title: Clinical development of leukocyte cyclooxygenase 2 activity as a systemic biomarker for cancer chemopreventive agents.
abstract: Advancement of cancer prevention and therapy requires clinical development of systemic biomarkers of pharmacological efficacy of the agent under scrutiny. Curcumin, a polyphenol derived from Curcuma spp., has shown wide-ranging chemopreventive activity in preclinical carcinogenic models, in which it inhibits cyclooxygenase (COX)-2 at the transcriptional level. COX-2 has been implicated in the development of many human cancers. To explore the inhibition of COX-2 activity as a systemic biomarker of drug efficacy, a biomarker of potential use in clinical trials of many chemopreventive drugs known to inhibit this enzyme, we measured COX-2 protein induction and prostaglandin E(2) (PGE(2)) production in human blood after incubation with lipopolysaccharide (LPS). When 1 microM curcumin was added in vitro to blood from healthy volunteers, LPS-induced COX-2 protein levels and concomitant PGE(2) production were reduced by 24% and 41%, respectively (P < 0.05 by ANOVA). To test whether effects on COX-2 activity could also be measured after oral dosing in humans, we conducted a dose-escalation pilot study of a standardized formulation of Curcuma extract in 15 patients with advanced colorectal cancer. Basal and LPS-mediated PGE(2) production was measured in blood, twice pretreatment and on days 1, 2, 8, and 29 of treatment. Analysis of basal and LPS-induced PGE(2) production during treatment demonstrated a trend toward dose-dependent inhibition (P < 0.005 by regression analysis), but there was no significant difference compared with values from pretreatment time points. Measurement of leukocyte COX-2 activity should be considered in clinical trials of other agents likely to inhibit this isozyme.
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: S M
authors.initials: SM
authors.lastname: Plummer
authors.forename: K A
authors.initials: KA
authors.lastname: Hill
authors.forename: M F
authors.initials: MF
authors.lastname: Festing
authors.forename: W P
authors.initials: WP
authors.lastname: Steward
authors.forename: A J
authors.initials: AJ
authors.lastname: Gescher
authors.forename: R A
authors.initials: RA
authors.lastname: Sharma
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D018890:Chemoprevention; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D030024:Curcuma; D003474:Curcumin / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects* / Q000378:metabolism*; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins; D010936:Plant Extracts / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000378:metabolism*; D012044:Regression Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007527:Isoenzymes; D008565:Membrane Proteins; D010936:Plant Extracts; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D003474:Curcumin