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Treatment of Human Metastatic Malignant Melanoma with High Dose Oral Melatonin

  • William A. Robinson
  • Lyndah Dreiling
  • Rene Gonzalez
  • Carol Balmer
Part of the NATO ASI Series book series (NSSA, volume 277)

Abstract

Cutaneous malignant melanoma (MM) is the most rapidly increasing cancer in Caucasians throughout the world(1,2). The cause of the current epidemic is increasing exposure to ultraviolet light in the form of sunshine that has occurred over the past 50 years from changes in clothing habits and lifestyle (3,4). Most MM develop in pre-existing nevi, primarily in sun exposed sites, in fair skinned, blue eyed, brown haired, upper middle class Caucasians who work indoors but spend large amounts of time outdoors in leisure time activities (5,6). Unlike cancers beginning in the epithelial skin, which usually remain localized, MM spreads rapidly from the primary site to other parts of the body via the blood and lymphatic systems. Early surgical excision may be curative but once the disease has spread beyond regional lymph nodes no form of therapy has been shown to be of consistent and long lasting benefit. Based on current figures 20 to 30% of all persons currently diagnosed with MM will develop metastatic disease, and most if not all, will die as a direct consequence. Numerous forms of therapy have, or are, being tried including chemo and immunotherapy, vaccines and recently gene therapy (7,8,9). All have some limited effect but most patients eventually develop brain metastases and no therapy has been shown to significantly prolong life when this occurs (10). With this background we have begun to seek new and novel agents for the treatment of metastatic MM. Melatonin has been previously examined as a possible anti-neoplastic agent by a number of investigators, including ourselves (11,12,13). In-vitro melatonin has been shown to suppress the growth of cancer cells, including MM (12). Likewise in animal models of MM, administration of melatonin has been shown to delay disease progression and death (13). Melatonin, both alone and with other agents, has been used to treat a variety of human cancers with variable results, but generally low response rates (11,14). We previously reported on a phase 1, dose escalation trial of oral melatonin in patients with metastatic cutaneous and ocular MM(11). In this initial trial there was little toxicity, even at very high daily doses of oral melatonin, and occasional patients appeared to have minor responses with partial regression of metastatic disease. No dose response curve was noted in this study. Patients receiving very high doses (700mg per M2) were no more likely to respond than those receiving much lower doses. We therefore elected to carry out a further study using a fixed dose of oral melatonin (200mg orally per day) in a larger group of patients with metastatic MM to determine more precisely the possible therapeutic benefit and toxicity. The results of this study are reported here.

Keywords

Malignant Melanoma Brain Metastasis Melatonin Administration Develop Brain Metastasis Significant Therapeutic Benefit 
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.

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References

  1. 1.
    S.J. Hoffmann, J.J. Yohn, D.A. Norris, C. Smith, and W.A. Robinson, Cutaneous malignant melanoma,Current Problems in Dermatology V(1): 1 (1993).Google Scholar
  2. 2.
    J.M. Elwood, Recent developments in melanoma epidemiology, Melanoma Research 3:149 (1993).PubMedCrossRefGoogle Scholar
  3. 3.
    A.M. Goldstein and M.A. Tucker, Etiology, epidemiology, risk factors, and public health issues of melanoma, Current Opinion in Oncology 5:358 (1993).PubMedCrossRefGoogle Scholar
  4. 4.
    A.J. Sober, F.A. Lew, H.K. Koh, and R.L. Barnhill, Epidemiology of cutaneous melanoma. An update,Dermatologic Clinics 9:617 (1991).PubMedGoogle Scholar
  5. 5.
    R.M. Rifkin, M.R. Thomas, T.I. Mughal, J.S. Kaur, L.U. Krebs, and W.A. Robinson, Malignant melanoma -profile of an epidemic, Western Journal of Medicine 149:43 (1988).PubMedGoogle Scholar
  6. 6.
    W.A. Robinson, J. Ferguson, and J.F. Robinson, Malignant melanoma: The dark side of the sun, at 40o north, Transactions of the Menzies Foundation (Melbourne, Australia) 15:121 (1989).Google Scholar
  7. 7.
    J.M. Richards, N. Mehta, K. Ramming, and P. Skosey, Sequential chemoimmunotherapy in the treatment of metastatic melanoma, J. Clin. Onc. 10:1338 (1992).Google Scholar
  8. 8.
    L.E. Flaherty, W.A. Robinson, B.G. Redman, R. Gonzalez, S. Martino, M. Kraut, M. Valdivieso, and A.Rudolf: Phase II study of dacarbazine and cisplatin in combination with outpatient administered interleukin-2 in metastatic malignant melanoma, Cancer 71:3250 (1993).CrossRefGoogle Scholar
  9. 9.
    G.J. Nabel, E.G. Nabel, Z.Y. Yang, B.A. Fox, G.E. Plautz, X. Gao, L. Huang, S. Shu, D. Gordon, and A.E. Chang, Direct gene transfer with DNA-liposome complexes in melanoma: Expression, biologic activity, and lack of toxicity in humans, Proc. Natl. Acad. Sci. USA 90:11307 (1993).PubMedCrossRefGoogle Scholar
  10. 10.
    K. Brega, W.A. Robinson, K. Winston, and W. Wittenberg, Surgical treatment of brain metastases in malignant melanoma, Cancer 66:2105 (1990).PubMedCrossRefGoogle Scholar
  11. 10.A
    U.R. Gonzalez, A. Sanchez, J.A. Ferguson, C. Balmer, C. Daniel, A. Cohn, and W.A. Robinson, Melatonin therapy of advanced human malignant melanoma, Melanoma Research 1:237 (1991).PubMedCrossRefGoogle Scholar
  12. 12.
    A. Slominski and D. Pruski, Melatonin inhibits proliferation and melanogenesis in rodent melanoma cells,Exp. Cell Res. 206:189 (1993).PubMedCrossRefGoogle Scholar
  13. 13.
    L.R. Stanberry, T.K. Das Gupta, and C.W. Beattie, Photoperiodic control of melanoma growth in hamster:Influence of pinealectomy and melatonin, Endocrinology 113:469 (1983).PubMedCrossRefGoogle Scholar
  14. 14.
    P. Lissoni, S. Barni, G. Tancini, A. Ardizzoia, G. Ricci, R. Aldeghi, F. Brivio, E. Tisi, F. Rovelli, R.Rescaldani, et al, A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma, Br. J. Cancer 69:196 (1994).PubMedCrossRefGoogle Scholar
  15. 15.
    D.B. McElhinney, S.J. Hoffman, W.A. Robinson, and J. Ferguson, Effect of melatonin on human skin color, J Invest Derm 102:258 (1994).PubMedCrossRefGoogle Scholar
  16. 16.
    M.A. Kane, A. Johnson, A.E. Nash, D. Boose, G. Mathai, C. Balmer, J.J. Yohn, and W.A. Robinson,Serum melatonin levels in melanoma patients after repeated oral administration, Melanoma Research 4:59 (1994).PubMedCrossRefGoogle Scholar
  17. 17.
    J.J. Nordlund and A.B. Lerner, The effects of oral melatonin on skin color and on the release of pituitary hormones, J. Clin. Endo. & Metab. 45:768 (1977).CrossRefGoogle Scholar
  18. 18.
    F. Waldhauser, G. Weiszenbacher, H. Frisch, U. Zeitlhuber, M. Waldhauser, and R.J. Wurtman, Fall in nocturnal serum melatonin during prepuberty and pubescence, Lancet 1:362 (1984).PubMedCrossRefGoogle Scholar
  19. 19.
    B.C. Boordouw, R Euser, R.E. Verdonk, B.T. ALberda, F.H. de Jong, A.C. Drogendijk, B.C. Fauser and M. Cohen, Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation, J. Clin. Endo. & Metab. 74:108 (1992).CrossRefGoogle Scholar
  20. 20.
    R.A. Helton, W.A. Harrison, K. Kelley, and M.A. Kane, Melatonin interactions with cultured murine B16 melanoma cells, Melanoma Research 3:403 (1993).PubMedCrossRefGoogle Scholar
  21. 21.
    S.T. Wilson, D.E. Blask, and A.M. Lemus-Wilson, Melatonin augments the sensitivity of MCF-7 human breast cancer cells to tamoxifen in vitro, J. Clin. Endo. & Metab. 75:669 (1992).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • William A. Robinson
    • 1
  • Lyndah Dreiling
    • 1
  • Rene Gonzalez
    • 1
  • Carol Balmer
    • 1
  1. 1.Melanoma Research Clinic, Division of Medical Oncology, Department of MedicineUniversity of Colorado Health Sciences CenterDenverUSA

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