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

Simple Summary Peptide receptor radionuclide therapy with Lu-177-DOTATATE is an efficient treatment for patients suffering from metastasized neuroendocrine tumours. Nevertheless, suboptimal effects have been observed in the majority of patients. Hence, strategies to improve Lu-177-DOTATATE efficacy are desirable. Lu-177 induces oxidative stress, eventually leading to tumour cell death. Inhibition of the antioxidant defence mechanisms, using buthionine sulfoximine (BSO), represents an attractive strategy to increase Lu-177-DOTATATE efficacy. In cells and an animal model, the combination of Lu-177-DOTATATE and BSO was more effective than Lu-177-DOTATATE alone. In addition, it did not result in additional toxicity. Targeting the antioxidant defence system opens new safe treatment combination opportunities with Lu-177-DOTATATE. Peptide receptor radionuclide therapy with Lu-177-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 Lu-177-DOTATATE. In the present study, the radiosensitizing potential and the safety of depleting glutathione (GSH) levels using buthionine sulfoximine (BSO) during Lu-177-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 Lu-177-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 Lu-177-DOTATATE efficacy without additional toxicity. Targeting the antioxidant defence system opens new safe treatment combination opportunities with Lu-177-DOTATATE.