PT - JOURNAL ARTICLE AU - Yukie Yoshii AU - Takako Furukawa AU - Mitsuyoshi Yoshimoto AU - Hiroki Matsumoto AU - Ming-Rong Zhang AU - Masayuki Inubushi AU - Yasuhisa Fujibayashi AU - Tsuneo Saga TI - <sup>64</sup>Cu-ATSM internal radiotherapy to treat colon cancer acquiring resistance to antiangiogenic therapy with bevacizumab DP - 2016 May 01 TA - Journal of Nuclear Medicine PG - 471--471 VI - 57 IP - supplement 2 4099 - http://jnm.snmjournals.org/content/57/supplement_2/471.short 4100 - http://jnm.snmjournals.org/content/57/supplement_2/471.full SO - J Nucl Med2016 May 01; 57 AB - 471Objectives Anti-VEGF antibody bevacizumab is an antiangiogenic agent in widespread clinical use for colon cancer and bevacizumab combined with standard chemotherapy is known to prolong survival in patients. Despite the initial positive effect, with the continued use of bevacizumab, tumors become resistant to treatment probably because of the induction of tumor hypoxia by bevacizumab treatment, thus additional strategies to treat the induced hypoxia are needed. Here, we examined efficacy of internal radiotherapy with 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), which is a promising theranostic agent targeting tumor hypoxia, with a human colon cancer HT-29 tumor-bearing mouse model acquiring bevacizumab resistance.Methods HT-29 tumor-bearing mice treated with bevacizumab (5 mg/kg twice a week) for 3 weeks (on day 21), which showed rapid tumor regrowth, were regarded as bevacizumab-resistant in this study. To characterize tumor vascularity and hypoxia in the bevacizumab-resistant HT29 tumors, dual-isotope SPECT/PET/CT imaging using the VECTor small-animal scanner (MILabs) with a blood pool-detecting agent(99mTc-labeled human serum albumin) and 64Cu-ATSM was performed and compared to bevacizumab-untreated control. Bevacizumab-resistant mice, on day 21, were intravenously injected with 64Cu-ATSM (37 MBq) or saline and continued to be treated with bevacizumab (bevacizumab+64Cu-ATSM or bevacizumab group). For comparison, groups without bevacizumab treatment were also examined: a group with 64Cu-ATSM (37 MBq) alone on day 21 (64Cu-ATSM alone-day 21); a group with 64Cu-ATSM (37 MBq) alone on day 7, on which day tumor size was similar to that in the bevacizumab-resistant mice on day 21 (64Cu-ATSM alone-day 7); a group without bevacizumab nor 64Cu-ATSM (control).Results Imaging study revealed that bevacizumab-resistant tumors had reduced vascularity and increased proportion of hypoxic areas within tumors, compared with bevacizumab-untreated control. Bevacizumab+64Cu-ATSM group showed greater inhibition of tumor growth, compared with bevacizumab group without side effect (P&lt;0.05). 64Cu-ATSM alone groups on day 21 and 7 showed a tendency of slowed tumor growth compared to the control, although no significant difference was observed. Tumor growth time (5-fold increase of tumor volume) was 42.2±2.4, 32.1±1.8, 19.8±6.0, 20.7±2.9, and 17.0±4.4 days for bevacizumab+64Cu-ATSM, bevacizumab, 64Cu-ATSM alone-day 21, 64Cu-ATSM alone-day 7, and control, respectively. These data demonstrated that 64Cu-ATSM+bevacizumab showed synergistic inhibition of tumor growth and that the effect of 64Cu-ATSM treatment is stronger against the bevacizumab-resistant tumors than untreated tumors.Conclusions 64Cu-ATSM effectively inhibited tumor growth in bevacizumab-resistant HT-29 tumors. 64Cu-ATSM internal radiotherapy could be a novel approach to treat antiangiogenic therapy-resistant tumors.