Laboratory of Medical Oncology, Cancer Research Institute, The Catholic University of Korea, Seoul, Republic of Korea.
Department of Biomedicine & Health Sciences, The Catholic University of Korea, Seoul, Republic of Korea.
BMC Cancer. 2020 Nov 3;20(1):1057. doi: 10.1186/s12885-020-07566-x.
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.
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.
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).
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.
已知缺氧肿瘤对放射治疗具有高度抗性，并导致非小细胞肺癌（NSCLC）患者预后不良。CKD-516 是一种新型的血管破坏剂（VDA），主要影响肿瘤中央区域的血管，并阻断微管聚合，从而破坏异常的肿瘤血管，导致血液迅速减少，从而迅速导致肿瘤细胞死亡。因此，我们评估了 CKD-516 与放疗（IR）联合使用的抗肿瘤功效，并在这项研究中检查了肿瘤坏死，肿瘤生长延迟以及与缺氧和血管生成相关的蛋白质的表达。
建立了肺鳞癌的异种移植小鼠模型，并每周 5 天对肿瘤进行 IR。在 IR 后 1 小时，用两种治疗方案（第 1 天或第 1 天和第 5 天）给予 CKD-516。治疗后，用苏木精和伊红，以及 pimonidazole 对肿瘤组织进行染色。使用免疫组织化学染色评估 HIF-1α，Glut-1，VEGF，CD31 和 Ki-67 的表达水平。
单独使用 IR 以及 CKD-516+IR（d1）短期治疗均显著降低了肿瘤体积（p=0.006 和 p=0.048）。用 CKD-516+IR（d1 和 d1，5）治疗导致血管数量明显减少（p<0.005）。更具体地说，CKD-516+IR（d1）导致最广泛的肿瘤坏死，从而导致缺氧区域明显扩大（p=0.02），并降低了 HIF-1α，Glut-1，VEGF 和 Ki-67 的表达。长期给予 CKD-516+IR 可降低肿瘤体积并延迟肿瘤生长。这种联合疗法还大大减少了血管数量（p=0.0006），并显著增强了肿瘤坏死（p=0.004）。CKD-516+IR 显著增加了 HIF-1α的表达（p=0.0047），但显著降低了 VEGF 的表达（p=0.0046）。
总之，我们的数据表明，在肺癌异种移植小鼠中，与单独使用相比，CKD-516 和 IR 联合使用可以显著增强抗肿瘤功效。
