褪黑素受体（MT_1）在骨肉瘤中的表达及临床意义
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摘要
研究背景骨肉瘤是威胁青少年生命的最常见恶性骨肿瘤,其肺转移发生率高且早,进展迅速,80%的病人在确诊时已有微小转移灶。近年来,随着新辅助化疗的应用、手术的进步,生存率明显提高,但其治疗也开始进入平台期。越来越多的学者开始关注生物调节治疗、免疫及基因治疗等,希望为骨肉瘤治疗开辟新的途径。实验证实褪黑素能有效抑制乳腺癌、前列腺癌等多种肿瘤的生长。有假说认为褪黑素作为化疗辅助用药可以改善患者的生活质量和临床预后。褪黑素发挥抗肿瘤作用主要是通过与其受MT1结合实现的。国内外关于MT1受体在骨肉瘤中的表达鲜有报道。
目的检测褪黑素受体(MT1)在骨肉瘤中的表达,探讨其临床意义,为褪黑素在治疗骨肉瘤中的应用提供理论依据。
材料和方法收集齐鲁医院2003年6月到2009年6月临床资料和病理资料完整的四肢长骨骨肉瘤标本40例,男26例,女14例,年龄8-39岁,平均年龄19.4岁：对照组骨软骨瘤20例,男12例,女8例,年龄12-32岁,平均年龄16.6岁。所有60例标本都采用MT1的免疫组织化学非生物素即用型二步法(Non-Biotin HRP Detection System)进行染色,观察不同标本细胞的染色情况。用医学统计学方法分析骨肉瘤中MT1表达与年龄、性别、肿瘤体积、Enneking分期、Dahlin's组织学分型和复发、转移等因素的关系。
结果MT1在骨肉瘤组的阳性表达率为70%(28例/40例),明显高于骨软骨瘤组35%(7例/20例),差异有统计学意义(P<0.05)。MT1的表达与骨肉瘤的Enneking分期、复发或转移呈正相关；在表达阳性的28例骨肉瘤标本中,复发或转移组的表达率较高(80.71%),并且大部分为强阳性表达(15例/18例),而无复发或转移组中强阳性仅4例,弱阳性6例,差异具有统计学意义(x2=5.535,P<0.05)。MT1的阳性表达与骨肉瘤患者的性别、年龄、肿瘤体积、Dahlin's组织学分型等没有相关性(P>0.05)。
结论本实验首次用免疫组织化学染色法检测了褪黑素受体(MT1)在骨肉瘤中的表达,发现MT1在骨肉瘤中高表达,并且与骨肉瘤的Enneking分期、复发或转移呈正相关。大量表达的MT1受体为外源性褪黑素提供了丰富的结合位点,为褪黑素在治疗骨肉瘤中的应用提供了理论依据及指导。
Background Osteosarcoma is the most common malignant bone tumor that threats the life of the juveniles, it has high rate of lung metastases and progresses rapidly,80% of patients have micrometastases at diagnosis.In recent years, the survival rate has been improved significantly with the application of neoadjuvant chemotherapy, surgical advances, but the treatment has begun to enter the plateau.More and more scholars began to focus on biological regulation therapy, immune and gene therapy in the hope that finding new ways to the treatment of osteosarcoma.Experiments confirmed that melatonin can inhibit the growth of breast cancer, prostate cancer and some other tumors.There has been hypothesized that melatonin can improve the quality of life and clinical prognosis of patients. Melatonin plays antitumor effect mainly through binding to its receptor MT1.To our knowledge,there has rarely report on the expression of MT1 in osteosarcoma.
Objective To detect the expression of melatonin receptors (MT1) in osteosarcoma, and its clinical significance, to provide a theoretical basis for the use of melatonin in the treatment of osteosarcoma.
Materials and Methods Paraffin tissue blocks of 40 cases of osteosarcoma and 20 cases of osteochondroma with a complete clinical data and pathological data were collected between June 2003 and June 2009 of Qilu Hospital. All 60 specimens were stained by immunohistochemical method. Then we analyzed associations between the receptor expression and known prognostic clinicopathologic parameters such as age, sex, tumor size, Enneking stage, Dahlin's histological type, recurrence and metastasis.
Results The majority of osteochondroma samples (13/20 [75%]) were negative, while moderate to strong reactivity was seen in most osteosarcoma samples (28/40 [70%]). Thus, although MT1 receptors were detectable in osteochondroma, high receptor level occurred more frequently in osteosarcoma samples (P<0.05), and tumors with moderate or strong reactivity were more likely to be with high Enneking stage and with recurrence or metastasis(P<0.05). No significant association was found for gender, age, tumor size, Dahlin's histological type(P>0.05).
Conclusion we report the first use of immunohistochemical analysis to determine the distribution of the high affinity melatonin receptor subtype, MT1, in osteosarcoma.We found that MT1 is abundantly expressed in osteosarcoma specimens.And tumors with moderate or strong reactivity were more likely to be with high Enneking stage and with recurrence or metastasis. High expression of MT1 provides a wealth of binding sites for melatonin. These findings may have implications for the use of melatonin in osteosarcoma therapy.
目的检测褪黑素受体(MT1)在骨肉瘤中的表达,探讨其临床意义,为褪黑素在治疗骨肉瘤中的应用提供理论依据。
材料和方法收集齐鲁医院2003年6月到2009年6月临床资料和病理资料完整的四肢长骨骨肉瘤标本40例,男26例,女14例,年龄8-39岁,平均年龄19.4岁：对照组骨软骨瘤20例,男12例,女8例,年龄12-32岁,平均年龄16.6岁。所有60例标本都采用MT1的免疫组织化学非生物素即用型二步法(Non-Biotin HRP Detection System)进行染色,观察不同标本细胞的染色情况。用医学统计学方法分析骨肉瘤中MT1表达与年龄、性别、肿瘤体积、Enneking分期、Dahlin's组织学分型和复发、转移等因素的关系。
结果MT1在骨肉瘤组的阳性表达率为70%(28例/40例),明显高于骨软骨瘤组35%(7例/20例),差异有统计学意义(P<0.05)。MT1的表达与骨肉瘤的Enneking分期、复发或转移呈正相关；在表达阳性的28例骨肉瘤标本中,复发或转移组的表达率较高(80.71%),并且大部分为强阳性表达(15例/18例),而无复发或转移组中强阳性仅4例,弱阳性6例,差异具有统计学意义(x2=5.535,P<0.05)。MT1的阳性表达与骨肉瘤患者的性别、年龄、肿瘤体积、Dahlin's组织学分型等没有相关性(P>0.05)。
结论本实验首次用免疫组织化学染色法检测了褪黑素受体(MT1)在骨肉瘤中的表达,发现MT1在骨肉瘤中高表达,并且与骨肉瘤的Enneking分期、复发或转移呈正相关。大量表达的MT1受体为外源性褪黑素提供了丰富的结合位点,为褪黑素在治疗骨肉瘤中的应用提供了理论依据及指导。
Background Osteosarcoma is the most common malignant bone tumor that threats the life of the juveniles, it has high rate of lung metastases and progresses rapidly,80% of patients have micrometastases at diagnosis.In recent years, the survival rate has been improved significantly with the application of neoadjuvant chemotherapy, surgical advances, but the treatment has begun to enter the plateau.More and more scholars began to focus on biological regulation therapy, immune and gene therapy in the hope that finding new ways to the treatment of osteosarcoma.Experiments confirmed that melatonin can inhibit the growth of breast cancer, prostate cancer and some other tumors.There has been hypothesized that melatonin can improve the quality of life and clinical prognosis of patients. Melatonin plays antitumor effect mainly through binding to its receptor MT1.To our knowledge,there has rarely report on the expression of MT1 in osteosarcoma.
Objective To detect the expression of melatonin receptors (MT1) in osteosarcoma, and its clinical significance, to provide a theoretical basis for the use of melatonin in the treatment of osteosarcoma.
Materials and Methods Paraffin tissue blocks of 40 cases of osteosarcoma and 20 cases of osteochondroma with a complete clinical data and pathological data were collected between June 2003 and June 2009 of Qilu Hospital. All 60 specimens were stained by immunohistochemical method. Then we analyzed associations between the receptor expression and known prognostic clinicopathologic parameters such as age, sex, tumor size, Enneking stage, Dahlin's histological type, recurrence and metastasis.
Results The majority of osteochondroma samples (13/20 [75%]) were negative, while moderate to strong reactivity was seen in most osteosarcoma samples (28/40 [70%]). Thus, although MT1 receptors were detectable in osteochondroma, high receptor level occurred more frequently in osteosarcoma samples (P<0.05), and tumors with moderate or strong reactivity were more likely to be with high Enneking stage and with recurrence or metastasis(P<0.05). No significant association was found for gender, age, tumor size, Dahlin's histological type(P>0.05).
Conclusion we report the first use of immunohistochemical analysis to determine the distribution of the high affinity melatonin receptor subtype, MT1, in osteosarcoma.We found that MT1 is abundantly expressed in osteosarcoma specimens.And tumors with moderate or strong reactivity were more likely to be with high Enneking stage and with recurrence or metastasis. High expression of MT1 provides a wealth of binding sites for melatonin. These findings may have implications for the use of melatonin in osteosarcoma therapy.
引文
[1]Picci P.Osteosarcoma(osteogenic sarcoma)[J].Orphanet J Rare Dis,2007,2:6.
[2]Uchida A. Recent advances in management of musculoskeletal tumors[J].Cancer Chemother,1999,26(Suppl 1):185.
[3]Bramwell VH. The role of chemotherapy in osteogenic sarcoma[J]. Crit Rev Oncol Hematol,1995,20:61-85.
[4]Jaffe N. Osteosarcoma:review of the past,impact on the future.The American experience[J].Cancer Treat Res,2010,152:239-262.
[5]张清,徐万鹏,郭卫等.我国骨肉瘤治疗现状及改进建议——17家骨肿瘤治疗中心1998～2008年资料分析[J].中国骨肿瘤骨病,2009,8(3)：129-132.
[6]Lissoni P.Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms[J].Pathol Biol (Paris).2007 Apr-May;55(3-4):201-4.
[7]Carlberg C. Gene regulation by melatonin[J]. Ann N Y Acad Sci 2000;917:387-96.
[8]Monograph. Melatonin[J].Altern Med Rev 2005; 10:326-36.
[9]Vijayalaxmi, Thomas CR, Jr., Reiter RJ, Herman TS.Melatonin:from basic research to cancer treatment clinics[J]. J Clin Oncol 2002;20:2575-601.
[10]Cohen M, Lippman M, Chabner B. Role of pineal gland in aetiology and treatment of breast cancer[J]. Lancet 1978;2:814-6.
[11]Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis[J]. J Pineal Res 2005;39:360-6.
[12]Lee CO.Complementary and alternative medicinespatients are talking about: melatonin[J]. Clin J Oncol Nurs 2006; 10:105-7.
[13]Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal[J]. Endocrine 2005;27:179-88.
[14]Monograph. Melatonin[J]. Altern Med Rev 2005;10:326-36.3.
[15]Vijayalaxmi, Thomas CR, Jr., Reiter RJ, Herman TS.Melatonin:from basic research to cancer treatment clinics[J]. J Clin Oncol 2002;20:2575-601.
[16]Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer:a systematic review of randomized controlled trials and meta-analysis[J]. J Pineal Res 2005;39:360-6.
[17]Reppert SM, Weaver DR, Ebisawa T . Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses[J]. Neuron 1994;13:1177-1185.
[18]Dubocovich ML, Cardinali DP, Delagrange P, Krause DN, Strosberg D,Sugden D et al. Melatonin Receptors. The IUPHAR Compendium of Receptor Characterization and Classification. IUPHARMedia:London.2001;270-277.
[19]Mazzucchelli C, Pannacci M, Nonno R, Lucini V, Fraschini F, Stankov BM. The melatonin receptor in the human brain:cloningexperiments and distribution studies[J]. Brain Res Mol Brain Res 1996;39:117-126.
[20]Dubocovich ML, Masana MI, Iacob S, Sauri DM. Melatoninreceptor antagonists that differentiate between the human Mel la and Mellb recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor[J].Naunyn Schmiedebergs Arch Pharmacol 1997;355:365-375.
[21]Weaver DR, Reppert SM. The Mella melatonin receptor gene is expressed in human suprachiasmatic nuclei [J]. NeuroReport 1996;8:109-112.
[22]Al-Ghoul WM, Herman MD, Dubocovich ML. Melatonin receptor subtype expression in human cerebellum[J]. NeuroReport 1998;9:4063-4068.
[23]Savaskan E, Jockers R, Ayoub M, Angeloni D, Fraschini F, Flammer J et al. The MT2 melatonin receptor subtype is present in human retina and decreases in Alzheimer's disease[J]. Curr Alzheimer Res 2007;4:47-51.
[24]Drew JE, Barrett P, Williams LM, Conway S, Morgan PJ. The ovine melatonin-related receptor:cloning and preliminary distribution and binding studies[J]. J Neuroendocrinol 1998;10:651-661.
[25]Niles LP, Wang J, Shen L, Lobb DK, and Younglai EV.Melatonin receptor mRNA expression in human granulosa cells[J]. Mol Cell Endocrinol 1999; 156:107-110.
[26]Brydon L, Petit L, Delagrange P, Strosberg AD, and Jockers R . Functional expression of MT2 (Mellb) melatonin receptors in human PAZ6 adipocytes. Endocrinology 2001; 142:4264-4271.
[27]Ekmekcioglu C, Haslmayer P, Philipp C, Mehrabi MR, Glogar HD, Grimm M,Leibetseder VJ, Thalhammer T, and Marktl W.Expression of the MT1 melatonin receptor subtype in human coronary arteries. J Recept Signal Transduct Res 2001;21:85-91.
[28]Song Y, Chan CW, Brown GM, Pang SF, and SilvermanM.Studies of the renal action of melatonin:evidence that the effects are mediated by 37 kDa receptors of the Mella subtype localized primarily to the basolateral membrane of the proximal tubule[J]. FASEB J 1997; 11:93-100.
[29]Savaskan E, Wirz-Justice A, Olivieri G et al.Distribution of melatonin MT1 receptor immunoreactivity in human retina[J]. J Histochem Cytochem 2002;50:519-526.
[30]Scher J, Wankiewicz E, Brown GM, and Fujieda H.MT(1) melatonin receptor in the human retina: expression and localization[J]. Invest Ophthalmol Vis Sci 2002;43:889-897.
[31]Masana MI, Doolen S, Ersahin C, Al-Ghoul WM, Duckles SP, Dubocovich ML, and Krause DN.MT(2) melatonin receptors are present and functional in rat caudal artery[J]. J Pharmacol Exp Ther 2002;302:1295-1302.
[32]Davis FC.Melatonin:role in development[J]. J Biol Rhythms 1997; 12:498-508.
[33]Masana MI, Benloucif S, and Dubocovich ML.Circadian rhythm of mtl melatonin receptor expression in the suprachiasmatic nucleus of the C3H/HeN mouse[J]. J Pineal Res 2000;28:185-192.
[34]Schuster C, Gauer F, Malan A, Recio J, Pe'vet P, and Masson-Pe'vet M. The circadian clock, light/dark cycle and melatonin are differentially involved in the expression of daily and photoperiodic variations in mt(1) melatonin receptors in the Siberian and Syrian hamsters[J]. Neuroendocrinology 2001;74:55-68.
[35]Poirel VJ, Masson-Pe'vet M, Peve't P, and Gauer F. MT1 melatonin receptor mRNA expression exhibits a circadian variation in the rat suprachiasmatic nuclei [J].Brain Res 2002;946:64-71.
[36]Kadekaro AL, Andrade LN, Floeter-Winter LM, Rollag MD, Virador V, Vieira W, and Castrucci AM.MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells[J]. J Pineal Res 2004;36:204-211.
[37]Collins A, Yuan L, Kiefer TL, Cheng Q, Lai L, and Hill SM. Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice[J]. Cancer Lett 2003; 189:49-57.
[38]Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy[J]. Curr Top Med Chem 2002;2:113-32.
[39]Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin[J]. Sleep Med Rev 2005;9:11-24.
[40]Lundberg P, Lerner UH. Expression and regulatory role of receptors for vasoactive intestinal peptide in bone cells[J]. Microsc Res Tech 2002; 58:98-103.
[41]Cardinali DP, Ladizesky MG, Boggio V et al. Melatonin effects on bone: experimental facts and clinical perspectives[J].J Pineal Res 2003; 34:81-87.
[42]Conti A, Conconi S, Hertens E et al. Evidence for melatonin synthesis in mouse and human bone marrow cells[J]. J Pineal Res 2000; 28:193-202.
[43]Roth JA, Kim BG, Lin WL et al. Melatonin promotes osteoblast differentiation and bone formation[J]. J Biol Chem 1999;274:22041-22047.
[44]Witt-Enderby PA, Radio NM, Doctor JS et al. Therapeutic treatments potentially mediated by melatonin receptors potential clinical uses in the prevention of osteoporosis,cancer and as an adjuvant therapy[J]. J Pineal Res 2006;41:297-305.13.
[45]Mills E, Wu P, Seely D et al. Melatonin in the treatment of cancer:a systematic review of randomized controlled trials and meta-analysis[J]. J Pineal Res 2005; 39:360-366.
[46]Satomura K, Tobiume S, Tokuyama R et al. Melatonin at pharmacological doses enhances human osteoblastic differentiation in vitro and promotes mouse cortical bone formation in vivo[J]. J Pineal Res 2007; 42:231-239.
[47]Jung B, Ahmad N. Melatonin in cancer management:progress and promise[J]. Cancer Res 2006; 66:9789-9793.
[48]Panzer A. Melatonin in osteosarcoma: an effective drug?[J]. MedHypotheses 1997; 48:523-525.
[49]Unni KK. Osteosarcoma of bone[J]. J Orthop Sci 1998; 3:287-294.
[50]Ekm ekcioglu C. Melaton in receptors in humans:biological role and clinical relevance[J]. B iomed Pharmacother,2006,60(3):97-108.
[51]Dubocovich ML,Mark owska M.Functional MT1 and MT2 melaton in receptors in mammals[J]. Endocrine,2005,27(2):101-110.
[52]Toma CD, Svoboda M,et al. Expression of the melatonin receptor (MT1) in benign and malignant human bone tumors[J].J Pineal Res.2007 Sep;43(2):206-13.
[53]Sainz RM, Mayo J C, Tan D X, et al. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independentmechanism[J]. Prostate,2005,63(1):29-43.
[54]Shiu S Y, Law I C, Lau KW, et al. Melatonin slowed the early biochemical p rogression of hormone2refractory p rostate cancer in a patientwhose prostate tumor tissue exp ressedMTl recep tor subtype [J]. J Pineal Res,2003,35 (3):177-82.
[55]Srinivasn V, Spence DW, Pandi2Perumal SR. Therapeutic actions of melatonin in cancer:possible mechanisms[J]. Integr Cancer Ther,2008,7:1892203.
[56]Kadekaro AL, Andrade LN, Floeter-Winter LM et al. MT1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells[J]. J Pineal Res 2004;36:204-211.
[57]Collins A, Yuan L, Kiefer TL, Cheng Q et al. Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice[J]. Cancer Lett 2003; 189:49-57.
[58]Yuan L, Collins AR, Dai J et al. MT1 melatonin receptor over expression enhances the growth suppressive effect of melatonin in human breast cancer cells[J]. Mol Cell Endocrinol 2002; 192:147-156.
[59]Hill SM, Cheng C, Yuan L et al.Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin[J].Breast Cancer Res Treat. 2010 Jun 12. [Epub ahead of print].
[60]Ekmekcioglu C. Melaton in receptors in humans:biological role and clinical relevance[J]. B iomed Pharmacother,2006,60(3):97-108.
[61]Dubocovich ML,Mark owska M.Functional MT1 and MT2 melatonin receptors inmammals[J]. Endocrine,2005,27(2):101-110.
[62]Dillon DC, Easley SE, Asch BB et al.Differential expression of high-affinity melatonin receptors (MT1) in normal and malignant human breast tissue.[J]Am J Clin Pathol.2002 Sep;118(3):451-8.
[63]Hendrick JC, Crasson M, Hagelstein MT et al. Urinary excretion of 6-sulphatoxymelatonin in normal subjects:statistical approach to the influence of age and sex[J]. Ann Endocrinol(Paris) 2002; 63:3-7.
[64]Kedziora-Kornatowska K, Szewczyk-Golec K, Czuczejko J et al. Effect of melatonin on the oxidative stress in erythrocytes of healthy young and elderly subjects[J]. J Pineal Res 2007; 42:153-158.
[65]Karasek M, Kowalski AJ, Suzin J et al.Serum melatonin circadian profiles in women suffering from cervical cancer[J] J Pineal Res.2005 Aug;39(1):73-6.
[1]Melatonin. Monograph. Altern Med Rev 2005; 10:326-36.
[2]Carlberg C. Gene regulation by melatonin. Ann N Y Acad Sci 2000;917:387-96.
[3]Vijayalaxmi, Thomas CR, Jr., Reiter RJ, Herman TS.Melatonin:from basic research to cancer treatment clinics. J Clin Oncol 2002;20:2575-601.
[4]Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005;9:11-24
[5]Kadekaro AL, Andrade LN, Floeter-Winter LM, Rollag MD, Virador V, Vieira W, and Castrucci AM (2004) MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells. J Pineal Res 36:204-211.
[6]Collins A, Yuan L, Kiefer TL, Cheng Q, Lai L, and Hill SM (2003) Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice. Cancer Lett 189:49-57.
[7]Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem 2002;2:113-32.
[8]Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005;9:11-24.
[9]Cohen M, Lippman M, Chabner B. Role of pineal gland in aetiology and treatment
of breast cancer. Lancet 1978;2:814-6.
[10]Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res 2005;39:360-6.
[11]Lee CO. Complementary and alternative medicines patients are talking about: melatonin. Clin J Oncol Nurs 2006; 10:105-7.
[12]Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine 2005;27:179-88.
[13]Martin V, Herrera F, Carrera-Gonzalez P, et al. Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res 2006;66:1081-8.
[14]朱华,许春芳,叶建新.褪黑素对胰腺癌细胞株SW1990体外增殖及凋亡的影响.中华胰腺病杂志,2009,9：1152117.
[15]Weinreb O, Mandel S, Yondim MB. cDNA gene expression pt2fdehomology of antioxidant s and t heir antiapoptotic and proa2 paptotic activities in human neumblastoma ceils. FASEB J,2003,17:9352937.
[16]Fischer TW, Zmijewski MA, Zbytek B, et al. Oncostatic effect s of the indole melatonin and expression of it s cytosolic and nuclear receptors in cultured human melanoma cell lines. Int J Oncol,2006,29:6652672.
[17]SaezM C, Barriga C, Garcia J J, et al. Melatonin increases the survival time of animalswith untreated mammary tumours:Neuroendocrine stabilization J]. Mol Cell B iochem,2005,278 (1-2):15-20.
[18]Stevens RG. Electric power use and breast cancer:a hypothesis. Am J Epidemiol 1987;125:556-61.
[19]Sanchez-Barcelo EJ, Cos S, Fernandez R, Mediavilla MD. Melatonin and mammary cancer:a short review. Endocr Relat Cancer 2003;10:153-9.
[20]Lissoni P, Paolorossi F, Meregalli S et al. Melatonin as Modulator of cancer endocrine therapy. In:Proceedings of 2nd Locarno Meeting on neuroendocrinoimmunity. Switzerland,1996:27.
[21]Lissoni P, Barni S, Ardizzoia A, et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology 1992;49:336-9.
[22]Lissoni P, Meregalli S, Fossati V, et al. A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer. Tumori 1994;80:464-7.
[23]Conti A, Maestroni GJ. The clinical neuroimmunotherapeutic role of melatonin in oncology. J Pi neal Res,1995;19 (3):103～10. [24] Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 1994;73:699-701.
[25]Neri B, Fiorelli C, Moroni F et al. Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma. A phase Ⅱ st udy Cancer,1994;73 (12):3015-9
[26]Lissoni P. Modulation of anticancer cytokines IL-2 and IL-12 by melatonin and the other pineal indoles 5-methoxytryptamine and 5-methoxytryptophol in the treatment of human neoplasms. Ann N Y Acad Sci 2000; 917:560-7.
[27]Aldeghi R, Lissoni P, Barni S et al. Low dose interleukin2 subcutaneous immunotherapy in association with the pineal hormone melatonin as a first2line terapy in locally advanced or metastatic hepatocellular carcinoma. Eur J Cancer 1994;30A(2):167-70.
[28]Sainz RM, Mayo J C, Tan D X, et al. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independentmechanism[J]. Prostate,2005,63(1):29-43.
[29]Shiu S Y, Law I C, Lau KW, et al. Melatonin slowed the early biochemical p rogression of hormone refractory prostate cancer in a patientwhose prostate tumor tissue expressed MT1 receptor subtype [J]. J Pineal Res,2003,35 (3):177-82.
[30]Srinivasn V, Spence DW, Pandi2Perumal SR. Therapeutic actions of melatonin in cancer:possible mechanisms. Integr Cancer Ther,2008,7:1892203.
[31]Davis S, Mirick DK, Stevens RG. Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 2001;93:1557-62.
[32]Davis S, Mirick DK. Circadian disruption, shift work,and the risk of cancer: a summary of the evidence and studies in Seattle. Cancer Causes Control 2006;17:539-45.27.
[33]Schernhammer ES, Laden F, Speizer FE, et al.Rotating night shifts and risk of breast cancer in women participating in the nurses'health study. J Natl Cancer Inst 2001;93:1563-8.
[34]Schernhammer ES, Laden F, Speizer FE, et al. Nightshift work and risk of colorectal cancer in the nurses"health study. J Natl Cancer Inst 2003;95:825-8.
[35]Beniashvili D, Avinoach I, Baazov D, et al . Household elect romagetic fields and breast cancer in elderly women. In vivo,2005,19:5632566.
[36]Grin W, Grunberger W. A significant correlation between melatonin deficiency and endometrial cancer.Gynecol Obstet Invest 1998;45:62-5.
[37]Panzer A, Viljoen M. The validity of melatonin as an oncostatic agent. J Pineal Res 1997;22:184-202.
[38]Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer 1999;35:1688--92.
[39]Miller SC, Pandi PS, Esquifino AI, Cardinali DP, Maestroni GJ. The role of melatonin in immunoenhancement:potential application in cancer. Int J Exp Pathol 2006;87:81-7.
[40]Kim C, Kim N, Joo H, et al. Modulation bymelatonin of the cardiotoxic and antitumor activities of adriamycin [J]. J Cardiovasc Pharm acol,2005,46 (2):200-10.
[2]Uchida A. Recent advances in management of musculoskeletal tumors[J].Cancer Chemother,1999,26(Suppl 1):185.
[3]Bramwell VH. The role of chemotherapy in osteogenic sarcoma[J]. Crit Rev Oncol Hematol,1995,20:61-85.
[4]Jaffe N. Osteosarcoma:review of the past,impact on the future.The American experience[J].Cancer Treat Res,2010,152:239-262.
[5]张清,徐万鹏,郭卫等.我国骨肉瘤治疗现状及改进建议——17家骨肿瘤治疗中心1998～2008年资料分析[J].中国骨肿瘤骨病,2009,8(3)：129-132.
[6]Lissoni P.Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms[J].Pathol Biol (Paris).2007 Apr-May;55(3-4):201-4.
[7]Carlberg C. Gene regulation by melatonin[J]. Ann N Y Acad Sci 2000;917:387-96.
[8]Monograph. Melatonin[J].Altern Med Rev 2005; 10:326-36.
[9]Vijayalaxmi, Thomas CR, Jr., Reiter RJ, Herman TS.Melatonin:from basic research to cancer treatment clinics[J]. J Clin Oncol 2002;20:2575-601.
[10]Cohen M, Lippman M, Chabner B. Role of pineal gland in aetiology and treatment of breast cancer[J]. Lancet 1978;2:814-6.
[11]Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis[J]. J Pineal Res 2005;39:360-6.
[12]Lee CO.Complementary and alternative medicinespatients are talking about: melatonin[J]. Clin J Oncol Nurs 2006; 10:105-7.
[13]Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal[J]. Endocrine 2005;27:179-88.
[14]Monograph. Melatonin[J]. Altern Med Rev 2005;10:326-36.3.
[15]Vijayalaxmi, Thomas CR, Jr., Reiter RJ, Herman TS.Melatonin:from basic research to cancer treatment clinics[J]. J Clin Oncol 2002;20:2575-601.
[16]Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer:a systematic review of randomized controlled trials and meta-analysis[J]. J Pineal Res 2005;39:360-6.
[17]Reppert SM, Weaver DR, Ebisawa T . Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses[J]. Neuron 1994;13:1177-1185.
[18]Dubocovich ML, Cardinali DP, Delagrange P, Krause DN, Strosberg D,Sugden D et al. Melatonin Receptors. The IUPHAR Compendium of Receptor Characterization and Classification. IUPHARMedia:London.2001;270-277.
[19]Mazzucchelli C, Pannacci M, Nonno R, Lucini V, Fraschini F, Stankov BM. The melatonin receptor in the human brain:cloningexperiments and distribution studies[J]. Brain Res Mol Brain Res 1996;39:117-126.
[20]Dubocovich ML, Masana MI, Iacob S, Sauri DM. Melatoninreceptor antagonists that differentiate between the human Mel la and Mellb recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor[J].Naunyn Schmiedebergs Arch Pharmacol 1997;355:365-375.
[21]Weaver DR, Reppert SM. The Mella melatonin receptor gene is expressed in human suprachiasmatic nuclei [J]. NeuroReport 1996;8:109-112.
[22]Al-Ghoul WM, Herman MD, Dubocovich ML. Melatonin receptor subtype expression in human cerebellum[J]. NeuroReport 1998;9:4063-4068.
[23]Savaskan E, Jockers R, Ayoub M, Angeloni D, Fraschini F, Flammer J et al. The MT2 melatonin receptor subtype is present in human retina and decreases in Alzheimer's disease[J]. Curr Alzheimer Res 2007;4:47-51.
[24]Drew JE, Barrett P, Williams LM, Conway S, Morgan PJ. The ovine melatonin-related receptor:cloning and preliminary distribution and binding studies[J]. J Neuroendocrinol 1998;10:651-661.
[25]Niles LP, Wang J, Shen L, Lobb DK, and Younglai EV.Melatonin receptor mRNA expression in human granulosa cells[J]. Mol Cell Endocrinol 1999; 156:107-110.
[26]Brydon L, Petit L, Delagrange P, Strosberg AD, and Jockers R . Functional expression of MT2 (Mellb) melatonin receptors in human PAZ6 adipocytes. Endocrinology 2001; 142:4264-4271.
[27]Ekmekcioglu C, Haslmayer P, Philipp C, Mehrabi MR, Glogar HD, Grimm M,Leibetseder VJ, Thalhammer T, and Marktl W.Expression of the MT1 melatonin receptor subtype in human coronary arteries. J Recept Signal Transduct Res 2001;21:85-91.
[28]Song Y, Chan CW, Brown GM, Pang SF, and SilvermanM.Studies of the renal action of melatonin:evidence that the effects are mediated by 37 kDa receptors of the Mella subtype localized primarily to the basolateral membrane of the proximal tubule[J]. FASEB J 1997; 11:93-100.
[29]Savaskan E, Wirz-Justice A, Olivieri G et al.Distribution of melatonin MT1 receptor immunoreactivity in human retina[J]. J Histochem Cytochem 2002;50:519-526.
[30]Scher J, Wankiewicz E, Brown GM, and Fujieda H.MT(1) melatonin receptor in the human retina: expression and localization[J]. Invest Ophthalmol Vis Sci 2002;43:889-897.
[31]Masana MI, Doolen S, Ersahin C, Al-Ghoul WM, Duckles SP, Dubocovich ML, and Krause DN.MT(2) melatonin receptors are present and functional in rat caudal artery[J]. J Pharmacol Exp Ther 2002;302:1295-1302.
[32]Davis FC.Melatonin:role in development[J]. J Biol Rhythms 1997; 12:498-508.
[33]Masana MI, Benloucif S, and Dubocovich ML.Circadian rhythm of mtl melatonin receptor expression in the suprachiasmatic nucleus of the C3H/HeN mouse[J]. J Pineal Res 2000;28:185-192.
[34]Schuster C, Gauer F, Malan A, Recio J, Pe'vet P, and Masson-Pe'vet M. The circadian clock, light/dark cycle and melatonin are differentially involved in the expression of daily and photoperiodic variations in mt(1) melatonin receptors in the Siberian and Syrian hamsters[J]. Neuroendocrinology 2001;74:55-68.
[35]Poirel VJ, Masson-Pe'vet M, Peve't P, and Gauer F. MT1 melatonin receptor mRNA expression exhibits a circadian variation in the rat suprachiasmatic nuclei [J].Brain Res 2002;946:64-71.
[36]Kadekaro AL, Andrade LN, Floeter-Winter LM, Rollag MD, Virador V, Vieira W, and Castrucci AM.MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells[J]. J Pineal Res 2004;36:204-211.
[37]Collins A, Yuan L, Kiefer TL, Cheng Q, Lai L, and Hill SM. Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice[J]. Cancer Lett 2003; 189:49-57.
[38]Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy[J]. Curr Top Med Chem 2002;2:113-32.
[39]Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin[J]. Sleep Med Rev 2005;9:11-24.
[40]Lundberg P, Lerner UH. Expression and regulatory role of receptors for vasoactive intestinal peptide in bone cells[J]. Microsc Res Tech 2002; 58:98-103.
[41]Cardinali DP, Ladizesky MG, Boggio V et al. Melatonin effects on bone: experimental facts and clinical perspectives[J].J Pineal Res 2003; 34:81-87.
[42]Conti A, Conconi S, Hertens E et al. Evidence for melatonin synthesis in mouse and human bone marrow cells[J]. J Pineal Res 2000; 28:193-202.
[43]Roth JA, Kim BG, Lin WL et al. Melatonin promotes osteoblast differentiation and bone formation[J]. J Biol Chem 1999;274:22041-22047.
[44]Witt-Enderby PA, Radio NM, Doctor JS et al. Therapeutic treatments potentially mediated by melatonin receptors potential clinical uses in the prevention of osteoporosis,cancer and as an adjuvant therapy[J]. J Pineal Res 2006;41:297-305.13.
[45]Mills E, Wu P, Seely D et al. Melatonin in the treatment of cancer:a systematic review of randomized controlled trials and meta-analysis[J]. J Pineal Res 2005; 39:360-366.
[46]Satomura K, Tobiume S, Tokuyama R et al. Melatonin at pharmacological doses enhances human osteoblastic differentiation in vitro and promotes mouse cortical bone formation in vivo[J]. J Pineal Res 2007; 42:231-239.
[47]Jung B, Ahmad N. Melatonin in cancer management:progress and promise[J]. Cancer Res 2006; 66:9789-9793.
[48]Panzer A. Melatonin in osteosarcoma: an effective drug?[J]. MedHypotheses 1997; 48:523-525.
[49]Unni KK. Osteosarcoma of bone[J]. J Orthop Sci 1998; 3:287-294.
[50]Ekm ekcioglu C. Melaton in receptors in humans:biological role and clinical relevance[J]. B iomed Pharmacother,2006,60(3):97-108.
[51]Dubocovich ML,Mark owska M.Functional MT1 and MT2 melaton in receptors in mammals[J]. Endocrine,2005,27(2):101-110.
[52]Toma CD, Svoboda M,et al. Expression of the melatonin receptor (MT1) in benign and malignant human bone tumors[J].J Pineal Res.2007 Sep;43(2):206-13.
[53]Sainz RM, Mayo J C, Tan D X, et al. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independentmechanism[J]. Prostate,2005,63(1):29-43.
[54]Shiu S Y, Law I C, Lau KW, et al. Melatonin slowed the early biochemical p rogression of hormone2refractory p rostate cancer in a patientwhose prostate tumor tissue exp ressedMTl recep tor subtype [J]. J Pineal Res,2003,35 (3):177-82.
[55]Srinivasn V, Spence DW, Pandi2Perumal SR. Therapeutic actions of melatonin in cancer:possible mechanisms[J]. Integr Cancer Ther,2008,7:1892203.
[56]Kadekaro AL, Andrade LN, Floeter-Winter LM et al. MT1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells[J]. J Pineal Res 2004;36:204-211.
[57]Collins A, Yuan L, Kiefer TL, Cheng Q et al. Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice[J]. Cancer Lett 2003; 189:49-57.
[58]Yuan L, Collins AR, Dai J et al. MT1 melatonin receptor over expression enhances the growth suppressive effect of melatonin in human breast cancer cells[J]. Mol Cell Endocrinol 2002; 192:147-156.
[59]Hill SM, Cheng C, Yuan L et al.Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin[J].Breast Cancer Res Treat. 2010 Jun 12. [Epub ahead of print].
[60]Ekmekcioglu C. Melaton in receptors in humans:biological role and clinical relevance[J]. B iomed Pharmacother,2006,60(3):97-108.
[61]Dubocovich ML,Mark owska M.Functional MT1 and MT2 melatonin receptors inmammals[J]. Endocrine,2005,27(2):101-110.
[62]Dillon DC, Easley SE, Asch BB et al.Differential expression of high-affinity melatonin receptors (MT1) in normal and malignant human breast tissue.[J]Am J Clin Pathol.2002 Sep;118(3):451-8.
[63]Hendrick JC, Crasson M, Hagelstein MT et al. Urinary excretion of 6-sulphatoxymelatonin in normal subjects:statistical approach to the influence of age and sex[J]. Ann Endocrinol(Paris) 2002; 63:3-7.
[64]Kedziora-Kornatowska K, Szewczyk-Golec K, Czuczejko J et al. Effect of melatonin on the oxidative stress in erythrocytes of healthy young and elderly subjects[J]. J Pineal Res 2007; 42:153-158.
[65]Karasek M, Kowalski AJ, Suzin J et al.Serum melatonin circadian profiles in women suffering from cervical cancer[J] J Pineal Res.2005 Aug;39(1):73-6.
[1]Melatonin. Monograph. Altern Med Rev 2005; 10:326-36.
[2]Carlberg C. Gene regulation by melatonin. Ann N Y Acad Sci 2000;917:387-96.
[3]Vijayalaxmi, Thomas CR, Jr., Reiter RJ, Herman TS.Melatonin:from basic research to cancer treatment clinics. J Clin Oncol 2002;20:2575-601.
[4]Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005;9:11-24
[5]Kadekaro AL, Andrade LN, Floeter-Winter LM, Rollag MD, Virador V, Vieira W, and Castrucci AM (2004) MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells. J Pineal Res 36:204-211.
[6]Collins A, Yuan L, Kiefer TL, Cheng Q, Lai L, and Hill SM (2003) Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice. Cancer Lett 189:49-57.
[7]Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem 2002;2:113-32.
[8]Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005;9:11-24.
[9]Cohen M, Lippman M, Chabner B. Role of pineal gland in aetiology and treatment
of breast cancer. Lancet 1978;2:814-6.
[10]Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res 2005;39:360-6.
[11]Lee CO. Complementary and alternative medicines patients are talking about: melatonin. Clin J Oncol Nurs 2006; 10:105-7.
[12]Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine 2005;27:179-88.
[13]Martin V, Herrera F, Carrera-Gonzalez P, et al. Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res 2006;66:1081-8.
[14]朱华,许春芳,叶建新.褪黑素对胰腺癌细胞株SW1990体外增殖及凋亡的影响.中华胰腺病杂志,2009,9：1152117.
[15]Weinreb O, Mandel S, Yondim MB. cDNA gene expression pt2fdehomology of antioxidant s and t heir antiapoptotic and proa2 paptotic activities in human neumblastoma ceils. FASEB J,2003,17:9352937.
[16]Fischer TW, Zmijewski MA, Zbytek B, et al. Oncostatic effect s of the indole melatonin and expression of it s cytosolic and nuclear receptors in cultured human melanoma cell lines. Int J Oncol,2006,29:6652672.
[17]SaezM C, Barriga C, Garcia J J, et al. Melatonin increases the survival time of animalswith untreated mammary tumours:Neuroendocrine stabilization J]. Mol Cell B iochem,2005,278 (1-2):15-20.
[18]Stevens RG. Electric power use and breast cancer:a hypothesis. Am J Epidemiol 1987;125:556-61.
[19]Sanchez-Barcelo EJ, Cos S, Fernandez R, Mediavilla MD. Melatonin and mammary cancer:a short review. Endocr Relat Cancer 2003;10:153-9.
[20]Lissoni P, Paolorossi F, Meregalli S et al. Melatonin as Modulator of cancer endocrine therapy. In:Proceedings of 2nd Locarno Meeting on neuroendocrinoimmunity. Switzerland,1996:27.
[21]Lissoni P, Barni S, Ardizzoia A, et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology 1992;49:336-9.
[22]Lissoni P, Meregalli S, Fossati V, et al. A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer. Tumori 1994;80:464-7.
[23]Conti A, Maestroni GJ. The clinical neuroimmunotherapeutic role of melatonin in oncology. J Pi neal Res,1995;19 (3):103～10. [24] Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 1994;73:699-701.
[25]Neri B, Fiorelli C, Moroni F et al. Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma. A phase Ⅱ st udy Cancer,1994;73 (12):3015-9
[26]Lissoni P. Modulation of anticancer cytokines IL-2 and IL-12 by melatonin and the other pineal indoles 5-methoxytryptamine and 5-methoxytryptophol in the treatment of human neoplasms. Ann N Y Acad Sci 2000; 917:560-7.
[27]Aldeghi R, Lissoni P, Barni S et al. Low dose interleukin2 subcutaneous immunotherapy in association with the pineal hormone melatonin as a first2line terapy in locally advanced or metastatic hepatocellular carcinoma. Eur J Cancer 1994;30A(2):167-70.
[28]Sainz RM, Mayo J C, Tan D X, et al. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independentmechanism[J]. Prostate,2005,63(1):29-43.
[29]Shiu S Y, Law I C, Lau KW, et al. Melatonin slowed the early biochemical p rogression of hormone refractory prostate cancer in a patientwhose prostate tumor tissue expressed MT1 receptor subtype [J]. J Pineal Res,2003,35 (3):177-82.
[30]Srinivasn V, Spence DW, Pandi2Perumal SR. Therapeutic actions of melatonin in cancer:possible mechanisms. Integr Cancer Ther,2008,7:1892203.
[31]Davis S, Mirick DK, Stevens RG. Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 2001;93:1557-62.
[32]Davis S, Mirick DK. Circadian disruption, shift work,and the risk of cancer: a summary of the evidence and studies in Seattle. Cancer Causes Control 2006;17:539-45.27.
[33]Schernhammer ES, Laden F, Speizer FE, et al.Rotating night shifts and risk of breast cancer in women participating in the nurses'health study. J Natl Cancer Inst 2001;93:1563-8.
[34]Schernhammer ES, Laden F, Speizer FE, et al. Nightshift work and risk of colorectal cancer in the nurses"health study. J Natl Cancer Inst 2003;95:825-8.
[35]Beniashvili D, Avinoach I, Baazov D, et al . Household elect romagetic fields and breast cancer in elderly women. In vivo,2005,19:5632566.
[36]Grin W, Grunberger W. A significant correlation between melatonin deficiency and endometrial cancer.Gynecol Obstet Invest 1998;45:62-5.
[37]Panzer A, Viljoen M. The validity of melatonin as an oncostatic agent. J Pineal Res 1997;22:184-202.
[38]Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer 1999;35:1688--92.
[39]Miller SC, Pandi PS, Esquifino AI, Cardinali DP, Maestroni GJ. The role of melatonin in immunoenhancement:potential application in cancer. Int J Exp Pathol 2006;87:81-7.
[40]Kim C, Kim N, Joo H, et al. Modulation bymelatonin of the cardiotoxic and antitumor activities of adriamycin [J]. J Cardiovasc Pharm acol,2005,46 (2):200-10.