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Abstract
Background: Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small cell lung cancer (NSCLC) patients. CKD-516, a novel vascular disrupting agent (VDA), mainly affects blood vessels in the central area of the tumor and blocks tubulin polymerization, thereby destroying the aberrant tumor vasculature with a rapid decrease in blood, resulting in rapid tumor cell death. Therefore, we evaluated the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examined tumor necrosis, delayed tumor growth, and expression of proteins involved in hypoxia and angiogenesis in this study.

Methods: A xenograft mouse model of lung squamous cell carcinoma was established, and the tumor was exposed to IR 5 days per week. CKD-516 was administered with two treatment schedules (day 1 or days 1 and 5) 1 h after IR. After treatment, tumor tissues were stained with hematoxylin and eosin, and pimonidazole. HIF-1α, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated using immunohistochemical staining.

Results: Short-term treatment with IR alone and CKD-516 + IR (d1) significantly reduced tumor volume (p = 0.006 and p = 0.048, respectively). Treatment with CKD-516 + IR (d1 and d1, 5) resulted in a marked reduction in the number of blood vessels (p < 0.005). More specifically, CKD-516 + IR (d1) caused the most extensive tumor necrosis, which resulted in a significantly large hypoxic area (p = 0.02) and decreased HIF-1α, Glut-1, VEGF, and Ki-67 expression. Long-term administration of CKD-516 + IR reduced tumor volume and delayed tumor growth. This combination also greatly reduced the number of blood vessels (p = 0.0006) and significantly enhanced tumor necrosis (p = 0.004). CKD-516 + IR significantly increased HIF-1α expression (p = 0.0047), but significantly reduced VEGF expression (p = 0.0046).

Conclusions: Taken together, our data show that when used in combination, CKD-516 and IR can significantly enhance anti-tumor efficacy compared to monotherapy in lung cancer xenograft mice.

Affiliations

Min-Young Kim  1   2 , Jung-Young Shin  1 , Jeong-Oh Kim  1 , Kyoung-Hwa Son  1   2 , Yeon Sil Kim  3 , Chan Kwon Jung  4 , Jin-Hyoung Kang  5   6   7
1 Laboratory of Medical Oncology, Cancer Research Institute, The Catholic University of Korea, Seoul, Republic of Korea.
2 Department of Biomedicine & Health Sciences, The Catholic University of Korea, Seoul, Republic of Korea.
3 Department of Radiation Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
4 Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
5 Laboratory of Medical Oncology, Cancer Research Institute, The Catholic University of Korea, Seoul, Republic of Korea. oncologykang@naver.com.
6 Department of Biomedicine & Health Sciences, The Catholic University of Korea, Seoul, Republic of Korea. oncologykang@naver.com.
7 Department of Medical Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea. oncologykang@naver.com.