机构：[1]Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachu‑ setts General Hospital, Harvard Medical School, 100 Blossom Street, Cox‑7, Boston, MA 02114, USA[2]Present Address: Guangdong Laboratory Animal Monitoring Institute, Guangzhou 510663, People’s Republic of China[3]Department of Spinal Surgery, Afliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, People’s Republic of China[4]Division of Urology, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.
Patients with metastatic HER2/neu-positive (HER2/neu +) breast cancer (BC) often experience treatment resistance, disease recurrences and metastases. Thus, new approaches for improving the treatment of HER2/neu + BC to prevent metastatic dissemination are urgently needed. Our previous studies have shown that losartan, an angiotensin receptor blocker, increases tumor perfusion and decreases hypoxia in a number of tumor models. Hypoxia reduces the efficacy of radiation and increases metastases. We therefore hypothesized that by modifying tumor stroma and increasing oxygenation, losartan will improve the outcome of radiotherapy and inhibit disease progression in a highly metastatic HER2/neu + murine BC model.
We established a metastatic HER2/neu + murine BC line (MCa-M3C) and used it to generate mammary fat pad isografts in syngeneic female FVB/N mice. Starting on day 3 after orthotopic tumor implantation, we administered a 7-day losartan treatment (40 mg/kg BW, gavage daily); or a 7-day losartan treatment followed by 20 Gy single dose local irradiation (S-IR) on day 10 (tumor size ~ 100 mm3), or 20 Gy local fractionated (5 × 4 Gy daily) irradiation (F-IR) on days 10-14. We analyzed tumor-growth delay (TGD), development of spontaneous lung metastases, animal survival, tumor vascular density, and tumor hypoxia.
Treatments with S-IR, F-IR, Losartan + S-IR, or Losartan + F-IR resulted in a significantly increased TGD (8-16 days) in MCa-M3C tumors versus controls. However, the combination of Losartan + S-IR and Losartan + F-IR further enhanced tumor response to radiation alone by increasing TGD an additional 5 to 8 days for both single and fractionated dose irradiation (P < 0.01), decreasing lung metastasis (Losartan + IR vs. Control, P < 0.025), and increasing animal survival (Losartan + IR vs. Control, P = 0.0303). In addition, losartan treatment significantly increased tumor vascularity (P = 0.0314) and decreased pimonidazole positive (hypoxic) area (P = 0.0002).
Combining losartan with local irradiation significantly enhanced tumor response, at least in part via reduced tumor hypoxia presumably due to increased tumor perfusion. Our findings suggest that combining losartan with radiotherapy is a potential new treatment strategy for local control and inhibiting metastasis in HER2 + BC.
基金：
This work was supported in part by NIH Grants P01-CA080124, R35-CA197743,
R01-CA208205 and U01-CA224173; NCI/Federal Share Proton Beam Program
Income; Advanced Medical Research Foundation; National Foundation for
Cancer Research; and Harvard Ludwig Cancer Center.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类|3 区医学
小类|3 区核医学4 区肿瘤学
最新[2025]版：
大类|2 区医学
小类|2 区核医学3 区肿瘤学
第一作者：
第一作者机构：[1]Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachu‑ setts General Hospital, Harvard Medical School, 100 Blossom Street, Cox‑7, Boston, MA 02114, USA[2]Present Address: Guangdong Laboratory Animal Monitoring Institute, Guangzhou 510663, People’s Republic of China
通讯作者：
推荐引用方式(GB/T 7714)：
Li Wende,Li Sen,Chen Ivy X,et al.Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model.[J].Radiation oncology (London, England).2021,16(1):48.doi:10.1186/s13014-021-01775-9.
APA：
Li Wende,Li Sen,Chen Ivy X,Liu Yujiao,Ramjiawan Rakesh R...&Huang Peigen.(2021).Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model..Radiation oncology (London, England),16,(1)
MLA：
Li Wende,et al."Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model.".Radiation oncology (London, England) 16..1(2021):48
