• 1
    American Cancer Society. Cancer Facts and Figures 2006. American Cancer Society, Atlanta, 2006.
  • 2
    Reiter RJ. The melatonin rhythm: both a clock and a calendar. Experientia 1993; 49:654664.
  • 3
    Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336:186195.
  • 4
    Lincoln GA, Clarke IJ, Hut RA et al. Characterizing a mammalian circannual pacemaker. Science 2006; 314:19411944.
  • 5
    Panzer A, Viljoen M. The validity of melatonin as an oncostatic agent. J Pineal Res 1997; 22:184202.
  • 6
    Reiter RJ. Mechanisms of cancer inhibition by melatonin. J Pineal Res 2004; 37:213214.
  • 7
    Jung B, Ahmad N. Melatonin in cancer management: progress and promise. Cancer Res 2006; 66:97899793.
  • 8
    Reiter RJ, Gultekin F, Manchester LC et al. Light pollution, melatonin suppression and cancer growth. J Pineal Res 2006; 40:357358.
  • 9
    Cohen M, Lippman M, Chabner B. Role of pineal gland in aetiology and treatment of breast cancer. Lancet 1978; 2:814816.
  • 10
    Danforth DN Jr, Tamarkin L, Lippman ME. Melatonin increases oestrogen receptor binding activity of human breast cancer cells. Nature 1983; 305:323325.
  • 11
    Tamarkin L, Danforth D, Lichter A et al. Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast cancer. Science 1982; 216:10031005.
  • 12
    Hill SM, Blask DE. Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 1988; 48:61216126.
  • 13
    Blask DE, Wilson ST, Zalatan F. Physiological melatonin inhibition of human breast cancer cell growth in vitro: evidence for a glutathione-mediated pathway. Cancer Res 1997; 57:19091914.
  • 14
    Sanchez-Barcelo EJ, Cos S, Fernandez R et al. Melatonin and mammary cancer: a short review. Endocr Relat Cancer 2003; 10:153159.
  • 15
    Prener A, Storm HH, Nielsen NH. Cancer of the male genital tract in circumpolar Inuit. Acta Oncol 1996; 35:589593.
  • 16
    Dewailly E, Mulvad G, Pedersen HS et al. Inuit are protected against prostate cancer. Cancer Epidemiol Biomarkers Prev 2003; 12:926927.
  • 17
    Feychting M, Ouml;sterlund B, Ahlbom A. Reduced cancer incidence among the blind. Epidemiology 1998; 9:490494.
  • 18
    Pukkala E, Ojamo M, Rudanko SL et al. Does incidence of breast cancer and prostate cancer decrease with increasing degree of visual impairment. Cancer Causes Control 2006; 17:573576.
  • 19
    Iguchi H, Kato KI, Ibayashi H. Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Metab 1982; 55:2729.
  • 20
    Sack RL, Lewy AJ, Erb DL et al. Human melatonin production decreases with age. J Pineal Res 1986; 3:379388.
  • 21
    Waldhauser F, Weiszenbacher G, Tatzer E et al. Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab 1988; 66:648652.
  • 22
    Zhao ZY, Xie Y, Fu YR et al. Aging and the circadian rhythm of melatonin; a cross-sectional study of Chinese subjects 30–110 yr of age. Chronobiol Int 2002; 19:11711182.
  • 23
    Bartsch C, Bartsch H, Schmidt A et al. Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and urine of primary prostate cancer patients; evidence for reduced pineal activity and relevance of urinary determinations. Clin Chim Acta 1992; 209:153167.
  • 24
    Xi SC, Tam PC, Brown GM et al. Potential involvement of mt1 receptor and attenuated sex-steroid-induced calcium influx in the direct anti-proliferative action of melatonin on androgen-responsive LNCaP human prostate cancer cells. J Pineal Res 2000; 29:172183.
  • 25
    Xi SC, Siu SWF, Fong SW et al. Inhibition of androgen-sensitive LNCaP prostate cancer growth in vivo by melatonin: association of antiproliferative action of the pineal hormone with mt1 receptor protein expression. Prostate 2001; 6:5261.
  • 26
    Siu SWF, Lau KW, Tam PC et al. Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor, and androgen sensitivity. Prostate 2002; 52:106122 [Erratum, Prostate 2002; 52:252].
  • 27
    Lupowitz Z, Zisapel N. Hormonal interactions in human prostate tumor LNCaP cells. J Steroid Biochem Mol Biol 1999; 68:8388.
  • 28
    Moretti RM, Marelli MM, Maggi R et al. Antiproliferative action of melatonin on human prostate cancer LNCaP cells. Oncol Rep 2000; 7:347351.
  • 29
    Sainz RM, Mayo JC, Tan DX et al. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate 2005; 63:2943.
  • 30
    Marelli MM, Limonta P, Maggi R et al. Growth-inhibitory activity of melatonin on human androgen-independent DU 145 prostate cancer cells. Prostate 2000; 45:238244.
  • 31
    Shiu SYW, Law IC, Lau KW et al. Melatonin slowed the early biochemical progression of hormone-refractory prostate cancer in a patient whose prostate tumor tissue expressed MT1 receptor subtype. J Pineal Res 2003; 35:177182.
  • 32
    Tam CW, Mo CW, Yao KM et al. Signaling mechanisms of melatonin in antiproliferation of hormone-refractory 22Rv1 human prostate cancer cells: implications for prostate cancer chemoprevention. J Pineal Res 2007; 42:191202.
  • 33
    Reppert SM, Weaver DR, Godson C. Melatonin receptors step into the light; cloning and classification of subtypes. Trends Pharmacol Sci 1996; 17:100102.
  • 34
    Tan DX, Reiter RJ, Manchester LC et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2002; 2:181197.
  • 35
    Tomas-Zapico C, Coto-Montes A. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 2005; 39:99104.
  • 36
    Kadekaro AL, Andrade LN, Floeter-Winter LM et al. MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells. J Pineal Res 2004; 36:204211.
  • 37
    Sauer LA, Dauchy RT, Blask DE et al. 13-Hydroxyoctadecadienoic acid is the mitogenic signal for linoleic acid-dependent growth in rat hepatoma 7288CTC in vivo. Cancer Res 1999; 59:46884692.
  • 38
    Blask DE, Sauer LA, Dauchy RT et al. Melatonin inhibition of cancer growth in vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transduction events. Cancer Res 1999; 59:46934701.
  • 39
    Sauer LA, Dauchy RT, Blask DE. Melatonin inhibits fatty acid transport in inguinal fat pads of hepatoma 7288CTC-bearing and normal Buffalo rats via receptor-mediated signal transduction. Life Sci 2001; 68:28352844.
  • 40
    Blask DE, Dauchy RT, Sauer LA et al. Melatonin uptake and growth prevention in rat hepatoma 7288CTC in response to dietary melatonin: melatonin receptor-mediated inhibition of tumor linoleic acid metabolism to the growth signaling molecule 13-hydroxyoctadecadienoic acid and the potential role of phytomelatonin. Carcinogenesis 2004; 25:951960.
  • 41
    Dillon DC, Easley SE, Asch BB et al. Differential expression of high-affinity melatonin receptors (MT1) in normal and malignant human breast tissue. Am J Clin Pathol 2002; 118:451458.
  • 42
    Ram PT, Dai J, Yuan L et al. Involvement of the mt1 melatonin receptor in human breast cancer. Cancer Lett 2002; 179:141150.
  • 43
    Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine 2005; 27:179188.
  • 44
    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; 66:10811088.
  • 45
    Sanchez-Barcelo EJ, Cos S, Mediavilla D et al. Melatonin-estrogen interactions in breast cancer. J Pineal Res 2005; 38:217222.
  • 46
    Cos S, Gonzalez A, Martinez-Campa C et al. Estrogen-signaling pathway: a link between breast cancer and melatonin oncostatic actions. Cancer Detect Prev 2006; 30:118128.
  • 47
    Lloyd RV, Erickson LA, Jin L et al. p27kip1: A multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 1999; 154:313323.
  • 48
    Mediavilla MD, Cos S, Sanchez-Barcelo EJ. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci 1999; 65:415420.
  • 49
    Cini G, Neri B, Pacini A et al. Antiproliferative activity of melatonin by transcriptional inhibition of cyclin D1 expression: a molecular basis for melatonin-induced oncostatic effects. J Pineal Res 2005; 39:1220.
  • 50
    Fernandez PL, Arce Y, Farre X et al. Expression of p27/kip1 is down-regulated in human prostate carcinoma progression. J Pathol 1999; 187:563566.
  • 51
    Sun H, Lesche R, Li DM et al. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A 1999; 96:61996204.
  • 52
    Graff JR, Konicek BW, Mcnulty AM et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem 2000; 275:2450024505.
  • 53
    Rimler A, Culig Z, Lupowitz Z et al. Nuclear exclusion of the androgen receptor by melatonin. J Steroid Biochem Mol Biol 2002; 81:7784.
  • 54
    Rimler A, Culig Z, Levy-Rimler G et al. Melatonin elicits nuclear exclusion of the human androgen receptor and attenuates its activity. Prostate 2001; 49:145154.
  • 55
    Lupowitz Z, Rimler A, Zisapel N. Evaluation of signal transduction pathways mediating the nuclear exclusion of the androgen receptor by melatonin. Cell Mol Life Sci 2001; 58:21292135.
  • 56
    Sampson SR, Lupowitz Z, Braiman L et al. Role of protein kinase Calpha in melatonin signal transduction. Mol Cell Endocrinol 2006; 252:8287.
  • 57
    Rimler A, Lupowitz Z, Zisapel N. Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells. Neuro Endocrinol Lett 2002; 23 (Suppl. 1): 4549.
  • 58
    Klein EA. Can prostate cancer be prevented? Nat Clin Pract Urol 2005; 2:2431.
  • 59
    Ekman P. Genetic and environmental factors in prostate cancer genesis: identifying high-risk cohorts. Eur Urol 1999; 35:362369.
  • 60
    Nwosu V, Carpten J, Trent JM et al. Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease. Hum Mol Genet 2001; 10:23132318.
  • 61
    Zlotta AR, Schulman CC. Clinical evolution of prostatic intraepithelial neoplasia. Eur Urol 1999; 35:498503.
  • 62
    Sakr WA, Haas GP, Cassin BF et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993; 150:379385.
  • 63
    Sakr WA, Grignon DJ, Haas GP et al. Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol 1996; 30:138144.
  • 64
    Nelson WG, De Marzo AM, Isaacs WB. Prostate cancer. N Engl J Med 2003; 349:366381.
  • 65
    Buchanan G, Irvine RA, Coetzee GA et al. Contribution of the androgen receptor to prostate cancer predisposition and progression. Cancer Metastasis Rev 2001; 20:207223.
  • 66
    Tomlins SA, Rhodes DR, Perner S et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310:644648.
  • 67
    Rubin MA, Chinnaiyan AM. Bioinformatics approach leads to the discovery of the TMPRSS2:ETS gene fusion in prostate cancer. Lab Invest 2006; 86:10991102.
  • 68
    Cerveira N, Ribeiro FR, Peixoto A et al. TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 2006; 8:826832.
  • 69
    Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349:215224.
  • 70
    Nickel JC. Comparison of clinical trials with finasteride and dutasteride. Rev Urol 2004; 6 (Suppl. 9): S31S39.
  • 71
    Thomas LN, Douglas RC, Vessey JP et al. 5alpha-reductase type 1 immunostaining is enhanced in some prostate cancers compared with benign prostatic hyperplasia epithelium. J Urol 2003; 170:20192025.
  • 72
    Nelson WG, De Marzo AM, Deweese TL et al. Preneoplastic prostate lesions: an opportunity for prostate cancer prevention. Ann N Y Acad Sci 2001; 952:135144.
  • 73
    Miller ER III, Pastor-Barriuso R, Dalal D et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005; 142:3746.
  • 74
    Steck PA, Pershouse MA, Jasser SA et al. Identification of a candidate tumor suppressor gene MMAC1 at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997; 15:356362.
  • 75
    Gray IC, Stewart LM, Phillips SM et al. Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br J Cancer 1998; 78:12961300.
  • 76
    Di Cristofano A, Pesce B, Cordon-Cardo C et al. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998; 19:348355.
  • 77
    Trotman LC, Niki M, Dotan ZA et al. Pten dose dictates cancer progression in the prostate. PLoS Biol 2003; 1:E59.
  • 78
    Wang S, Gao J, Lei Q et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003; 4:209221.
  • 79
    Sharpless NE, Depinho RA. Cancer: crime and punishment. Nature 2005; 436:636637.
  • 80
    Fernandez PL, Arce Y, Farre X et al. Expression of p27/Kip1 is down-regulated in human prostate carcinoma progression. J Pathol 1999; 187:563566.
  • 81
    Doganavsargil B, Simsir A, Boyacioglu H et al. A comparison of p21 and p27 immunoexpression in benign glands, prostatic intraepithelial neoplasia and prostate adenocarcinoma. BJU Int 2006; 97:644648.
  • 82
    Di Cristofano A, De Acetis M, Koff A et al. Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 2001; 27:222224.
  • 83
    Chen Z, Trotman LC, Shaffer D et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005; 436:725730.
  • 84
    Aus G, Abbou CC, Pacik D et al. EAU guidelines on prostate cancer. Eur Urol 2001; 40:97101.
  • 85
    Wirth MP, Hakenberg OW. Curative treatment of prostate cancer. Urol Int 1999; 63:7279.
  • 86
    Barry MJ. Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med 2001; 344:13731377.
  • 87
    Klotz L. Active surveillance for prostate cancer: for whom? J Clin Oncol 2005; 23:81658169.
  • 88
    Klotz L. Active surveillance versus radical treatment for favorable-risk localized prostate cancer. Curr Treat Options Oncol 2006; 7:355362.
  • 89
    Miyamoto H, Messing EM, Chang C. Androgen deprivation therapy for prostate cancer: current status and future prospects. Prostate 2004; 61:332353.
  • 90
    Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med 2004; 351:14881490.
  • 91
    Chang SS, Benson MC, Campbell SC et al. Society of Urologic Oncology position statement: redefining the management of hormone-refractory prostate carcinoma. Cancer 2005; 103:1121.
  • 92
    Attard G, Sarker D, Reid A et al. Improving the outcome of patients with castration-resistant prostate cancer through rational drug development. Br J Cancer 2006; 95:767774.
  • 93
    Reiter RJ, Tan DX, Sainz RM et al. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol 2002; 54:12991321.
  • 94
    Lissoni P. Is there a role for melatonin in supportive care? Support Care Cancer 2002; 10:110116.
  • 95
    Collins R, Trowman R, Norman G et al. A systematic review of the effectiveness of docetaxel and mitoxantrone for the treatment of metastatic hormone-refractory prostate cancer. Br J Cancer 2006; 95:457462.
  • 96
    Vijayalaxmi, Reiter RJ, Tan DX et al. Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys 2004; 59:639653.
  • 97
    Seabra ML, Bignotto M, Pinto LR et al. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 2000; 29:193200.
  • 98
    Buscemi N, Vandermeer B, Hooton N et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006; 332:385393.
  • 99
    Buscemi N, Vandermeer B, Pandya R et al. Melatonin for Treatment of Sleep Disorders. Evidence Report/Technology Assessment No. 108. (Prepared by the University of Alberta Evidence-based Practice Center, under Contract No. 290-02-0023.) AHRQ Publication No. 05-E002-2. Agency for Healthcare Research and Quality, Rockville, MD, 2004.
  • 100
    Carver BS, Pandolfi PP. Mouse modeling in oncologic preclinical and translational research. Clin Cancer Res 2006; 12:53055311.
  • 101
    Vijayalaxmi, Thomas CR Jr, Reiter RJ et al. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol 2002; 20:25752601.
  • 102
    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 Pineal Res 2005; 39:360366.