Developing Topical Prodrugs for Skin Cancer Prevention

  • Elaine L. Jacobson
  • Hyuntae Kim
  • Moonsun Kim
  • Georg T. Wondrak
  • Myron K. Jacobson


Skin Cancer Stratum Corneum Skin Cell Genotoxic Stress Skin Damage 
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  1. Agar, N.S., G.M. Halliday, et al. (2004). "The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: A role for UVA in human skin carcinogenesis." PNAS 101: 4954–4959.CrossRefPubMedGoogle Scholar
  2. Alberts, D.S., R. Goldman, et al. (1996). "Disposition and metabolism of topically administered alpha-tocopherol acetate: a common ingredient of commercially available sunscreens and cosmetics." Nutr Cancer 26(2): 193–201.PubMedGoogle Scholar
  3. Almand, B., J.I. Clark, et al. (2001). "Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer." J Immunol 166(1): 678–689.PubMedGoogle Scholar
  4. Ames, B. N. (2001). "DNA damage from micronutrient deficiencies is likely to be a major cause of cancer." Mutat Res 475(1–2): 7–20.PubMedGoogle Scholar
  5. Ananthaswamy, H.N., S.E. Ullrich, et al. (1999). "Inhibition of solar simulator-induced p53 mutations and protection against skin cancer development in mice by sunscreens." J Invest Dermatol 112(5): 763–768.CrossRefPubMedGoogle Scholar
  6. Anderson, B.D., W.I. Higuchi, et al. (1988). "Heterogeneity effects on permeability-partition coefficient relationships in human stratum corneum." Pharm Res 5(9): 566–573.CrossRefPubMedGoogle Scholar
  7. Berton, T.R., C.J. Conti, et al. (1998). "The effect of vitamin E acetate on ultraviolet-induced mouse skin carcinogenesis." Mol Carcinog 23(3): 175–184.CrossRefPubMedGoogle Scholar
  8. Beyer, R.E. (1994). "The role of ascorbate in antioxidant protection of biomembranes: interaction with vitamin E and coenzyme Q." J Bioenerg Biomembr 26(4): 349–358.CrossRefPubMedGoogle Scholar
  9. Branda, R. F. and J.W. Eaton (1978). "Skin color and nutrient photolysis: an evolutionary hypothesis." Science 201(4356): 625–626.PubMedGoogle Scholar
  10. Burke, K. E., J. Clive, et al. (2000). "Effects of topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh:2 hairless mice." Nutr Cancer 38(1): 87–97.CrossRefPubMedGoogle Scholar
  11. Chamlin, S.L., J. Kao, et al. (2002). "Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity." J Am Acad Dermatol 47(2): 198–208.CrossRefPubMedGoogle Scholar
  12. Chen, A.T., J.A. Reidy, et al. (1989). "Increased chromosome fragility as a consequence of blood folate levels, smoking status, and coffee consumption." Environ Mol Mutagen 13(4): 319–324.PubMedGoogle Scholar
  13. Chen, W., M. Barthelman, et al. (1997). "Inhibition of cyclobutane pyrimidine dimer formation in epidermal p53 gene of UV-irradiated mice by alpha-tocopherol." Nutr Cancer 29(3): 205–211.PubMedGoogle Scholar
  14. Choi, S.W., Y.I. Kim, et al. (1998). "Folate depletion impairs DNA excision repair in the colon of the rat." Gut 43(1): 93–99.PubMedGoogle Scholar
  15. Choi, S.W. and J.B. Mason (2000). "Folate and carcinogenesis: an integrated scheme." J Nutr 130(2): 129–132.PubMedGoogle Scholar
  16. Cruz, P. D., Jr., R. E. Tigelaar, et al. (1990). "Langerhans cells that migrate to skin after intravenous infusion regulate the induction of contact hypersensitivity." J Immunol 144(7): 2486–2492.PubMedGoogle Scholar
  17. Duthie, S.J. and A. Hawdon (1998). "DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro." Faseb J 12(14): 1491–1497.PubMedGoogle Scholar
  18. Elmets, C.A., P.R. Bergstresser, et al. (1983). "Analysis of the mechanism of unresponsiveness produced by haptens painted on skin exposed to low dose ultraviolet radiation." J Exp Med 158(3): 781–794.CrossRefPubMedGoogle Scholar
  19. Fang, J.Y., S.D. Xiao, et al. (1997). "Relationship of plasma folic acid and status of DNA methylation in human gastric cancer." J Gastroenterol 32(2): 171–175.PubMedGoogle Scholar
  20. Fourtanier, A., A. Gueniche, et al. (2000). "Improved protection against solar-simulated radiation-induced immunosuppression by a sunscreen with enhanced ultraviolet A protection." J Invest Dermatol 114(4): 620–627.CrossRefPubMedGoogle Scholar
  21. Geesin, J.C., D. Darr, et al. (1988). "Ascorbic acid specifically increases type I and type III procollagen messenger RNA levels in human skin fibroblast." J Invest Dermatol 90(4): 420–424.CrossRefPubMedGoogle Scholar
  22. Gensler, H.L., T. Williams, et al. (1999). "Oral niacin prevents photocarcinogenesis and photoimmunosuppression in mice." Nutr Cancer 34(1): 36–41.CrossRefPubMedGoogle Scholar
  23. Guenthner, S.T., R.M. Hurwitz, et al. (1999). "Cutaneous squamous cell carcinomas consistently show histologic evidens-b of in situ changes: a clinicopathologic correlation." J Am Acad Dermatol 41(3 Pt 1): 443–448.PubMedGoogle Scholar
  24. Guo, Q. and L. Packer (2000). "Ascorbate-dependent recycling of the vitamin E homologue Trolox by dihydrolipoate and glutathione in murine skin homogenates." Free Radic Biol Med 29(3–4): 368–374.CrossRefPubMedGoogle Scholar
  25. Heath, C.W., Jr. (1966). "Cytogenetic observations in vitamin B12 and folate deficiency." Blood 27(6): 800–815.PubMedGoogle Scholar
  26. Hill, L.L., A. Ouhtit, et al. (1999). "Fas ligand: a sensor for DNA damage critical in skin cancer etiology." Science 285(5429): 898–900.CrossRefPubMedGoogle Scholar
  27. Hoppe, U., J. Bergemann, et al. (1999). "Coenzyme Q10, a cutaneous antioxidant and energizer." Biofactors 9(2–4): 371–378.PubMedGoogle Scholar
  28. Horowitz, R.M. and L.E. Monger (1995). "Solar keratosis: an evolving squamous cell carcinoma: benign or malignant?" Dermatol Surg 21: 183.CrossRefPubMedGoogle Scholar
  29. Jablonski, N.G. and G. Chaplin (2000). "The evolution of human skin coloration." J Hum Evol 39(1): 57–106.CrossRefPubMedGoogle Scholar
  30. Jacobson, E.L., K.M. Antol, et al. (1983). "Poly(ADP-ribose) metabolism in ultraviolet irradiated human fibroblasts." J Biol Chem 258(1): 103–107.PubMedGoogle Scholar
  31. Jacobson, E.L., A.J. Dame, et al. (1995). "Evaluating the role of niacin in human carcinogenesis." Biochimie 77(5): 394–398.CrossRefPubMedGoogle Scholar
  32. Jacobson, E.L., P.U. Giacomoni, et al. (2001). "Optimizing the energy status of skin cells during solar radiation." J Photochem Photobiol B 63(1–3): 141–147.CrossRefPubMedGoogle Scholar
  33. Jacobson, E.L., W.M. Shieh, et al. (1999). "Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis." Mol Cell Biochem 193(1–2): 69–74.CrossRefPubMedGoogle Scholar
  34. Jacobson, M.K. and E.L. Jacobson (1999). "Discovering new ADP-ribose polymer cycles: protecting the genome and more." Trends Biochem Sci 24(11): 415–417.CrossRefPubMedGoogle Scholar
  35. Jacobson, M. K., H. Kim, et al. (2002). "A topical niacin prodrug enhances wound healing by stimulation of leptin secretion." J Invest Dermatol 118: 840.Google Scholar
  36. Jeffes, E.W., 3rd and E.H. Tang (2000). "Actinic keratosis. Current treatment options." Am J Clin Dermatol 1(3): 167–179.PubMedGoogle Scholar
  37. Kagan, V., E. Serbinova, et al. (1990). "Antioxidant effects of ubiquinones in microsomes and mitochondria are mediated by tocopherol recycling." Biochem Biophys Res Commun 169(3): 851–857.CrossRefPubMedGoogle Scholar
  38. Kagan, V., E. Witt, et al. (1992). "Ultraviolet light-induced generation of vitamin E radicals and their recycling. A possible photosensitizing effect of vitamin E in skin." Free Radic Res Commun 16(1): 51–64.PubMedGoogle Scholar
  39. Kagan, V. E., E.A. Serbinova, et al. (1990). "Generation and recycling of radicals from phenolic antioxidants." Arch Biochem Biophys 280(1): 33–39.CrossRefPubMedGoogle Scholar
  40. Karagas, M.R., E.R. Greenberg, et al. (1999). "Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. New Hampshire Skin Cancer Study Group." Int J Cancer 81(4): 555–559.CrossRefPubMedGoogle Scholar
  41. Kim, H., M.K. Jacobson, et al. (2002). "A Topical Niacin Prodrug Enhances Wound Healing by Stimulation of Leptin Secretion." Journal of Investigative Dermatology 119: 8405.Google Scholar
  42. Kim, H., Kim, M., Qasem, J.G., Coyle, D.L., Jacobson, M.K. and Jacobson, E.L. (2002). "A Topical Niacin Prodrug for Skin Cancer Prevention." Proc Am Asso Cancer Res 43: 1144.Google Scholar
  43. Liebler, D.C. and J.A. Burr (2000). "Effects of UV light and tumor promoters on endogenous vitamin E status in mouse skin." Carcinogenesis 21(2): 221–225.CrossRefPubMedGoogle Scholar
  44. Lober, B.A., C.W. Lober, et al. (2000). "Actinic keratosis in squamous cell carcinoma." J Am Acad Dermatol 43(5): 881.CrossRefGoogle Scholar
  45. McVean, M. and D.C. Liebler (1997). "Inhibition of UVB induced DNA photodamage in mouse epidermis by topically applied alpha-tocopherol." Carcinogenesis 18(8): 1617–1622.CrossRefPubMedGoogle Scholar
  46. Moodycliffe, A.M., M. Norval, et al. (1993). "Characterization of a monoclonal antibody to cis-urocanic acid: detection of cis-urocanic acid in the serum of irradiated mice by immunoassay." Immunology 79(4): 667–672.PubMedGoogle Scholar
  47. Nocentini, S., M. Guggiari, et al. (2001). "Exacerbating effect of vitamin E supplementation on DNA damage induced in cultured human normal fibroblasts by UVA radiation." Photochem Photobiol 73(4): 370–377.CrossRefPubMedGoogle Scholar
  48. Peng, Y.M., Y.S. Peng, et al. (1993). "Micronutrient concentrations in paired skin and plasma of patients with actinic keratoses: effect of prolonged retinol supplementation." Cancer Epidemiol Biomarkers Prev 2(2): 145–150.PubMedGoogle Scholar
  49. Pentland, A. P., J.W. Schoggins, et al. (1999). "Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition." Carcinogenesis 20(10): 1939–1944.CrossRefPubMedGoogle Scholar
  50. Perchellet, J.P. and E.M. Perchellet (1989). "Antioxidants and multistage carcinogenesis in mouse skin." Free Radic Biol Med 7(4): 377–408.CrossRefPubMedGoogle Scholar
  51. Podda, M. and M. Grundmann-Kollmann (2001). "Low molecular weight antioxidants and their role in skin ageing." Clin Exp Dermatol 26(7): 578–582.CrossRefPubMedGoogle Scholar
  52. Podda, M., M. Rallis, et al. (1996). "Kinetic study of cutaneous and subcutaneous distribution following topical application of [7,8-14C]rac-alpha-lipoic acid onto hairless mice." Biochem Pharmacol 52(4): 627–633.CrossRefPubMedGoogle Scholar
  53. Potts, R.O. and R. Guy (1993). The prediction of precutaneous penetration, a mechanistic model. Dermal and Transdermal Drug Delivery. R. Gurny and A. Teubner, Wiss Verlagsges. 153–160.Google Scholar
  54. Prinz-Langenohl, R., I. Fohr, et al. (2001). "Beneficial role for folate in the prevention of colorectal and breast cancer." Eur J Nutr 40(3): 98–105.PubMedGoogle Scholar
  55. Reeve, V.E., M. Bosnic, et al. (1998). "Ultraviolet A radiation (320–400 nm) protects hairless mice from immunosuppression induced by ultraviolet B radiation (280–320 nm) or cis-urocanic acid." Int Arch Allergy Immunol 115(4): 316–322.CrossRefPubMedGoogle Scholar
  56. Roberts, M.J., G.T. Wondrak, et al. (2003). "DNA damage by carbonyl stress in human skin cells." Mutat Res 522(1–2): 45–56.PubMedGoogle Scholar
  57. Roberts, M.S., R.A. Anderson, et al. (1978). "The percutaneous absorption of phenolic compounds: the mechanism of diffusion across the stratum corneum." J Pharm Pharmacol 30(8): 486–490.PubMedGoogle Scholar
  58. Rolli, V., R. Armin, et al. (2000). Poly(ADP-ribose) polymerase: structure and function. Poly ADP-ribosylation reactions: From DNA damage and stress signalling to cell death. G.d.M.a.S. Shall. Oxford, Oxford University Press. 35–67.Google Scholar
  59. Shindo, Y., E. Witt, et al. (1994). "Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin." J Invest Dermatol 102(1): 122–124.CrossRefPubMedGoogle Scholar
  60. Shreedhar, V., T. Giese, et al. (1998). "A cytokine cascade including prostaglandin E2, IL-4, and IL-10 is responsible for UV-induced systemic immune suppression." J Immunol 160(8): 3783–3789.PubMedGoogle Scholar
  61. Smart, R.C. and C. L. Crawford (1991). "Effect of ascorbic acid and its synthetic lipophilic derivative ascorbyl palmitate on phorbol ester-induced skin-tumor promotion in mice." Am J Clin Nutr 54(6 Suppl): 1266S–1273S.PubMedGoogle Scholar
  62. Strickland, F.M. (2001). "Immune regulation by polysaccharides: implications for skin cancer." J Photochem Photobiol B 63(1–3): 132–410.CrossRefPubMedGoogle Scholar
  63. Sugibayashi, K., T. Hayashi, et al. (1999). "Simultaneous transport and metabolism of ethyl nicotinate in hairless rat skin after its topical application: the effect of enzyme distribution in skin." J Control Release 62(1–2): 201–218.CrossRefPubMedGoogle Scholar
  64. Thuillier, P., G.J. Anchiraico, et al. (2000). "Activators of peroxisome proliferator-activated receptor-alpha partially inhibit mouse skin tumor promotion." Mol Carcinog 29(3): 134–142.CrossRefPubMedGoogle Scholar
  65. Tomasetti, M., G. P. Littarru, et al. (1999). "Coenzyme Q10 enrichment decreases oxidative DNA damage in human lymphocytes." Free Radic Biol Med 27(9–10): 1027–1032.CrossRefPubMedGoogle Scholar
  66. Tsai, R.S., N.E. Tayar, et al. (1992). "Physicochemical properties and transport behavior of piridil: considerations on its membrane-crossing potential." Int J Pharm 80: 39–49.CrossRefGoogle Scholar
  67. Ullrich, S. E. (2002). "Photoimmune suppression and photocarcinogenesis." Front Biosci 7: D684–703.PubMedGoogle Scholar
  68. Webber, H., K. Meyer-Trumpener, et al. (1994). "Ester des Naproxens als potentielle prodrugs zur Hautpenetration." Arch Pharm 327: 337–345.Google Scholar
  69. Wondrak, G.T., D. Cervantes-Laurean, et al. (2002). "Identification of alpha-dicarbonyl scavengers for cellular protection against carbonyl stress." Biochem Pharmacol 63(3): 361–373.CrossRefPubMedGoogle Scholar
  70. Wondrak, G.T., E. L. Jacobson, et al. (2002). "Photosensitization of DNA damage by glycated proteins." Photochem Photobiol Sci 1(5): 355–363.CrossRefPubMedGoogle Scholar
  71. Wondrak, G.T., M.J. Roberts, et al. (2003). "Proteins of the extracellular matrix are sensitizers of photo-oxidative stress in human skin cells." J Invest Dermatol 121(3): 578–586.CrossRefPubMedGoogle Scholar
  72. Wondrak, G.T., M.J. Roberts, et al. (2002). "Photosensitized growth inhibition of cultured human skin cells: mechanism and suppression of oxidative stress from solar irradiation of glycated proteins." J Invest Dermatol 119(2): 489–498.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2005

Authors and Affiliations

  • Elaine L. Jacobson
    • 1
  • Hyuntae Kim
    • 1
  • Moonsun Kim
    • 1
  • Georg T. Wondrak
    • 1
  • Myron K. Jacobson
    • 1
  1. 1.College of Pharmacy and Arizona Cancer CenterUniversity of ArizonaTucson

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