Presentation 64Cu-ATSM internal radiotherapy to treat tumors with bevacizumab-induced vascular decrease and hypoxia: Imaging analysis with dual-isotope simultaneous SPECT/PET/CT

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

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, which results in drug delivery deficiency and induction of malignant behaviors in tumors. To address this, we focused on a theranostic agent, 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), which possesses high tissue permeability and can target the over-reduced state under hypoxia within tumors. The efficacy of internal radiotherapy with 64Cu-ATSM was examined in mice bearing tumors with bevacizumab-induced vascular decrease and hypoxia. Methods: Human colon carcinoma HT-29 tumor-bearing mice were treated with bevacizumab (5 mg/kg twice a week) for 3 weeks to produce a model for tumors with bevacizumab-induced vascular decrease and hypoxia. Characteristics within the bevacizumab-treated tumors were examined. Dual-isotope simultaneous SPECT/PET/CT imaging with a blood pool-detecting agent 99mTc-labeled human serum albumin and 64Cu-ATSM was performed. In vivo treatment study was then performed. Results: The bevacizumab-treated HT-29 tumors showed decreased blood vessel density, activation of the HIF-1 signaling pathway and upregulation of genes involved in this pathway, and increased uptake of 64Cu-ATSM, compared to the control. SPECT/PET/CT imaging showed reduced vascularity and increased proportion of hypoxic areas in the bevacizumab-treated tumors. 64Cu-ATSM therapy was effective to inhibit tumor growth and prolong survival in the bevacizumab-treated tumor-bearing mice without major adverse effects. Conclusion: 64Cu-ATSM therapy effectively enhanced anti-tumor effects in tumors with bevacizumab-induced vascular decrease and hypoxia. 64Cu-ATSM therapy could be an additional treatment to antiangiogenic therapy.

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