表皮生长因子受体酪氨酸激酶抑制剂Gefitinib对鼻咽癌荷瘤裸鼠移植瘤生长作用的实验研究

Effect of Epidermal Growth Factor Receptor-selective Tyrosine Kinase Inhibitor Gefitinib on Nasopharyngeal Carcinoma Xenografts

背景与目的:Gefitinib是一种喹唑啉类化合物,它是一种口服的选择性的表皮生长因子受体酪氨酸激酶抑制剂,已被美国FDA批准用于治疗晚期非小细胞肺癌。我们在体外的研究结果显示Gefitinib对鼻咽低分化鳞癌细胞株CNE2和SUNE1以及鼻咽高分化鳞癌细胞株CNE1的增殖皆有明显的抑制作用。本实验通过体内研究方法初步探讨Gefitinib对鼻咽癌荷瘤裸鼠移植瘤的生长有无抑制作用,同时探讨Gefitinib与细胞毒药物顺铂合用在体内对鼻咽癌生长的影响。方法:将处于对数生长期的CNE2细胞制成1×107/ml的细胞悬液,取0.2ml的CNE2细胞悬液接种于裸鼠右侧腋窝皮下,7天后肿瘤体积在100～200mm3之间,根据性别分层,按肿瘤体积大小将裸鼠随机分成溶剂对照组、Gefitinib(100mg/kg)组、Gefitinib(200mg/kg)组、DDP组、Gefitinib(100mg/kg)+DDP组。每组动物数8只,雌雄各半。Gefitinib灌胃给药,1周内连续5天,连用4周;DDP腹腔注射给药,每周1次,共4次。药物处理前及处理后每2天测量每只裸鼠肿瘤的长、宽最大垂直直径的大小,计算肿瘤体积。用药结束后2天,处死裸鼠,取出肿瘤组织,称重,计算抑瘤率。结果:治疗后各组裸鼠肿瘤体积的生长曲线显示溶剂对照组的生长速度在各时间点上均快于治疗组。进一步统计学分析显示治疗结束时。

BACKGROUND &OBJECTIVE: Gefitinib,an anilinoquinazoline,is an ora ll y active,selective epidermal growth factor receptor(EGFR) tyrosine kinase inhibi tor,which has been approved for the treatment of advanced non-small cell lung cancer. We have found that the proliferation of nasopharyngeal carcinoma (NPC) c ell lines CNE1,CNE2,and SUNE1 was inhibited by Gefitinib.The present study was d esigned to evaluate the effect of Gefitinib alone or in combination with cisplat in (DDP) on NPC CNE2 xenografts. METHODS: Exponentially growing CNE2 cells were prepared into cell suspension (1×107 cells/ml). Suspension of 200 靗 of CNE2 c ells was injected s.c. into the right flank area of the mice. After 7 days,when well-established tumors of 100-200 mm3 were detected,mice were randomized into five groups: control group,Gefitinib (100 mg/kg) group,Gefitinib (200 mg/kg) gr oup,DDP group,and Gefitinib (100 mg/kg) plus DDP group. Gefitinib was administer ed by oral gavage on days 1-5 of each week for 4 weeks. DDP was administered i. p. once a week for 4 weeks. Tumor volume was determined by direct measurement wi th caliper and calculated by the formula 1/2×(large diameter)×(small diameter) 2. The mice were sacrificed at two days after the treatment ended; tumor masses were removed and weighed. The tumor inhibition rates were calculated. The studen ts test was used to evaluated the statistical significance of the results. RES ULTS: Growth curves showed that tumor masses of control group grew more rapidly than ones of every treatment group. The average tumor volume was significantly s maller in Gefitinib (200 mg/kg) group than in control group (P=0.02). The averag e tumor volume had no significant difference between Gefitinib (100 mg/kg) group and control group. The average tumor volume of DDP or Gefitinib (100 mg/kg) plu s DDP group was smaller than that of control group(P=0.007 and 0.001,respectivel y). The average tumor volume had no significant difference between DDP and Gefit inib (100 mg/kg) in combination with DDP group. The tumor inhibition rates of Ge fitinib (100 mg/kg) group,Gefitinib (200 mg/kg) group,DDP group,and Gefitinib (1 00 mg/kg) plus DDP group were 26.3%,30.6%,45.7%and 54.8%,respectively. The a verage tumor weight after treatment had no significant difference between Gefiti nib (100 mg/kg) group and control group.The average tumor weights of Gefitinib ( 200 mg/kg) group,DDP group,Gefitinib (100 mg/kg) plus DDP group were all smaller than that of control group. The average tumor weight had no significant differe nce between DDP group and Gefitinib (100 mg/kg) plus DDP group. CONCLUSION: Gefi tinib could inhibit the growth of NPC CNE2 xenografts. Gefitinib in combination with DDP did not significantly potentiate the effect of DDP on NPC CNE2 xenograf ts.