Abstract
IntroductionGastric cancer often metastasizes to liver in its advanced stage. Liver metastasis of gastric cancer (LMGC) is a fetal medical condition and the patients with LMGC have extremely poor prognosis because of the lack of efficient therapeutics. Therefore, the development of new therapeutic options has been eagerly awaited. The aim of this study is to evaluate targeted alpha-particle radiation therapy for LMGC in a preclinical mouse model.Material and methodsAstatine-211 (At-211), an alpha-particle emitter radionuclide, was produced by irradiation of alpha-particles to bismuth-209 using an AVF accelerator at our institute. An anti-HER2 antibody trastuzumab was conjugated with At-211 to produce alpha-emitting antibodies targeting HER2 ([At-211]-trastuzumab). To generate a mouse model of LMGC, we injected luciferase-labelled HER2-positive human metastatic NCI-N87 GC cells into splenic vein of severe combined immunodeficiency mouse. Tissue and tumour distribution of [At-211]-trastuzumab was examined in the LMGC mouse model. Therapeutic efficacy and toxicities of [At-211]-trastuzumab were evaluated in the animal model. All animal experiments conducted in this study were approved by the Animal Care and Use Committee of our institute and were undertaken in compliance with the institutional guidelines regarding animal care and handling.Results and discussionsBiodistribution studies showed that the maximum uptake of [At-211]trastuzumab in the liver metastatic tumours was approximately 12% of injected dose per tissue gram at 24 hours after injection.A systemic injection of [At-211]trastuzumab (1 MBq) significantly reduced a tumour burden in the liver and extended the survival of model mouse. Transient leukocytopenia was observed in mice received 1 MBq of [At-211]trastuzumab at 5–7 days after injection. No body weight loss was so far found in the mice treated with [At-211]trastuzumab.ConclusionOur preclinical study provides the evidence that targeted alpha-therapy using [At-211]-trastuzumab is effective for LMGC.
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