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Abstract
PURPOSE:
Several clinical trials have combined anti-angiogenic agents and radiotherapy, but evidence of its clinical benefit is insufficient. In this study, we rationalized and investigated the combination of VEGF-Grab, an anti-angiogenic drug that inhibits VEGF-A and PlGF, and radiotherapy for anti-cancer therapy.

METHODS AND MATERIALS:
To observe for changes in PlGF after radiation, HCT116, HCT15, SW480, BxPC3, and RAW264.7 cells and LLC and BxPC3 tumors were given 10 Gy of radiation and changes in the expression of PlGF were analyzed. Patients scheduled for radiotherapy on solid tumor mass were recruited and their plasma VEGF-A and PlGF were analyzed at baseline and 2 and 4 weeks after start of radiotherapy. To assess the effects of combining VEGF-Grab and radiotherapy, mice bearing LLC tumors were given 10 Gy of radiation once and 25 mg/kg of VEGF-Grab every 2 days for 5 times. To show that VEGF-Grab is effective in human tumors, mice bearing BxPC3 xenografts were given 2 doses of 15 mg/kg of VEGF-Grab or VEGF-Trap. To assess the efficacy of combination therapy in BxPC3 xenografts, the same experiment as in LLC model was performed.

RESULTS:
We demonstrated that PlGF is increased as a direct consequence of irradiation in vitro and in vivo, as well as in the plasma of patients being treated with radiation. Then, using a syngeneic tumor model, we showed that the combination of VEGF-Grab and radiotherapy most effectively inhibited tumor growth through anti-angiogenesis, tumor vessel maturation, and tumor-associated macrophage polarization from pro-tumorigenic M2-type to anti-tumorigenic M1-type. Finally, we demonstrated similar enhanced anti-tumor effect using a human xenograft model.

CONCLUSIONS:
This study shows that PlGF is a potential target in patients being treated with radiotherapy and suggests VEGF-Grab as a viable therapeutic option in the context of inhibiting secondarily activated pathways responsible for tumor recurrence.

Author information

Park I1, Yang H1, Park JS2, Koh GY3, Choi EK4.
1
Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
2
Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea.
3
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.
4
Institute for Innovative Cancer Research, Asan Medical Center, Seoul, 05505, Korea; Center for Advancing Cancer Therapeutics, Asan Medical Center, Seoul, 05505, Korea; Department of Radiation Oncology, Asan Medical Center, Seoul, 05505, Korea. Electronic address: ekchoi@amc.seoul.kr.