Antitumor effects of radionuclide treatment using \u03b1-emitting meta-211At-astato-benzylguanidine in a PC12 pheochromocytoma model

Yasuhiro Ohshima,Atsushi B Tsuji,Tatsuya Higashi,Noriko S Ishioka,Kotaro Nagatsu,Yoichi M Ito,Keiichiro Yoshinaga,Hitomi Sudo,Tetsuya Sakashita,Shigeki Watanabe

doi:10.1007/s00259-017-3919-6

Abstract

PurposeTherapeutic options for patients with malignant pheochromocytoma are currently limited, and therefore new treatment approaches are being sought. Targeted radionuclide therapy provides tumor-specific systemic treatments. The β-emitting radiopharmaceutical meta-131I-iodo-benzylguanidine (131I-MIBG) provides limited survival benefits and has adverse effects. A new generation of radionuclides for therapy using α-particles including meta-211At-astato-benzylguanidine (211At-MABG) are expected to have strong therapeutic effects with minimal side effects. However, this possibility has not been evaluated in an animal model of pheochromocytoma. We aimed to evaluate the therapeutic effects of the α-emitter 211At-MABG in a pheochromocytoma model.MethodsWe evaluated tumor volume-reducing effects of 211At-MABG using rat pheochromocytoma cell line PC12 tumor-bearing mice. PC12 tumor-bearing mice received intravenous injections of 211At-MABG (0.28, 0.56, 1.11, 1.85, 3.70 and 5.55 MBq; five mice per group). Tumor volumes were evaluated for 8 weeks after 211At-MABG administration. The control group of ten mice received phosphate-buffered saline.ResultsThe 211At-MABG-treated mice showed significantly lower relative tumor growth during the first 38 days than the control mice. The relative tumor volumes on day 21 were 509.2% ± 169.1% in the control mice and 9.6% ± 5.5% in the mice receiving 0.56 MBq (p < 0.01). In addition, the mice treated with 0.28, 0.56 and 1.11 MBq of 211At-MABG showed only a temporary weight reduction, with recovery in weight by day 10.Conclusion211At-MABG exhibited a strong tumor volume-reducing effect in a mouse model of pheochromocytoma without weight reduction. Therefore, 211At-MABG might be an effective therapeutic agent for the treatment of malignant pheochromocytoma.

Highlights

10% to 25% of patients with pheochromocytoma have systemic metastasis known as malignant pheochromocytoma [1,2,3]
The cell uptake assay showed that the product was rapidly transported into PC12 cells that have high norepinephrine transporter expression (Supplementary Fig. 2a)
The inhibition assay showed that desipramine (DMI), a selective inhibitor of the norepinephrine transporter, and dl-norepinephrine significantly inhibited cell uptake of the product (p < 0.01, Supplementary Fig. 2b), and uptake was significantly suppressed by incubation at 4 °C

Summary

Introduction

10% to 25% of patients with pheochromocytoma have systemic metastasis known as malignant pheochromocytoma [1,2,3]. Tumor mass effects and catecholamine induce several pathological conditions [1, 4, 5]. Patients with malignant pheochromocytoma have limited treatment options that include chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) [6, 7], and radionuclide therapy using β-emitting meta-131I-iodo-benzylguanidine (131I-MIBG). The effects of CVD are of limited duration [6, 8] Of these treatments, 131I-MIBG has been shown to prolong survival [8]

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