1: Cancer Epidemiol Biomarkers Prev. 2001 Dec;10(12):1295-9.Clinical development of leukocyte cyclooxygenase 2 activity as a systemicbiomarker for cancer chemopreventive agents.Plummer SM, Hill KA, Festing MF, Steward WP, Gescher AJ, Sharma RA.MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom. Advancement of cancer prevention and therapy requires clinical development ofsystemic biomarkers of pharmacological efficacy of the agent under scrutiny.Curcumin, a polyphenol derived from Curcuma spp., has shown wide-rangingchemopreventive activity in preclinical carcinogenic models, in which it inhibitscyclooxygenase (COX)-2 at the transcriptional level. COX-2 has been implicated inthe development of many human cancers. To explore the inhibition of COX-2activity as a systemic biomarker of drug efficacy, a biomarker of potential usein clinical trials of many chemopreventive drugs known to inhibit this enzyme, we measured COX-2 protein induction and prostaglandin E(2) (PGE(2)) production inhuman blood after incubation with lipopolysaccharide (LPS). When 1 microMcurcumin was added in vitro to blood from healthy volunteers, LPS-induced COX-2protein 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 couldalso be measured after oral dosing in humans, we conducted a dose-escalationpilot study of a standardized formulation of Curcuma extract in 15 patients withadvanced colorectal cancer. Basal and LPS-mediated PGE(2) production was measuredin blood, twice pretreatment and on days 1, 2, 8, and 29 of treatment. Analysisof basal and LPS-induced PGE(2) production during treatment demonstrated a trendtoward 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 trialsof other agents likely to inhibit this isozyme.Publication Types:Clinical TrialResearch Support, Non-U.S. Gov'tPMID: 11751448 [PubMed - indexed for MEDLINE]2: Anticancer Res. 2001 Jul-Aug;21(4B):2895-900.Phase I clinical trial of curcumin, a chemopreventive agent, in patients withhigh-risk or pre-malignant lesions.Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR,Ming-Shiang W, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH,Wang YJ, Tsai CC, Hsieh CY.Department of Internal Medicine, National Taiwan University College of Medicine,Taipei. andrew@ha.mc.ntu.edu.twCurcumin (diferuloylmethane), a yellow substance from the root of the plantCurcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murineskin, stomach, intestine and liver. However, the toxicology, pharmacokinetics andbiologically effective dose of curcumin in humans have not been reported. Thisprospective phase-I study evaluated these issues of curcumin in patients with oneof the following five high-risk conditions: 1) recently resected urinary bladdercancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervicalintraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasiaof the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesionsites was done immediately before and 3 months after starting curcumin treament.The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in atleast 3 successive patients, the dose was then escalated to another level in theorder of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of
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