title: Basal cell carcinoma chemoprevention with nonsteroidal anti-inflammatory drugs in genetically predisposed PTCH1+/- humans and mice.
abstract: In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1(+/-) mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1(+/-)) patients with the basal cell nevus syndrome. In Ptch1(+/-) mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (P(difference) = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1(+/-) mice and had a significant anti-BCC effect in humans with less severe disease.
authors.affiliation: The Children's Hospital of Oakland Research Institute, CA 94609, USA.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
authors.forename: Michelle
authors.initials: M
authors.lastname: Aszterbaum
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.forename: Franco
authors.initials: F
authors.lastname: Barsanti
authors.forename: Carol
authors.initials: C
authors.lastname: Cappola
authors.forename: Nini
authors.initials: N
authors.lastname: Estevez
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hebert
authors.forename: Jimmy
authors.initials: J
authors.lastname: Hwang
authors.forename: Yefim
authors.initials: Y
authors.lastname: Khaimskiy
authors.forename: Arianna
authors.initials: A
authors.lastname: Kim
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: So
authors.forename: Xiuwei
authors.initials: X
authors.lastname: Tang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kohn
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCulloch
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: David R
authors.initials: DR
authors.lastname: Bickers
authors.forename: Ervin H
authors.initials: EH
authors.lastname: Epstein
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001478:Basal Cell Nevus Syndrome / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000517:prevention & control*; D000068579:Celecoxib; D018890:Chemoprevention; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D004311:Double-Blind Method; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011720:Pyrazoles / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics / Q000517:prevention & control*; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011720:Pyrazoles; D011956:Receptors, Cell Surface; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib