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Organic cation transporter 3 mediates the non-norepinephrine transporter driven uptake of meta-[211At]astato-benzylguanidine.
Ohshima, Yasuhiro; Sasaki, Ichiro; Watanabe, Shigeki; Sakashita, Tetsuya; Higashi, Tatsuya; Ishioka, Noriko S.
Afiliación
  • Ohshima Y; Department of Radiation-Applied Biology Research, Quantum Beam Science Research Directorate, National Institutes for Quantum Science and Technology, Takasaki 370-1292, Japan. Electronic address: ohshima.yasuhiro@qst.go.jp.
  • Sasaki I; Department of Radiation-Applied Biology Research, Quantum Beam Science Research Directorate, National Institutes for Quantum Science and Technology, Takasaki 370-1292, Japan.
  • Watanabe S; Department of Radiation-Applied Biology Research, Quantum Beam Science Research Directorate, National Institutes for Quantum Science and Technology, Takasaki 370-1292, Japan.
  • Sakashita T; Department of Radiation-Applied Biology Research, Quantum Beam Science Research Directorate, National Institutes for Quantum Science and Technology, Takasaki 370-1292, Japan.
  • Higashi T; Department of Molecular Imaging and Theranostics, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • Ishioka NS; Department of Radiation-Applied Biology Research, Quantum Beam Science Research Directorate, National Institutes for Quantum Science and Technology, Takasaki 370-1292, Japan.
Nucl Med Biol ; 112-113: 44-51, 2022.
Article en En | MEDLINE | ID: mdl-35802985
INTRODUCTION: Meta-[211At]astato-benzylguanidine ([211At]MABG) accumulates in pheochromocytoma via norepinephrine transporter (NET) and leads to a strong antitumor effect, but it also distributed in normal tissues non-specifically. Meta-[131I]iodo-benzylguanidine ([131I]MIBG), an iodine-labeled analog of [211At]MABG, is known to be transported by not only NET but also organic cation transporter (OCT). The involvement of OCT in [211At]MABG uptake is still largely unknown. We investigated the involvement of OCT in the non-NET-driven uptake of [211At]MABG both in vitro and in vivo. METHODS: [123I]MIBG and [211At]MABG uptake was investigated in PC-12 (rat pheochromocytoma cell line), NIH/3T3 (mouse fibroblasts cell line), ACHN (human renal cancer cell line), and BxPC-3 (human pancreatic cancer cell line). Herein, we used desipramine and dl-norepinephrine to inhibit NET, and we used steroids (hydrocortisone and prednisolone) to inhibit OCT3. The [211At]MABG uptake in OCT3-knockdown cells established with OCT3-selective siRNA was also investigated. We investigated the biodistribution of [211At]MABG in PC-12 tumor-bearing mice after a preloading of phosphate-buffered saline (PBS) or hydrocortisone solution. RESULTS: The uptake of both [123I]MIBG and [211At]MABG was significantly inhibited by desipramine in PC-12 cells but not the other cell lines. The expression of OCT3 was relatively higher than those of the other OCT subtypes in ACHN and BxPC-3 cells. The expression of OCTs was not observed in NIH/3T3 cells. The uptake of both [123I]MIBG and [211At]MABG in ACHN and BxPC-3 cells was significantly inhibited by the steroid treatments. The [211At]MABG uptake was also reduced in OCT3-knockdown cells (p < 0.001). The radioactivity of [211At]MABG was significantly reduced in normal tissues by the preloading of hydrocortisone. In contrast, there was an increasing trend of [211At]MABG uptake in the PC-12 tumors. The tumor-to-normal tissue ratio was significantly increased by the preloading of hydrocortisone compared to that of PBS. CONCLUSION: Our results suggest that OCT3 is involved in non-NET-driven [211At]MABG uptake. The preloading of hydrocortisone selectively reduced [211At]MABG accumulation in normal organs in vivo. OCT3 inhibition may therefore be beneficial for a reduction of the radiation risk in healthy organs in the treatment of malignant pheochromocytomas.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Feocromocitoma / Neoplasias de las Glándulas Suprarrenales Límite: Animals / Humans Idioma: En Revista: Nucl Med Biol Asunto de la revista: BIOLOGIA / MEDICINA NUCLEAR Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Feocromocitoma / Neoplasias de las Glándulas Suprarrenales Límite: Animals / Humans Idioma: En Revista: Nucl Med Biol Asunto de la revista: BIOLOGIA / MEDICINA NUCLEAR Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos