Evaluation of tamoxifen and metabolites by LC-MS/MS and HPLC methods.

Epidemiological and laboratory evidence suggests that quantification of serum or plasma levels of tamoxifen and its metabolites, 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), Z-4-hydroxytamoxifen (4HT), N-desmethyl-tamoxifen (ND-tam), is a clinically useful tool in the assessment and monitoring of breast cancer status in patients taking adjuvant tamoxifen. A liquid chromatographic mass spectrometric method (LC-MS/MS) was used to measure the blood levels of tamoxifen and its metabolites. This fully automated analytical method is specific, accurate and sensitive. The LC-MS/MS automated technique has now become a widely accepted reference method. This study analysed a randomly selected batch of blood samples from participants enrolled in a breast cancer study to compare results from this reference method in 40 samples with those obtained from a recently developed high-performance liquid chromatography (HPLC) method with fluorescence detection. The mean (SD) concentrations for the LC-MS/MS method (endoxifen 12.6 [7.5] ng/mL, tamoxifen 105 [44] ng/mL, 4-HT 1.9 [1.0] ng/mL, ND-tam 181 [69] ng/mL) and the HPLC method (endoxifen 13.1 [7.8] ng/mL, tamoxifen 108 [55] ng/mL, 4-HT 1.8 [0.8] ng/mL, ND-tam 184 [81] ng/mL) did not show any significant differences. The results confirm that the HPLC method offers an accurate and comparable alternative for the quantification of tamoxifen and tamoxifen metabolites.

Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas.

BACKGROUND: The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial. METHODS: Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75-100%) vs the lower three quartiles (0-25, 25-50 and 50-75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation. RESULTS: A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1-3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08-0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53-4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates. CONCLUSION: These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled.

Validating stage of change measures for physical activity and dietary behaviors for overweight women.

OBJECTIVE: To investigate the construct, concurrent and predictive validity of stage of change measures for physical activity (PA), and intakes of fruit and vegetables (FVs), dietary fiber (FB) and dietary fat (DF) among a sample of overweight women. DESIGN: Subjects were 401 women (mean age=41, s.d.=8.7 years; mean body mass index=32.35, s.d.=4.6) recruited to participate in a 12-month weight loss intervention trial. Concurrent validity tests included (1) self-report of current behavior, (2) decisional balance (for example, pros and cons of behavior change), (3) self-efficacy, (4) the MTI Actigraph accelerometer (for the PA staging measure), and (5) a food-frequency questionnaire (for all dietary staging measures). Predictive validity was assessed through tests of the relationship between the baseline stage of change measures and their corresponding behavior 1-year later. RESULTS: Coefficient alpha-tests of internal consistency exceeded 0.70 on the majority of scales. Concurrent validity tests indicated strong validity evidence for three staging measures and little validity for the DF staging measure (eta(2) range, 0.02-0.18). All staging algorithms demonstrated predictive validity (eta(2) range, 0.04-0.126). CONCLUSION: Staging measures can determine motivational readiness for overweight women, contribute to the standardization of stage of change assessment and facilitate cross-study comparisons.

Insulin Resistance Improves More in Women than In Men in Association with a Weight Loss Intervention.

BACKGROUND: Fasting glucose and homeostatic model assessment-insulin resistance (HOMA-IR) are important measures of the risk for metabolic syndrome and diabetes. Weight loss interventions are considered part of the first line of therapy for those who develop disease states associated with insulin resistance, such as pre-diabetes, diabetes, or metabolic syndrome. Sex differences in insulin resistance have been extensively reported, but sex differences in the ability to improve insulin sensitivity are not well-established. This study sought to identify factors that predict change in HOMA-IR in response to weight loss. METHODS: Non-diabetic subjects who were overweight/obese (n=100) were randomly assigned to a walnut-enriched reduced-energy diet or a standard reduced-energy-density diet in a 6-month weight loss intervention. There were no significant differences in weight change, glucose, insulin, or HOMA-IR between the two diet groups. These subjects were combined into a single cohort and analyzed with multivariate analysis. RESULTS: The combined groups lost an average of 8.7 kg (p<0.0001), decreased serum glucose by an average 0.2 mmol/L (p<0.001), and decreased HOMA-IR by an average of 1.4 (p<0.0001). Change in HOMA-IR (R2=0.69) was positively associated with weight change (p<0.0001) and male sex (p<0.01), and negatively associated with baseline HOMA-IR (p<0.0001). CONCLUSION: Findings from this study suggest that men may have a more difficult time improving insulin sensitivity as compared with women with an equivalent weight loss and baseline HOMA-IR. One hypothesis to explain the differences across sexes may be due to sex differences in visceral adipose fat (VAT). This may mean that insulin resistant men require more aggressive intervention than women to prevent progression to metabolic syndrome or diabetes.

Factors Associated with Visceral Fat Loss in Response to a Multifaceted Weight Loss Intervention.

BACKGROUND: Visceral adipose tissue is more metabolically active than other fat depots and is more closely associated with obesity-related diseases, such as cardiovascular disease and type 2 diabetes, than indicators of obesity, such as body mass index. Across various strategies to promote weight loss, including energy-reduced diet and exercise, variable effects on VAT compared to loss of total body fat have been reported. METHODS: To examine the effect of a behavioral weight loss intervention using portion-controlled prepackaged entrées on VAT, we examined data and measurements from overweight/obese men and women (N=183) who were assigned to a weight loss intervention and prescribed a reduced-energy diet with either portion-controlled prepackaged entrées or self-selected meals in a randomized clinical trial. VAT was estimated with dual-energy X-ray absorptiometry at baseline and study end (12 weeks). RESULTS: VAT loss was greater for the prepackaged entrees group (p=0.02), with an average loss of 29% compared to an average loss of 19% among participants consuming self-selected meals. VAT (mean [SEM]) was 1651 (71) g and 1546 (157) g at baseline and 1234 (59) g and 1278 (118) g at study end in the prepackaged entrees and self-selected meal groups, respectively. Greater VAT loss was associated with higher baseline weight and VAT, and greater weight loss, but not associated with age or physical activity. CONCLUSION: Prescribing portion-controlled prepackaged entrees in a behavioral weight loss intervention promotes a reduction in VAT, which should promote improved metabolic profile and reduced cardiovascular disease risk.

Suppression of human colorectal mucosal prostaglandins: determining the lowest effective aspirin dose.

BACKGROUND: A variety of studies have supported the finding that regular intake of aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory agents can affect colorectal cancer carcinogenesis. These agents inhibit the synthesis of prostaglandins. High levels of prostaglandins are observed in colon cancer tissues. PURPOSE: Experiments were planned to determine the lowest dose of aspirin that can markedly suppress the levels of mucosal prostaglandins E2 and F(2alpha) in colorectal mucosa and to determine whether a relationship exists between these levels and plasma levels of both acetylsalicylic acid and its metabolite, salicylic acid. METHODS: Healthy men and women aged 18 years or older participated in the study. The participants took a single, daily dose of aspirin (40.5, 81, 162, 324, or 648 mg) or a placebo for 14 days. Colorectal biopsy specimens were taken at baseline, 24 hours after the first dose of aspirin, and 24-30 hours and 72-78 hours after the last, i.e., fourteenth, daily dose of aspirin. The biopsy specimens were assayed for prostaglandins E2 and F(2alpha) by use of a competitive enzyme immunoassay. Plasma concentrations of acetylsalicylic acid and salicylic acid were determined by use of high-performance liquid chromatography. All P values are two-sided. RESULTS: A total of 65 subjects (10 receiving placebo, groups of 10 each receiving 40.5, 81, 162, or 324 mg of aspirin, and a group of 15 receiving 648 mg of aspirin) completed the protocol. One subject reported unacceptable drug-induced toxic effects and did not complete the protocol; other subjects reported acceptable side effects. The lowest dose to significantly suppress colorectal mucosal prostaglandin E2 concentrations from baseline at 24 hours after the first dose (by 22.6%; P = .002) and at 24-30 hours after the last dose (by 14.2%; P = .021) was 162 mg. At 72-78 hours after the last dose, there was significant suppression for subjects receiving 81 mg (by 23.7%; P = .008). The lowest dose to significantly suppress colorectal mucosal prostaglandin F(2alpha) concentrations from baseline at 24 hours after the first dose (by 18.3%; P = .032) was 324 mg. The lowest dose causing a marked reduction in the level of prostaglandin F(2alpha) at 24-30 hours (by 15.1%; P = .003) and 72-78 hours (by 23.0%; P = .0002) after the last dose was 40.5 mg. No detectable amounts of acetylsalicylic acid or salicylic acid were present in the plasma at any of the biopsy time points. CONCLUSIONS: The lowest doses of aspirin taken daily for 14 days to significantly suppress concentrations of colorectal mucosal prostaglandins E2 and F(2alpha) were 81 and 40.5 mg, respectively. The suppression occurred without detectable amounts of aspirin or salicylic acid in the plasma at the time points studied. On the basis of these observations, we recommend a single, daily dose of 81 mg of aspirin in future studies of this drug as a chemopreventive agent for colorectal cancer.

Carotenoids: biology and treatment.

Carotenoids are pigments found in plants and microorganisms, but not synthesized in animals. Fewer than 10% of the carotenoids can function as vitamin A precursors in mammals. Carotenoids and retinoids have chemical and metabolic similarities and differences, and some overlap in biological activities. Carotenoids in tissues reflect food choices. Carotenoids exhibit biological activities as antioxidants, affect cell growth regulation, and modulate gene expression and immune response. Epidemiologic evidence links higher carotenoid intakes and tissue concentrations with reduced cancer and cardiovascular disease risk, although results from clinical trials do not support beta-carotene supplementation as a strategy to reduce risk. Continued research in this area is likely to stimulate better intervention strategies with clinical and public health applications.

Changes in diet, weight, and serum lipid levels associated with olestra consumption.

BACKGROUND: Specially manufactured low-fat and nonfat foods have become increasingly available over the past 2 decades and controversy has surrounded the issue of whether these products have beneficial or adverse effects on the health and nutritional status of Americans. METHODS: This study examines the association of olestra consumption with changes in dietary intakes of energy, fat, and cholesterol and changes in weight and serum lipid concentrations. Data are from a cohort of 335 participants in the Olestra Post-Marketing Surveillance Study sentinel site in Marion County (Indianapolis, Ind). Diet, weight, and serum lipid levels were assessed before the market release of olestra and 1 year later, after olestra-containing foods were widely available. Olestra intake at the 1-year follow-up was categorized as none, low (>0 to 0.4 g/d), moderate (0.4 to 2.0 g/d), and heavy (>2.0 g/d). RESULTS: Participants in the heavy olestra consumption category significantly reduced dietary intake of percentage of energy from fat (2.7 percentage points, P for trend,.003) and saturated fat (1.1 percentage points, P for trend,.02). Consumers in the highest category of olestra consumption had statistically significantly reduced total serum cholesterol levels of -0.54 mmol/L (-21 mg/dL)compared with -0.14 mmol/L (-5 mg/dL) among olestra nonconsumers (P for trend,.03). CONCLUSIONS: These results indicate that introduction of a new fat substitute (olestra) in the US market was associated with healthful changes in dietary fat intake and serum cholesterol concentrations among consumers who chose to consume olestra-containing foods.

Prevention of cervix cancer.

Cervix carcinoma is an important health problem world-wide, being the second most common cancer among women, ranking first in many developing countries. A number of important epidemiological risk factors have been identified as contributing to the development of CIN and invasive cervix carcinoma. Of key importance is infection with human papillomavirus (HPV), which is the primary risk factor. There are evolving primary and secondary preventive strategies that could further reduce the burden from cervical carcinoma. The possible primary preventive strategies include risk reduction, diet or dietary supplements, HPV vaccines, and other chemopreventive agents. The possible advances in secondary preventive strategies include new technologies for Pap smears, HPV typing triage, and other adjuvant screening procedures. The impact of these strategies will depend upon evidence to support their use along with the characteristics of the population and environment in which they are used.

Plasma beta-carotene response in humans after meals supplemented with dietary pectin.

The purpose of this study was to determine the effect of pectin on plasma response to beta-carotene in humans. Using a crossover design, we evaluated the effect on plasma beta-carotene in seven subjects when 12 g citrus pectin was added to a 2092 kJ (500 kcal) controlled meal with 25 mg beta-carotene. Plasma samples were collected at 0, 8, 30, 48, and 192 h after the meals. Plasma beta-carotene was quantified with the use of HPLC. The increase in plasma beta-carotene concentration was significantly reduced by pectin at 30 and 192 h (paired t test; P less than 0.005 and less than 0.05, respectively). Mean percent increase in plasma beta-carotene concentration at 30 h after the meal with beta-carotene was reduced by more than one-half when pectin was added to the meal. These results indicate that the inhibitory effect of pectin may provide one explanation for observations of reduced plasma beta-carotene response in humans after the ingestion of carotenoid-rich foods when compared with equivalent doses of beta-carotene supplements.

The influence of genetic taste markers on food acceptance.

Genetically mediated sensitivity to the bitter taste of phenylthiocarbamide (PTC) and 6-n-propylthiouracil (Prop) has long been associated with enhanced sensitivity to other sweet and bitter compounds. New studies suggest that tasters and supertasters of Prop may also differ from notasters in their taste preferences and in their patterns of food rejection and food acceptance. One question is whether the acceptability of bitter-tasting vegetables is influenced by Prop taster status. Cruciferous vegetables are among the major dietary sources of potentially chemoprotective agents in cancer control, and their consumption is reported to alter cancer risk. Strategies aimed at dietary change in individuals or groups should consider the role of genetic taste markers and their potential influences on food preferences and dietary habits.

Nutritional characteristics, eating pathology, and hormonal status in young women.

Ovulatory dysfunction is common in patients with eating disorders. However, many women engage in pathologic dieting behaviors without meeting the current diagnostic criteria for anorexia or bulimia nervosa. Clinical eating disorders are only the most extreme form of pathologic eating attitudes and behaviors that are present in many young women. Specific food choices and nutrient intakes may be associated with altered gonadal hormone status of these dieters. This cross-sectional study was conducted to describe the nutritional characteristics of college-aged women defined by their eating attitudes and behaviors with a previously described questionnaire. We evaluated dietary intake, body composition, and selected biochemical indicators in 76 undergraduate women. Serum concentrations of estradiol, progesterone, lipids, and carotenoids were measured on days 6, 21, and 28 of one menstrual cycle. Dietary assessment was based on food records at two 3-d intervals during the cycle. Ovulatory status was definitively determined on the basis of biochemical data for 46 of the women. Increased degree of pathologic dieting was associated with a significantly lower intake of dietary fat (P < 0.02), despite similar mean body mass index and body composition across the eating pathology groups. Serum concentration of alpha-carotene was significantly greater (P < 0.005) in association with a greater degree of eating pathology. With ovulation as a between-group factor, serum lutein concentration and dietary intake of energy and fat differed significantly between groups (P < 0.003). Nutritional characteristics associated with pathologic dieting behavior may also be associated with menstrual irregularities in young women.

Validation of the Healthy Eating Index with use of plasma biomarkers in a clinical sample of women.

BACKGROUND: The Healthy Eating Index (HEI) is a 100-point analytic scoring tool used to measure compliance with dietary recommendations and guidelines. OBJECTIVE: The objective was to calculate HEI scores for a sample of women and to link the HEI scores to plasma biomarkers of dietary exposure. DESIGN: Respondents were 340 women aged 21-80 y who were enrolled in a case-control study of diet and breast cancer. The sample included 172 patients with newly diagnosed cancer (case subjects), 149 cancer-free control subjects, and 19 women at high risk of breast cancer. Dietary intake assessment was based on 3-d food records. HEI scores were calculated for all respondents. Venous blood was collected for measurements of plasma carotenoids, vitamin C, and folate. CONCLUSIONS: Higher HEI scores were associated most strongly with greater dietary variety (r = 0.71), higher intakes of fruit (r = 0.57), and lower intakes of fat and saturated fat. HEI scores were also associated with higher intakes of energy, carbohydrates, fiber, folate, and vitamin C. Higher HEI scores were associated with higher plasma concentrations of alpha-carotene (r = 0.40), beta-carotene (r = 0.28), beta-cryptoxanthin (r = 0.41), lutein (r = 0.23), and vitamin C (r = 0.26) after age and vitamin supplement use were controlled for in a regression model. There was a further association between HEI scores and socioeconomic variables. Women with higher HEI scores were more likely to be older, married, and better educated and to have higher household incomes.

Racial group differences in plasma concentrations of antioxidant vitamins and carotenoids in hemodialysis patients.

Approximately 50% of the mortality in hemodialysis patients is due to cardiovascular disease. Antioxidant vitamins and carotenoids may be protective because oxidation of low-density lipoproteins appears to be a necessary prerequisite for the development of atherogenesis, and hemodialysis itself may stimulate the generation of oxygen reactive species. African Americans comprise a substantial proportion of dialysis patients because they have higher rates of hypertension, glomerulonephritis, and diabetic end-stage renal disease than do whites. The purpose of this cross-sectional study was to determine the plasma concentrations of antioxidant vitamins and carotenoids in hemodialysis patients and to investigate whether differences in these concentrations in the major racial or ethnic groups exist. Plasma concentrations of alpha- and gamma-tocopherol, carotenoids, and retinol were measured with HPLC and plasma vitamin C was measured with a spectrophotometric method in 109 white and African American hemodialysis patients. Dietary intakes of selected micronutrients were also compared by using data from a food-frequency questionnaire. Overall, plasma vitamin C and alpha-tocopherol concentrations were comparable but plasma carotenoid concentrations were lower than those reported for other populations. African American patients had significantly higher mean plasma concentrations of retinol (P < 0.04), lutein (P < 0.02), and total carotenoids minus lycopene (P < 0.04); whites had significantly higher mean plasma concentrations of alpha-tocopherol (P < 0.02), independent of age and plasma lipid concentrations. Diabetes comorbidity had an independent negative association with plasma beta-carotene concentration but was not associated with other measures.

Serum beta-carotene and vitamin C as biomarkers of vegetable and fruit intakes in a community-based sample of French adults.

Relatively high intakes of vegetables and fruit and relatively low intakes of fat are associated with lower rates of heart disease and many types of cancer. Biomarkers for vegetable and fruit consumption are most useful when applicable across different ages, body weights, diets, and varying patterns of fat intake. This study examined two biomarkers, serum concentrations of beta-carotene and vitamin C, as a function of anthropometric, dietary, and lifestyle factors in a community-based sample of French adults. The interview-based dietary-history method was used to assess dietary intakes of 361 males and 476 females aged 18-94 y resident in the Val-de-Marne district southeast of Paris. Serum beta-carotene was quantified by HPLC and vitamin C was measured by using an automated method. Serum beta-carotene and vitamin C concentrations were positively associated with vegetable and fruit intakes and were negatively linked to the consumption of energy, alcohol, and fat. Multiple-regression analyses showed that serum beta-carotene concentration was predicted by fruit and vegetable intakes but was inversely associated with body mass, energy and alcohol intakes, and tobacco use. Serum vitamin C concentration was positively associated with fruit consumption but was negatively associated with age, body mass, and tobacco use. Serum beta-carotene and vitamin C concentrations are useful biomarkers of vegetable and fruit consumption in the French diet. However, other dietary and lifestyle factors also have a significant effect on circulating concentrations of these antioxidant micronutrients.

Carotenoids and menstrual cycle phase in young women.

An association between serum carotenoid concentrations and risk for certain cancers has been observed in epidemiological studies. Determinants of serum carotenoid concentrations are known to include dietary intake, plasma lipid concentrations, and body mass. Menstrual cycle phase, which has not been adequately addressed in previous studies, has been suggested to be a possible additional factor to consider in the interpretation of these values in women. We evaluated hormonal status, serum carotenoids, cholesterol, and triglycerides in 48 healthy women at early follicular, mid-luteal, and late luteal phases of one menstrual cycle. Eating patterns were assessed with diet records at two 3-day intervals during the cycle. Analysis was focused on the 30 subjects who were determined to have ovulated during the menstrual cycle under observation. Serum cholesterol was significantly decreased (P < 0.05) in the late luteal phase of an ovulatory cycle. Lutein concentration was increased in the early follicular phase (P < 0.05) and alpha-carotene was increased in the mid-luteal phase (P < 0.05) only if uncorrected for total cholesterol. Other carotenoids did not vary across the menstrual cycle, whether corrected or uncorrected for total cholesterol concentration. In normal healthy ovulating women, serum carotenoids do not appear to vary with menstrual cycle phase when corrected for serum cholesterol concentrations.

Low-energy reporting in women at risk for breast cancer recurrence. Women's Healthy Eating and Living Group.

This study examined the extent of low-energy reporting and its relationship with demographic and lifestyle factors in women previously treated for breast cancer. This study used data from a large multisite clinical trial testing the efficacy of a dietary intervention to reduce risk for breast cancer recurrence (Women's Healthy Eating and Living Study). Using the Schofield equation to estimate energy needs and four 24-h dietary recalls to estimate energy intakes, we identified women who reported lower than expected energy intakes using criteria developed by G. R. Goldberg et al. (Eur. J. Clin. Nutr., 45: 569-581, 1991). We examined data from 1137 women diagnosed with stage I, stage II, or stage IIIA primary, operable breast cancer. Women were 18-70 years of age at diagnosis and were enrolled in the Women's Healthy Eating and Living Study between August 19, 1995, and April 1, 1998, within 4 years after diagnosis. The Goldberg criteria classified about one-quarter (25.6%) as low-energy reporters (LERs) and 10.8% as very LERs. Women who had a body mass index >30 were almost twice (odds ratio, 1.95) as likely to be LERs. Women with a history of weight gain or weight fluctuations were one and a half times as likely (odds ratio, 1.55) to be LERs as those who were weight stable or weight losers. Age, ethnicity, alcohol intake, supplement use, and exercise level were also related to LER. Characteristics (such as body mass index, age, ethnicity, and weight history) that are associated with low-energy reporting in this group of cancer survivors are similar to those observed in other populations and might affect observed diet and breast cancer associations in epidemiological studies.

Comparison of serum carotenoid responses between women consuming vegetable juice and women consuming raw or cooked vegetables.

The objective of this study was to examine serum concentrations of alpha-carotene, beta-carotene, lutein, lycopene, and beta-cryptoxanthin due to consumption of vegetable juice versus raw or cooked vegetables. Subjects included female breast cancer patients who had undergone surgical resection and who were enrolled in a feasibility study for a trial examining the influence of diet on breast cancer recurrence. A high-vegetable, low-fat diet was the focus of the intervention, and some of the subjects were specifically encouraged to consume vegetable juice. At 12 months, blood samples were collected and analyzed for carotenoid concentrations via high-performance liquid chromatography methodology. Matched analysis and paired t test were conducted on two groups: those who consumed vegetable juice (the juice group) and those who consumed raw or cooked vegetables (no juice group). Serum concentrations of alpha-carotene and lutein were significantly higher in the vegetable juice group than in the raw or cooked vegetable group (P < 0.05 and P = 0.05, respectively). Paired t test analysis did not demonstrate a significant difference in serum values of beta-carotene, lycopene, and beta-cryptoxanthin between subjects consuming juice and those not consuming any juice. These results suggest that alpha-carotene and lutein appear to be more bioavailable in the juice form than in raw or cooked vegetables. Therefore, the food form consumed may contribute to the variability in serum carotenoid response to vegetable and fruit interventions in clinical studies.

Colonic mucosal prostaglandin E2 and cyclooxygenase expression before and after low aspirin doses in subjects at high risk or at normal risk for colorectal cancer.

UNLABELLED: Development of potential cancer chemopreventive drugs involves the systematic evaluation of these drugs in preliminary Phase I and II studies in human beings to identify the optimal drug dose, drug toxicity, and surrogate end point biomarker modulation. OBJECTIVES: We tested the hypothesis that aspirin, at a single, once-daily 81-mg dose, will reduce colonic mucosal concentration of prostaglandin estradiol (E2) in individuals at high risk for colorectal cancer development similar to our prior observations in a young normal-risk population. METHODS: Aspirin was administered at a dose of 81 mg once daily for 28 days in a cohort of 92 matched high-risk and normal-risk colorectal cancer subjects. Prostaglandin E2 and cyclooxygenase expression were assayed from distal sigmoid biopsies from all of the subjects before and after treatment. RESULTS: The mean prostaglandin E2 for normal-risk subjects before aspirin treatment was 11.3 +/- 1.7 pg/microg (mean +/- SE) tissue protein and after aspirin treatment was 4.9 +/- 0.91 pg/microg tissue protein (P < 0.0001). In high-risk subjects, mean pretreatment prostaglandin E2 was 14.4 +/- 1.7 pg/microg tissue protein and after aspirin treatment was 4.7 +/- 0.70 pg/microg tissue protein (P < 0.0001). Aspirin treatment did not alter cyclooxygenase-1 protein expression. CONCLUSIONS: Aspirin treatment at a dose of 81 mg reduces colorectal mucosal prostaglandin E2 concentration after 28 daily doses. Risk for colorectal carcinoma did not modify colorectal mucosal baseline or post-aspirin prostaglandin E2, or cyclooxygenase expression. Colorectal mucosal prostaglandin concentration may be used as a "drug-effect surrogate biomarker," that is, a surrogate to assess sufficient delivery and tissue effect of a chemopreventive agent.