ascorbic-acid and Adenomatous-Polyposis-Coli

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). Prophylactic colectomy, usually by age 40, is the gold-standard therapy to mitigate this risk. However, colectomy is associated with morbidity and fails to prevent extra-colonic disease manifestations, including gastric polyposis, duodenal polyposis and cancer, thyroid cancer, and desmoid disease. Substantial research has investigated chemoprevention medications in an aim to prevent disease progression, postponing the need for colectomy and temporizing the development of extracolonic disease. An ideal chemoprevention agent should have a biologically plausible mechanism of action, be safe and easily tolerated over a prolonged treatment period, and produce a durable and clinically meaningful effect. To date, no chemoprevention agent tested has fulfilled these criteria. New agents targeting novel pathways in FAP are needed. Substantial preclinical literature exists linking the molecular target of rapamycin (mTOR) pathway to FAP. A single case report of rapamycin, an mTOR inhibitor, used as chemoprevention in FAP patients exists, but no formal clinical studies have been conducted. Here, we review the prior literature on chemoprevention in FAP, discuss the rationale for rapamycin in FAP, and outline a proposed clinical trial testing rapamycin as a chemoprevention agent in patients with FAP.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antibiotics, Antineoplastic; Ascorbic Acid; Aspirin; Capsules; Celecoxib; Chemoprevention; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Therapy, Combination; Eflornithine; Erlotinib Hydrochloride; Fatty Acids, Nonesterified; Genes, APC; Humans; Sirolimus; Sulindac; TOR Serine-Threonine Kinases; Vitamins

Longitudinal studies are often concerned with estimating the recurrence rate of a non-fatal event. In many cases, only the total number of events occurring during successive time intervals is known. We compared a mixed Poisson-gamma regression method proposed by Thall and a quasi-likelihood method proposed by Zeger and Liang for the analysis of such data, in the case where the mean was correctly specified, using simulation techniques with large samples. Both methods produced similar standard errors in most situations, except in the case of time-dependent covariates with non-Poisson-gamma data where they were seriously underestimated by the Thall method. A simple method for discriminating between the variance forms of the two methods is described. The findings are applied to the analyses of clinical trials of non-melanoma skin cancer and familial polyposis. This study extends the findings of Breslow concerning variance misspecification in overdispersed Poisson and quasi-likelihood models to the longitudinal setting.

Topics: Adenomatous Polyposis Coli; Adjuvants, Immunologic; Ascorbic Acid; beta Carotene; Carotenoids; Combined Modality Therapy; Data Interpretation, Statistical; Dietary Fiber; Double-Blind Method; Female; Humans; Likelihood Functions; Longitudinal Studies; Male; Models, Statistical; Morbidity; Poisson Distribution; Risk Factors; Skin Neoplasms; Vitamin E

Over a 4-year period in a chemoprevention trial on large bowel neoplasia, 58 patients with familial adenomatous polyposis were treated with 4 g of ascorbic acid (vitamin C)/day plus 400 mg of alpha-tocopherol (vitamin E)/day alone or with a grain fiber supplement (22.5 g/day). In this randomized, double-blind, placebo-controlled study, we determined the effects of these supplements on rectal polyps in these patients. Analysis by intent to treat suggested that the high-fiber supplement had a limited effect. Analysis adjusted for patient compliance showed a stronger benefit from the high-fiber supplement during the middle 2 years of the trial. The results provide evidence for inhibition of benign large bowel neoplasia by grain fiber supplements in excess of 11 g/day in this study population. The findings are consistent with the hypothesis that dietary grain fiber and total dietary fat act as competing variables in the genesis of large bowel neoplasia.

Topics: Adenomatous Polyposis Coli; Adult; Ascorbic Acid; Clinical Trials as Topic; Diet; Dietary Fiber; Double-Blind Method; Humans; Patient Compliance; Placebos; Polyps; Random Allocation; Rectal Diseases; Triticum; Vitamin E

A high level of compliance with an assigned treatment regimen is fundamental to accurate assessment of treatment effectiveness in any clinical trial. If compliance is poor, an effective treatment may be confounded by inadequate delivery of the regimen. Although much research has focused on broad aspects of compliance dealing with clinical therapeutic situations, there was a need for further research dealing specifically with adherence issues in a long-term chemoprevention trial since subject motivation in the latter is likely to differ from that of the former. Examining subject-reported compliance over the first 2-year treatment periods of a long-term chemoprevention trial for familial adenomatous polyposis, it was found that (1) compliance decreased over time, (2) fiber compliance was lower than vitamin compliance, and (3) four explanatory variables which may be amenable to individualized study-team interventions emerged as useful prognosticators of fiber compliance.

Topics: Activities of Daily Living; Adenomatous Polyposis Coli; Ascorbic Acid; Attitude to Health; Clinical Protocols; Clinical Trials as Topic; Diet; Dietary Fiber; Double-Blind Method; Edible Grain; Female; Habits; Humans; Life Style; Male; Patient Compliance; Social Adjustment; Triticum; Vitamin E

Taste perception may influence dietary preferences and nutrient intakes contributing to diet-related disease susceptibility. This study examined bitter taste genetics and whether variation in the TAS2R38 gene at three polymorphic loci (A49P, V262A and I296V) could alter dietary and systemic folate levels and dietary vitamin C intake, and whether a nutrigenetic circuit existed that might link bitter taste, folate/antioxidant status and risk for a colonic adenomatous polyp. TAS2R38 diplotype predicted bitter taste (PROP) phenotype (p value <0.00001) and red cell folate status (p=0.0179) consistent with the diplotype that has the broadest range of bitter perception (AVI/PAV) also possessing the highest average red cell folate value. However, TAS2R38 diplotype did not predict dietary intake of methylfolic acid, pteroylmonoglutamic acid or total folic acid. Neither did it predict dietary intake of vitamin C. Despite this, intake of dietary folate predicts red cell folate with analysis pointing to a key nutrient-nutrient interaction between vitamin C intake and systemic folate status. Analysis of 38 patients with an adenomatous polyp and 164 controls showed that individually, dietary nutrient intake, nutrient status and taste diplotype did not influence polyp risk. However, red cell folate status (in individuals below the population median value) did interact with bitter taste diplotype (AVI/PAV) to predict polyp risk (p=0.0145). Furthermore, synthetic folic acid (below median intake) was statistically associated with adenoma occurrence (p=0.0215); individuals with adenomatous polyps had a 1.77× higher intake than controls. Additionally, stepwise regression taking account of all dietary nutrients showed a tight relationship between methylfolic acid (but not pteroylmonoglutamic acid) intake and red cell folate level in those with a low folate status and occurrence of an adenomatous polyp (p=0.0039). These findings point to a role for folate in the pathoaetiology of adenomatous polyps, with the natural and synthetic vitamers not necessarily having the same biological effect.

Topics: Adenomatous Polyposis Coli; Adult; Aged; Aged, 80 and over; Ascorbic Acid; Diet; Erythrocytes; Folic Acid; Folic Acid Deficiency; Genetic Variation; Genotype; Humans; Middle Aged; Polymorphism, Genetic; Receptors, G-Protein-Coupled; Taste Perception

Familial Adenomatous Polyposis (FAP) is a model for the adenoma-carcinoma sequence in several respects. One important area in which FAP serves as a model is chemoprevention. Early prevention trials mainly utilized micronutrients and were largely unsuccessful in preventing or causing regression of adenomas. A new era was ushered in by the recognition that antiarthritic doses of a nonsteroidal anti-inflammatory agent (NSAID), sulindac, could actually induce regression of colorectal adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal adenomas, but sulindac appears to lack significant benefit in regressing duodenal adenomas or preventing initial occurrence of adenomas in APC mutation carriers. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some duodenal activity as well. Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of NSAID research in chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic adenoma prevention trials. Whether NSAIDs will have a significant future in FAP chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial adenomas, a problem with even greater societal impact. The historical development of chemoprevention in FAP will be presented, with an emphasis on issues of trial design.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Ascorbic Acid; Celecoxib; Chemoprevention; Clinical Trials as Topic; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2 Inhibitors; Drug Therapy, Combination; Eflornithine; Humans; Lactones; Pyrazoles; Sulfonamides; Sulfones; Sulindac; Vitamins

Topics: Adenomatous Polyposis Coli; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; beta Carotene; Bias; Chemoprevention; Colorectal Neoplasms; Humans; Incidence; Randomized Controlled Trials as Topic; Risk; Survival Analysis; Treatment Outcome; Vitamin E

The prooxidant/antioxidant imbalance in familial adenomatous polyposis (FAP) is suggested by (i) the intimate connection between APC and prostaglandin H synthase-2 genes, (ii) the increase of the free radical-generating enzyme xanthine oxidase, and (iii) the decrease of antioxidant defences. In this research work we evaluated lipid peroxidation measuring the thiobarbituric acid (TBA) reactive products and we studied the activities of superoxide dismutase (SOD) and catalase as well as the levels of ascorbate and tocopherols in the peripheral blood cells from a total of 27 FAP patients and 83 normal controls. TBA-reactive products were determined according to a previously published method. SOD and catalase activities were determined by the spectrophotometric monitoring of the inhibition of pyrogallol autoxidation and the hydrogen peroxide decomposition rate, respectively. Ascorbate levels were determined by a modified 2,4-dinitrophenylhydrazine method and tocopherol levels by a modified Emmerie-Engle method. The levels of TBA-reactive products were higher in FAP patients than in normal controls. Although no statistically significant differences in SOD and catalase activities were observed between FAP patients and normal controls, we found that ascorbate and tocopherol levels were significantly lower in FAP patients than in normal controls, as assessed by the Mann-Whitney test. Hence, this finding of an imbalance in the prooxidant/antioxidant status may contribute towards new strategies for prevention and therapy in FAP patients.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Ascorbic Acid; Biomarkers, Tumor; Family Health; Humans; Lipid Peroxidation; Malondialdehyde; Middle Aged; Oxidative Stress; Reactive Oxygen Species; Vitamin E

Topics: Adenomatous Polyposis Coli; Adult; Ascorbic Acid; Duodenum; Female; Humans; Leukocytes; Male; Middle Aged