title: A pilot surrogate endpoint biomarker study of celecoxib in oral premalignant lesions.
abstract: This study evaluated changes in prostaglandin E(2) (PGE(2)) levels and related biomarkers in oral premalignant lesions (OPL) in response to celecoxib treatment. Twenty-two subjects were enrolled and treated with celecoxib. Pretreatment and 12-week biopsies were done. Subjects whose biopsy showed >or=30% decrease in PGE(2) remained on celecoxib for a total of 12 months when repeat biopsy was done. Biopsies were examined to assess degree of dysplasia, DNA ploidy, and immunohistochemical expression of BCL2, pAKT-Ser473, Ki-67, and CD31 (microvessel density). In 18 paired biopsies available at baseline and 12 weeks, mean normalized PGE(2) levels decreased by 38% (P = 0.002). After 12 months, PGE(2) decreased by 31% (P = 0.340). Twelve biopsies (67%; P = 0.0129) showed improvement in degree of dysplasia after 12 weeks, and 8 of 11 biopsies (73%; P = 0.0703) continued to show an improvement in the degree of dysplasia after 12 months. Trends suggested down-modulation of cyclooxygenase-2 and Ki-67 in some tissues, increased pAKT-Ser473 expression, and an inverse relationship between PGE(2) and BCL2 expression. This study documents the feasibility of measuring potential surrogate endpoint biomarkers of chemopreventive agent response in OPLs. Treatment with celecoxib in subjects with OPLs favorably modulates the primary mediator of cyclooxygenase-2 activity, PGE(2), after 12 weeks.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Wirth
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Krane
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Megan
authors.initials: M
authors.lastname: Othus
authors.forename: Amy E
authors.initials: AE
authors.lastname: Moran
authors.forename: David M
authors.initials: DM
authors.lastname: Dorfman
authors.forename: Charles M
authors.initials: CM
authors.lastname: Norris
authors.forename: Laura
authors.initials: L
authors.lastname: Goguen
authors.forename: Marshall R
authors.initials: MR
authors.lastname: Posner
authors.forename: Robert I
authors.initials: RI
authors.lastname: Haddad
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000517:prevention & control*; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000517:prevention & control*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010865:Pilot Projects; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051058:Oncogene Protein v-akt; D000068579:Celecoxib; D015232:Dinoprostone