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Disturbing the Redox Balance Using Buthionine Sulfoximine Radiosensitized Somatostatin Receptor-2 Expressing Pre-Clinical Models to Peptide Receptor Radionuclide Therapy with ¹⁷⁷Lu-DOTATATE.

ABSTRACT: Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE improves the outcome of patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumours. Nevertheless, stable disease has been the main response pattern observed, with some rare complete responses. Lu-177 exerts about two-thirds of its biological effects via the indirect effects of ionizing radiation that generate reactive oxygen species, eventually leading to oxidative damage and cell death. This provides a rationale for targeting the antioxidant defence system in combination with ¹⁷⁷Lu-DOTATATE. In the present study, the radiosensitizing potential and the safety of depleting glutathione (GSH) levels using buthionine sulfoximine (BSO) during ¹⁷⁷Lu-DOTATATE therapy were assessed in vitro and in vivo using a xenograft mouse model. In vitro, the combination resulted in a synergistic effect in cell lines exhibiting a BSO-mediated GSH decrease. In vivo, BSO neither influenced ¹⁷⁷Lu-DOTATATE biodistribution nor induced liver, kidney or bone marrow toxicity. In terms of efficacy, the combination resulted in reduced tumour growth and metabolic activity. Our results showed that disturbing the cell redox balance using a GSH synthesis inhibitor increased ¹⁷⁷Lu-DOTATATE efficacy without additional toxicity. Targeting the antioxidant defence system opens new safe treatment combination opportunities with ¹⁷⁷Lu-DOTATATE.

SUBMITTER: Delbart W

PROVIDER: S-EPMC10137255 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Disturbing the Redox Balance Using Buthionine Sulfoximine Radiosensitized Somatostatin Receptor-2 Expressing Pre-Clinical Models to Peptide Receptor Radionuclide Therapy with <sup>177</sup>Lu-DOTATATE.

Delbart Wendy W Marin Gwennaëlle G Stamatopoulos Basile B de Wind Roland R Sirtaine Nicolas N Demetter Pieter P Vercruyssen Marie M Woff Erwin E Karfis Ioannis I Ghanem Ghanem E GE Flamen Patrick P Wimana Zéna Z

Cancers 20230417 8

Peptide receptor radionuclide therapy with <sup>177</sup>Lu-DOTATATE improves the outcome of patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumours. Nevertheless, stable disease has been the main response pattern observed, with some rare complete responses. Lu-177 exerts about two-thirds of its biological effects via the indirect effects of ionizing radiation that generate reactive oxygen species, eventually leading to oxidative damage and cell death. This provides a ration ...[more]

PMID: 37190261

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Project description:BackgroundReceptor saturation during peptide receptor radionuclide therapy (PRRT) could result in altered [177Lu]Lu-HA-DOTATATE uptake in tumors and organs. Therefore, receptor expression status and effects of different (unlabeled) administered peptide amounts during PRRT need to be evaluated. The aim of this study was to assess potential receptor saturation during PRRT by comparing organ and tumor uptake after administration of [177Lu]Lu-HA-DOTATATE with low, standard and high administered peptide amounts in patients with advanced metastatic neuroendocrine tumors (NETs).MethodsData of NET patients that received 7.4 GBq 177-Lutetium labeled to a low or high amount of HA-DOTATATE were retrospectively included. From included patients other PRRT cycles, containing standard administered peptide amounts, were included for intra-patient comparison. Uptake quantification was performed for spleen, liver, kidney, bone marrow, blood pool and tumor lesions on post-treatment SPECT/CT scans. A paired Wilcoxon signed-rank test was performed to determine uptake differences between two adjacent cycles for each patient.ResultsThirteen patients received [177Lu]Lu-HA-DOTATATE with a high administered peptide amount (mean 346 µg vs 178 µg standard peptide amount). Low peptide amounts were administered to fifteen patients (mean 109 µg vs 202 µg standard peptide amount). High administered peptide amount resulted in significantly lower [177Lu]Lu-HA-DOTATATE uptake in the spleen (p = 0.00012), kidney (p = 0.013) and tumor lesions (p < 0.0001) versus standard peptide amounts. For low administered peptide amount, uptake was increased in the spleen (p = 0.015), while tumor uptake was significantly reduced (p = 0.015) compared to uptake after administration of standard peptide amounts.ConclusionsThese findings confirmed a peptide amount-dependent organ and tumor accumulation for [177Lu]Lu-HA-DOTATATE, with receptor saturation in spleen for high and standard peptide amounts, while tumor and kidney receptor saturation occur only with high administered peptide amounts. A high peptide amount (~ 350 µg) is not recommended for standard-dose PRRT and standard amounts (~ 200 µg) seem more suitable to achieve optimal tumor accumulation with limited organ uptake.

Dataset Information

Disturbing the Redox Balance Using Buthionine Sulfoximine Radiosensitized Somatostatin Receptor-2 Expressing Pre-Clinical Models to Peptide Receptor Radionuclide Therapy with ¹⁷⁷Lu-DOTATATE.

Publications

Disturbing the Redox Balance Using Buthionine Sulfoximine Radiosensitized Somatostatin Receptor-2 Expressing Pre-Clinical Models to Peptide Receptor Radionuclide Therapy with <sup>177</sup>Lu-DOTATATE.

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Dataset Information

Disturbing the Redox Balance Using Buthionine Sulfoximine Radiosensitized Somatostatin Receptor-2 Expressing Pre-Clinical Models to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE.

Publications

Disturbing the Redox Balance Using Buthionine Sulfoximine Radiosensitized Somatostatin Receptor-2 Expressing Pre-Clinical Models to Peptide Receptor Radionuclide Therapy with <sup>177</sup>Lu-DOTATATE.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Disturbing the Redox Balance Using Buthionine Sulfoximine Radiosensitized Somatostatin Receptor-2 Expressing Pre-Clinical Models to Peptide Receptor Radionuclide Therapy with ¹⁷⁷Lu-DOTATATE.