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Clinical Applications and the Roles of Transporters in Disposition, Tumor Targeting, and Tissue Toxicity of meta-Iodobenzylguanidine (mIBG)

Antonio J Lopez Quiñones, Leticia Salvador Vieira and Joanne Wang
Drug Metabolism and Disposition February 22, 2022, DMD-MR-2021-000707; DOI: https://doi.org/10.1124/dmd.121.000707
Antonio J Lopez Quiñones
1Pharmaceutics, University of Washington - Seattle, United States
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Leticia Salvador Vieira
2Pharmaceutics, University of Washington, United States
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Joanne Wang
3Dept. of Pharmaceutics, University of Washington, United States
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  • For correspondence: jowang@u.washington.edu
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Abstract

Transporters on the plasma membrane of tumor cells are promising molecular "Trojan horses" to deliver drugs and imaging agents into cancer cells. Radioiodine-labeled meta-iodobenzylguanidine (mIBG) is used as a diagnostic agent (123I-mIBG) and a targeted radiotherapy (131I-mIBG) for neuroendocrine cancers. mIBG enters cancer cells through the norepinephrine transporter (NET) where the radioactive decay of 131I causes DNA damage, cell death, and tumor necrosis. mIBG is predominantly eliminated unchanged by the kidney. Despite its selective uptake by neuroendocrine tumors, mIBG accumulates in several normal tissues and leads to tissue-specific radiation toxicities. Emerging evidences suggest that the polyspecific organic cation transporters play important roles in systemic disposition and tissue-specific uptake of mIBG. In particular, human organic cation transporter 2 (hOCT2) and toxin extrusion proteins 1 and 2-K (hMATE1/2-K) likely mediate renal secretion of mIBG whereas hOCT1 and hOCT3 may contribute to mIBG uptake into normal tissues such as the liver, salivary glands, and heart. This mini-review focuses on the clinical applications of mIBG in neuroendocrine cancers and the differential roles of NET, OCT and MATE transporters in mIBG disposition, response and toxicity. Understanding the molecular mechanisms governing mIBG transport in cancer and normal cells is a critical step for developing strategies to optimize the efficacy of 131I-mIBG while minimizing toxicity in normal tissues.

Significance Statement Radiolabeled mIBG has been used as a diagnostic tool and as radiotherapy for neuroendocrine cancers and other diseases. NET, OCT and MATE transporters play differential roles in mIBG tumor targeting, systemic elimination, and accumulation in normal tissues. The clinical use of mIBG as a radiopharmaceutical in cancer diagnosis and treatment can be further improved by taking a holistic approach considering mIBG transporters in both cancer and normal tissues.

  • cancer
  • drug disposition
  • Organic cation uptake / efflux (OCTs, ENTs)
  • toxicity
  • transporters
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (5)
Drug Metabolism and Disposition
Vol. 50, Issue 5
1 May 2022
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mIBG and role of transporters

Antonio J Lopez Quiñones, Leticia Salvador Vieira and Joanne Wang
Drug Metabolism and Disposition February 22, 2022, DMD-MR-2021-000707; DOI: https://doi.org/10.1124/dmd.121.000707

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OtherMinireview

mIBG and role of transporters

Antonio J Lopez Quiñones, Leticia Salvador Vieira and Joanne Wang
Drug Metabolism and Disposition February 22, 2022, DMD-MR-2021-000707; DOI: https://doi.org/10.1124/dmd.121.000707
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