Melatonin Cancer Therapy

  • William J. M. Hrushesky


Melatonin prevents and delays chemical carcinogenisis and cancer growth in vivo in the mouse and rat. Blind people have robust, albeit mostly free-running melatonin circadian rhythms and they are at lower risk for the development of many, if not all, cancers. Women with breast cancer and men with prostate cancer have diminished nighttime melatonin secretion.

Each proven melatonin biological effect — the transduction of circadian and circannual temporal information from the environmental light/dark schedule to each cell within the body, the induction and enhancement of sleep, the diminishment of core body temperature, and the resetting of circadian clocks — is entirely dependent upon the temporal context, i.e., the circadian/circannual stage of melatonin availability/administration. The host-cancer balance is likewise rhythmically coordinated in time by endogenous and exogenous circadian and circannual internal pacemakers and external zeitgebers. Each of the targets of cancer treatment is differentially available in both normal host cells and cancer cells at different times within these biological cycles. This chronobiology is faithfully reflected by the fact that the circadian/circannual timing of cancer chemotherapy determines to a medically meaningful extent the damage done to normal cells, the amount of drug that can be safely given, and the antitumor efficacy of that drug.

Giving a chronobiotic agent, like melatonin, without regard to its circadian/ circannual scheduling is not logical and should not be expected to reveal its true utility as an anticancer agent. Despite the fact that the timing of melatonin has been either ignored or stipulated arbitrarily, clinical anticancer activity has been uncovered. Lissoni’s work shows an anticancer effect in a variety of solid tumors and his work has been confirmed by others for melanoma and renal cell carcinoma. In many of these trials, meaningful clinical benefit, as well as antitumor activity, has been demonstrated.

It will be essential to the ultimate determination of melatonin’s place in cancer therapy to determine the circadian schedule that optimizes its medical benefit. Such clinical studies must employ a double-blind, placebo-controlled comparison among times of day for melatonin treatment, alone and in combination with surgery, radiation, chemotherapy, and/or biological therapies. Measures of quality of life, fatigue, the latency timing, quality and quantity of daily sleep, and the timing and intensity of daily activity should be assessed, along with melatonin’s anticancer activity, in each of these studies. Without chronobiologically adequate clinical studies, the use of melatonin will continue to depend upon belief and opinion rather than upon knowledge and understanding.


Pineal Gland Circadian Timing Cortisol Excretion Circadian Organization Biol Rhythm 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arendt J, Skene D, Middleton B, Deacon S (1997) Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythms 12: 604–617PubMedCrossRefGoogle Scholar
  2. Barni S, Lissoni P, Cazzaniga M Ardizzoia A, Meregalli S Fossati V, Fumagalli L, Brivio F, Tancini G (1995) A randomized study of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colorectal cancer patients progressing under 5-fluorouracil and folates. Oncology 52: 243–245PubMedCrossRefGoogle Scholar
  3. Bartlett P, Haus E, Tuason T, Sacket-Lundeen L, Lakatua D (1984) Circadian rhythm in number of erythroid and granulocytic colony forming units in culture (ECFU-C and GCFU-C) in bone marrow of BDF1 male mice. In: Haus E, Kabat HF (eds) Proc 15th International Conference on Chronobiology. S. Karger, Basel, pp 160–164Google Scholar
  4. Bartsch C, Bartsch H, Jain A, Laumas K, Wetterberg L (1981) Urinary melatonin levels in human breast cancer patients. J Neural Transm 52: 281–294PubMedCrossRefGoogle Scholar
  5. Bartsch C, Bartsch H, Fliichter S,Attanasio A, Gupta D (1985) Evidence for modulation of melatonin secretion in men with benign and malignant tumors of the prostate: relationship with the pituitary hormones. J Pineal Res 2: 121–132Google Scholar
  6. Bartsch C, Bartsch H, Fuchs U, Lippert TH, Bellmann O, Gupta D (1989) Stage-dependent depres-sion of melatonin in patients with primary breast cancer: correlation with prolactin, thyroid stimulating hormone, and steroid receptors. Cancer 64: 426–433PubMedCrossRefGoogle Scholar
  7. Bartsch C, Bartsch H, Bellmann O, Lippert TH (1991) Depression of serum melatonin in patients with primary breast cancer is not due to an increased peripheral metabolism. Cancer 67: 1681–1684PubMedCrossRefGoogle Scholar
  8. Bartsch C, Bartsch H, Schmidt A, Ilg S, Bichler K, Fliichter S (1992) Melatonin and 6-sulfatoxy- melatonin circadian rhythms in serum and urine of primary prostate cancer patients: evidence for reduced pineal activity and relevance of urinary determinations. Clin Chim Acta 209: 153–167PubMedCrossRefGoogle Scholar
  9. Blask D (1993) Melatonin in oncology. In:Yu H, Reiter RJ (eds) Melatonin: Biosynthesis, Physio-logical Effects, and Clinical Applications. CRC Press, Boca Raton, FL, pp 448–464Google Scholar
  10. Blask DE (1997) Systemic, cellular, and molecular aspects of melatonin action on experimental breast carcinogenesis. In: Stevens R, Wilson B, and Anderson L (eds) The Melatonin Hypothesis - Breast Cancer and the Use of Electric Power. Battelle Press, Columbus, OH, pp 189–230Google Scholar
  11. Blask DE, Hill SM (1986) Effects of melatonin on cancer: studies on MCF-7 human breast cancer cells in culture. J Neural Transm Suppl 21: 433–449PubMedGoogle Scholar
  12. Blumenfeld C (1943) Studies of normal and of abnormal mitotic activity. Arch of Path 35: 667–673Google Scholar
  13. Brainard G, Rollag M, Hanifin J (1997) Photic regulation of melatonin in humans: ocular and neural signal transduction. J Biol Rhythms 12: 537–546PubMedCrossRefGoogle Scholar
  14. Brown WR (1991) A review and mathematical analysis of circadian rhythms in cell proliferation in mouse, rat, and human epidermis. J Invest Dermatol 97: 273–280PubMedCrossRefGoogle Scholar
  15. Buchi KN, Moore JG, Hrushesky WJM, Sothern RB, Rubin NH (1991) Circadian rhythm of cellular proliferation in the human rectal mucosa. Gastroenterology 101: 410–415PubMedGoogle Scholar
  16. Cagnacci A, Elliott J, Yen S (1992) Melatonin: a major regulator of the circadian rhythm of core temperature in humans. J Clin Endocrinol Metab 75: 447–452PubMedCrossRefGoogle Scholar
  17. Cagnacci A, Soldani R, Laughlin G, Yen S (1996) Modification of circadian body temperature rhythm during the luteal menstrual phase: role of melatonin. J Appl Physiol 80: 25–29PubMedCrossRefGoogle Scholar
  18. Cagnacci A, Kräuchi K, Wirz- Justice A, Volpe A (1997) Homeostatic versus circadian effects of melatonin on core body temperature in humans. J Biol Rhythms 12: 509–517PubMedCrossRefGoogle Scholar
  19. Cassone V (1990) Melatonin: time in a bottle. Oxford Rev Reprod Biol 12: 319–367Google Scholar
  20. Cassone V, Natesan A (1997) Time and time again: the phylogeny of melatonin as a transducer of biological time. J Biol Rhythms 12: 489–497PubMedCrossRefGoogle Scholar
  21. Cooper Z (1939) Mitotic rhythm in human epidermis. J Invest Derm 2: 289–300CrossRefGoogle Scholar
  22. Cos S, Blask D (1990) Effects of the pineal hormone melatonin on the anchorage-independent growth of human breast cancer cells (MCF-7) in a clonogenic culture system. Cancer Lett 50: 115–119PubMedCrossRefGoogle Scholar
  23. Cos S, Blask D (1994) Melatonin modulates growth factor activity in MCF-7 human breast cancer cells. J Pineal Res 17: 25–32PubMedCrossRefGoogle Scholar
  24. Cos S, Sanchez-Barcelo E (1994) Differences between pulsatile or continuous exposure to melatonin on MCF-7 human breast cancer cell proliferation. Cancer Lett 85: 105–109PubMedCrossRefGoogle Scholar
  25. Cos S, Sanchez-Barcelo E (1995) Melatonin inhibition of MCF-7 human breast cancer cells growth: influence of cell proliferation rate. Cancer Lett 93: 207–212PubMedCrossRefGoogle Scholar
  26. Czeisler C (1997) Commentary: evidence for melatonin as a circadian phase-shifting agent. J Biol Rhythms 12: 618–623PubMedCrossRefGoogle Scholar
  27. Czeisler C, Kronauer R, Allan J, Duffy J, Jewett M, Brown E, Ronda J (1989) Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science 244: 1328–1333PubMedCrossRefGoogle Scholar
  28. Dahlitz M, Alvarez B, Vignau J, English J, Arendt J, Parkes J (1991) Delayed sleep phase syndrome response to melatonin. Lancet 337: 1121–1124PubMedCrossRefGoogle Scholar
  29. Daneryd P, Svanberg E, Korner U, Lindholm E, Sandstrom R, Brevinge H, Petterson C, Boseaus I Lundholm K (1998) Protection of metabolic and exercise capacity in unselected weight-losing cancer patients following treatment with recombinant erythropoietin: a randomized prospec¬tive study. Cancer Res 58: 5374–5379PubMedGoogle Scholar
  30. Danforth D, Tamarkin L, Mulvihill J, Bagley C, Lippman M (1985) Plasma melatonin and the hormone-dependency of human breast cancer. J Clin Oncol 3: 941–948PubMedGoogle Scholar
  31. Dauchy RT, Sauer LA, Blask DE, Vaughan GM (1997) Light contamination during the dark phase in “photoperiodically controlled” animal rooms: effect on tumor growth and metabolism in rats. Lab Anim Sci 47: 511–518PubMedGoogle Scholar
  32. Dawson D, Encel N (1993) Melatonin and sleep in humans. J Pineal Res 15: 1–12PubMedCrossRefGoogle Scholar
  33. Durie BMG, Salmon SE, Russell DH (1977) Polyamines as markers of response and disease activity in cancer chemotherapy. Cancer Res 36: 214–221Google Scholar
  34. Feychting M, Österlund B, Ahlbom A (1998) Reduced cancer incidence among the blind. Epidemiology 9: 490–494PubMedCrossRefGoogle Scholar
  35. Freedman R, Norton D, Woodward S, Cornelissen G, Halberg F (1994) Circadian rhythms of hot flashes and body temperature in menopausal women. In: Zeisberger E, Schonbaum E, Lomax P (eds) Thermal Balance in Health and Disease. Advances in Pharmacological Sciences. Springer, New YorkGoogle Scholar
  36. Freedman M, Lucas R, Soni B, von Schantz M, Munoz M, David-Gray Z, Foster R (1999) Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284: 502–504PubMedCrossRefGoogle Scholar
  37. Garcia-Sainz M, Halberg F (1966) Mitotic rhythms in human cancer reevaluated by electronic computer programs. Evidence for chronopathology. J Natl Cancer Inst 37: 279–292PubMedGoogle Scholar
  38. Garfinkel D, Laudon M, Nof D, Zisapel N (1995) Improvement of sleep quality in elderly people bycontrolled-release melatonin. Lancet 346: 541–544PubMedCrossRefGoogle Scholar
  39. Glaspy J (1997) Fatigue may be most under-recognized, undertreated cancer-related symptom. Oncology News Int 6: 30–38Google Scholar
  40. Gonzalez R, Sanchez A, Ferguson J A, Balmer C, Daniel C, Cohn A, Robinson WA (1991) Melatonin therapy of advanced human malignant melanoma. Melanoma Res 1: 237–243PubMedCrossRefGoogle Scholar
  41. Hahn R (1991) Profound bilateral blindness and the incidence of breast cancer. Epidemiology 2: 208–210PubMedCrossRefGoogle Scholar
  42. Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N (1995) Melatonin replacement therapy of elderly insomniacs. Sleep 18: 598–603PubMedGoogle Scholar
  43. Halberg F, Bingham C, Cornelissen G (1993) Clinical trials: the larger the better? Chronobiologia 20: 193–211PubMedGoogle Scholar
  44. Haus E, Lakatua DJ, Swoyer J, Sackett LL (1983) Chronobiology in hematology and immunology. Am J Anat 168: 467–517PubMedCrossRefGoogle Scholar
  45. Hill SM, Blask DE (1988) Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 48: 6121–6126PubMedGoogle Scholar
  46. Hill SM, Spriggs L, Simon M, Muraoka H, Blask DE (1992) The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system. Cancer Lett 64: 249–256PubMedCrossRefGoogle Scholar
  47. Holdaway I, Mason B, Gibbs E, Rajasoorya C, Hopkins K (1991) Seasonal changes in serum melatonin in women with previous breast cancer. Br J Cancer 64: 149–153PubMedCrossRefGoogle Scholar
  48. Hrushesky WJM (1985) Circadian timing of cancer chemotherapy. Science 228: 73–75PubMedCrossRefGoogle Scholar
  49. Hrushesky WJM (ed) (1994) Circadian Cancer Therapy. CRC Press, Boca Raton, FLGoogle Scholar
  50. Hrushesky WJM, Bjarnason G (1993 a) Circadian cancer therapy. J Clin Oncol 11: 1403–1417Google Scholar
  51. Hrushesky WJM, Bjarnason GA (1993b) The application of circadian chronobiology to cancer chemotherapy. In: DeVita VT, Hellman Sand, Rosenberg SA (eds) Cancer: Principles & Practice of Oncology. JB Lippincott, Philadelphia, pp 2666–2686Google Scholar
  52. Hrushesky WJM, Murphy G (1977) Current status of the therapy of advanced renal carcinoma. J Surg Oncol 9: 277PubMedCrossRefGoogle Scholar
  53. Hrushesky WJM, Merdink J, Abdel-Monem M (1983) Circadian rhythmicity characterizes monoacetyl polyamine urinary excretion. Cancer Res 43: 3944–3947PubMedGoogle Scholar
  54. Hrushesky WJM, Haus E, Lakatua DJ, Halberg F, Langevin T, Kennedy BJ (1984) Marker rhythms for cancer chrono-chemotherapy. In: Haus E, Kabat HF (eds) Chronobiology 1982–1983. Karger, New York, pp 493–499Google Scholar
  55. Hrushesky WJM, von Roemeling R, Lanning R, Rabatin J (1990) Circadian-shaped infusion of floxuridine for progressive metastatic renal cell carcinoma. J Clin Oncol 8: 1504–1513PubMedGoogle Scholar
  56. Hrushesky WJM, Langevin T, Kim YJ, Wood PA (1994) Circadian dynamics of tumor necrosis factor-α (cachectin) lethality. J Exp Med 180: 1059–1065PubMedCrossRefGoogle Scholar
  57. Janne J, Poso H, Raina A (1978) Polyamines in rapid growth and cancer. Biochem Biophys Acta 473: 241–243PubMedGoogle Scholar
  58. Killman SA, Cronkite EP, Fliedner TM, Bond VP (1962) Mitotic indices of human bone marrow cells. I. Number and cytologic distribution of mitosis. Blood 19: 743–750Google Scholar
  59. Klevecz RR, Shymko RM, Blumenfeld D, Braly PS (1987) Circadian gating of S phase in human ovarian cancer. Cancer Res 47: 6267–6271PubMedGoogle Scholar
  60. Kräuchi K, Wirz-Justice A (1994) Circadian rhythm of heat production, heart rate, and skin and core temperature under unmasking conditions in men. Am J Physiol 267: R819–R829PubMedGoogle Scholar
  61. Kräuchi K, Cajochen C, Wirz-Justice (1997 a) Melatonin and orthostasis: interactions of posture with subjective sleepiness, heart rate and skin and core temperature. Sleep Res 26: 79Google Scholar
  62. Kräuchi K, Cajochen C, Wirz-Justice A (1997b) A relationship between heat loss and sleepiness: effects of postural change and melatonin administration. J Appl Physiol 83: 134–139PubMedGoogle Scholar
  63. Laerum OD, Aardal NP (1981) Chronobiological aspects of bone marrow and blood cells. In: von Mayersbach H, Scheving LE, Pauli JE (eds) 11th International Congress of Anatomy, part C, Biological rhythms in structure and function. Alan R. Liss, New York, pp 87–97Google Scholar
  64. Laerum OD, Sletvold O, Riise T (1988) Circadian and circannual variation of the cell cycle distribution in the mouse bone marrow. Chronobiol Int 5: 19–35PubMedCrossRefGoogle Scholar
  65. Laerum OD, Smaaland R (1989) Circadian and infradian aspects of the cell cycle: From past to future. Chronobiologia 16: 441–453PubMedGoogle Scholar
  66. Laerum OD, Smaaland R, Sletvold O (1989) Rhythms in blood and bone marrow: potential therapeutic implications. In: Lemmer B (ed) Chronopharmacology: cellular and biochemical interactions. Marcel Dekker, New York, pp 371–393Google Scholar
  67. Langevin T, Young J, Walker K, von Roemeling R, Nygaard S, Hrushesky WJM (1987) The toxicity of tumor necrosis factor (TNF) is reproducibly different at specific times of the day. Proc Ann Meet Am Assoc Cancer Res 28: A1580Google Scholar
  68. Lapin V, Ebels I (1976) Effects of some low molecular weight sheep pineal fractions and melatonin on different tumors in rats and mice. J Neural Transm 52: 269–279Google Scholar
  69. Lerner A, Case J, Takahashi Y, Lee T, Mori W (1958) Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc 80: 2587CrossRefGoogle Scholar
  70. Lévi FA, Zidani R, Vannetzel JM, Perpoint B, Focan C, Faggiuolo R, Chollet P, Garufi C, Itzhaki M, Dogliotti L, Iacobelli S, Adam R, Kunstlinger F, Gastiaburu J, Bismuth H, Jasmin C, Misset J (1994) Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. J Natl Cancer Inst 86: 1608–1617PubMedCrossRefGoogle Scholar
  71. Lewy A, Sack R (1997) Exogenous melatonin’s phase-shifting effects on the endogenous melatonin profile in sighted humans: a brief review and critique of the literature. J Biol Rhythms 12: 588–594PubMedCrossRefGoogle Scholar
  72. Lieberman H, Waldhauser F, Garfield G, Lynch H, Wurtman R (1984) Effects of melatonin on human mood and performance. Brain Res 323: 201–207PubMedCrossRefGoogle Scholar
  73. Lissoni P, Barni S, Tancini G, Crispino S, Paolorossi F, Lucini V, Mariani M, Cattaneo G, Esposti D, Esposti G (1987) Clinical study of melatonin in untreatable advanced cancer patients. Tumori 73: 475 - 480PubMedGoogle Scholar
  74. Lissoni P, Barni S, Crispino S, Tancini G, Fraschini F (1989) Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Cancer Clin Oncol 25: 789–795PubMedCrossRefGoogle Scholar
  75. Lissoni P, Barni S, Cattaneo G, Tancini G, Esposti G, Esposti D, Fraschini F (1991) Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 48: 448–450PubMedCrossRefGoogle Scholar
  76. Lissoni P, Barni S, Ardizzoia A, Paolorossi F, Crispino S, Tancini G, Tisi E, Archili C, De Toma D, Pipino G, Conti A, Maestroni G (1992) 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 49: 336–339PubMedCrossRefGoogle Scholar
  77. Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G (1994 a) A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 73: 699–701Google Scholar
  78. Lissoni P, Barni S, Cazzaniga M, Ardizzoia A, Rovelli F, Brivio F, Tancini G (1994b) Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low-dose IL-2 in patients with advanced solid tumors who had progressed on IL-2 alone. Oncology 51: 344–347PubMedCrossRefGoogle Scholar
  79. Lissoni P, Meregalli S, Fossati V, Paolorossi F, Barni S, Tancini G, Frigerio F (1994 c) 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 nonsmall cell lung cancer. Tumori 80: 464–467Google Scholar
  80. Lissoni P, Ardizzoia A, Barni S, Paolorossi F, Tancini G, Meregalli S, Esposti G, Zubelewicz B, Braczowski R (1995 a) A randomized study of tamoxifen alone versus tamoxifen plus melatonin in estrogen receptor-negative heavily pretreated metastatic breast cancer patients. Oncol Rep 2: 871–873Google Scholar
  81. Lissoni P, Barni S, Fossati V, Ardizzoia A, Cazzaniga M, Tancini G, Frigerio F (1995 b) A randomized study of neuroimmunotherapy with low-dose subcutaneous interleukin-2 plus melatonin compared to supportive care alone in patients with untreatable metastatic solid tumour. Support Care Cancer 3: 194–197Google Scholar
  82. Lissoni P, Meregalli S, Nosetto L, Barni S, Tancini G, Fossati V, Maestroni G (1996 a) Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 53: 43–46Google Scholar
  83. Lissoni P, Brivio O, Brivio F, Barni S, Tancini G, Crippa D, Meregalli S (1996b) Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma. J Pineal Res 21: 239–242PubMedCrossRefGoogle Scholar
  84. Lucas R, Freedman M, Munoz M, Garcia-Fernández J, Foster R (1999) Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284: 505–507PubMedCrossRefGoogle Scholar
  85. Mauer AM (1965) Diurnal variation of proliferative activity in the human bone marrow. Blood 26: 1–7PubMedGoogle Scholar
  86. Mclntyre I, Norman T, Burrows G, Armstrong S (1989) Human melatonin suppression by light is intensity dependent. J Pineal Res 6: 149–156CrossRefGoogle Scholar
  87. Mhatre M, Shah P, Juneja H (1984) Effect of varying photoperiods on mammary morphology, DNA synthesis, and hormone profile in female rats. J Natl Cancer Inst 72: 1411–1415PubMedGoogle Scholar
  88. Miaskowski C, Portenoy R (1998) Update on the assessment and management of cancer-related fatigue. Principles and Practice of Supportive Oncology Updates 1: 1–10Google Scholar
  89. Morley AA (1966) A neutrophil cycle in healthy individuals. Lancet ii: 1220Google Scholar
  90. Mormont M, Claustrat B, Waterhouse J, Touitou Y, Levi F (1998) Clinical relevance of circadian rhythm assessment in cancer patients. In: Touitou Y (ed) Biological Clocks. Mechanisms and applications. Elsevier Science, Amsterdam, pp 497–505Google Scholar
  91. Nash RE, Echave Llanos JM (1971) Circadian variation in DNA synthesis of fast-growing and slow-growing hepatoma: DNA synthesis rhythm in hepatoma. J Natl Cancer Inst 47: 1007–1012PubMedGoogle Scholar
  92. Neri B, Fiorelli C, Moroni F, Nicita G, Paolotti M Ponchietti R, Raugel A, Santoni G, Trippitelli A, Grechi G (1994) Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma. A phase II study. Cancer 73: 3015–3019PubMedCrossRefGoogle Scholar
  93. Oldani A, Ferini-Strambi L, Zucconi M, Stankov B, Fraschini F, Smirne S (1994) Melatonin and delayed sleep phase syndrome: ambulatory polygraphic evaluation. Neuroreport 6: 132–134PubMedCrossRefGoogle Scholar
  94. Panzer A, Wiljoen M (1997) The validity of melatonin as an oncostatic agent. J Pineal Res 22: 184–202PubMedCrossRefGoogle Scholar
  95. Pittendrigh C (1960) Circadian rhythms and the circadian organization of living systems. Cold Spring Harbor Symp Quant Biol 25: 159–184PubMedGoogle Scholar
  96. Ponassi A, Morra L, Bonanni F, Molinari A, Gigli G, Vercelli M, Sacchetti C (1979) Normal range of blood colony-forming cells (CFU-C) in humans: influence of experimental conditions, age, sex, and diurnal variations. Blut 39: 257–263PubMedCrossRefGoogle Scholar
  97. Raloff J (1998) Does light have a dark side? Nighttime illumination might elevate cancer risk. Science News 154: 248–250CrossRefGoogle Scholar
  98. Reiter RJ (1988) Pineal gland, cellular proliferation and neoplastic growth: an historical account. In: Gupta D, Attanasio A, Reiter RJ (eds) The pineal gland and cancer. Brain Research Promotion, Tübingen, pp 41–64Google Scholar
  99. Reiter RJ, Tan TX, Poeggeler B, Menendez-Pelaez A, Chen LD, Saarela S (1994) Melatonin as a free-radical scavenger: Implications for aging and age-related processes. Ann NY Acad Sci 719: 1–12PubMedCrossRefGoogle Scholar
  100. Reppert S (1997) Melatonin receptors: molecular biology of a new family of G protein-coupled receptors. J Biol Rhythms 12: 528–531PubMedCrossRefGoogle Scholar
  101. Rivard G, Infante-Rivard C, Hoyoux C, Champagne J (1985) Maintenance chemotherapy for childhood acute lymphoblastic leukemia: better in the evening. Lancet ii: 1264–1266Google Scholar
  102. Robinson W, Dreiling L, Gonzalez R, Balmer C (1995) Treatment of human metastatic malignant melanoma with high dose oral melatonin. In: Fraschini F, Reiter RJ, Stankov B (eds) The Pineal Gland and Its Hormones: Fundamentals and Clinical Perspectives. Plenum Press, New York, pp 219–225CrossRefGoogle Scholar
  103. Ross DD, Pollak A, Akman SA, Bachur NR (1980) Diurnal variation of circulating human myeloidGoogle Scholar
  104. progenitor cells. Exp Hematol 8:954–960Google Scholar
  105. Rubin NH, Hokanson JW, Mayschak JW, Tsai TH, Barranco SC, Scheving LE (1983) Several cytokinetic methods for showing circadian variation in normal murine tissue and in a tumor. Am J Anat 168: 15–26PubMedCrossRefGoogle Scholar
  106. Sanchez S, Hrushesky W, Wood P, Vyzula R (1993) Host-tumor balance depends upon IL-2 circadian timing. Proc AACR, Orlando, FLGoogle Scholar
  107. Scheving LE (1959) Mitotic activity in the human epidermis. Anat Rec 135: 7–19PubMedCrossRefGoogle Scholar
  108. Scheving LE (1981) Circadian rhythms in cell proliferation: their importance when investigating the basic mechanism of normal versus abnormal growth. In: von Mayersbach H, Scheving LE, Pauli JE (eds) 11th International Congress of Anatomy, part C, Biological rhythms in structure and function. Alan R. Liss, New York, pp 39–79Google Scholar
  109. Scheving LE, Burns ER, Pauli JE, Tsai TH (1978) Circadian variation in cell division of the mouse alimentary tract, bone marrow and corneal epithelium. Anat Rec 191: 479–486PubMedCrossRefGoogle Scholar
  110. Scheving LE, Tsai TS, Feuers RJ, Scheving LA (1989) Cellular mechanisms involved in the action of anticancer drugs. In: Lemmer B (ed) Chronopharmacology: cellular and biochemical interactions. Marcel Dekker, New York, pp 317–369Google Scholar
  111. Schipper H, Turley E, Baum M (1996) A new biological framework for cancer research. Lancet 348: 1149–1153PubMedCrossRefGoogle Scholar
  112. Shanahan T, Zeitzer J, Czeisler C (1997) Resetting the melatonin rhythm with light in humans. J Biol Rhythms 12: 556–567PubMedCrossRefGoogle Scholar
  113. Skene D, Bojkowski C, Currie J, Wright J, Boulter P, Arendt J (1990) 6-sulphatoxymelatonin production in breast cancer patients. J Pineal Res 8: 269–276Google Scholar
  114. Smaaland R, Laerum OD, Lote K, Sletvold O, Sothern R, Bjerknes R (1991) DNA synthesis in human bone marrow is circadian stage dependent. Blood 77: 2603–2611PubMedGoogle Scholar
  115. Smaaland R, Lote K, Sothern RB, Laerum OD (1993) DNA synthesis and ploidy in non-Hodgkin’s lymphomas demonstrate intrapatient variation depending on circadian stage of cell sampling. Cancer Res 53: 3129–3138PubMedGoogle Scholar
  116. Starr KW (1970) Growth and new growth: environmental carcinogens in the process of ontogeny. Prof Clin Cancer 4: 1–29Google Scholar
  117. Stoney PJ, Halberg F, Simpson HW (1975) Circadian variation in colony-forming ability of presumably intact murine bone marrow cells. Chronobiologia 2: 319–324PubMedGoogle Scholar
  118. Tähti E (1956) Studies of the effect of x-radiation on 24-hour variations in the mitotic activity in human malignant tumors. Acta Path Microbiol Scand, Suppl 117: 1–61Google Scholar
  119. Tamarkin L, Cohen M, Roselle D, Reichert C, Lippman M, Chabner B (1981) Melatonin inhibition and pinealectomy enhancement of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the rat. Cancer Res 41: 432–436Google Scholar
  120. Tamarkin L, Danforth D, Lichter A, DeMoss E, Cohen M, Chabner B, Lippman M (1982) Decreased nocturnal plasma melatonin peak in patients with estrogen recepter positive breast cancer. Science 216: 1003–1005PubMedCrossRefGoogle Scholar
  121. Tzischinsky O, Lavie P (1994) Melatonin possesses time-dependent hypnotic effects. Sleep 17: 638–645PubMedGoogle Scholar
  122. Tzischinsky O, Shlitner A, Lavie P (1993) The association between the nocturnal sleep gate and nocturnal onset of urinary 6-sulfatoxymelatonin. J Biol Rhythms 8: 199–209PubMedCrossRefGoogle Scholar
  123. Ubeda A, Trillo MA, House DF, Blackman CF (1995) Melatonin enhances junctional transfer in normal CH3H/10T1/2 cells. Cancer Lett 91: 241–245PubMedCrossRefGoogle Scholar
  124. Vollrath L, Semm P, Gammel G (1981) Sleep induction by intranasal application of melatonin. Adv Biosci 29: 327–329Google Scholar
  125. Voutilainen A (1953) Über die 24-Stunden-Rhythmik der Mitosefrequenz in malignen Tumoren. Acta Path Microbiol Scan 99 (suppl.): 1–104Google Scholar
  126. Waalen J (1993) Nighttime light studied as possible breast cancer risk. J Natl Cancer Inst 85: 1712–1713PubMedCrossRefGoogle Scholar
  127. Wehr TA (1992) Improvement of depression and triggering of mania by sleep deprivation. J AmGoogle Scholar
  128. Med Assoc 267:548–551Google Scholar
  129. Wehr TA (1997) Melatonin and seasonal rhythms. J Biol Rhythms 12: 518–527PubMedCrossRefGoogle Scholar
  130. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. New Engl J Med 340: 253–259PubMedCrossRefGoogle Scholar
  131. Wood P, Hrushesky W (1996) Circadian rhythms and cancer chemotherapy. Crit Rev EukaryoticGoogle Scholar
  132. Gene Expression 6:299–343Google Scholar
  133. Wurtman R, Zhdanova I (1995) Improvement of sleep quality by melatonin. Lancet 346: 1491PubMedCrossRefGoogle Scholar
  134. Zhang R, Diasio R (1994) Pharmacologic basis for circadian pharmacodynamics. Hrushesky WJM (ed) Circadian Cancer Therapy. CRC Press, Boca Raton, FL, pp 61–103Google Scholar
  135. Zhdanova I, Wurtman R, Lynch H (1995) Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 57: 552–558PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2001

Authors and Affiliations

  • William J. M. Hrushesky

There are no affiliations available

Personalised recommendations