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

Autor: Delbart W; Nuclear Medicine Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium.; Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Marin G; Medical Physics Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Stamatopoulos B; Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., de Wind R; Pathology Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Sirtaine N; Pathology Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Demetter P; Pathology Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Vercruyssen M; Haematology Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Woff E; Nuclear Medicine Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Karfis I; Nuclear Medicine Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Ghanem GE; Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Flamen P; Nuclear Medicine Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium., Wimana Z; Nuclear Medicine Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium.; Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2023 Apr 17; Vol. 15 (8). Date of Electronic Publication: 2023 Apr 17.
DOI: 10.3390/cancers15082332
Abstrakt: Peptide receptor radionuclide therapy with 177 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 rationale for targeting the antioxidant defence system in combination with 177 Lu-DOTATATE. In the present study, the radiosensitizing potential and the safety of depleting glutathione (GSH) levels using buthionine sulfoximine (BSO) during 177 Lu-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 177 Lu-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 177 Lu-DOTATATE efficacy without additional toxicity. Targeting the antioxidant defence system opens new safe treatment combination opportunities with 177 Lu-DOTATATE.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje