Radioimmunotherapy of pancreatic cancer xenografts in nude mice using 90Y-labeled anti-α6β4 integrin antibody
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Winn Aung1, Atsushi B. Tsuji1, Hitomi Sudo1, Aya Sugyo1, Yoshinori Ukai2, Katsushi Kouda2, Yoshikazu Kurosawa3, Takako Furukawa1, Tsuneo Saga1
1Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
2Perseus Proteomics Inc., Tokyo, Japan
3Innovation Center for Advanced Medicine, Fujita Health University, Toyoake, Japan
Winn Aung, email: [email protected]
Keywords: targeted radioimmunotherapy, pancreatic tumor, α6β4 integrin, yttrium-90, radiolabeled antibody
Received: December 10, 2015 Accepted: May 04, 2016 Published: May 26, 2016
The contribution of integrin α6β4 (α6β4) overexpression to the pancreatic cancer invasion and metastasis has been previously shown. We have reported immunotargeting of α6β4 for radionuclide-based and near-infrared fluorescence imaging in a pancreatic cancer model. In this study, we prepared yttrium-90 labeled anti-α6β4 antibody (90Y-ITGA6B4) and evaluated its radioimmunotherapeutic efficacy against pancreatic cancer xenografts in nude mice. Mice bearing xenograft tumors were randomly divided into 5 groups: (1) single administration of 90Y-ITGA6B4 (3.7MBq), (2) double administrations of 90Y-ITGA6B4 with once-weekly schedule (3.7MBq x 2), (3) single administration of unlabeled ITGA6B4, (4) double administrations of unlabeled ITGA6B4 with once-weekly schedule and (5) the untreated control. Biweekly tumor volume measurements and immunohistochemical analyses of tumors at 2 days post-administration were performed to monitor the response to treatments. To assess the toxicity, body weight was measured biweekly. Additionally, at 27 days post-administration, blood samples were collected through cardiac puncture, and hematological parameters, hepatic and renal functions were analyzed. Both 90Y-ITGA6B4 treatment groups showed reduction in tumor volumes (P < 0.04), decreased cell proliferation marker Ki-67-positive cells and increased DNA damage marker p-H2AX-positive cells, compared with the other groups. Mice treated with double administrations of 90Y-ITGA6B4, exhibited myelosuppression. There were no significant differences in hepatic and renal functions between the 2 treatment groups and the other groups. Our results suggest that 90Y-ITGA6B4 is a promising radioimmunotherapeutic agent against α6β4 overexpressing tumors. In the future studies, dose adjustment for fractionated RIT should be considered carefully in order to get the optimal effect while avoiding myelotoxicity.
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