福莫特罗、吲哚美辛、罗红霉素联合治疗癌症恶病质的实验研究
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摘要
目的研究福莫特罗、吲哚美辛和罗红霉素对癌症恶病质小鼠的联合治疗作用并探讨其可能机制。
方法于皮下接种小鼠结肠腺癌Colon26 (C26)细胞株于雄性Babl/c小鼠后9天建立癌症模型。72只小鼠按析因设计随机分为9组,每组8只;从第9天开始每天按分组情况分别给予不同的药物治疗。FM剂量1 mg/kg/d, IND剂量0.5 mg/kg/d,RM剂量50 mg/kg/d,以上药物全部采用腹腔注射给药,连用7天。每天监测小鼠进食量,每天称量小鼠体质量,从皮下可触及肿瘤后每天测量肿瘤体积。第16天处死各组小鼠,检测IL-6、TNF-α及白蛋白、甘油三酯、血糖水平。数据使用SPSS10.0统计软件包处理。
结果:
1癌性恶病质各组,皮下接种C26细胞4-5天后,肿瘤开始可以皮下触及,小鼠出现精神萎靡,活动减少。9天左右肿瘤长至平均约1cm3,小鼠开始出现全身毛色发暗且杂乱无序、活动迟缓、消瘦等表现,体质量亦出现下降,至第9天,全部接种肿瘤小鼠进入癌性恶病质状态。
2腓肠肌重量实验结束时B组小鼠左侧腓肠肌重量降至A组的67%(P<0.05)。析因分析示:罗红霉素、吲哚美辛、福莫特罗用与不用在增加腓肠肌重量方面有差异(P<0.05),三种药物两两组合之间在增加左侧腓肠肌重量方面未发现有统计学意义(P>0.05),三中药物组合之间亦无交互作用(P>0.05),福莫特罗、吲哚美辛、罗红霉素三药联合组增加腓肠肌重量最多。
3生化指标B组小鼠与A组小鼠相比,白蛋白、甘油三酯及血糖水平差异有显著性(P<0.05)。对于甘油三酯,福莫特罗、吲哚美辛和罗红霉素能使其水平降低(P<0.05),三种药物两两之间无交互作用(P>0.05),但三者之间存在交互作用(P<0.05),以三药联合用药组降低甘油三酯最多。对于血糖析因分析结果表明:福莫特罗、吲哚美辛、罗红霉素能使血糖升高(P<0.05),三种药物两两之间无交互作用(P>0.05),但三者之间存在交互作用(P<0.05)以三药联合用药组升高血糖最多。而对白蛋白析因分析结果表明:三药在升高白蛋白方面均没有统计学意义(P>0.05)。
4血清细胞因子B组小鼠细胞因子TNF-α,IL-6和正常小鼠A组相比均有升高(p<0.05)。IL-6析因分析结果表明:吲哚美辛两水平间有差异(P<0.05),表明吲哚美辛能降低恶病质小鼠IL-6。而另外两药虽能降低IL-6,但无统计学意义(P>0.05),且药物间没有发现有交互作用(P>0.05)。TNF-α析因分析显示福莫特罗、吲哚美辛、罗红霉素主效应有统计学意义(P<0.001),表明三种药物单独应用都能降低TNF-α。福莫特罗与罗红霉素间有交互作用,且此三种药物间宜有交互作用,以三药联合用药组降低TNF-α最多。
结论
1. Colon26结肠腺癌诱导的癌症恶病质模型与人类癌症恶病质相似,是研究癌症恶病质发病机制及药物治疗实验的理想模型。
2.癌症恶病质小鼠去瘤体质量下降、腓肠肌重量下降、严重的代谢紊乱,血清TNF-α, IL-6含量增高,提示代谢紊乱产生的TNF-α, IL-6等细胞因子与癌症恶病质的发生、发展密切相关,是癌症恶病质发生的一个重要机制。
3.福莫特罗、吲哚美辛、罗红霉素在抗癌症恶病质代谢紊乱与组织消耗及降低血清中升高的TNF-α, IL-6方面都有着不同程度的作用。将促合成代谢药物(福莫特罗)和抗细胞因子药物(吲哚美辛、罗红霉素)联合应用治疗CC在某些方面可以产生相互的交互作用,治疗效果在某些方面优于单一应用。
Objective To observe the effect of the Combinative Supplementation of Formoterol(FM), Indomethacin (IND)and Roxithromycin (RM) on cancer cachexia (CC) and to study the mechanism with an animal cancer cachetic model.
Methods Male BALB/c mice bearing colon 26 adenocarcinoma for 9 days were served as models of cancer cachexia. The 72 models were divided randomly into nine treating groups basing on factorial design. Formoterol was used at a dose of 1 mg/kg/d, indomethacin was used at a dose of 0.5 mg/kg/d, roxithromycin was used at a dose of 50mg/kg/d. All of drugs were injected through intraperitoneal injection. FM, IND, FM and saline were given daily for 7days from the onset of cachexia to sacrifice. Physiological conditions, bodyweight and food intake were documented every day, tumor volume were documented every day after the tumors were palpable. Serum levels of cytokine and nutritional markers were detected 7 days after treatment. Data were expressed as means±SE. Statistical significance was determined by factorial design ANOVA and Student's t-test using SPSS 10.0. P<0.05 was considered statistically significant.
RESULT
1 Cancer cachexia model Tumors were palpable in mice initially on day4 or 5 after inoculation of tumor cells, Mice becomes listless and less move. Tumor grew about 1cm3 after 9 days. Color pattern of mice lose luster and disorderly. Their action become sluggish, they become emaciation. Body weight of mice also begins to decrease. All mice get into cancer cachexia on the 9th day. Cachexia symptoms were observed, such as obviously poor physical activity, asthenia, piloerection, pelage lost gloss and sheded.
2 left gastrocnemius weight When the experiment was finished, the left gastrocnemius weight of group B was cut down to 67% of group A(P<0.05). This experiment using three-factorial analysis showed that roxithromycin, indomethacin, formoterol can increase the left gastrocnemius alone(P<0.05), Any two of the three drugs have no interaction on elevating the left gastrocnemius weight. The three drugs combinative supplementation can mostly improve the weight of left gastrocemius.
3. Biochemical indicators The levels of serum Glu and Alb in B group were obvious lower than group A (p<0.05), but the levels of TG were significant higher than group A (p<0.05). Factorial analysis indicate that FM, IND, RM can decrease the levels of TG(P<0.05). Any two of the three drugs have no interaction on decrease the levels of TG(P>0.05), but the three drugs have interaction on decrease the levels of TG(P<0.05). The three drugs combinative supplementation can mostly bring down the levels of TG. About alb factorial analysis indicate that FM, IND, RM can elevate the levels of GLU(P<0.05). Any two of the three drugs have no interaction on elevate the levels of glucose(P>0.05), but the three drugs have interaction on elevating the levels of GLU(P<0.05). The three drugs combinative supplementation can mostly improve the levels of GLU. Although Alb of groups with drugs treatment were raised, no statistical significance was detected in those groups (p >0.05). Factorial analysis indicate that FM, IND, RM have no statistical difference in elevating the levels of alb(P>0.05).
4. Serum cytokines levels Comparing with normal mice, the cytokines TNF-αand IL-6 levels were raised significantly (p<0.05). After treatment with drugs, the results show that IND could decrease the levels of IL-6 (p<0.05), but FM and RM could not(p>0.05) and there are not interactions among FM , IND and RM in IL-6 level(sP>0.05). About TNF-αfactorial analysis indicate that FM, IND, RM can lower the levels of TNF-α(P<0.001. There are not only interactions between FM and RM in decreasing the levels of TNF-α, but also the three drugs have interactions in decreasing the levels of TNF-α. The three drugs combinative supplementation can mostly decrease the levels of TNF-α.
Conclusion
1. This experiment had established an animal model of cancer cachexia successfully that was very similar human’s by inoculating BALB/c mice with colon-26.It provides contribution for further studying cancer cachexia theory foundation and efficacy of drugs in treating cancer chachexia.
2. The result of body weight decreasing, metabolic disorder and the levels of IL-6、TNF-αincreasing showed that mice in cancer cachexia condition appearance significantly metabolic disorder of glucose, lipoids and albumin. It may have correlation with cytokines. It showed that the participation of cytokines probably is one of important mechanism that is lead to happen cancer cachexia.
3. Three drugs: FM, IND and RM had their own positive effects on CC mice. Drugs combination in tumor-bearing mice with cancer cachexia could produce synergistic action.
方法于皮下接种小鼠结肠腺癌Colon26 (C26)细胞株于雄性Babl/c小鼠后9天建立癌症模型。72只小鼠按析因设计随机分为9组,每组8只;从第9天开始每天按分组情况分别给予不同的药物治疗。FM剂量1 mg/kg/d, IND剂量0.5 mg/kg/d,RM剂量50 mg/kg/d,以上药物全部采用腹腔注射给药,连用7天。每天监测小鼠进食量,每天称量小鼠体质量,从皮下可触及肿瘤后每天测量肿瘤体积。第16天处死各组小鼠,检测IL-6、TNF-α及白蛋白、甘油三酯、血糖水平。数据使用SPSS10.0统计软件包处理。
结果:
1癌性恶病质各组,皮下接种C26细胞4-5天后,肿瘤开始可以皮下触及,小鼠出现精神萎靡,活动减少。9天左右肿瘤长至平均约1cm3,小鼠开始出现全身毛色发暗且杂乱无序、活动迟缓、消瘦等表现,体质量亦出现下降,至第9天,全部接种肿瘤小鼠进入癌性恶病质状态。
2腓肠肌重量实验结束时B组小鼠左侧腓肠肌重量降至A组的67%(P<0.05)。析因分析示:罗红霉素、吲哚美辛、福莫特罗用与不用在增加腓肠肌重量方面有差异(P<0.05),三种药物两两组合之间在增加左侧腓肠肌重量方面未发现有统计学意义(P>0.05),三中药物组合之间亦无交互作用(P>0.05),福莫特罗、吲哚美辛、罗红霉素三药联合组增加腓肠肌重量最多。
3生化指标B组小鼠与A组小鼠相比,白蛋白、甘油三酯及血糖水平差异有显著性(P<0.05)。对于甘油三酯,福莫特罗、吲哚美辛和罗红霉素能使其水平降低(P<0.05),三种药物两两之间无交互作用(P>0.05),但三者之间存在交互作用(P<0.05),以三药联合用药组降低甘油三酯最多。对于血糖析因分析结果表明:福莫特罗、吲哚美辛、罗红霉素能使血糖升高(P<0.05),三种药物两两之间无交互作用(P>0.05),但三者之间存在交互作用(P<0.05)以三药联合用药组升高血糖最多。而对白蛋白析因分析结果表明:三药在升高白蛋白方面均没有统计学意义(P>0.05)。
4血清细胞因子B组小鼠细胞因子TNF-α,IL-6和正常小鼠A组相比均有升高(p<0.05)。IL-6析因分析结果表明:吲哚美辛两水平间有差异(P<0.05),表明吲哚美辛能降低恶病质小鼠IL-6。而另外两药虽能降低IL-6,但无统计学意义(P>0.05),且药物间没有发现有交互作用(P>0.05)。TNF-α析因分析显示福莫特罗、吲哚美辛、罗红霉素主效应有统计学意义(P<0.001),表明三种药物单独应用都能降低TNF-α。福莫特罗与罗红霉素间有交互作用,且此三种药物间宜有交互作用,以三药联合用药组降低TNF-α最多。
结论
1. Colon26结肠腺癌诱导的癌症恶病质模型与人类癌症恶病质相似,是研究癌症恶病质发病机制及药物治疗实验的理想模型。
2.癌症恶病质小鼠去瘤体质量下降、腓肠肌重量下降、严重的代谢紊乱,血清TNF-α, IL-6含量增高,提示代谢紊乱产生的TNF-α, IL-6等细胞因子与癌症恶病质的发生、发展密切相关,是癌症恶病质发生的一个重要机制。
3.福莫特罗、吲哚美辛、罗红霉素在抗癌症恶病质代谢紊乱与组织消耗及降低血清中升高的TNF-α, IL-6方面都有着不同程度的作用。将促合成代谢药物(福莫特罗)和抗细胞因子药物(吲哚美辛、罗红霉素)联合应用治疗CC在某些方面可以产生相互的交互作用,治疗效果在某些方面优于单一应用。
Objective To observe the effect of the Combinative Supplementation of Formoterol(FM), Indomethacin (IND)and Roxithromycin (RM) on cancer cachexia (CC) and to study the mechanism with an animal cancer cachetic model.
Methods Male BALB/c mice bearing colon 26 adenocarcinoma for 9 days were served as models of cancer cachexia. The 72 models were divided randomly into nine treating groups basing on factorial design. Formoterol was used at a dose of 1 mg/kg/d, indomethacin was used at a dose of 0.5 mg/kg/d, roxithromycin was used at a dose of 50mg/kg/d. All of drugs were injected through intraperitoneal injection. FM, IND, FM and saline were given daily for 7days from the onset of cachexia to sacrifice. Physiological conditions, bodyweight and food intake were documented every day, tumor volume were documented every day after the tumors were palpable. Serum levels of cytokine and nutritional markers were detected 7 days after treatment. Data were expressed as means±SE. Statistical significance was determined by factorial design ANOVA and Student's t-test using SPSS 10.0. P<0.05 was considered statistically significant.
RESULT
1 Cancer cachexia model Tumors were palpable in mice initially on day4 or 5 after inoculation of tumor cells, Mice becomes listless and less move. Tumor grew about 1cm3 after 9 days. Color pattern of mice lose luster and disorderly. Their action become sluggish, they become emaciation. Body weight of mice also begins to decrease. All mice get into cancer cachexia on the 9th day. Cachexia symptoms were observed, such as obviously poor physical activity, asthenia, piloerection, pelage lost gloss and sheded.
2 left gastrocnemius weight When the experiment was finished, the left gastrocnemius weight of group B was cut down to 67% of group A(P<0.05). This experiment using three-factorial analysis showed that roxithromycin, indomethacin, formoterol can increase the left gastrocnemius alone(P<0.05), Any two of the three drugs have no interaction on elevating the left gastrocnemius weight. The three drugs combinative supplementation can mostly improve the weight of left gastrocemius.
3. Biochemical indicators The levels of serum Glu and Alb in B group were obvious lower than group A (p<0.05), but the levels of TG were significant higher than group A (p<0.05). Factorial analysis indicate that FM, IND, RM can decrease the levels of TG(P<0.05). Any two of the three drugs have no interaction on decrease the levels of TG(P>0.05), but the three drugs have interaction on decrease the levels of TG(P<0.05). The three drugs combinative supplementation can mostly bring down the levels of TG. About alb factorial analysis indicate that FM, IND, RM can elevate the levels of GLU(P<0.05). Any two of the three drugs have no interaction on elevate the levels of glucose(P>0.05), but the three drugs have interaction on elevating the levels of GLU(P<0.05). The three drugs combinative supplementation can mostly improve the levels of GLU. Although Alb of groups with drugs treatment were raised, no statistical significance was detected in those groups (p >0.05). Factorial analysis indicate that FM, IND, RM have no statistical difference in elevating the levels of alb(P>0.05).
4. Serum cytokines levels Comparing with normal mice, the cytokines TNF-αand IL-6 levels were raised significantly (p<0.05). After treatment with drugs, the results show that IND could decrease the levels of IL-6 (p<0.05), but FM and RM could not(p>0.05) and there are not interactions among FM , IND and RM in IL-6 level(sP>0.05). About TNF-αfactorial analysis indicate that FM, IND, RM can lower the levels of TNF-α(P<0.001. There are not only interactions between FM and RM in decreasing the levels of TNF-α, but also the three drugs have interactions in decreasing the levels of TNF-α. The three drugs combinative supplementation can mostly decrease the levels of TNF-α.
Conclusion
1. This experiment had established an animal model of cancer cachexia successfully that was very similar human’s by inoculating BALB/c mice with colon-26.It provides contribution for further studying cancer cachexia theory foundation and efficacy of drugs in treating cancer chachexia.
2. The result of body weight decreasing, metabolic disorder and the levels of IL-6、TNF-αincreasing showed that mice in cancer cachexia condition appearance significantly metabolic disorder of glucose, lipoids and albumin. It may have correlation with cytokines. It showed that the participation of cytokines probably is one of important mechanism that is lead to happen cancer cachexia.
3. Three drugs: FM, IND and RM had their own positive effects on CC mice. Drugs combination in tumor-bearing mice with cancer cachexia could produce synergistic action.
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36. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management [J]. Ca Cancer J Clin, 2002, 52 (2):72-91.
37. Kurebayashi J. Regulation of interleukin26 secretion from breast cancer cells and it s clinical implications [J]. Breast Cancer, 2000, 7 (2):124-129.
38. Gagnon B, Bruera E. A reviewof t he drug t reatment of cachexia associated wit h cancer [J]. Drugs, 1998, 55 (5): 675-688.
39. Laviano A, Muscaritolia M, Cascino A, et al. Branched chain amino acids: the best compromise to achieve anabolism? [J].Curr Opin Clin Nut r Metab Care, 2005, 8 (4): 408-414.
40. Bartlett DL, Stein P, Torosian MH. Effect of growth hormone and protein intake on tumor growth and host cachexia [J].Surgery, 1995, 117 (2):260-267.
41.周伟,江志伟,姜军,等.一种癌性恶病质动物模型的建立[J].中华实验外科杂志, 2004,21(4: 490-491.
42. TanakaY, Eda H, Tanaka T, et al. Experi mental cancer cachexia induced by transplantable colon 26 adenocarcinoma in mice [ J ].Cancer Res, 1990, 50 (8) : 2290- 2295.
43. Lynch GS, Schertzer JD, Ryall JG. Therapeutic approaches for muscle wasting disorders [J]. Pharmacol Ther, 2007, 113(3):461-487.
44. Gordon S. Lynch, James G. Ryall. Role ofβ-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease [J]. Physiol Rev.2008, 88(2):729-767.
45. Yang YT, McElligott MA. Multiple actions ofβ-adrenergic agonists on skeletal muscle and adipose tissue [J].BiochemJ, 1989, 261(1):1-10.
46. Cardoso LA, Stock MJ. Effect of clenbuterol on growth and body composition during food restriction in rats [J].J Anim Sci, 1996, 74(9):2245-2252.
47. Doheny M H. WaterfieldCJ. Timbrell J A. The effects of the beta2-agonist drug clenbuterol on taurine levels in heart and other tissues in the rat [J].Amino Acids, 1998, 15(1-2):13-25.
48. Smith DJ. The pharmacokinetics, metabolism, an tissue residues of beta-adrenergic agonists in livestock [J].J Anim Sci, 1998, 76(1):173-194
49. Young RB, Moriarity DM, Gee MC, et al. Protein metabolism in chicken muscle cell cultures treated with cimatesol [J].J Anim Sci, 1990, 68(4):1158-1169.
50. Busquets S, Figueras MT, Fuster G, et al. Anticachectic Effects of Formoterol: A Drug for Potential Treatment of Muscle Wasting [J]. Cancer Research, 2004, 64(18):6725-6731.
51. Busquets S, Figueras MT, Fuster G, et al. Are Peroxisome Proliferator-Activated Receptors Involved in Skeletal Muscle Wasting during Experimental Cancer Cachexia? Role of ?2-Adrenergic Agonists [J]. Cancer Research, 2007, 67(13):6512–6519.
52. Akio Nakamura, Edward James Johns, Akira Imaizumi et al. ?2-Adrenoceptor agonist suppresses renal tumour necrosis factor and enhances interleukin-6 gene expression induced by endotoxin[J]. Nephrol Dial Transplant, 2000, 15: 1928-1934.
53. Coulie B, Tack J, Peeters T, et al. Involvement of two different pathways in the motor effects of erythromycin on the gastric antrum in humans[J]. Gut, 1998, 43(3):395-400.
54.王晓斌,贾斌,赵澎涛,等.罗红霉素对LPS诱导的肺泡巨噬细胞NF-κB活化及对TNF-α, IL-10释放的影响[J].第四军医大学学报, 2005, 26(5):450-454.
55. Ou XM, Feng YL, Wen FQ, et al. Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-kappaB [J].Respirology, 2008, 13(1):63-72.
56. Mitsuharu Ogino, Makoto Hanazono. Indomethacin acts as an antitumor and anticachexic agent in colon 26 bearing CDF 1 mice. IntJ Clin Oncol, 1998,3:176~181.
57. Eli Y, Przedecki F, Levin G, et al. Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo [J]. Biochem Pharmacol, 2001, 61 (5):565-571.
58. Lundholm K, Gelin J, Hyltander A, et al. Anti-inflammolatory treatment may prolong survival in undernourished patients with metastatic solid tumors [J]. Cancer Res, 1994, 54 (21): 5602-5606.
59.周伟,江志伟,刘放南等.吲哚美辛对癌症恶病质小鼠肌肉泛素-蛋白酶途径的影响[J].肠外肠内营养, 2004, 11 (6):348-352.
60. Ferreri NR, McGiff JC, Carroll MA, et al. Renal cox-2 cytokines and 20 hete: Tubular and vascular mechanisms[J]. Curr Parm Design, 2004, 10 (6):613.
61. Argiles JM, Almendro V, Busquets S, et al. The pharmacological treatment of cachexia. Curr Drug Tagets, 2004, 5 (3):265.
[1] Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein NF-kappa B by a posttranslational mechanism [J].Cell, 1986, 47(6):921-928.
[2] Thranos D, Maniatis T. NF-Kappa B: a lesson in family values [J] .Cell, 1995, 80(4):529-532.
[3] OpConnor S, Markovina S, Miyamoto S. Evidence for phosphorylation- independent role for Ser32 and 36 in proteasome inhibitor-resistant (PIR) I kappa B alpha degradation in B cells [J].Exp Cell Res, 2005, 307(1):15-25.
[4] Qing G, Qu Z, Xiao G. Stabilization of basally translated NF-Kappa B- inducing kinase (NIK)protein functions as a molecular switch of processing of NF-κB2 p100 [J]. J Biol Chem, 2005, 280(49):40578-40582.
[5]王晓蔚,康凯夫.NF-κB与炎症相关性肝癌[J].国际病理科学与临床杂志, 2008, 28(4):315-318.
[6] Melstrom LG, Melstrom Jr KA, Ding XZ, et al. Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia [J].Histol Histopathol, 2007, 22(7):805-814.
[7] Li YP, Reid MB. NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes [J].Am J Physiol Requl Inteqr Comp Physiol, 2000, 279(4): 1165–1170.
[8] Smith HJ, Wyke SM, Tisdale MJ. Role of protein kinase C and NF-κB in proteolysis-inducing factor induced proteasome expression in C2C12 myotubes [J].Br J Cancer 2004, 90(9): 1850–1857.
[9] Wyke SM, Tisdale MJ. NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle [J].Br J Cancer, 2005, 92(4): 711-721.
[10] Watchorn TM, Dowidar N, Dejong CH, et al .The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes [J]. Int J Oncol, 2005, 27 (4):1105-1111.
[11]佴永军,江志伟,汪志明,等.核因子-κB抑制剂调控癌性恶病质的实验研究[J].肠外与肠内营养, 2007, 14(5):270-274.
[12] Cai D, Frantz JD, Tawa NE Jr, et al .IKKbeta /NF-kappa B activation causes severe muscle wasting in mice [J].Cell,2004,119(2):285-298.
[13] Costelli P, Muscaritoli M, Bossola M, et al. Skeletal muscle wasting in tumor-bearing rats is associated with MyoD down-regulation [J]. Int J Oncol, 2005, 26(6)1663-1668.
[14] Guttridge DC, Mayo M W, Madrid LV, et al. NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia [J].Science, 2000, 289(5488):2293-2294.
[15] Di Marco S, Mazroui R, Dallaire P, et al. NF-kB-Mediated MyoD Decay during Muscle Wasting Requires Nitric Oxide Synthase mRNA Stabilization, HuR Protein, and Nitric Oxide Release [J]. Mol cell biol, 2005, 25(15):6533–6545.
[16] Dogra C, Changotra H, Mohan S, et al. Tumor Necrosis Factor-like Weak Inducer of Apoptosis Inhibits Skeletal Myogenesis through Sustained Activation of Nuclear Factor- kB and Degradation of MyoD Protein [J].J Biol Chem, 2006, 281(15):10327-10336.
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[23] Kuroda K, Horiguchi Y, Nakashima J, et al. Prevention of Cancer Cachexia by a Novel Nuclear Factor kappaB Inhibitor in Prostate Cancer[J].Clin Cancer Res, 2005, 11(15) : 5590-5594.
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35. Lissoni P, Paolorossi F, Tancini G, et al. Is there a role for melatonin in the t reatment of neoplastic cachexia [J]. Eur J Cancer, 1996, 32 A (8):1340-1343.
36. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management [J]. Ca Cancer J Clin, 2002, 52 (2):72-91.
37. Kurebayashi J. Regulation of interleukin26 secretion from breast cancer cells and it s clinical implications [J]. Breast Cancer, 2000, 7 (2):124-129.
38. Gagnon B, Bruera E. A reviewof t he drug t reatment of cachexia associated wit h cancer [J]. Drugs, 1998, 55 (5): 675-688.
39. Laviano A, Muscaritolia M, Cascino A, et al. Branched chain amino acids: the best compromise to achieve anabolism? [J].Curr Opin Clin Nut r Metab Care, 2005, 8 (4): 408-414.
40. Bartlett DL, Stein P, Torosian MH. Effect of growth hormone and protein intake on tumor growth and host cachexia [J].Surgery, 1995, 117 (2):260-267.
41.周伟,江志伟,姜军,等.一种癌性恶病质动物模型的建立[J].中华实验外科杂志, 2004,21(4: 490-491.
42. TanakaY, Eda H, Tanaka T, et al. Experi mental cancer cachexia induced by transplantable colon 26 adenocarcinoma in mice [ J ].Cancer Res, 1990, 50 (8) : 2290- 2295.
43. Lynch GS, Schertzer JD, Ryall JG. Therapeutic approaches for muscle wasting disorders [J]. Pharmacol Ther, 2007, 113(3):461-487.
44. Gordon S. Lynch, James G. Ryall. Role ofβ-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease [J]. Physiol Rev.2008, 88(2):729-767.
45. Yang YT, McElligott MA. Multiple actions ofβ-adrenergic agonists on skeletal muscle and adipose tissue [J].BiochemJ, 1989, 261(1):1-10.
46. Cardoso LA, Stock MJ. Effect of clenbuterol on growth and body composition during food restriction in rats [J].J Anim Sci, 1996, 74(9):2245-2252.
47. Doheny M H. WaterfieldCJ. Timbrell J A. The effects of the beta2-agonist drug clenbuterol on taurine levels in heart and other tissues in the rat [J].Amino Acids, 1998, 15(1-2):13-25.
48. Smith DJ. The pharmacokinetics, metabolism, an tissue residues of beta-adrenergic agonists in livestock [J].J Anim Sci, 1998, 76(1):173-194
49. Young RB, Moriarity DM, Gee MC, et al. Protein metabolism in chicken muscle cell cultures treated with cimatesol [J].J Anim Sci, 1990, 68(4):1158-1169.
50. Busquets S, Figueras MT, Fuster G, et al. Anticachectic Effects of Formoterol: A Drug for Potential Treatment of Muscle Wasting [J]. Cancer Research, 2004, 64(18):6725-6731.
51. Busquets S, Figueras MT, Fuster G, et al. Are Peroxisome Proliferator-Activated Receptors Involved in Skeletal Muscle Wasting during Experimental Cancer Cachexia? Role of ?2-Adrenergic Agonists [J]. Cancer Research, 2007, 67(13):6512–6519.
52. Akio Nakamura, Edward James Johns, Akira Imaizumi et al. ?2-Adrenoceptor agonist suppresses renal tumour necrosis factor and enhances interleukin-6 gene expression induced by endotoxin[J]. Nephrol Dial Transplant, 2000, 15: 1928-1934.
53. Coulie B, Tack J, Peeters T, et al. Involvement of two different pathways in the motor effects of erythromycin on the gastric antrum in humans[J]. Gut, 1998, 43(3):395-400.
54.王晓斌,贾斌,赵澎涛,等.罗红霉素对LPS诱导的肺泡巨噬细胞NF-κB活化及对TNF-α, IL-10释放的影响[J].第四军医大学学报, 2005, 26(5):450-454.
55. Ou XM, Feng YL, Wen FQ, et al. Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-kappaB [J].Respirology, 2008, 13(1):63-72.
56. Mitsuharu Ogino, Makoto Hanazono. Indomethacin acts as an antitumor and anticachexic agent in colon 26 bearing CDF 1 mice. IntJ Clin Oncol, 1998,3:176~181.
57. Eli Y, Przedecki F, Levin G, et al. Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo [J]. Biochem Pharmacol, 2001, 61 (5):565-571.
58. Lundholm K, Gelin J, Hyltander A, et al. Anti-inflammolatory treatment may prolong survival in undernourished patients with metastatic solid tumors [J]. Cancer Res, 1994, 54 (21): 5602-5606.
59.周伟,江志伟,刘放南等.吲哚美辛对癌症恶病质小鼠肌肉泛素-蛋白酶途径的影响[J].肠外肠内营养, 2004, 11 (6):348-352.
60. Ferreri NR, McGiff JC, Carroll MA, et al. Renal cox-2 cytokines and 20 hete: Tubular and vascular mechanisms[J]. Curr Parm Design, 2004, 10 (6):613.
61. Argiles JM, Almendro V, Busquets S, et al. The pharmacological treatment of cachexia. Curr Drug Tagets, 2004, 5 (3):265.
[1] Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein NF-kappa B by a posttranslational mechanism [J].Cell, 1986, 47(6):921-928.
[2] Thranos D, Maniatis T. NF-Kappa B: a lesson in family values [J] .Cell, 1995, 80(4):529-532.
[3] OpConnor S, Markovina S, Miyamoto S. Evidence for phosphorylation- independent role for Ser32 and 36 in proteasome inhibitor-resistant (PIR) I kappa B alpha degradation in B cells [J].Exp Cell Res, 2005, 307(1):15-25.
[4] Qing G, Qu Z, Xiao G. Stabilization of basally translated NF-Kappa B- inducing kinase (NIK)protein functions as a molecular switch of processing of NF-κB2 p100 [J]. J Biol Chem, 2005, 280(49):40578-40582.
[5]王晓蔚,康凯夫.NF-κB与炎症相关性肝癌[J].国际病理科学与临床杂志, 2008, 28(4):315-318.
[6] Melstrom LG, Melstrom Jr KA, Ding XZ, et al. Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia [J].Histol Histopathol, 2007, 22(7):805-814.
[7] Li YP, Reid MB. NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes [J].Am J Physiol Requl Inteqr Comp Physiol, 2000, 279(4): 1165–1170.
[8] Smith HJ, Wyke SM, Tisdale MJ. Role of protein kinase C and NF-κB in proteolysis-inducing factor induced proteasome expression in C2C12 myotubes [J].Br J Cancer 2004, 90(9): 1850–1857.
[9] Wyke SM, Tisdale MJ. NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle [J].Br J Cancer, 2005, 92(4): 711-721.
[10] Watchorn TM, Dowidar N, Dejong CH, et al .The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes [J]. Int J Oncol, 2005, 27 (4):1105-1111.
[11]佴永军,江志伟,汪志明,等.核因子-κB抑制剂调控癌性恶病质的实验研究[J].肠外与肠内营养, 2007, 14(5):270-274.
[12] Cai D, Frantz JD, Tawa NE Jr, et al .IKKbeta /NF-kappa B activation causes severe muscle wasting in mice [J].Cell,2004,119(2):285-298.
[13] Costelli P, Muscaritoli M, Bossola M, et al. Skeletal muscle wasting in tumor-bearing rats is associated with MyoD down-regulation [J]. Int J Oncol, 2005, 26(6)1663-1668.
[14] Guttridge DC, Mayo M W, Madrid LV, et al. NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia [J].Science, 2000, 289(5488):2293-2294.
[15] Di Marco S, Mazroui R, Dallaire P, et al. NF-kB-Mediated MyoD Decay during Muscle Wasting Requires Nitric Oxide Synthase mRNA Stabilization, HuR Protein, and Nitric Oxide Release [J]. Mol cell biol, 2005, 25(15):6533–6545.
[16] Dogra C, Changotra H, Mohan S, et al. Tumor Necrosis Factor-like Weak Inducer of Apoptosis Inhibits Skeletal Myogenesis through Sustained Activation of Nuclear Factor- kB and Degradation of MyoD Protein [J].J Biol Chem, 2006, 281(15):10327-10336.
[17] Canicio J, Ruiz-Lozano P, Carrasco M, et al. Nuclear factor kappa B-inducing kinase and I kappa B kinase-alpha signal skeletal muscle cell differentiation[J]. J Biol Chem, 2001, 276(23):20228–20233.
[18] Baeza-Raja B, Mu?oz-Cánoves P. p38 MAPK-induced Nuclear Factor-B Activity Is Required for Skeletal Muscle Differentiation: Role of Interleukin-6[J].Mol Bio Cell, 2004, 15(4):2013–2026.
[19] Bakkar N, Wang J, Ladner KJ, et al. IKK/NF-B regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis [J]. J Cell Biol, 2008, 180(4):787-802.
[20] Busquets S, Carbo N, AlmendroV, et al. Curcumin, a natural product present in turmeric, decreases tumor growth but does not behave as an anti-cachectic compound in a rat model [J].Cancer Lett, 2001, 167(1):33-38.
[21] Wyke SM, Russell ST, Tisdale MJ. Induction of proteasome expression inskeletal muscle is attenuated by inhibitors of NF-kB activation [J]. Br J Cancer, 2004, 91(9):1742-1750.
[22] Busquets S, Fuster G, Ametller E, et al .Resveratrol does not ameliorate muscle wasting in different types of cancer cachexia models [J]. Clin Nutr, 2007, 26(2): 239-244.
[23] Kuroda K, Horiguchi Y, Nakashima J, et al. Prevention of Cancer Cachexia by a Novel Nuclear Factor kappaB Inhibitor in Prostate Cancer[J].Clin Cancer Res, 2005, 11(15) : 5590-5594.