scholarly journals Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma

2020 ◽  
Author(s):  
Min-Young Kim ◽  
Jung-Young Shin ◽  
Jeong-Oh Kim ◽  
Kyoung-Hwa Son ◽  
Yeon Sil Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Mouse Model ◽  
Tumor Growth ◽  
Blood Vessels ◽  
Tumor Necrosis ◽  
Tumor Volume ◽  
Lung Squamous Cell Carcinoma ◽  
Ki 67 ◽  
Glut 1

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 massive apoptotic 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.

scholarly journals Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma

2020 ◽  
Author(s):  
Min-Young Kim ◽  
Jung-Young Shin ◽  
Jeong-Oh Kim ◽  
Kyoung-Hwa Son ◽  
Yeon Sil Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Mouse Model ◽  
Tumor Growth ◽  
Blood Vessels ◽  
Tumor Necrosis ◽  
Tumor Volume ◽  
Lung Squamous Cell Carcinoma ◽  
Ki 67 ◽  
Glut 1

Abstract Background: Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small-cell lung cancer (NSCLC) patients. Vascular disrupting agents (VDAs) mainly affect blood vessels located in the central area of the tumor and lead to a rapid decrease in blood, resulting in massive apoptotic tumor cell death. Thus, we evaluate the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examine 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 the treatment, tumor tissues were stained with hematoxylin and eosin and pimonidazole. HIF-1α, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated by 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.

scholarly journals Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Min-Young Kim ◽  
Jung-Young Shin ◽  
Jeong-Oh Kim ◽  
Kyoung-Hwa Son ◽  
Yeon Sil Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Mouse Model ◽  
Tumor Growth ◽  
Blood Vessels ◽  
Tumor Necrosis ◽  
Tumor Volume ◽  
Lung Squamous Cell Carcinoma ◽  
Ki 67 ◽  
Glut 1

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.

scholarly journals Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft lung cancer mouse model

2019 ◽  
Author(s):  
Min-Young Kim ◽  
Jung-Young Shin ◽  
Jeong-Oh Kim ◽  
Kyoung-Hwa Son ◽  
Chan-Kwon Jung ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Blood Vessels ◽  
Tumor Size ◽  
Tumor Necrosis ◽  
Ki 67 ◽  
Glut 1 ◽  
Term Administration ◽  
Xenograft Mice

Abstract Background: To evaluate the anti-tumor efficacy of CKD-516 in combined with irradiation (IR) and examine tumor necrosis, delayed tumor growth, and expression of molecules involved in hypoxia and angiogenesis. Methods : A xenograft mouse model of lung cancer was established. The tumor was exposed to irradiation (IR) for 5 days per week. CKD-516 was administered with ​​two treatment schedules (day 1 or days 1 and 5) at one hour after IR. After the administration, tumor tissues were stained with hematoxylin and eosin and pimonidazole. HIF1 , Glut-1, VEGF, CD31 and Ki-67 expression were evaluated by Immunohistochemical staining. Results: With short-term administration, IR and CKD-516+IR (d1) significantly reduced tumor size ( p = 0.0062 and p = 0.0051, respectively). CKD-516+IR groups were remarkably reduced blood vessels ( p < 0.005). In particular, CKD-516+IR (d1) resulted in the most extensive tumor necrosis, which was significantly increased with large hypoxic area ( p = 0.02) and decreased HIF1 , Glut-1, VEGF, and Ki-67 expressions. Long-term administration of CKD-516+IR reduced tumor size 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 notably increased HIF1 expression ( p = 0.0047), but significantly diminished VEGF expression ( p = 0.0046). Conclusion: Taken together, our results demonstrate that CKD-516 in combination with IR can significantly enhance the anti-tumor efficacy compared to CKD-516 or IR alone in lung cancer xenograft mice. Keywords: Irradiation, Tumor necrosis, Hypoxia, Squamous cell carcinoma of lung, Xenograft mice

scholarly journals Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma

2020 ◽  
Author(s):  
Min-Young Kim ◽  
Jung-Young Shin ◽  
Jeong-Oh Kim ◽  
Kyoung-Hwa Son ◽  
Yeon Sil Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Blood Vessels ◽  
Tumor Size ◽  
Tumor Necrosis ◽  
Ki 67 ◽  
Xenograft Mouse Model ◽  
Glut 1 ◽  
Term Administration

Abstract Background: To evaluate the anti-tumor efficacy of CKD-516 in combined with irradiation (IR) and examine tumor necrosis, delayed tumor growth, and expression of molecules involved in hypoxia and angiogenesis. Methods : A xenograft mouse model of lung cancer was established. The tumor was exposed to irradiation (IR) for 5 days per week. CKD-516 was administered with ​​two treatment schedules (day 1 or days 1 and 5) at one hour after IR. After the administration, tumor tissues were stained with hematoxylin and eosin and pimonidazole. HIF1 , Glut-1, VEGF, CD31 and Ki-67 expression were evaluated by Immunohistochemical staining. Results: With short-term administration, IR and CKD-516+IR (d1) significantly reduced tumor size ( p = 0.0062 and p = 0.0051, respectively). CKD-516+IR groups were remarkably reduced blood vessels ( p < 0.005). In particular, CKD-516+IR (d1) resulted in the most extensive tumor necrosis, which was significantly increased with large hypoxic area ( p = 0.02) and decreased HIF1 , Glut-1, VEGF, and Ki-67 expressions. Long-term administration of CKD-516+IR reduced tumor size 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 notably increased HIF1 expression ( p = 0.0047), but significantly diminished VEGF expression ( p = 0.0046). Conclusions : Taken together, our results demonstrate that CKD-516 in combination with IR can significantly enhance the anti-tumor efficacy compared to CKD-516 or IR alone in lung cancer xenograft mice.

scholarly journals Relationship between the invasion of lymphocytes and cytokines in the tumor microenvironment and the interval after single brachytherapy hypofractionated radiotherapy and conventional fractionation radiotherapy in non-small cell lung Cancer

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Lin Li ◽  
Hong Cheng Yue ◽  
Yun Wei Han ◽  
Wei Liu ◽  
Liang Geng Xiong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Tumor Necrosis ◽  
Tumor Volume ◽  
Small Cell ◽  
Small Cell Lung ◽  
Ki 67 ◽  
Expression Levels ◽  
Conventional Fractionation ◽  
Ifn Γ

Abstract Background The effect of brachytherapy on lymphocytes and cytokines in the tumor microenvironment is unclear. This study aimed to analyze the relationship between the invasion of lymphocytes and cytokines in the tumor microenvironment and the interval after single brachytherapy hypofractionated radiotherapy (SBHFRT) and conventional fractionation radiotherapy (CFRT) in non-small cell lung cancer (NSCLC). Methods Lewis tumor-bearing mice were randomly divided into control, CFRT, and SBHFRT groups. On days 7 and 14 after radiation, the expression levels of CD86+, CD4+, CD8+, and Foxp3+ cells, and levels of Ki-67+ protein were detected by immunohistochemistry, and the tumor necrosis rate was calculated. Following this, the levels of interleukin-10 (IL-10), IL-12, and interferon-γ (IFN-γ) were detected by enzyme-linked immunosorbent assay. The apoptosis rate was evaluated via flow cytometry. The tumor volume and tumor growth inhibition rate (TGIR) were calculated on day 14. Tumor metabolism was assessed via 18F-FDG micropositron emission tomography/computer tomography. Results The tumor volume reduced by 22.0% and TGIR increased by 92.2% (p < 0.05) in the SBHFRT group. Further, on days 7 and 14 after radiation, tumor metabolism, Ki-67+ and Foxp3+ expression levels, and IL-10 levels were lower, and tumor necrosis and apoptosis rates; CD86+, CD4+, and CD8+ expression levels; and IL-12 and IFN-γ levels were higher in the SBHFRT group than in the CFRT group, particularly on day 7. Conclusion SBHFRT could lead to more accumulation of dendritic cells, anti-tumor lymphocytes, and cytokines, and further reduce the aggregation of immunosuppressive lymphocytes and cytokines in the tumor microenvironment compared with CFRT, and the difference was the most obvious on day 7 after radiation. The clinical significance of the findings remains to be further verified.

scholarly journals Relationship Between the Invasion of Lymphocytes and Cytokines in the Tumor Microenvironment and the Interval After Single Brachytherapy Hypofractionated Rradiotherapy and Conventional Fractionation Radiotherapy in Non-Small Cell Lung Cancer

2020 ◽  
Author(s):  
Lin Li ◽  
Hong Cheng Yue ◽  
Yun Wei Han ◽  
Wei Liu ◽  
Liang Geng Xiong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Small Cell Lung Cancer ◽  
Tumor Necrosis ◽  
Tumor Tissue ◽  
Tumor Volume ◽  
Small Cell ◽  
Small Cell Lung ◽  
Ki 67 ◽  
Conventional Fractionation

Abstract Background Lymphocytes and cytokines in tumor microenvironment are the key to immunotherapy, The effect of brachytherapy on tumor microenvironment is not clear. The aim of our study was to analyze the relationship between the invasion of lymphocytes and cytokines in the tumor microenvironment and the interval after single brachytherapy hypofractionated radiotherapy (SBHFRT) and conventional fractionation radiotherapy (CFRT) in non-small cell lung cancer (NSCLC). Methods Lewis tumor-bearing mice were randomly divided into control, CFRT and SBHFRT groups. On the days 7 and 14 after radiation, the expression rates of CD4+, CD8+, Foxp3+, and CD86 + cells and levels of Ki-67 + protein were detected by immunohistochemical analysis, and the tumor necrosis rate was calculated. Following this, interleukin-10 (IL-10), IL-12, and interferon-γ (INF-γ) levels were detected by enzyme-linked immunosorbent assay. The apoptosis rate was evaluated via flow cytometry. The tumor volume and tumor growth inhibition rate (TGIR) were calculated on day 14. Tumor metabolism was assessed via micro 18F-FDG positron emission tomography/computer tomography. Results The tumor volume in the SBHFRT group reduced by 22.0% and TGIR increased by 92.2% (P < 0.05). Further, on days 7 and 14 after radiation, tumor metabolism, Ki-67 + and Foxp3 + expression rates, and IL-10 levels were lower and tumor necrosis and apoptosis rates; CD86+, CD4+, and CD8 + expression rates; and IL-12 and INF-γ levels were higher in SBHFRT group than in the CFRT group, particularly on day 7. Conclusion SBHFRT could lead to more accumulation of dendritic cells and anti-tumor lymphocytes and cytokines in the tumor tissue, and further reduce the aggregation of immunosuppressive lymphocytes and cytokines in the tumor tissue compared with CFRT, and the difference was the most obvious was day 7 after radiation. Hypofractionated radiotherapy combined with immunotherapy may be better for treating NSCLC, as observed on day 7 after radiation.

scholarly journals Ki-67 labeling index affects tumor infiltration patterns of lung squamous cell carcinoma

2015 ◽  
Vol 12 (5) ◽  
pp. 7303-7309 ◽  
Author(s):  
DAISUKE MASUDA ◽  
RYOTA MASUDA ◽  
TOMOHIKO MATSUZAKI ◽  
NAOKO IMAMURA ◽  
NAOHIRO ARUGA ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Labeling Index ◽  
Tumor Infiltration ◽  
Ki 67

scholarly journals UBE2D1 RNA Expression Was an Independent Unfavorable Prognostic Indicator in Lung Adenocarcinoma, but Not in Lung Squamous Cell Carcinoma

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Liyan Hou ◽  
Yingbo Li ◽  
Ying Wang ◽  
Dongqiang Xu ◽  
Hailing Cui ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Lung Adenocarcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Survival Data ◽  
Lung Squamous Cell Carcinoma ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Rna Expression

In this study, we investigated the potential prognostic value of ubiquitin-conjugating enzyme E2D1 (UBE2D1) RNA expression in different histological subtypes of non-small-cell lung cancer (NSCLC). A retrospective study was performed by using molecular, clinicopathological, and survival data in the Cancer Genome Atlas (TCGA)—Lung Cancer. Results showed that both lung adenocarcinoma (LUAD) (N=514) and lung squamous cell carcinoma (LUSC) (N=502) tissues had significantly elevated UBE2D1 RNA expression compared to the normal tissues (p<0.001 and p=0.036, respectively). UBE2D1 RNA expression was significantly higher in LUAD than in LUSC tissues. Increased UBE2D1 RNA expression was independently associated with shorter OS (HR: 1.359, 95% CI: 1.031–1.791, p=0.029) and RFS (HR: 1.842, 95% CI: 1.353–2.508, p<0.001) in LUAD patients, but not in LUSC patients. DNA amplification was common in LUAD patients (88/551, 16.0%) and was associated with significantly upregulated UBE2D1 RNA expression. Based on these findings, we infer that UBE2D1 RNA expression might only serve as an independent prognostic indicator of unfavorable OS and RFS in LUAD, but not in LUSC.

scholarly journals Deep Learning Based Automated Orthotopic Lung Tumor Segmentation in Whole-Body Mouse CT-Scans

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4585
Author(s):  
Wouter R. P. H. van de Worp ◽  
Brent van der Heyden ◽  
Georgios Lappas ◽  
Ardy van Helvoort ◽  
Jan Theys ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Deep Learning ◽  
Tumor Growth ◽  
Tumor Volume ◽  
Learning Algorithm ◽  
Lung Tumor ◽  
Whole Body ◽  
Ct Scans ◽  
Therapeutic Effects ◽  
Deep Learning Algorithm

Lung cancer is the leading cause of cancer related deaths worldwide. The development of orthotopic mouse models of lung cancer, which recapitulates the disease more realistically compared to the widely used subcutaneous tumor models, is expected to critically aid the development of novel therapies to battle lung cancer or related comorbidities such as cachexia. However, follow-up of tumor take, tumor growth and detection of therapeutic effects is difficult, time consuming and requires a vast number of animals in orthotopic models. Here, we describe a solution for the fully automatic segmentation and quantification of orthotopic lung tumor volume and mass in whole-body mouse computed tomography (CT) scans. The goal is to drastically enhance the efficiency of the research process by replacing time-consuming manual procedures with fast, automated ones. A deep learning algorithm was trained on 60 unique manually delineated lung tumors and evaluated by four-fold cross validation. Quantitative performance metrics demonstrated high accuracy and robustness of the deep learning algorithm for automated tumor volume analyses (mean dice similarity coefficient of 0.80), and superior processing time (69 times faster) compared to manual segmentation. Moreover, manual delineations of the tumor volume by three independent annotators was sensitive to bias in human interpretation while the algorithm was less vulnerable to bias. In addition, we showed that besides longitudinal quantification of tumor development, the deep learning algorithm can also be used in parallel with the previously published method for muscle mass quantification and to optimize the experimental design reducing the number of animals needed in preclinical studies. In conclusion, we implemented a method for fast and highly accurate tumor quantification with minimal operator involvement in data analysis. This deep learning algorithm provides a helpful tool for the noninvasive detection and analysis of tumor take, tumor growth and therapeutic effects in mouse orthotopic lung cancer models.

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