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Oncotarget. 2017 Sep 28;8(51):88815-88826. doi: 10.18632/oncotarget.21323. eCollection 2017 Oct 24.

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

Author information

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.

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 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.

KEYWORDS:

64Cu-ATSM; angiogenesis; bevacizumab; hypoxia; vascular decrease

Conflict of interest statement

CONFLICTS OF INTEREST Hiroki Matsumoto is an employee of Nihon Medi-Physics Co., Ltd. All the other authors declare no competing financial interests.

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