Cytochrome P450 2C9 Variants Influence Response to Celecoxib for Prevention of Colorectal Adenoma

Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Gastroenterology (Impact Factor: 16.72). 03/2009; 136(7):2127-2136.e1. DOI: 10.1053/j.gastro.2009.02.045
Source: PubMed


Variants in the cytochrome P450 2C9 (CYP2C9) gene are associated with impaired metabolism of celecoxib. We examined the influence of CYP2C9*2 (R144C) and CYP2C9*3 (I359L) variants on dose-related response or toxicity in a randomized trial of celecoxib.
We identified individuals with CYP2C9*2 and CYP2C9*3 genotypes (>or=1 variant allele) in the Adenoma Prevention with Celecoxib trial. Following adenoma removal, patients were assigned randomly to groups given placebo or low-dose (200 mg twice daily) or high-dose (400 mg twice daily) celecoxib and underwent follow-up colonoscopies at 1 and/or 3 years.
Among 1660 patients, 21% were CYP2C9*2, and 12% were CYP2C9*3 genotypes. Overall, celecoxib was associated with a dose-dependent reduction in adenoma, compared with placebo, with relative risks (RR) of 0.65 (95% confidence interval [CI]: 0.56-0.76) for the low-dose and 0.54 (95% CI: 0.46-0.63) for the high-dose groups. However, the additional protective effect of the high dose, compared with the low-dose, was observed only in those with CYP2C9*3 genotypes (RR, 0.51; 95% CI: 0.30-0.87). The high dose, compared with low dose, was not associated with significant risk reduction among those with CYP2C9*2 (RR, 0.83; 95% CI: 0.57-1.21) or wild-type (RR, 0.89; 95% CI: 0.72-1.11) genotypes. Compared with placebo, a higher incidence of cardiovascular events was associated with both doses among patients with wild-type genotypes but only with the high dose among patients with variant genotypes.
The greater efficacy of high-dose celecoxib, compared with the low-dose, in preventing colorectal adenoma appears confined to individuals with slow metabolizer (CYP2C9*3) genotypes. Genetic variability influences susceptibility to the potential benefits and hazards of celecoxib.

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    • "For the above-mentioned reasons we decided to undertake the study in a population in which a positive effect of CYP2C9 polymorphism in colorectal cancer risk had already been identified. Because CYP2C9*2 and CYP2C8*3 variant alleles are at linkage disequilibrium (Yasar et al., 2002; Martinez et al., 2005, 2007), it could be expected that the association observed between the CYP2C9 genotypes and colorectal cancer risk (Martinez et al., 2001; Chan et al., 2004, 2009; Cleary et al., 2010; Northwood et al., 2010), could be partly related to the presence of the CYP2C8*3 variant allele. However, the findings obtained in the present study indicate that no major association of the CYP2C8*3 variant allele and colorectal cancer risk is present in the population analyzed. "
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    ABSTRACT: In addition to the known effects on drug metabolism and response, functional polymorphisms of genes coding for xenobiotic-metabolizing enzymes (XME) play a role in cancer. Genes coding for XME act as low-penetrance genes and confer modest but consistent and significant risks for a variety of cancers related to the interaction of environmental and genetic factors. Consistent evidence supports a role for polymorphisms of the cytochrome P450 CYP2C9 gene as a protecting factor for colorectal cancer susceptibility. It has been shown that CYP2C8 and CYP2C9 overlap in substrate specificity. Because CYP2C8 has the common functional polymorphisms rs11572080 and rs10509681 (CYP2C8*3), it could be speculated that part of the findings attributed to CYP2C9 polymorphisms may actually be related to the presence of polymorphisms in the CYP2C8 gene. Nevertheless, little attention has been paid to the role of the CYP2C8 polymorphism in colorectal cancer. We analyzed the influence of the CYP2C8*3 allele in the risk of developing colorectal cancer in genomic DNA from 153 individuals suffering colorectal cancer and from 298 age- and gender-matched control subjects. Our findings do not support any effect of the CYP2C8*3 allele (OR for carriers of functional CYP2C8 alleles = 0.50 (95% CI = 0.16-1.59; p = 0.233). The absence of a relative risk related to CYP2C8*3 did not vary depending on the tumor site. We conclude that the risk of developing colorectal cancer does not seem to be related to the commonest functional genetic variation in the CYP2C8 gene.
    Frontiers in Genetics 12/2012; 3:278. DOI:10.3389/fgene.2012.00278
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    • "This process removes all the liquids (water and organic) at once, thus the nanodroplets of the drug solution convert into nanoparticles of the drug, together with all the non-volatile components of the microemulsion. The celecoxib that is used here as a model for a water-insoluble drug (Fig. 1a), is a specific cyclooxygenase-2 (COX-2) inhibitor that is successfully used for treating arthritis (Detrembleur et al., 2005; Kivitz et al., 2007; Yelland et al., 2007), pain alleviating (Lu et al., 2006), treating familial adenomatous polyposis and preventing colorectal adenocarcinomas (Dannenberg and Subbaramaiah, 2003; Bertagnolli et al., 2006; Auman et al., 2008; Chan et al., 2009). The aqueous solubility of celecoxib is 3–7 ␮g/ml at pH 7 and 40 • C. The absolute bioavailability after oral administration of the solid dosage form of celecoxib in dogs is 22–40% (Paulson et al., 2001). "
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    ABSTRACT: A new composition of a fully water-dilutable microemulsion system stabilized by natural surfactants is presented as a template for preparation of celecoxib nanoparticles. Nanoparticles are obtained as a dry powder upon rapid conversion of microemulsion droplets with dissolved celecoxib into nanoparticles, followed by evaporation of all the liquid in a spray dryer. The resultant powder is easily re-dispersible in water to form a clear, transparent dispersion. The celecoxib nanoparticles are amorphous and their average size in the dispersion is 17 nm, in agreement with cryo-TEM results and concentration measurements after filtration. As a result of the nanometric size and amorphous state, about 10-fold increase in dissolution of the powder was obtained, compared to that for particulate celecoxib in the presence of surfactants.
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    ABSTRACT: We present an optical molecular imaging approach to measure the efficacy of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on tumor growth rate through its effect on matrix metalloproteinase (MMP) activity. A xenograft model of colorectal cancer was generated in nude mice, which were then randomized to receive celecoxib versus vehicle. MMP activity was measured by an enzyme-activatable optical molecular probe. A novel genetically engineered mouse (GEM) model of colorectal cancer was also used to assess celecoxib's effect on MMP activity, which was measured by quantitative fluorescence colonoscopy. Subcutaneously implanted xenograft tumors were 84% (SD 20.2%) smaller in volume in the treatment group versus the control group. Moreover, treated animals exhibited only a 7.6% (SEM 9%) increase in MMP activity versus 106% (SEM 8%) for untreated animals. There was an apparent linear relationship (r  =  .91) between measured MMP activity and tumor growth rate. Finally, in the GEM model experiment, treated murine tumors remained relatively unchanged in volume and MMP activity; however, untreated tumors grew significantly and showed an increase in MMP activity. This method may provide for the improved identification of patients for whom COX-2 inhibition therapy is indicated by allowing one to balance the patient's cardiovascular risk with the cancer's responsiveness to celecoxib.
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