64 Cu-ATSM internal radiotherapy to treat tumors with bevacizumab-induced vascular decrease and hypoxia in human colon carcinoma xenografts

// Yukie Yoshii 1 , Mitsuyoshi Yoshimoto 2 , Hiroki Matsumoto 3 , Takako Furukawa 1, 4 , Ming-Rong Zhang 1 , Masayuki Inubushi 5 , Atsushi B. Tsuji 1 , Yasuhisa Fujibayashi 1 , Tatsuya Higashi 1 and Tsuneo Saga 1, 6 1 National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan 2 Division of Functional Imaging, National Cancer Center Hospital East, Kashiwa, Japan 3 Research Centre, Nihon Medi-Physics Co., Ltd., Sodegaura, Japan 4 Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan 5 Department of Nuclear Medicine, Kawasaki Medical School, Kurashiki, Japan 6 Department of Diagnostic Radiology, Kyoto University Hospital, Kyoto, Japan Correspondence to: Yukie Yoshii, email: yoshii.yukie@qst.go.jp Keywords: 64 Cu-ATSM, angiogenesis, bevacizumab, hypoxia, vascular decrease Received: July 19, 2017     Accepted: August 17, 2017     Published: September 28, 2017 ABSTRACT Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, is an antiangiogenic agent clinically used for various cancers. However, repeated use of this agent leads to tumor-decreased vascularity and hypoxia with activation of an HIF-1 signaling pathway, which results in drug delivery deficiency and induction of malignant behaviors in tumors. Here, we developed a novel strategy to treat tumors with bevacizumab-induced vascular decrease and hypoxia using 64 Cu-diacetyl-bis ( N 4 -methylthiosemicarbazone) ( 64 Cu-ATSM), a potential theranostic agent, which possesses high tissue permeability and can target over-reduced conditions under hypoxia in tumors, with a human colon carcinoma HT-29 tumor-bearing mouse model. The long-term treatment with bevacizumab caused decreased blood vessel density and activation of an HIF-1 signaling pathway; increased uptake of 64 Cu-ATSM was also observed despite limited blood vessel density in HT-29 tumors. In vivo high-resolution SPECT/PET/CT imaging confirmed reduced vascularity and increased proportion of 64 Cu-ATSM uptake areas within the bevacizumab-treated tumors. 64 Cu-ATSM therapy was effective to inhibit tumor growth and prolong survival of the bevacizumab-treated tumor-bearing mice without major adverse effects. In conclusion, 64 Cu-ATSM therapy effectively enhanced anti-tumor effects in tumors with bevacizumab-induced vascular decrease and hypoxia. 64 Cu-ATSM therapy could represent a novel approach as an add-on to antiangiogenic therapy.