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

Yoshii, Yukie  ,  Yoshimoto, Mitsuyoshi  ,  Matsumoto, Hiroki  ,  Furukawa, Takako  ,  Ming-Rong, Zhang  ,  Inubushi, Masayuki  ,  Tsuji, Atsushi  ,  Fujibayashi, Yasuhisa  ,  Higashi, Tatsuya  ,  Saga, Tsuneo

8 ( 54 )  , pp.88815 - 88826 , 2017-09 , Inpact Journals
Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, is anantiangiogenic agent clinically used for various cancers. However, repeated use ofthis agent leads to tumor-decreased vascularity and hypoxia with activation of anHIF-1 signaling pathway, which results in drug delivery deficiency and induction ofmalignant behaviors in tumors. Here, we developed a novel strategy to treat tumorswith bevacizumab-induced vascular decrease and hypoxia using 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential theranostic agent, whichpossesses high tissue permeability and can target over-reduced conditions underhypoxia in tumors, with a human colon carcinoma HT-29 tumor-bearing mouse model.The long-term treatment with bevacizumab caused decreased blood vessel densityand activation of an HIF-1 signaling pathway; increased uptake of 64Cu-ATSM was alsoobserved despite limited blood vessel density in HT-29 tumors. In vivo high-resolutionSPECT/PET/CT imaging confirmed reduced vascularity and increased proportion of64Cu-ATSM uptake areas within the bevacizumab-treated tumors. 64Cu-ATSM therapywas effective to inhibit tumor growth and prolong survival of the bevacizumab-treatedtumor-bearing mice without major adverse effects. In conclusion, 64Cu-ATSM therapyeffectively enhanced anti-tumor effects in tumors with bevacizumab-induced vasculardecrease and hypoxia. 64Cu-ATSM therapy could represent a novel approach as an add-on to antiangiogenic therapy.

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