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

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 metaiodobenzylguanidine (mIBG) is used as a diagnostic agent ( 123 I-mIBG) and a targeted radiotherapy ( 131 I-mIBG) for neuroendocrine cancers. mIBG enters cancer cells through the norepinephrine transporter (NET) where the radioactive decay of 131 I 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 tissuespecific 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 131 I-mIBG while minimizing toxicity in normal tissues.

Norepinephrine transporter and vesicular monoamine transporter 2 tumor expression as a predictor of response to 131I‐MIBG in patients with relapsed/refractory neuroblastoma

“…17 Moreover, other transporters play a role in renal excretion of MIBG, including human organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K). 17 A better understanding of these mediators of 131 I-MIBG efflux and clearance may lead to an improved prediction of clinical outcomes. Finally, while it is tempting to try to link NET and VMAT2 protein expression mechanistically with response to 131 I-MIBG therapy, it is important to note that our findings represent statistical associations and cannot speak to the mechanism of the findings.…”

“…It is also important to note that there are likely several other important contributing factors mediating radiation responsiveness as well as 131 I‐MIBG uptake, retention, and efflux. For example, the role of multidrug resistance protein 1 and 4 (MRP1/4; ABCC1/4) in efflux has recently been reported 17 . Moreover, other transporters play a role in renal excretion of MIBG, including human organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2‐K (hMATE1/2‐K) 17 .…”

“…For example, the role of multidrug resistance protein 1 and 4 (MRP1/4; ABCC1/4) in efflux has recently been reported 17 . Moreover, other transporters play a role in renal excretion of MIBG, including human organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2‐K (hMATE1/2‐K) 17 . A better understanding of these mediators of 131 I‐MIBG efflux and clearance may lead to an improved prediction of clinical outcomes.…”

Interaction of ALK Inhibitors with Polyspecific Organic Cation Transporters and the Impact of Substrate-Dependent Inhibition on the Prediction of Drug–Drug Interactions

“…Notably, OCT3 has been identified as the primary transporter facilitating mIBG into the heart and salivary glands [ 44 ]. We and others have thus proposed that inhibition of OCT3 could be a viable clinical strategy to improve the safety and tumor selectivity of mIBG in cancer patients [ 25 , 45 , 46 ]. Here, we showed that brigatinib exhibits potent and preferential in vitro inhibition of hOCT3 ( Figure 2 and Table 1 ).…”

Genetic preservation of SLC22A3 in the Admixed and Xhosa populations living in the Western Cape

“…The ubiquitously expressed hOCT3 has not only been implicated in the transport of anti-cancer drugs, but also as a biomarker for cancer pathogenesis [39]. For example, in colorectal cancers hOCT together with its paralogues, hOCT1 and hOCT2, have been shown to be determinants of oxaliplatin cytotoxicity [8,[39][40][41]. Moreover, SLC22A3 expression in renal cell carcinoma cell lines enhances the sensitivity of these cell lines towards the chemotherapeutic agents melphalan, irinotecan, and vincristine [9].…”