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放射联合常山酮增强肺癌疗效及机制动物实验研究
林润龙,伊帅,巩琳琳,刘维帅,王鹏,刘宁波,赵路军,王平
300060 天津,国家肿瘤临床医学研究中心天津市肿瘤防治重点实验室天津医科大学肿瘤医院放疗科
Role of radiotherapy combined with halofuginone in enhancing therapeutic effect on Lewis lung cancer transplanted in mice and related mechanisms
Lin Runlong,Yi Shuai,Gong Linlin,Liu Weishuai,Wang Peng,Liu Ningbo,Zhao Lujun,Wang Ping
Department of Radiation Oncology,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center of Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin 300060,China
Abstract：Objective To investigate the role of radiotherapy combined with halofuginone in enhancing the therapeutic effect on Lewis lung cancer (LLC) and influence on tumor invasion and metastasis, and to explore possible molecular mechanisms. Methods The model mice with LLC xenograft were randomly divided into blank control group, halofuginone group, irradiation group, and combination group. On day 3 after the treatment ended, 4 mice in each group were randomly sacrificed, and immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were performed. The other mice were observed for survival time and liver/lung metastases. Analysis of variance was applied for comparison of results between groups. Results On the ninth day of treatment, the mean tumor volume was 175.2 mm3 in the blank control group, 118.5 mm3 in the halofuginone group, 106.6 mm3 in the irradiation group, and 85.6 mm3 in the combination group (P=0.000). The median survival times for these groups were 39 days, 61.5 days, 78.5 days, and 84.5 days, respectively (P=0.002). The combination group had the lowest number of liver and lung metastases. The results of immunohistochemistry and ELISA showed that compared with the blank control group, the irradiation group had a higher level of transforming growth factor-β1(TGF-β1), while the combination group had a lower level of TGF-β1. The combination group had a lower mean tumor vascular density than the blank control group. The blank control group and the irradiation group had higher expression levels of collagen, while the halofuginone group and the combination group had lower expression levels of collagen. Conclusions Radiotherapy combined with halofuginone may enhance the effect of antitumor therapies, and potential mechanisms still need further investigation.
Lin Runlong,Yi Shuai,Gong Linlin et al. Role of radiotherapy combined with halofuginone in enhancing therapeutic effect on Lewis lung cancer transplanted in mice and related mechanisms[J]. Chinese Journal of Radiation Oncology, 2016, 25(2): 175-178.
[1]Torre LA,Bray F,Siegel RL,et al. Global cancer statistics,2012[J].CA Cancer J Clin,2015,65(2):87-108.DOI:10.3322/caac.21262. [2]Le Chevalier T,Arriagada R,Quoix E,et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer:first analysis of a randomized trial in 353 patients[J].J Natl Cancer Inst,1991,83(6):417-423.DOI:10.1093/jnci/83.6.417. [3]Zhao L,Ji W,Zhang L,et al. Changes of circulating transforming growth factor-beta1 level during radiation therapy are correlated with the prognosis of locally advanced non-small cell lung cancer[J].J Thorac Oncol,2010,5(4):521-525.DOI:10.1097/JTO.0b013e3181cbf761. [4]Massagué J.TGFbeta in cancer[J].Cell,2008,134(2):215-230.DOI:10.1016/j.cell.2008.07.001. [5]van Kempen LC,Rijntjes J,Mamor-Cornelissen I,et al. Type I collagen expression contributes to angiogenesis and the development of deeply invasive cutaneous melanoma[J].Int J Cancer,2008,122(5):1019-1029.DOI:10.1002/ijc.23147. [6]Vanhaesebroeck B,Mareel M,van Roy F,et al. Expression of the tumor necrosis factor gene in tumor cells correlates with reduced tumorigenicity and reduced invasiveness in vivo[J].Cancer Res,1991,51(8):2229-2238. [7]Shimizu M,Saitoh Y,Itoh H.Immunohistochemical staining of Ha-ras oncogene product in normal,benign,and malignant humanpancreatic tissues[J].Hum Pathol,1990,21(6):607-612.DOI:10.1016/S0046-8177(96)90006-4. [8]Chargari C,Leteur C,Angevin E,et al. Preclinical assessment of JNJ-26854165(Serdemetan),a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts[J].Cancer Lett,2011,312(2):209-218.DOI:10.1016/j.canlet.2011.08.011. [9]Nakata E,Hunter N,Mason K,et al. C225 antiepidermal growth factor receptor antibody enhances the efficacy of docetaxel chemoradiotherapy[J].Int J Radiat Oncol Biol Phys,2004,59(4):1163-1173.DOI:10.1016/j.ijrobp.2004.02.050. [10]Kong FM,Jirtle RL,Huang DH,et al. Plasma transforming growth factor-beta1 level before radiotherapy correlates with long term outcome of patients with lung carcinoma[J].Cancer,1999,86(9):1712-1719.DOI:10.1002/(SICI)1097-0142(19991101)86:9<1712::AID-CNCR12>3.0.CO;2-V. [11]Kong FM,Washington MK,Jirtle RL,et al. Plasma transforming growth factor-beta 1 reflects disease status in patients with lung cancer after radiotherapy:a possible tumor marker[J].Lung Cancer,1996,16(1):47-59.DOI:10.1016/S0169-5002(96)00611-3. [12]Dancea HC,Shareef MM,Ahmed MM.Role of radiation-induced TGF-beta signaling in cancer therapy[J].Mol Cell Pharmacol,2009,1(1):44-56. [13]Vujaskovic Z,Groen HJ.TGF-beta,radiation-induced pulmonary injury and lung cancer[J].Int J Radiat Biol,2000,76(4):511-516.DOI:10.1080/095530000138510. [14]Yoon YH,Rha KS,Kim DH,et al. Is there any synergic effect for coadministration of mitomycin C and halofuginone on the skin wound healing?[J].Am J Otolaryngol,2011,32(2):130-134.DOI:10.1016/j.amjoto.2009.12.002. [15]Dabak H,Karlidag T,Akpolat N,et al. The effects of methylprednisolone and halofuginone on preventing esophageal and hypopharyngeal fibrosis in delivered radiotherapy[J].Eur Arch Otorhinolaryngol,2010,267(9):1429-1435.DOI:10.1007/s00405-010-1242-y. [16]Spector I,Honig H,Kawada N,et al. Inhibition of pancreatic stellate cell activation by halofuginone prevents pancreatic xenograft tumor development[J].Pancreas,2010,39(7):1008-1015.DOI:10.1097/MPA.0b013e3181 da8aa3. [17]Nevo Y,Halevy O,Genin O,et al. Fibrosis inhibition and muscle histopathology improvement in laminin-alpha2-deficient mice[J].Muscle Nerve,2010,42(2):218-229.DOI:10.1002/mus.21706. [18]Ishii H,Choudhuri R,Mathias A,et al. Halofuginone mediated protection against radiation-induced leg contracture[J].Int J Oncol,2009,35(2):315-319.DOI:10.3892/ijo_00000342. [19]Hirshoren N,Eliashar R.Wound-healing modulation in upper airway stenosis-Myths and facts[J].Head Neck,2009,31(1):111-126.DOI:10.1002/hed.20925. [20]Cook JA,Choudhuri R,Degraff W,et al. Halofuginone enhances the radiation sensitivity of human tumor cell lines[J].Cancer Lett,2010,289(1):119-126.DOI:10.1016/j.canlet.2009.08.009. [21]Roffe S,Hagai Y,Pines M,et al. Halofuginone inhibits Smad3 phosphorylation via the PI3K/Akt and MAPK/ERK pathways in muscle cells:effect on myotube fusion[J].Exp Cell Res,2010,316(6):1061-1069.DOI:10.1016/j.yexcr.2010.01.003. [22]Carmeliet P,Jain RK.Angiogenesis in cancer and other diseases[J].Nature,2000,407(6801):249-257.DOI:10.1038/35025220. [23]Gross DJ,Reibstein I,Weiss L,et al. Treatment with halofuginone results in marked growth inhibition of a von Hippel-Lindau pheochromocytoma in vivo[J].Clin Cancer Res,2003,9(10 Pt 1):3788-3793.
2016, Vol. 25 
