塞来昔布对小鼠胱肿瘤的抑制作用
摘要
目的近年来研究发现,长期服用非甾体类抗炎药(NSAID)有与抗炎作用无关的抗肿瘤功能,至今,其对抗肿瘤的确切机制还未完全明了,本文章主要探讨选择性环氧化酶-2抑制剂塞来昔布对膀胱肿瘤的抑制作用及其机制。
方法建立小鼠膀胱肿瘤模型并随机分为对照组、实验1组和实验2组,分别给与生理盐水和不同剂量的塞来昔布灌胃,观察肿瘤的生长情况,测量肿瘤体积、质量并计算抑瘤率；免疫组织化学方法检测肿瘤原癌基因bcl-2和半胱氨酸天门冬氨酸蛋白酶-3(caspase-3)的表达情况并计算其免疫组化评分(HIS)。
结果实验1、实验2组肿瘤的平均质量明显低于对照组,差异有显著性(P<0.05)。实验1、实验2组的抑瘤率分别为43%、58%。在bcl-2免疫组化切片中,bcl-2主要表达于细胞浆中,对照组,实验一组,实验二组,免疫组化的颜色逐渐减淡,染色细胞数量减少；而caspase-3也主要表达于细胞浆中,但随着塞来昔布剂量的增加,免疫组化的颜色逐渐加深,所表达的细胞数量也增加3组间bcl-2HIS比较差异有显著性(F=25.08,q=3.75～9.91,P<0.05)；3组间caspase-3的HIS比较差异有显著性(F=16.82,q=3.26～8.15,P<0.05)。
结论塞来昔布能抑制小鼠膀胱肿瘤的生长,其机制可能与抑制bcl-2,增强caspase-3的表达有关。该实验为临床中抑制肿瘤的生长的化疗药物提出了新的方向和选择。
Objective To detect whether cyclooxygenase-2 inhibitor celecoxib could prevent mice urinary bladder cancer and to explore the mechanisms of the effect.
Methods The mouse bladder tumors model was successfully established, then all mice were randomly divided into control group and test 1,2 group. Celecoxib in suspension was administered to mice in the test group orally, while saline to the mice in the control group. During the test, the growth of tumor mass was observed, the volume and weight of transplantation tumor, and the rate of tumor inhibition were detected. The protein expression of bcl-2 and caspase-3 were examined by immunohistochemical method.The immunohistochemical scores (IHS) were calculated by combining an estimate of the percentage of immunoreactive cells with that of the stain intensity.
Result The average quality of experiment 1, experimental group 2 tumors were significantly lower than the control group, the difference was significant (P<0.05). The inhibited rates of experiment 1, experimental group 2 were 43%,58%. The difference of bcl-2 HIS was significant among the 3 groups (F=25.08,q=3.75～9.91,P<0.05), The difference of caspase-3 HIS was significant among the 3 groups (F=16.82,q=3.26-8.15,P<0.05).
Conclusion Different doses of celecoxib can significantly suppress tumor growth in a dose-dependent manner, it maybe have something with the decrease of bcl-2'expression but the increase of caspase-3'expression.
方法建立小鼠膀胱肿瘤模型并随机分为对照组、实验1组和实验2组,分别给与生理盐水和不同剂量的塞来昔布灌胃,观察肿瘤的生长情况,测量肿瘤体积、质量并计算抑瘤率；免疫组织化学方法检测肿瘤原癌基因bcl-2和半胱氨酸天门冬氨酸蛋白酶-3(caspase-3)的表达情况并计算其免疫组化评分(HIS)。
结果实验1、实验2组肿瘤的平均质量明显低于对照组,差异有显著性(P<0.05)。实验1、实验2组的抑瘤率分别为43%、58%。在bcl-2免疫组化切片中,bcl-2主要表达于细胞浆中,对照组,实验一组,实验二组,免疫组化的颜色逐渐减淡,染色细胞数量减少；而caspase-3也主要表达于细胞浆中,但随着塞来昔布剂量的增加,免疫组化的颜色逐渐加深,所表达的细胞数量也增加3组间bcl-2HIS比较差异有显著性(F=25.08,q=3.75～9.91,P<0.05)；3组间caspase-3的HIS比较差异有显著性(F=16.82,q=3.26～8.15,P<0.05)。
结论塞来昔布能抑制小鼠膀胱肿瘤的生长,其机制可能与抑制bcl-2,增强caspase-3的表达有关。该实验为临床中抑制肿瘤的生长的化疗药物提出了新的方向和选择。
Objective To detect whether cyclooxygenase-2 inhibitor celecoxib could prevent mice urinary bladder cancer and to explore the mechanisms of the effect.
Methods The mouse bladder tumors model was successfully established, then all mice were randomly divided into control group and test 1,2 group. Celecoxib in suspension was administered to mice in the test group orally, while saline to the mice in the control group. During the test, the growth of tumor mass was observed, the volume and weight of transplantation tumor, and the rate of tumor inhibition were detected. The protein expression of bcl-2 and caspase-3 were examined by immunohistochemical method.The immunohistochemical scores (IHS) were calculated by combining an estimate of the percentage of immunoreactive cells with that of the stain intensity.
Result The average quality of experiment 1, experimental group 2 tumors were significantly lower than the control group, the difference was significant (P<0.05). The inhibited rates of experiment 1, experimental group 2 were 43%,58%. The difference of bcl-2 HIS was significant among the 3 groups (F=25.08,q=3.75～9.91,P<0.05), The difference of caspase-3 HIS was significant among the 3 groups (F=16.82,q=3.26-8.15,P<0.05).
Conclusion Different doses of celecoxib can significantly suppress tumor growth in a dose-dependent manner, it maybe have something with the decrease of bcl-2'expression but the increase of caspase-3'expression.
引文
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[3]李春,邹桂华,彭瑞元,等.塞来昔布抑制SD大鼠膀胱癌作用的实验室研究[J].中华肿瘤防治杂志,2008,15(14)：1061-1063.
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[5]GRUBBS C J, LUBET R A, KOKIA T, et al. Celecoxib inhibits Nbutyl-N(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancer in male B6D2F1 mice and female Fischer Fischer-344 rats[J]. Cancer Res,2000,60(20):5599-5602.
[6]周晓彬,纪新强,徐莉.医用统计学软件PPMS1.5的组成和应用特点[J].齐鲁医学杂志,2009,24(1)：29-32.
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[23]De Boer Ec, Rooijakkers SJ. Schamhart DH, et al. Cytokine gene expression in a mouse model: the first instillations with viable bacillus Calmette.. Guerin determine the succeeding Thl response EJ3. J Urol,2003,70(5):2004-2008.
[24]Morales A, Chin JL, Ramsey Ew. Mycobacterial cell wall extract for treatment of carcinoma in situ of the bladder EJ3. Jurol,001,66(5):1633.1637.
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[2]SOSLOW R A, DANNENBERG A J, RUSH I, et al. Cox-2 is expressed in human pulmonary colonic and mammary tumors[J], Cancer,2000,89(12):2637-2611.
[3]李春,邹桂华,彭瑞元,等.塞来昔布抑制SD大鼠膀胱癌作用的实验室研究[J].中华肿瘤防治杂志,2008,15(14)：1061-1063.
[4]JACOBY R F, SEIBERT K, COLE C E, et al. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis[J]. Cancer Res,2000,60(18):5040-5044.
[5]GRUBBS C J, LUBET R A, KOKIA T, et al. Celecoxib inhibits Nbutyl-N(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancer in male B6D2F1 mice and female Fischer Fischer-344 rats[J]. Cancer Res,2000,60(20):5599-5602.
[6]周晓彬,纪新强,徐莉.医用统计学软件PPMS1.5的组成和应用特点[J].齐鲁医学杂志,2009,24(1)：29-32.
[7]RICHTER M, WEISS M, WEINBERGER I, et al. Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitor[J]. Carcinogenesis,2001,22(1):17-25.
[8]HONG S P, HA S H, PARK IS, et al. Induction of apoptosis in colon cancer cell by non-steroidal anti-inflammatory drugs[J]. Yonsei Med J,1998,3(9):287.
[9]王婷婷；阎胜利.硒对自身免疫性甲状腺炎大鼠甲状腺细胞Caspase-3, Bcl-2和Bax蛋白表达影响[J].齐鲁医学杂志,2009,24(4)：324-326
[10]PACKHAM G, CLEVELAND J I. C-myc and apoptosis[J]. Biochem Biophys Acta, 1995,12(42):11
[11]JACOBY R F, SEIBERT K, COLE C E, et al. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis[J]. Cancer Res,2000,60(18):5040-5044.
[12]Kirschenbaum A, LiuX, Yao S, et al. The role of cyclooxygenase-2 in prostate cancer[J]. Urology,2001,58:127-131.
[13]Song X, Lin HP, Johnson AJ,et al. Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells[J] Natl Cancer Inst.2002, 94:585-591.
[14]DUBINETT S M,SHARMA S, HUANG M, et al.Cyclooxygenase-2 in lung cancer [J]. Prog Exp Tumor Res,2003,37:138-162.
[15]TANAKA T, DELONG PA, AMIN K,et al.Treatment of lung cancer using clinically relevant oral doses of the cyclooxygenase-2 inhibitor rofecoxib potential value as adjuvant therapy after surgery[J].Ann Surg,2005,241(1),168-178.
[16]任亮,侯树坤,王晓峰,等.塞来昔布对膀胱癌裸鼠皮下移植瘤及移植瘤细胞凋亡的影响[J].中华泌尿外科杂志,2006,27(4)：30-32.
[17]MASFERRER JL, LEAHY KM, KOKI AT, et al. Antiangiogenic and antitumor activities of eyelooxygenase —2 inhibitors[J]. Cancer Res.2000,60(5):1306-1311.
[18]KRYSAN K, MERCHANT FH, ZHUL, et al. COX-2-dependent stabilization of survivin in non. small cell lung cancer[J]. FASEB J.2004,18(1):206-208.
[19]Hockenbery D M, Zutter M, Hickey W, et al. Bcl-2 Protein is topographically restricted in tissue characterized apoptotic cell death[J]. Proc Natl Acad Sci USA,2001,3619.
[20]Pidgeon G P, Barr M P, Harmey J H, et al. Vascular endothelial growth factor (VEGF) upregulates Bcl22 and inhibits apoptosis in human and murine mammary adenocarcinoma cells [J]. British Journal of Cancer,2001,273-278.
[21]Miyake H, Hara I, Yamanaka K, et al. Elevation of serum level of vascular endothelial growth factor as a new predictor of recurrence and disease progression in patients with superficial urothelial cancer[J]. Urology,1999,302-307.
[22]Iric A, Uchida T, Yamashita H, et al. Sufficient prophylactic efficacy with m inor adverse effects by intravesical instillation of lowose bacillus Chalmette. Guerin for superficial bladder cancer recurrence EJ3. Int J Urol,003,0(4):183.89.
[23]De Boer Ec, Rooijakkers SJ. Schamhart DH, et al. Cytokine gene expression in a mouse model: the first instillations with viable bacillus Calmette.. Guerin determine the succeeding Thl response EJ3. J Urol,2003,70(5):2004-2008.
[24]Morales A, Chin JL, Ramsey Ew. Mycobacterial cell wall extract for treatment of carcinoma in situ of the bladder EJ3. Jurol,001,66(5):1633.1637.
[25]Dhar N, Rao V, Tyagi AK. Skewing of the Th1/Th2 responses in mice due to variation in thelevel of expression of an antigen in a recombinant BCG system [J]. Immune Lett,2003,8(3): 175.84.
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