Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy.
Radiotherapy is a widely used treatment for many tumors. Combination therapy using anti-angiogenic agents and radiation has shown promise; however, these combined therapies are reported to have many limitations in clinical trials. Here, we show that radiation transformed tumor endothelial cells (ECs) to fibroblasts, resulting in reduced vascular endothelial growth factor (VEGF) response and increased Snail1, Twist1, Type I collagen, and transforming growth factor (TGF)-β release. Irradiation of radioresistant Lewis lung carcinoma (LLC) tumors greater than 250 mm³ increased collagen levels, particularly in large tumor vessels. Furthermore, concomitant sunitinib therapy did not show a significant difference in tumor inhibition versus radiation alone. Thus, we evaluated multimodal therapy that combined pirfenidone, an inhibitor of TGF-induced collagen production, with radiation and sunitinib treatment. This trimodal therapy significantly reduced tumor growth, as compared to radiation alone. Immunohistochemical analysis revealed that radiation-induced collagen deposition and tumor microvessel density were significantly reduced with trimodal therapy, as compared to radiation alone. These data suggest that combined therapy using pirfenidone may modulate the radiation-altered tumor microenvironment, thereby enhancing the efficacy of radiation therapy and concurrent chemotherapy.
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
Seo-Hyun
SH
Choi
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
Jae-Kyung
JK
Nam
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
Junho
J
Jang
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea. Electronic address: hjlee@kcch.re.kr.
Hae-June
HJ
Lee
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea. Electronic address: yjlee8@kcch.re.kr.
Yoon-Jin
YJ
Lee
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D003131:Combined Modality Therapy; D007211:Indoles / Q000008:administration & dosage*; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D011728:Pyridones / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D011836:Radiation Tolerance / Q000187:drug effects; D000077210:Sunitinib; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011728:Pyridones; D011758:Pyrroles; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; C093844:pirfenidone; D000077210:Sunitinib
Lewis lung carcinoma; Pirfenidone; Radiotherapy; Sunitinib; Transforming growth factor-β