Abstract

BackgroundHypoxic 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.MethodsA 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.ResultsShort-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).ConclusionsTaken 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.

Highlights

  • Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in nonsmall cell lung cancer (NSCLC) patients

  • Squamous cell carcinoma (SqCC), which accounts for approximately 30% of NSCLCs, still has a poor prognosis owing to limited treatment options [4]

  • After counting the number of blood vessels, we found that the number of positively Cluster of differentiation 31 (CD31) stained blood vessels was significantly reduced in mice treated with CKD-516 alone (52%, p < 0.001) compared to the vehicle (Fig. 2c)

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Summary

Introduction

Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in nonsmall cell lung cancer (NSCLC) patients. Lung cancer is histologically classified as small cell lung cancer or non-small cell lung cancer (NSCLC) The latter accounts for approximately 85% of all lung cancers [2, 3]. Squamous cell carcinoma (SqCC), which accounts for approximately 30% of NSCLCs, still has a poor prognosis owing to limited treatment options [4]. Concomitant chemotherapy combined with radiation has traditionally been regarded as the standard treatment for locally advanced stage III NSCLC [5]. There is an urgent need to develop new treatment strategies that enhance local effects, and minimize side effects when anticancer drugs are simultaneously or sequentially combined with radiation

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