Basal cell carcinoma chemoprevention with nonsteroidal anti-inflammatory drugs in genetically predisposed PTCH1+/- humans and mice.
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.
Tang
Jean Y
JY
The Children's Hospital of Oakland Research Institute, CA 94609, USA.
Aszterbaum
Michelle
M
Athar
Mohammad
M
Barsanti
Franco
F
Cappola
Carol
C
Estevez
Nini
N
Hebert
Jennifer
J
Hwang
Jimmy
J
Khaimskiy
Yefim
Y
Kim
Arianna
A
Lu
Ying
Y
So
Po-Lin
PL
Tang
Xiuwei
X
Kohn
Michael A
MA
McCulloch
Charles E
CE
Kopelovich
Levy
L
Bickers
David R
DR
Epstein
Ervin H
EH
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*
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