies are needed to clarify the mechanisms by which priming improves the uptake of 177 Lu-octreotate in tumor tissue, as well as the dose-response relation between administered activity and SSTR expression. We have previously reported an increased tumor uptake of 111 In-octreotide following 7.5 MBq 177 Lu-octreotate in GOT1 xenografts, but not following 30 MBq 177 Lu-octreotate [12, 13]. Thus, the 15 MBq single administration may be too high to result in detectable SSTR up-regulation.…”

“…Human NE tumors xenografted to immunosuppressed mice provide such a model for evaluation of different treatment regimes. In a mouse xenograft model with the human small intestine-neuroendocrine tumor (SI-NET) GOT1 cell line xenotransplanted to nude mice, the uptake of a subsequent injection of 0.5 MBq 111 In-octreotate in tumor was higher following an injection of 7.5 MBq 177 Lu-octreotate (a non-curative amount) than following an injection of 30 MBq 177 Lu-octreotate (a curative amount) [12, 13]. Furthermore, the optimal time between administration of 177 Lu-octreotate and higher concentration of 111 In-octreotide was 1 day or 3–13 days in GOT1 tumors on nude mice.…”

Identification of Potential MR-Derived Biomarkers for Tumor Tissue Response to 177Lu-Octreotate Therapy in an Animal Model of Small Intestine Neuroendocrine Tumor

“…, due to impaired delivery to central tumor or reduced radiosensitivity due to hypoxic conditions [47] . The latter explanation is in agreement with a previous study of the GOT1 tumor model, where higher proliferation was found in peripheral tumor parts, although there was a higher uptake of 177 Lu-octreotate in central tumor parts [48] .The proliferation would facilitate apoptosis induced by DNA damage, and the central uptake of 177 Lu-octreotate indicates adequate delivery and that the lower response must be caused by something else, such as hypoxia.…”

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53^{wild type} Neuroendocrine Tumor Cell Line GOT1

“…wild type GOT1 Tumor Cells in vitro Antitumoral effects of the somatostatin analogs octreotide and lanreotide in patients with NETs have been proven in clinical phase III studies [64][65][66][67] [70][71][72][73] . Therefore, we aimed to investigate the effects of octreotide in GOT1 cells in vitro alone and in combination with NVP-CGM097.…”