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

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.

書誌情報

Oncotarget

巻 8, 号 54, p. 88815-88826, 発行日 2017-09

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Inpact Journals

PubMed番号

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PMID

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2023-05-15 23:28:22.712847

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