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Pediatric Advisory Committee Topical Immunosuppressants Inhibit DNA Repair

Pediatric Advisory Committee Topical Immunosuppressants Inhibit DNA Repair. Daniel B. Yarosh, Ph.D. AGI Dermatics Freeport, NY February 15, 2005 Disclaimer. Tacrolimus. Calcineurin Inhibitors Immunosuppressants. Ascomycin (FK506) Family. Cyclosporine A. Pimecrolimus.

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Pediatric Advisory Committee Topical Immunosuppressants Inhibit DNA Repair

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  1. Pediatric Advisory CommitteeTopical Immunosuppressants Inhibit DNA Repair Daniel B. Yarosh, Ph.D. AGI Dermatics Freeport, NY February 15, 2005 Disclaimer

  2. Tacrolimus Calcineurin InhibitorsImmunosuppressants Ascomycin (FK506) Family Cyclosporine A Pimecrolimus Use: Transplant, iv psoriasis Transplant, Topical AD Topical AD Immunophilin: cyclophilin FKBP FKBP Target:calcineurin calcineurincalcineurin

  3. Skin Cancer inOrgan Transplant Patients Immunosuppressive Drugs Cyclosporine ATacrolimus Berg and Otley, JAAD 47:1-17, 2002

  4. Cyclosporine A Inhibits DNA Repair Human KeratinocytesDot-blots for DNA Damage Submitted for publication

  5. Calcineurin Inhibitors Reduce DNA Repair HaCaT Keratinocytes Irradiated with 500 J/m2 UVB Submitted for publication

  6. Calcineurin Inhibitors Reduce ApoptosisProgrammed cell death from excessive DNA damage APOPTOSIS Submitted for publication

  7. Skin Cancer The combination of • Persistent DNA damage • Inhibition of apoptosis are the early steps of skin cancer. Summarized in: Leffell and Brash, Scientific American July 1996, p38

  8. Animal Carcinogenesis Studies • Cyclosporine A strongly linked to carcinogenesisVogt et al., J Invest Dermatol 124:263, 2005 • Topical Tacrolimus accelerated skin carcinogenesis by DMBA Niwa et al., Br J Derm 149:960, 2003 • Photocarcinogenesis: One study was submitted for each NDA of Tacrolimus and Pimecrolimus. Both studies were significantly flawed because the vehicle alone accelerated carcinogenesis.

  9. Human Safety Studies Published safety studies are underpowered to detect changes in skin cancer <1 year duration is too short <100 patients is too few Longer studies are unpublished

  10. Risk in Childhood UV Exposure Cumulative UV exposure is a risk factor for non-melanoma skin cancer, esp. SCC Kricker et al. Int. J. Cancer 60:482, 1995 Childhood UV exposure and the number of painful sunburns before age 15 are risk factors for BCC and melanomaKricker et al. Int. J. Cancer 48:650, 1991 Vlajinac et al. Acta Oncologica 39:1, 2000 Jema et al., JNCI 92:811, 2000

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