Genetic polymorphisms of flavin monooxygenase 3 in sulindac-induced regression of colorectal adenomas in familial adenomatous polyposis.

Sulindac is a nonsteroidal antiinflammatory drug with a chemopreventive effect in patients with familial adenomatous polyposis (FAP). In vivo, the active form of sulindac is sulindac sulfide, which is inactivated by the hepatic microsomal enzyme, flavin monooxygenase 3 (FMO3). In humans, numerous polymorphisms exist in FMO3, which alter enzymatic activity and subsequent substrate metabolism. We recently showed that certain polymorphic forms of FMO3 with reduced activity were associated with a more favorable response to sulindac in preventing the formation of adenomas in patients with FAP without polyps at baseline. Here, we determined whether these FMO3 polymorphisms correlated with the ability of sulindac to regress polyposis in patients with FAP who had polyps prior to treatment. Nineteen patients were treated with 150 mg sulindac twice a day for 6 months. The size and number of polyps in each patient was assessed at baseline (prior to the administration of sulindac), and at 3 and 6 months. Genotyping was done on seven established FMO3 polymorphisms with functional significance-M66I, E158K, P153L, V257M, E305X, E308G, and R492W. Statistical analyses were done with Wilcoxon rank sum test. Of the loci examined, only E158K and E308G showed polymorphic changes. Six patients exhibited polymorphisms in both E158K and E308G loci and were designated as genotype combination 1. The remaining patients were designated as genotype combination 2. Over the course of treatment, patients with genotype combination 1 had a greater reduction in both the size and number of polyps than those with genotype combination 2. These results suggest that combined polymorphic changes in the E158K and E308G alleles may protect against polyposis in patients with FAP treated with sulindac.

Genetic polymorphisms of human flavin monooxygenase 3 in sulindac-mediated primary chemoprevention of familial adenomatous polyposis.

PURPOSE: Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) effective in regressing adenomas in patients with familial adenomatous polyposis (FAP). However, a recent randomized trial showed that sulindac, when compared with placebo, failed to prevent the development of adenomatous polyps in genotypically positive but phenotypically negative FAP patients. The present study determined whether polymorphisms in the gene encoding flavin monooxygenase 3 (FMO3), a hepatic microsomal enzyme that inactivates sulindac, played a role in determining the efficacy of sulindac in preventing polyposis in this cohort of FAP patients. EXPERIMENTAL DESIGN: Genotyping was performed on seven established FMO3 polymorphisms previously shown to have functional relevance-M66I, P153L, E158K, V257M, E305X, E308G, and R492W-in 21 and 20 FAP patients, who received sulindac and placebo, respectively. RESULTS: None of the 41 patients exhibited heterozygous or homozygous M66I and R492W variant alleles, or homozygous P153L, V257M, and E305X variant alleles. Among sulindac-treated patients who did not develop adenomas ("responders"), 4 (33%) were homozygous for E158K and 2 (17%) were homozygous for E308G variant alleles. In contrast, none of the patients on sulindac who developed adenomas ("nonresponders") exhibited homozygosity for either of the two variant alleles. In addition, polymorphisms in the E158K or E308G allele were associated with a significant reduction in mucosal prostanoid levels in patients treated with sulindac. CONCLUSIONS: Polymorphisms in FMO3, particularly at the E158K and E308G loci, may reduce activity in catabolizing sulindac and result in an increased efficacy to prevent polyposis in FAP.

HIV/AIDS and Colorectal Cancer: A Review in the Era of Antiretrovirals.

Since the discovery of HIV/AIDS and the introduction of antiretroviral therapy, there have been many observations regarding the causes of HIV/AIDS deaths, opportunistic infections, and coexisting diseases such as non-AIDS-defining malignancies. The bulk of the literature worldwide has been epidemiologic and has involved cross-linkage of both HIV/AIDS and cancer registries. Prior retrospective studies have also utilized death certificates. Initial large-scale studies have not identified an increased risk of colon cancer in the HIV/AIDS population, and scrutiny of the literature has elucidated major limitations, most notably the lack of screening data. Only recently have there been studies addressing the rate of colon cancer screening in the HIV/AIDS population. There have also been reports suggesting an elevated risk and earlier age of onset of colonic neoplasia in the HIV/AIDS population. This review summarizes literature from the last two decades regarding HIV/AIDS and colorectal cancer and endeavors to stimulate interest in further investigation of a possible association.

Pharmacogenetics and diseases of the colon.

PURPOSE OF REVIEW: The deciphering of the human genome sequence has enabled the identification of genetic polymorphisms that are responsible for inter-individual variation in the response to drug therapy. This field is referred to as pharmacogenetics. We review the impact of pharmacogenetics on therapy in diseases of the colon using three common variant enzyme systems as examples. RECENT FINDINGS: Many enzyme systems impact the treatment of diseases of the colon. Examples include thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase and flavin monooxygenase 3. They affect the management of inflammatory bowel disease, colorectal cancer and the chemoprevention of colorectal adenoma by influencing the metabolism of their respective substrates, azathioprine/6-mercaptopurine, 5-fluorouracil and sulindac. Recent studies have implicated the significance of genetic polymorphisms in each of the three drug-metabolizing enzymes, which impacts on the therapeutic outcome of the stated diseases. These studies highlight the potential role of pharmacogenetics in the design of a therapeutic plan which would increase efficacy and limit toxicity. SUMMARY: Pharmacogenetics of drug-metabolizing systems continues to gain significance in the drug therapy of a variety of disease states including those of the gastrointestinal tract.