64Cu-ATSM internal radiotherapy to treat tumors with bevacizumab-induced vascular decrease and hypoxia in human colon carcinoma xenografts
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Yukie Yoshii1, Mitsuyoshi Yoshimoto2, Hiroki Matsumoto3, Takako Furukawa1,4, Ming-Rong Zhang1, Masayuki Inubushi5, Atsushi B. Tsuji1, Yasuhisa Fujibayashi1, Tatsuya Higashi1 and Tsuneo Saga1,6
1National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
2Division of Functional Imaging, National Cancer Center Hospital East, Kashiwa, Japan
3Research Centre, Nihon Medi-Physics Co., Ltd., Sodegaura, Japan
4Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
5Department of Nuclear Medicine, Kawasaki Medical School, Kurashiki, Japan
6Department of Diagnostic Radiology, Kyoto University Hospital, Kyoto, Japan
Yukie Yoshii, email: email@example.com
Keywords: 64Cu-ATSM, angiogenesis, bevacizumab, hypoxia, vascular decrease
Received: July 19, 2017 Accepted: August 17, 2017 Published: September 28, 2017
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 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-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 64Cu-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 64Cu-ATSM uptake areas within the bevacizumab-treated tumors. 64Cu-ATSM therapy was effective to inhibit tumor growth and prolong survival of the bevacizumab-treated tumor-bearing mice without major adverse effects. In conclusion, 64Cu-ATSM therapy effectively enhanced anti-tumor effects in tumors with bevacizumab-induced vascular decrease and hypoxia. 64Cu-ATSM therapy could represent a novel approach as an add-on to antiangiogenic therapy.
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