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Combination therapy with bevacizumab and a CCR2 inhibitor for human ovarian cancer : An in vivo validation study
| Title: | Combination therapy with bevacizumab and a CCR2 inhibitor for human ovarian cancer : An in vivo validation study |
| Authors: | Zhai, Tianyue Browse this author | | Mitamura, Takashi Browse this author →KAKEN DB | | Wang, Lei Browse this author | | Kubota, Shimpei I. Browse this author | | Murakami, Masaaki Browse this author | | Tanaka, Shinya Browse this author | | Watari, Hidemichi Browse this author →KAKEN DB |
| Keywords: | angiogenesis | | antiangiogenic drug | | bevacizumab | | CCR2 inhibitor | | preclinical drug evaluation |
| Issue Date: | Apr-2023 |
| Publisher: | John Wiley & Sons |
| Journal Title: | Cancer medicine |
| Volume: | 12 |
| Issue: | 8 |
| Start Page: | 9697 |
| End Page: | 9708 |
| Publisher DOI: | 10.1002/cam4.5674 |
| Abstract: | BackgroundAnti-angiogenic therapy with bevacizumab (BEV), an anti-VEGF antibody, plays a critical role in the treatment of ovarian cancer. However, despite an encouraging initial response, most tumors become resistant to BEV over time, and a new strategy that enables sustainable treatment using BEV is therefore needed. MethodsTo overcome the resistance to BEV in patients with ovarian cancer, we performed a validation study of combination therapy with BEV (10 mg/kg) and the CCR2 inhibitor BMS CCR2 22 (20 mg/kg) (BEV/CCR2i) using 3 consecutive patient-derived xenografts (PDXs) of immunodeficient mice. ResultsBEV/CCR2i demonstrated a significant effect of growth suppression in the BEV-resistant serous PDX and BEV-sensitive serous PDX compared with BEV (30.4% after the second cycle and 15.5% after the first cycle, respectively), and treatment cessation did not attenuate this effect. Tissue clearing and immunohistochemistry with an anti-alpha-SMA antibody suggested that BEV/CCR2i suppressed angiogenesis from the host mice more than BEV. In addition, human CD31 immunohistochemistry revealed that BEV/CCR2i decreased microvessels originating from the patients to a significantly greater degree than BEV. Regarding the BEV-resistant clear cell PDX, the effect of BEV/CCR2i was unclear during the first five cycles, but the following two cycles of increased-dose BEV/CCR2i (CCR2i 40 mg/kg) significantly suppressed tumor growth compared with BEV (28.3%) by inhibiting the CCR2B-MAPK pathway. ConclusionsBEV/CCR2i showed a sustained anticancer immunity-independent effect in human ovarian cancer that was more significant in serous carcinoma than in clear cell carcinoma. |
| Type: | article |
| URI: | http://hdl.handle.net/2115/89268 |
| Appears in Collections: | 北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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