ascorbic-acid and Colonic-Neoplasms

Molecular mechanisms and observational studies have found that diet-derived antioxidants are associated with digestive system cancers, whereas there is a lack of causal evidence from randomized clinical trials. In this study, we aimed to assess the causality of these associations through a Mendelian randomization (MR) study. Single nucleotide polymorphisms of diet-derived circulating antioxidants (i.e., α- and γ-tocopherol, ascorbate, retinol, β-carotene, lycopene, and urate), accessed by absolute levels and relative metabolite concentrations, were used as genetic instruments. Summary statistics for digestive system cancers were obtained from the UK Biobank and FinnGen studies. Two-sample MR analyses were performed in each of the two outcome databases, followed by a meta-analysis. The inverse-variance weighted MR was adopted as the primary analysis. Five additional MR methods (likelihood-based MR, MR-Egger, weighted median, penalized weighted median, and MR-PRESSO) and replicate MR analyses for outcomes from different sources were used as sensitivity analyses. Genetically determined antioxidants were not significantly associated with five digestive system cancers, after correcting for multiple tests. However, we found suggestive evidence that absolute ascorbate levels were negatively associated with colon cancer in UK Biobank-the odds ratio (OR) per unit increase in ascorbate was 0.774 (95% confidence interval [CI] 0.608-0.985,

Topics: Antioxidants; Ascorbic Acid; Colonic Neoplasms; Diet; Digestive System Neoplasms; Food; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; United Kingdom; Vitamin A

Given the safety and potential benefits of intravenous ascorbic acid (AA) administration in cancer patients, there is merit in further exploring this therapeutic concept. In this review, we discuss the potential benefits of intravenous AA administration on colorectal cancer and we specifically focus on its effect on glycolysis in mutant and wild type

Topics: Animals; Ascorbic Acid; Colonic Neoplasms; Humans; Mutation; Proto-Oncogene Proteins B-raf; Signal Transduction

In developed countries, colonoscopy volume has increased dramatically over the past 15 years and is the principle method used to screen for colon cancer. Preparations used for colon cleaning have evolved over the past 30 years. Some preparations have been shown to be unsafe and are now used on a limited basis. There has been progress on limiting the volume required and on taste improvement.. This review provides an account of preparations used from 1980 when PEG-based preparations became widely available, until the present day. The review highlights their mechanism of action and principle toxicities. The handling of solutes and solute-free fluid by the colon is also reviewed.. The reader will gain a perspective on the factors considered in developing colonic purgatives and the rationale for choosing selected preparations based on patient factors such as age, co-morbidities and concomitant medications.. Although generally safe and effective, colonic purgatives have both acute and permanent toxicities. The safest preparations utilize PEG combined with a balanced electrolyte solution. Limitations of this preparation center on the volume required and poor taste. Alternative formulations are now available; however, those using sodium phosphate have fallen out of favor due to a risk of renal toxicity.

Topics: Ascorbic Acid; Calcium Phosphates; Cathartics; Citric Acid; Colonic Neoplasms; Colonoscopy; Humans; Hyperphosphatemia; Hypocalcemia; Nephrocalcinosis; Organometallic Compounds; Phosphates; Preoperative Care; Randomized Controlled Trials as Topic; Therapeutic Irrigation

To evaluate the associations between intakes of vitamins A, C, and E and risk of colon cancer.. Using the primary data from 13 cohort studies, we estimated study- and sex-specific relative risks (RR) with Cox proportional hazards models and subsequently pooled RRs using a random effects model.. Among 676,141 men and women, 5,454 colon cancer cases were identified (7-20 years of follow-up across studies). Vitamin A, C, and E intakes from food only were not associated with colon cancer risk. For intakes from food and supplements (total), the pooled multivariate RRs (95% CI) were 0.88 (0.76-1.02, >4,000 vs. ≤ 1,000 μg/day) for vitamin A, 0.81 (0.71-0.92, >600 vs. ≤ 100 mg/day) for vitamin C, and 0.78 (0.66-0.92, > 200 vs. ≤ 6 mg/day) for vitamin E. Adjustment for total folate intake attenuated these associations, but the inverse associations with vitamins C and E remained significant. Multivitamin use was significantly inversely associated with colon cancer risk (RR = 0.88, 95% CI: 0.81-0.96).. Modest inverse associations with vitamin C and E intakes may be due to high correlations with folate intake, which had a similar inverse association with colon cancer. An inverse association with multivitamin use, a major source of folate and other vitamins, deserves further study.

Topics: Ascorbic Acid; Case-Control Studies; Cohort Studies; Colonic Neoplasms; Dietary Supplements; Dose-Response Relationship, Drug; Europe; Female; Folic Acid; Follow-Up Studies; Humans; Incidence; Male; Multivariate Analysis; North America; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; Reproducibility of Results; Risk Assessment; Vitamin A; Vitamin E; Vitamins

Topics: Adult; Aged; Ascorbic Acid; beta Carotene; Breast Neoplasms; Case-Control Studies; Cohort Studies; Colonic Neoplasms; Diet; Dietary Fats; Ethanol; Female; Fruit; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Prospective Studies; Rectal Neoplasms; Risk Factors; Smoking; Stomach Neoplasms; Vegetables; Vitamin E

A literature review was made to critically evaluate the ability of ascorbic acid to modulate the incidence of gastrointestinal cancer. A comparison of preclinical, clinical, and epidemiological studies indicated that evidence for ascorbic acid as an inhibitor of carcinogenesis is stronger with regard to gastric cancer and weaker with regard to esophageal and colon/rectal cancer. Insufficient evidence currently exists regarding the oral cavity and the use of ascorbic acid in precancerous conditions such as polyposis and leukoplakia.

Topics: Animals; Anticarcinogenic Agents; Ascorbic Acid; Colonic Neoplasms; Esophageal Neoplasms; Gastrointestinal Neoplasms; Humans; Rectal Neoplasms; Stomach Neoplasms

A Round Table Discussion was held at the Fourth International Conference on Anticarcinogenesis and Radiation Protection. Scientists from government and academia were brought together to discuss the evidence for the preventive effect of foods, specific nutrients and drugs against cancer, and the most appropriate methods of initiating nutritional cancer prevention activities to improve the health of the public. The panel reviewed the epidemiological evidence of the role of diet and specific micronutrients for the prevention of cancer, the doses of specific micronutrients required for preventive effects and their safety, the evidence for aspirin as a chemopreventive agent, the issue of foods versus specific micronutrients in the prevention of cancer, food safety, and approaches to prevention such as food fortification or dietary supplements. The remarks of the panel members are summarized.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Ascorbic Acid; Aspirin; Colonic Neoplasms; Diet; Food; Food, Fortified; Humans; Neoplasms; Nutritional Physiological Phenomena; Vitamin E

Epidemiologic studies of the relationship of diet to cancer etiology are hampered by methodologic difficulties which can be overcome by careful trial design. The use of appropriate dietary assessment instruments is necessary to minimize bias and improve accuracy of diet assessment. Population studies implicate dietary fat intake in the etiology of colorectal carcinogenesis, and the incidence of colorectal malignancies around the world is positively correlated with meat and fat consumption and total calorie intake. Retrospective studies of fat intake yield equivocal results, whereas prospective studies have failed to show a relationship between fat intake and colon cancer risk. An inverse relationship exists between fiber consumption and colorectal cancer incidence and mortality rates. The positive observational studies are supported by laboratory studies of experimental carcinogenesis which show a greater number of tumors in animals fed high-fat or high-calorie diets. Increased fiber intake appears to offer some protection against colorectal cancer. Plausible mechanisms have been proposed in animals for the role of fat and fiber in colorectal carcinogenesis; the mechanisms in human populations await further description. The interrelationships between fat consumption and consumption of dietary fiber and micronutrients have made it difficult to assess the roles of these substances in the etiology of colorectal cancer. Calcium offers protection in animal systems, and the data in humans are suggestive but not yet conclusive. Data on the role of alcohol in colorectal carcinogenesis remain inconclusive. Little evidence exists for a protective effect of retinoids and carotenoids; the evidence for selenium and vitamin C is limited and evolving.

Topics: Adult; Animals; Ascorbic Acid; Calcium, Dietary; Cholesterol, Dietary; Colonic Neoplasms; Colorectal Neoplasms; Diet; Diet Surveys; Dietary Fats; Dietary Fiber; Energy Intake; Epidemiologic Methods; Ethanol; Female; Humans; Male; Middle Aged; Rats; Risk Factors; Selenium; Vitamin A

Animal tumor experiments and epidemiologic studies suggest that several agents may be of potential value in blocking the development of colon adenomas and carcinoma. Recent laboratory investigations have demonstrated several intermediate markers that are altered in the colonic epithelium of high-risk individuals and that can be modulated by several possible chemopreventive agents. Calcium and ascorbic acid are two agents that have been investigated in preliminary studies. Although the results have not been striking, these studies have pointed up methodologic issues that must be addressed and will contribute greatly to the design of the next generation of trials. Given the advances in the elucidation of the carcinogenic processes in colon cancer, it is reasonable to hope that the next decade of research will discover chemoprevention strategies that will protect individuals from the development of the most common tumor in Western society.

Topics: Adenoma; Ascorbic Acid; Calcium; Colonic Neoplasms; Humans; Research Design

Topics: Animals; Antioxidants; Ascorbic Acid; Colonic Neoplasms; Feces; Nitrosamines; Vitamin E

This review focuses on specific effects of diet on cancer risk and the relevance of these dietary effects to the risk of cancer in the elderly. The authors address the impact of certain dietary factors on cancer risk by reviewing their roles in two distinct phases of carcinogenesis: "imitation" and "promotion."

Topics: Age Factors; Aged; Aged, 80 and over; Animals; Ascorbic Acid; Calcium, Dietary; Carcinogens; Colonic Neoplasms; Diet; Dietary Fats; Dietary Fiber; Female; Food Contamination; Humans; Male; Mice; Neoplasms; Nitrosamines; Nutritional Physiological Phenomena; Rectal Neoplasms

Topics: Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carcinogens; Colonic Neoplasms; Ethoxyquin; Glutathione Transferase; Mammary Neoplasms, Experimental; Methylnitronitrosoguanidine; Neoplasms, Experimental; Phenobarbital; Propyl Gallate; Rats; Rats, Inbred F344; Saccharin; Stomach Neoplasms; Substrate Specificity; Urinary Bladder Neoplasms

Evidence pertaining to the role of dietary factors in carcinogenesis comes from both epidemiological studies and laboratory experiments. In 1982, the Committee on Diet, Nutrition, and Cancer of the National Research Council conducted a comprehensive evaluation of this evidence. That assessment as well as recent epidemiological and laboratory investigations suggest that a high fat diet is associated with increased susceptibility to cancer of different sites, particularly the breast and colon, and to a lesser extent, the prostate. Current data permit no definitive conclusions about other dietary macroconstituents including cholesterol, total caloric intake, protein, carbohydrates and total dietary fiber. Specific components of fiber, however, may have a protective effect against colon cancer. In epidemiological studies, frequent consumption of certain fruits and vegetables, especially citrus fruits and carotene-rich and cruciferous vegetables, is associated with a lower incidence of cancers at various sites. The specific components responsible for these effects are not clearly identified, although the epidemiological evidence appears to be most consistent for a protective effect of carotene on lung cancer and less so for vitamins A and C and various cancer sites. The laboratory evidence is most consistent for vitamin A deficiency and enhanced tumorigenesis, and for the ability of various nonnutritive components in cruciferous vegetables to block in-vivo carcinogenesis. The data for minerals and carcinogenesis are extremely limited, although preliminary evidence from both epidemiological and laboratory studies suggests that selenium may protect against overall cancer risk. Frequent consumption of cured, pickled, or smoked foods, possibly because they may contain nitrosamines or polycyclic aromatic hydrocarbons, appears to increase the risk of esophageal or stomach cancer, however, the specific causative agents in these foods are not clearly identified. Excessive alcohol consumption among smokers appears to be associated with an elevated risk of cancers of the oral cavity, esophagus, larynx, and respiratory tract. The mechanisms of action of dietary factors on carcinogenesis are poorly understood. The NRC committee, and more recently, the National Cancer Institute and the American Cancer Society have proposed interim dietary guidelines to lower the risk of cancer. These guidelines are consistent with general dietary recommendations proposed by U.S. government

Topics: Animals; Ascorbic Acid; Breast Neoplasms; Calcium; Carcinogens; Cholesterol; Colonic Neoplasms; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Fiber; Dietary Proteins; Energy Intake; Environmental Pollutants; Ethanol; Food; Forecasting; Humans; Iron; Minerals; Mutagens; Neoplasms; Nutritional Physiological Phenomena; Research; Retinoids; Risk; Selenium; Vitamin D; Vitamin E; Vitamins; Zinc

Topics: Adenocarcinoma; Animals; Ascorbic Acid; Colonic Neoplasms; Humans; Male; Rats; Rectal Neoplasms

Topics: Alcohol Drinking; Animals; Ascorbic Acid; Cerebrovascular Disorders; Colonic Neoplasms; Diet; Esophageal Neoplasms; Female; Fishes; Food Preservation; Food Preservatives; Humans; Hypertension; Male; Nitrites; Risk; Smoking; Stomach Neoplasms

Topics: Animals; Animals, Laboratory; Ascorbic Acid; Breast Neoplasms; Carcinogens; Colonic Neoplasms; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Female; Humans; Male; Mammary Neoplasms, Experimental; Mice; Neoplasms; Neoplasms, Experimental; Rats; Selenium; Vitamin A

Topics: Ammonia; Animal Nutritional Physiological Phenomena; Animals; Ascorbic Acid; Colonic Neoplasms; Copper; Cricetinae; Dietary Fats; Dietary Fiber; Dietary Proteins; Energy Intake; Female; Humans; Iodine; Lipotropic Agents; Liver Neoplasms; Mammary Neoplasms, Experimental; Mice; Neoplasms; Neoplasms, Experimental; Nutritional Physiological Phenomena; Rats; Riboflavin; Selenium; Skin Neoplasms; Vitamin A; Vitamin B Complex; Zinc

To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC).. Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription.. The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only.. High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Glucosephosphate Dehydrogenase; Humans; Leucovorin; Rectal Neoplasms

Because of its volume, adequate bowel preparation remains problematic in physically unfit patients.. This study aimed to compare a small-volume sodium picosulfate/magnesium citrate preparation with a 2-L ascorbic acid-enriched polyethylene glycol solution plus bisacodyl.. This study has a noninferiority design, assuming that ascorbic acid-enriched polyethylene glycol solution plus bisacodyl is 70% efficacious in achieving an Ottawa score ≤7 and accepting a difference in success rate of <15% with a target enrollment of 146 patients per group.. This study was conducted in an outpatient department.. Patients referred for diagnostic colonoscopy were randomly assigned. Key exclusion criteria were severe kidney disease, ASA class ≥III, and hospital admission.. Patients were randomly assigned to receive sodium picosulfate/magnesium citrate or ascorbic acid-enriched polyethylene glycol solution plus bisacodyl according to a split-dose regimen. Patients in the sodium picosulfate/magnesium citrate group received advice on the recommended 4-L fluid intake. Patients in the ascorbic acid-enriched polyethylene glycol solution plus bisacodyl group received 2 bisacodyl tablets 2 days before and advice on the additionally recommended 2-L fluid intake.. To assess bowel-cleansing adequacy, the Ottawa, Aronchick, and Boston scores were used. Colonoscopy quality measures were obtained. Safety was assessed for a 30-day follow-up period.. Overall, 341 patients (169 men, mean age 57.0 years; BMI 26.2 kg/m) were included. Comorbidities were present in 76.2% of patients, and 75.4% of patients used medication. An adequate Ottawa score was obtained in 81.4% and 75.8% of patients receiving ascorbic acid-enriched polyethylene glycol solution plus bisacodyl and sodium picosulfate/magnesium citrate (difference of 5.6% (95% CI, -3.5 to -14.6; p = 0.023)), showing noninferiority of the sodium picosulfate/magnesium citrate therapy. Ottawa segmental scores were lower for sodium picosulfate/magnesium citrate in the right and transverse colon. In both groups, successful ileocecal intubation was achieved in 95%. No medication-related adverse events were reported.. These results in a physically disabled ambulant population cannot be extrapolated to immobile, hospitalized patients.. Sodium picosulfate/magnesium citrate proved to be noninferior to ascorbic acid-enriched polyethylene glycol solution plus bisacodyl in efficacy and safety. Timing of the colonoscopy and addition of bisacodyl to sodium picosulfate/magnesium citrate warrants further consideration. See Video Abstract at http://links.lww.com/DCR/A461.

Topics: Adult; Aged; Ascorbic Acid; Awareness; Bisacodyl; Cathartics; Citrates; Citric Acid; Colonic Neoplasms; Colonoscopy; Disabled Persons; Dose-Response Relationship, Drug; Drug Combinations; Early Detection of Cancer; Female; Humans; Male; Middle Aged; Organometallic Compounds; Patient Compliance; Picolines; Polyethylene Glycols

BACKGROUND [color=black]Bowel preparation is an important factor for an optimal outcome of colonoscopy. Recently, polyethylene glycol (PEG) solution has been in common use for bowel cleansing for colonoscopy, but some patients are intolerant of PEG because of taste or volume. A low-volume PEG administered with ascorbic acid solution (PEG-Asc) was designed to improve tolerability, but the administration of this method is more complex than that with PEG alone. This study aimed to compare bowel cleansing efficacy, safety, and tolerability of 1 L PEG-Asc with a 2 L PEG preparation with use of sennosides and mosapride.[/color] MATERIAL AND METHODS [color=black]This was a prospective, single-center, non-inferiority trial that included 112 patients (PEG-Asc group, 68; PEG group, 44). The primary endpoint was the efficacy of colon cleansing assessed by endoscopists using a validated 4-point scale according to the Aronchick scale and was verified by a blinded investigator. Acceptability, tolerability, and adenoma detection rate (ADR) of these 2 regimens were secondary endpoints.[/color][color=black] [/color] RESULTS [color=black]We found no statistically significant differences between the groups in colon-cleansing efficacy or in the adenoma detection rate (ADR). Moreover, overall, patients significantly favored PEG-Asc over PEG, reflecting better acceptance of PEG-Asc. Additionally, more patients favored PEG-Asc over PEG for a hypothetical future colonoscopy. [/color] CONCLUSIONS [color=black]The alternate 1 L PEG-Asc regimen and standard 2 L PEG regimen were clinically equivalent with respect to cleansing efficacy, safety, and ADR, and more patients favored PEG-Asc than PEG. This alternate regimen may improve patient compliance and acceptance of surveillance colonoscopy.[/color].

Topics: Adenoma; Adult; Aged; Ascorbic Acid; Benzamides; Colitis, Ulcerative; Colonic Neoplasms; Colonoscopy; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Morpholines; Polyethylene Glycols; Senna Extract; Sennosides; Surveys and Questionnaires; Young Adult

To compare the bowel cleansing efficacy of same day ingestion of 4-L sulfa-free polyethylene glycol (4-L SF-PEG) vs 2-L polyethylene glycol solution with ascorbic acid (2-L PEG + Asc) in patients undergoing afternoon colonoscopy.. 206 patients (mean age 56.7 years, 61% male) undergoing outpatient screening or surveillance colonoscopies were prospectively randomized to receive either 4-L SF-PEG (n = 104) or 2-L PEG + Asc solution (n = 102). Colonoscopies were performed by two blinded endoscopists. Bowel preparation was graded using the Ottawa scale. Each participant completed a satisfaction and side effect survey.. There was no difference in patient demographics amongst groups. 4-L SF-PEG resulted in better Ottawa scores compared to 2-L PEG + Asc, 4.2 vs 4.9 (P = 0.0186); left colon: 1.33 vs 1.57 respectively (P = 0.0224), right colon: 1.38 vs 1.63 respectively (P = 0.0097). No difference in Ottawa scores was found for the mid colon or amount of fluid. Patient satisfaction was similar for both arms but those assigned to 4-L SF-PEG reported less bloating: 23.1% vs 11.5% (P = 0.0235). Overall polyp detection, adenomatous polyp and advanced adenoma detection rates were similar between the two groups.. Morning only 4-L SF-PEG provided superior cleansing with less bloating as compared to 2-L PEG + Asc bowel preparation for afternoon colonoscopy. Thus, future studies evaluating efficacy of morning only preparation for afternoon colonoscopy should use 4-L SF-PEG as the standard comparator.

Topics: Adenoma; Ascorbic Acid; Cathartics; Colonic Neoplasms; Colonic Polyps; Colonoscopy; Drug Administration Schedule; Female; Florida; Humans; Male; Middle Aged; Patient Satisfaction; Polyethylene Glycols; Predictive Value of Tests; Prospective Studies; Single-Blind Method; Surveys and Questionnaires; Therapeutic Irrigation; Time Factors

Low serum cholesterol has been associated with an increased risk of cancer mortality in various studies, which has led to uncertainty regarding the benefit of lower blood cholesterol.. The aim of our study was to evaluate the association between low blood cholesterol (<5.16 mmol/L) and cancer at sites that have rarely been evaluated. We placed special emphasis on the potential confounding effect of antioxidant vitamins.. Plasma concentrations of cholesterol and antioxidant vitamins were measured in 1971-1973 in 2974 men working in Basel, Switzerland. In 1990, the vital status of all participants was assessed.. Two hundred ninety of the participants had died from cancer, 87 from lung, 30 from prostate, 28 from stomach, and 22 from colon cancer. Group means for plasma cholesterol concentrations did not differ significantly between survivors and those who died from cancer at any of the studied sites. With plasma cholesterol, vitamins C and E, retinol, carotene, smoking, and age accounted for in a Cox model, an increase in total cancer mortality in lung, prostate, and colon but not in stomach cancer mortality was observed in men >60 y of age with low plasma cholesterol. When data from the first 2 y of follow-up were excluded from the analysis, the relative risk estimates remained practically unchanged with regard to lung cancer but decreased for colon, prostate, and overall cancer.. Increased cancer mortality risks associated with low plasma cholesterol were not explained by the confounding effect of antioxidant vitamins, but were attributed in part to the effect of preexisting cancer.

Topics: Age Factors; Ascorbic Acid; Cholesterol; Cohort Studies; Colonic Neoplasms; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Prospective Studies; Prostatic Neoplasms; Risk Factors; Smoking; Stomach Neoplasms; Switzerland; Vitamin A; Vitamin E

It has been claimed that high-dose vitamin C is beneficial in the treatment of patients with advanced cancer, especially patients who have had no prior chemotherapy. In a double-blind study 100 patients with advanced colorectal cancer were randomly assigned to treatment with either high-dose vitamin C (10 g daily) or placebo. Overall, these patients were in very good general condition, with minimal symptoms. None had received any previous treatment with cytotoxic drugs. Vitamin C therapy showed no advantage over placebo therapy with regard to either the interval between the beginning of treatment and disease progression or patient survival. Among patients with measurable disease, none had objective improvement. On the basis of this and our previous randomized study, it can be concluded that high-dose vitamin C therapy is not effective against advanced malignant disease regardless of whether the patient has had any prior chemotherapy.

Topics: Aged; Ascorbic Acid; Clinical Trials as Topic; Colonic Neoplasms; Double-Blind Method; Female; Humans; Male; Middle Aged; Patient Compliance; Prospective Studies; Random Allocation; Rectal Neoplasms

Topics: Ascorbic Acid; Clinical Trials as Topic; Colonic Neoplasms; Colonic Polyps; Diet; Dietary Fats; Humans

Cameron and Pauling have reported large survival increases in terminal cancer patients treated with Vitamin C. Their trials, which have been criticised because not based on random, double-blind principles, are reviewed here using a broad inductive method that relies on diverse data of varying quality. Conclusions are offered both on the value of Vitamin C and on this broad method, as follows: There is a strong possibility that Vitamin C very approximately doubled survival time as measured from the start of Vitamin C treatment, regardless of whether this was after termination of conventional treatment or much earlier. A recent Mayo Clinic trial which concluded that Vitamin C is valueless in the terminal stage may be given an alternative interpretation which supports this view. Despite a speculative element because based only on the condensed, published data, these conclusions have sufficient possibility of validity as to call for full further investigation. The conclusions on method are that the broad, inductive approach may have potential value when the randomized method cannot be used; that it also may facilitate, to the public's benefit, the release of probably valuable, inexpensive, non-toxic treatments pending decisive proof; and a greater return on the research dollar might result from a formal acceptance of the probabilistic element in scientific proof.

Topics: Ascorbic Acid; Clinical Trials as Topic; Colonic Neoplasms; Follow-Up Studies; Humans; Models, Biological; Neoplasms; Placebos; Prognosis

The possibility of pharmacological control of large bowel adenomas has been suggested by effectiveness of antioxidants in experimental tumor models and by the results of a limited clinical study using ascorbic acid. Over a two year period we tested this hypothesis in a randomized, double-blind study of 49 patients with polyposis coli. Of 36 patients who were evaluable at completion, 19 had received ascorbic acid, 3 g/day, and 17 had received a placebo. We found a reduction in polyp area in the ascorbic acid-treated group at nine months of follow-up (P less than 0.03) and trends toward reduction in both number and area of rectal polyps during the middle of the trial. A labeling study of rectal epithelium with tritiated thymidine also hinted at a treatment effect. Our data suggest that ascorbic acid temporarily influenced polyp growth or turnover. Although these results have no current therapeutic value, our findings support continued studies of chemoprevention in this and other high risk settings.

Topics: Adult; Ascorbic Acid; Clinical Trials as Topic; Colonic Neoplasms; Diet; Double-Blind Method; Epithelium; Female; Humans; Male; Middle Aged; Polyps; Probability; Random Allocation; Rectal Neoplasms; Time Factors

Some studies have shown anticarcinogenic effects of high dose L-Ascorbic Acid. However, there are controversies around the therapeutic administration of Ascorbic acid as an anticancer medicine.. We conducted a case-control study to investigate the role of pharmacologic concentration of Ascorbic acid on viability and angiogenesis of the human colon cancer (HT29) cell line.. The HT29 cells were cultured in DMEM-HG and treated with 10 mM ascorbic acid for 3h. The culture medium was exchanged, and after incubation at 37 ºC for 24 h, the cells were collected and utilized to evaluate viability, ROS production, gene expression and protein expression levels. The control group consisted of untreated HT29 cells. The viability of the cells was determined using the MTT method. Moreover, Nitro Blue Tetrazolium (NBT) was used to detect the ROS production capacity. The mRNA transcript's level and protein expression were evaluated by Real-time PCR and Western blotting, respectively.. The ascorbic acid-treated group showed a significant increase in ROS production and an obvious reduction in viability compared to the control group. The treated group showed significantly increased levels of both early apoptotic markers (Bax, Cyt C, Caspase3, and Caspase 9) and late apoptotic markers (Caspase 8). Bcl2 expression showed significantly decreased levels relative to the control group. Ascorbic acid therapy substantially reduced the expression of bFGF, bFGFR, PDGF, PDGFR and PLC- γ compared to the control group.. The results confirm that high-dose L-ascorbic acid reduces HT29 cell line viability in vitro.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Ascorbic Acid; Case-Control Studies; Cell Proliferation; Colonic Neoplasms; HT29 Cells; Humans; Reactive Oxygen Species

Recent observational studies and meta-analyses have shown that vitamin C reduces cancer incidence and mortality, but the underlying mechanisms remain unclear. We conducted a comprehensive pan-cancer analysis and biological validation in clinical samples and animal tumor xenografts to understand its prognostic value and association with immune characteristics in various cancers.. We used the Cancer Genome Atlas gene expression data involving 5769 patients and 20 cancer types. Vitamin C index (VCI) was calculated using the expression of 11 genes known to genetically predict vitamin C levels, which were classified into high and low subgroups. The correlation between VCI and patient overall survival (OS), tumor mutational burden (TMB), microsatellite instability (MSI), and immune microenvironment was evaluated, using Kaplan-Meier analysis method and ESTIMATE (https://bioinformatics.mdanderson.org/estimate/). Clinical samples of breast cancer and normal tissues were used to validate the expression of VCI-related genes, and animal experiments were conducted to test the impact of vitamin C on colon cancer growth and immune cell infiltration.. Significant changes in expression of VCI-predicted genes were observed in multiple cancer types, especially in breast cancer. There was a correlation of VCI with prognosis in all samples (adjusted hazard ratio [AHR] = 0.87; 95% confidence interval [CI] = 0.78-0.98;. VCI is significantly correlated with OS and immunotypes in multiple cancers, and vitamin C might have therapeutic potential in colon cancer.

Topics: Animals; Ascorbic Acid; Breast Neoplasms; Carcinoma, Renal Cell; Colonic Neoplasms; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Mice; Rectal Neoplasms; Tumor Microenvironment; Vitamins

Cancers of digestive tract such as colorectal cancer (CRC) and gastric cancer (GC) are the most commonly detected types of cancer worldwide and their origin can be associated with oxidative stress conditions. Commonly known and followed antioxidants, such as vitamin C and E, are widely considered as potential anti-cancer agents. Raman spectra have great potential in the biochemical characterization of matter based on the fact that each molecule has its own unique vibrational properties. Raman spectroscopy allows to precisely characterize components (proteins, lipids, nucleic acids). The paper presents the application of the Raman spectroscopy technique for the analysis of tissue samples and cells of the human colon and stomach. The main goal of this study is to show the differences between healthy and cancerous tissues from the human digestive tract and human normal and cancer colon and gastric cell lines. The paper presents the spectroscopic characterization of normal colon cells, CCD-18 Co, in physiological and oxidative conditions and effect of oxidative injury of normal colon cells upon supplementation with vitamin C at various concentrations based on Raman spectra. The obtained results were related to the Raman spectra recorded for human colon cancer cells-CaCo-2. In addition, the effect of the antioxidant in the form of vitamin E on gastric cancer cells, HTB-135, is presented and compared with normal gastric cells-CRL-7869. All measured gastric samples were biochemically and structurally characterized by means of Raman spectroscopy and imaging. Statistically assisted analysis has shown that normal, ROS injured and cancerous human gastrointestinal cells can be distinguished based on their unique vibrational properties. ANOVA tests, PCA (Principal Component Analysis) and PLSDA (Partial Least Squares Discriminant Analysis) have confirmed the main role of nucleic acids, proteins and lipids in differentiation of human colon and stomach normal and cancer tissues and cells. The conducted research based on Raman spectra proved that antioxidants in the form of vitamin C and E exhibit anti-cancer properties. In consequence, conducted studies proved that label-free Raman spectroscopy may play an important role in clinical diagnostic differentiation of human normal and cancerous gastrointestinal tissues and may be a source of intraoperative information supporting histopathological analysis.

Topics: Ascorbic Acid; Caco-2 Cells; Colonic Neoplasms; Dietary Supplements; Humans; Lipids; Nucleic Acids; Principal Component Analysis; Spectrum Analysis, Raman; Stomach Neoplasms

Several studies have been conducted to investigate the anti-cancer effects of vitamin C (VC). However, the effect of high-dose VC administration on tumor angiogenesis remains unclear. Focusing on our high-dose VC, our study investigated the effect of high-dose VC (4 g/kg) on vascular endothelial growth in mice with xenografts of a rectal cancer cell line referred to as Colon 26. Male mice harboring Colon 26 tumors were established, and high-dose VC solution was orally administered once daily for 14 d. On the final day of the study, the lower limb tumor tissues and serum samples were collected and analyzed for the expression of tumor angiogenesis related proteins as well as the levels of reactive oxygen species (ROS). Oral VC administration decreased tumor volumes and increased p53 and endostatin levels. In addition, plasma and in tumor part ROS levels and tissue hypoxia inducible factor-1α (HIF-1α) were reduced by VC administration. In addition, the levels of vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor D (VEGFD) were decreased by VC administration. These results suggest that VC exerts its anti-cancer effects by suppressing angiogenesis.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Cell Line, Tumor; Colonic Neoplasms; Endostatins; Heterografts; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice, Inbred BALB C; Neovascularization, Pathologic; Reactive Oxygen Species; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor D; Vitamins

Colorectal cancer is the second most frequently diagnosed cancer worldwide. Conventional diagnostics methods of colorectal cancer can detect it at an advanced stage. Spectroscopic methods, including Raman spectroscopy and imaging, are becoming more and more popular in medical applications, and allow fast, precise, and unambiguous differentiation of healthy and cancerous samples. The most important advantage of Raman spectroscopy is the ability to identify biomarkers that help in the differentiation of healthy and cancerous cells based on biochemistry of sample and spectra typical for lipids, proteins, and DNA. The aim of the study was to evaluate the biochemical and structural features of human colon cell lines based on Raman spectroscopy and imaging: normal cells CCD-18 Co, normal cells CCD-18 Co under oxidative stress conditions, and normal cells CCD-18 Co at first treated by using tert-Butyl hydroperoxide and then supplemented by vitamin C in high concentration to show the protective role of vitamin C in micromolar concentrations against ROS (Reactive Oxygen Species). Raman data obtained for normal cells injured by ROS were compared with spectra typical for cancerous cells. Statistically assisted analysis has shown that normal ROS-injured and cancerous human colon cells can be distinguished based on their unique vibrational properties. The research carried out proves that label-free Raman spectroscopy may play an important role in clinical diagnostics differentiation of normal and cancerous colon cells and may be a source of intraoperative information supporting histopathological analysis.

Topics: Ascorbic Acid; Biomarkers; Cell Line, Tumor; Colonic Neoplasms; Humans; Oxidative Stress; Reactive Oxygen Species; Spectrum Analysis, Raman

Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) lead to metabolic alterations and a sustained formation of 2-hydroxyglutarate (2-HG). 2-HG is an oncometabolite as it inhibits the activity of α-ketoglutarate-dependent dioxygenases such as ten-eleven translocation (TET) enzymes. Inhibitors of mutant IDH enzymes, like ML309, are currently tested in order to lower the levels of 2-HG. Vitamin C (VC) is an inducer of TET enzymes. To test a new therapeutic avenue of synergistic effects, the anti-neoplastic activity of inhibition of mutant IDH1 via ML309 in the presence of VC was investigated in the colon cancer cell line HCT116

Topics: Acetamides; Antineoplastic Agents; Apoptosis; Ascorbic Acid; Benzimidazoles; Colonic Neoplasms; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Drug Synergism; Gene Silencing; HCT116 Cells; Humans; Isocitrate Dehydrogenase; Mixed Function Oxygenases; Mutation; Proto-Oncogene Proteins

Vitamin C (ascorbate) acts as an antioxidant and enzyme cofactor, and plays a vital role in human health. Vitamin C status can be affected by illness, with low levels being associated with disease due to accelerated turnover. However, robust data on the ascorbate status of patients with cancer are sparse. This study aimed to accurately measure ascorbate concentrations in plasma from patients with cancer, and determine associations with patient or tumor characteristics. We recruited 150 fasting patients with cancer (of 199 total recruited) from two cohorts, either prior to cancer surgery or during cancer chemo- or immunotherapy. A significant number of patients with cancer had inadequate plasma ascorbate concentrations. Low plasma status was more prevalent in patients undergoing cancer therapy. Ascorbate status was higher in women than in men, and exercising patients had higher levels than sedentary patients. Our study may prompt increased vigilance of ascorbate status in cancer patients.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Breast Neoplasms; Colonic Neoplasms; Exercise; Female; Health Surveys; Humans; Male; Middle Aged; Neoplasms; Nutritional Status; Risk Factors; Sedentary Behavior; Vitamins

Pharmacological doses (> 1mM) of ascorbate (a.k.a., vitamin C) have been shown to selectively kill cancer cells through a mechanism that is dependent on the generation of H

Topics: Ascorbic Acid; Catalase; Cell Survival; Colonic Neoplasms; Deferoxamine; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; HCT116 Cells; HT29 Cells; Humans; Hydrogen Peroxide; Iron; Iron Chelating Agents; Oxidative Stress

Intravenous pharmacological dose of ascorbate has been proposed as a potential antitumor therapy; however, its therapeutic efficacy is limited due to the slow autoxidation. Here, we report that palladium (Pd) nanocrystals, which possess intrinsic oxidase-like activity, accelerate the autoxidation of ascorbate, leading to the enhancement of its antitumor efficacy. The oxidase-like activity of Pd nanocrystals was facet-dependent, with the concave nanostructure enclosed by high-index facets catalyzing ascorbate autoxidation more efficiently than the planar nanostructure enclosed by low-index facets. Our first-principles calculations provide the underlying molecular mechanisms for the facet-dependent activation of O

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Catalysis; Colonic Neoplasms; Female; Fluorouracil; HCT116 Cells; Humans; Metal Nanoparticles; Mice; Mice, Nude; Nanoparticles; Oxaliplatin; Oxidation-Reduction; Palladium; Reactive Oxygen Species; Surface Properties; Treatment Outcome; Xenograft Model Antitumor Assays

Background: Chemoprevention refers to the use of specificnatural or synthetic chemical agents to suppress the\ development and progression to carcinoma. The purpose of this study was to assess the effect of aspirin, vitamin C\ or zinc on the metallothionein (MT) mRNA gene expression as well as MT protein content byimmunohistochemistry\ andradioimmunoassay (RIA) in 1, 2-dimethyl hydrazine (DMH) induced cancerous colonic tissuein rats. Methods:\ Rats were randomly divided into three groups, group 1 (aspirin), group 2 (vitamin C) group 3 (zinc), each of which\ was further sub divided into two groups and given subcutaneous injections of DMH (30 mg/kg body weight) twice a\ week for 3 months and sacrificed at either 4 months (A-precancer model) or at 6 months (B-cancer model).The control\ groups were administered 0.5 ml saline subcutaneously. All the 3 groups were simultaneouslyadministered aspirin,\ vitamin Cor zinc supplement respectively from the beginning till the end of the study. Results: It was observed that\ rats co-treated with aspirin, vitamin C or zinc resulted in a significant increase in the colonic MT mRNA expression in\ the precancer and cancer model as compared to the saline only controls. MT protein expression showed a 60%, 64%\ and 78% immunopositivity in the co-treated groups respectively.The mean MT content in the precancer and the cancer\ model was restored to near normal levels in all the three co-treated groups. Conclusion: These results suggest that\ co-administration of aspirin, vitamin C or zinc resulted in a significant increase in MT mRNA gene expression, MT\ protein expression and MT protein content which could possibly be one of the reasons for a chemo protective effect\ against progression to colonic cancer in a chemically induced DMH model in rat.Zinc supplement had a greater effect\ on metallothionein expression than aspirin or vitamin C.

Topics: 1,2-Dimethylhydrazine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Ascorbic Acid; Aspirin; Colon; Colonic Neoplasms; Dietary Supplements; Metallothionein; Precancerous Conditions; Rats; Rats, Wistar; Trace Elements; Vitamins; Zinc

Colorectal cancer is one of the global causes of cancer deaths. Cancer stem cells (CSCs) inside the tumour niche responsible for metastasis and relapses, and hence need to be targeted for cancer therapeutics. Although dietary fibre and lifestyle changes have been recommended as measures for colorectal cancer prevention, no such recommendations are available for using water soluble vitamins as prophylaxis measure for colorectal cancers. High dose of Vitamin C has been proven to selectively kill colon cancer cells having BRAF and KRAS mutations by inducing oxidative stress. In this study, we show for the first time the opposing effects of the low and high dose of Vitamin C and vitamin B3 on colon CSCs isolated from HT-29 and HCT-15 colorectal carcinoma cell lines. At small doses, both of these vitamins exerted a cell proliferative effect only on CSCs, while there was no change in the proliferation status of non-stem cancer cells and wild-type (WT) populations. On the other hand, the death effects induced by high doses of Vitamin C and B3 were of the order of 50-60% and ∼30% on CSCs from HT-29 and HCT15, respectively. Interestingly, the control fibroblast cell line (NIH3T3) was highly refractory all the tested concentrations of Vitamin C and B3, except for the highest dose - 10,000 μg of Vitamin C that induced only 15% of cell death. Hence, these results indicate the future scope of use of therapeutic doses of Vitamin C and B3 especially in patients with advanced colorectal cancer.

Topics: Animals; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Dose-Response Relationship, Drug; HT29 Cells; Humans; Mice; Neoplastic Stem Cells; Niacin; NIH 3T3 Cells; Vitamins

Asiatic acid (AA), a pentacyclic triterpenoid, derived from the tropical medicinal plant Centella asiatica is known to exhibit numerous pharmacological properties. We hypothesized that AA will have chemopreventive potential against 1,2-dimethylhydrazine (DMH)-induced experimental colon carcinogenesis in male Wistar rats. Rats were arbitrarily divided into six groups. Group I rats were processed as control. Group II rats received AA (8 mg/kg b.w., p.o.) and groups III-VI rats received subcutaneous injections of DMH (20 mg/kg b.w.) once a week, for the first four weeks. In addition, groups IV-VI rats received AA at the doses of 2, 4 and 8 mg/kg b.w., respectively, for 16 weeks. Our results discovered that supplementation with AA to the DMH-exposed rats significantly decreased the incidence of polyps and Aberrant crypt foci (ACF) as compared to the DMH-alone-exposed rats. Moreover, in the AA-supplemented DMH-exposed rats, we ascertained increased activities of the antioxidants and decreased levels of lipid peroxidation (LPO) in the liver and circulation and enhanced levels of both LPO and antioxidants in the colon, which were altered in the DMH-alone-exposed rats. Furthermore, we also observed altered activities of vitamins C and E and biotransforming enzymes in DMH-alone-exposed rats, which were reversed on AA supplementation. All the observations were supported by our histological findings. Thus, we can conclude that, AA could be used as an effective chemopreventive agent against DMH-induced colon carcinogenesis.

Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; Ascorbic Acid; Biotransformation; Catalase; Colon; Colonic Neoplasms; Dose-Response Relationship, Drug; Male; Oxidative Stress; Pentacyclic Triterpenes; Precancerous Conditions; Rats, Wistar; Superoxide Dismutase; Vitamin E

Colon cancer patients with mutant KRAS are resistant to cetuximab, an antibody directed against the epidermal growth factor receptor, which is an effective clinical therapy for patients with wild-type KRAS. Numerous combinatorial therapies have been tested to overcome the resistance to cetuximab. However, no combinations have been found that can be used as effective therapeutic strategies. In this study, we demonstrate that L-ascorbic acid partners with cetuximab to induce killing effects, which are influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human colon cancer cells with a mutant KRAS. L-Ascorbic acid treatment of human colon cancer cells that express a mutant KRAS differentially and synergistically induced cell death with cetuximab in a SVCT-2-dependent manner. The ectopic expression of SVCT-2 induced sensitivity to L-ascorbic acid treatment in human colon cancer cells that do not express SVCT-2, whereas the knockdown of endogenous SVCT-2 induced resistance to L-ascorbic acid treatment in SVCT-2-positive cells. Moreover, tumor regression via the administration of L-ascorbic acid and cetuximab in mice bearing tumor cell xenografts corresponded to SVCT-2 protein levels. Interestingly, cell death induced by the combination of L-ascorbic acid and cetuximab resulted in both apoptotic and necrotic cell death. These cell death mechanisms were related to a disruption of the ERK pathway and were represented by the impaired activation of RAFs and the activation of the ASK-1-p38 pathway. Taken together, these results suggest that resistance to cetuximab in human colon cancer patients with a mutant KRAS can be bypassed by L-ascorbic acid in an SVCT-2-dependent manner. Furthermore, SVCT-2 in mutant KRAS colon cancer may act as a potent marker for potentiating L-ascorbic acid co-treatment with cetuximab.

Topics: Animals; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Cetuximab; Colonic Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Humans; MAP Kinase Signaling System; Mice; Proto-Oncogene Proteins p21(ras); Sodium-Coupled Vitamin C Transporters; Xenograft Model Antitumor Assays

KRAS mutation is often present in many hard-to-treat tumors such as colon and pancreatic cancer and it is tightly linked to serious alterations in the normal cell metabolism and clinical resistance to chemotherapy.In 1931, the winner of the Nobel Prize in Medicine, Otto Warburg, stated that cancer was primarily caused by altered metabolism interfering with energy processing in the normal cell. Increased cell glycolytic rates even in the presence of oxygen is fully recognized as a hallmark in cancer and known as the Warburg effect.In the late 1970's, Linus Pauling and Ewan Cameron reported that vitamin C may have positive effects in cancer treatment, although deep mechanistic knowledge about this activity is still scarce.We describe a novel antitumoral mechanism of vitamin C in KRAS mutant colorectal cancer that involves the Warburg metabolic disruption through downregulation of key metabolic checkpoints in KRAS mutant cancer cells and tumors without killing human immortalized colonocytes.Vitamin C induces RAS detachment from the cell membrane inhibiting ERK 1/2 and PKM2 phosphorylation. As a consequence of this activity, strong downregulation of the glucose transporter (GLUT-1) and pyruvate kinase M2 (PKM2)-PTB dependent protein expression are observed causing a major blockage of the Warburg effect and therefore energetic stress.We propose a combination of conventional chemotherapy with metabolic strategies, including vitamin C and/or other molecules targeting pivotal key players involved in the Warburg effect which may constitute a new horizon in anti-cancer therapies.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Cell Line, Tumor; Cetuximab; Colonic Neoplasms; Female; Humans; Mice; Mice, Nude; Mutation; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species; Xenograft Model Antitumor Assays

Sulindac has anti-neoplastic properties against colorectal cancers; however, its use as a chemopreventive agent has been limited due to toxicity and efficacy concerns. Combinatorial treatment of colorectal cancers has been attempted to maximize anti-cancer efficacy with minimal side effects by administrating NSAIDs in combination with other inhibitory compounds or drugs such as l-ascorbic acid (vitamin C), which is known to exhibit cytotoxicity towards various cancer cells at high concentrations. In this study, we evaluated a combinatorial strategy utilizing sulindac and vitamin C. The death of HCT116 cells upon combination therapy occurred via a p53-mediated mechanism. The combination therapeutic resistance developed in isogenic p53 null HCT116 cells and siRNA-mediated p53 knockdown HCT116 cells, but the exogenous expression of p53 in p53 null isogenic cells resulted in the induction of cell death. In addition, we investigated an increased level of intracellular ROS (reactive oxygen species), which was preceded by p53 activation. The expression level of PUMA (p53-upregulated modulator of apoptosis), but not Bim, was significantly increased in HCT116 cells in response to the combination treatment. Taken together, our results demonstrate that combination therapy with sulindac and vitamin C could be a novel anti-cancer therapeutic strategy for p53 wild type colon cancers.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Ascorbic Acid; Carcinoma; Colonic Neoplasms; Combined Modality Therapy; Dietary Supplements; Drug Resistance, Neoplasm; Food-Drug Interactions; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Osmolar Concentration; Oxidants; Proto-Oncogene Proteins; Reactive Oxygen Species; RNA Interference; Sulindac; Tumor Suppressor Protein p53

Certain phenolic phytochemicals can kill cancer cells. Possible interference from antioxidants is a concern, and this issue has not been studied appreciably. Therefore, the effect of ascorbate and N-acetylcysteine on the ability of epigallocatechin gallate (EGCG) and curcumin to kill HCT116 colon cancer cells was examined. EGCG and curcumin each caused DNA damage in the cells. The DNA-damaging ability of EGCG, but not curcumin, was hindered by either ascorbate or NAC, which was also shown in HT29 and SW480 colon cancer cells. Also, iron chelators (deferoxamine and 2,2'-dipyridyl) inhibited the ability of EGCG, but not curcumin, to cause damage to the DNA in HCT116 cells. Interestingly, curcumin, but not EGCG, increased the expression of growth arrest and DNA damage-inducible gene 153 and also heme oxygenase-1, and this stress gene upregulation by curcumin was antioxidant-insensitive. With prolonged incubation of HCT116 cells with either EGCG or curcumin, cell shrinkage, membrane blebbing, apoptotic bodies, and chromatin condensation/fragmentation were observed. These morphological changes were not apparent in EGCG-treated cells that had been pretreated with either ascorbate or NAC. However, the ascorbate and NAC pretreatments did not prevent the occurrence of the morphological changes in curcumin-treated cells. Thus, these findings suggest that ascorbate and NAC interfere with the ability of EGCG, but not curcumin, to kill HCT116 cells. This basic knowledge may help to better plan and optimize strategies for chemoprevention or chemotherapy.

Topics: Acetylcysteine; Antioxidants; Apoptosis; Ascorbic Acid; Catechin; Cell Line, Tumor; Colonic Neoplasms; Curcumin; DNA Damage; Drug Interactions; Gene Expression; HCT116 Cells; Heme Oxygenase-1; HT29 Cells; Humans; Iron Chelating Agents

The present study was aimed to investigate the chemopreventive potential of troxerutin on 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the antioxidant and lipid peroxidation (LPO) status. Rats were randomly divided into six groups. Group I rats served as control. Group II rats received troxerutin (50 mg/kgb.w., p.o.) for 16 weeks. Groups III-VI rats received subcutaneous injections of DMH (20 mg/kgb.w., s.c.) once a week, for the first 4 weeks. In addition to DMH, groups IV-VI rats received troxerutin at the doses of 12.5, 25 and 50 mg/kgb.w., respectively. In DMH treated rats, our results showed decreased activities of antioxidants and increased levels of LPO in the liver. Moreover, LPO and antioxidants in the colon were found to be significantly diminished in DMH the treated rats. Furthermore, enhanced activity of colonic vitamin C and vitamin E levels were observed in DMH alone treated rats (group III), which was significantly reversed on troxerutin supplementation. Troxerutin at the dose of 25 mg/kgb.w. had shown profound beneficial effects by exhibiting near normal biochemical profile and well-preserved colon histology as compared to the other two tested doses (12.5 and 50 mg/kgb.w.). These findings suggest that troxerutin could serve as a novel agent for colon cancer chemoprevention.

Topics: 1,2-Dimethylhydrazine; Administration, Oral; Animals; Antineoplastic Agents; Ascorbic Acid; Carcinogens; Catalase; Colon; Colonic Neoplasms; Glutathione; Hydroxyethylrutoside; Lipid Peroxidation; Liver; Male; Rats; Rats, Wistar; Superoxide Dismutase; Vitamin E

Carotenoids and vitamins A, C and E are possibly associated with a reduced colorectal cancer (CRC) risk through antioxidative properties. The association of prediagnostic plasma concentrations and dietary consumption of carotenoids and vitamins A, C and E with the risk of colon and rectal cancer was examined in this case-control study, nested within the European Prospective Investigation into Cancer and Nutrition study. Plasma concentrations of carotenoids (α- and β-carotene, canthaxanthin, β-cryptoxanthin, lutein, lycopene, zeaxanthin) and vitamins A (retinol), C and E (α-, β- and γ- and δ-tocopherol) and dietary consumption of β-carotene and vitamins A, C and E were determined in 898 colon cancer cases, 501 rectal cancer cases and 1,399 matched controls. Multivariable conditional logistic regression models were performed to estimate incidence rate ratios (IRR) and corresponding 95% confidence intervals (CIs). An association was observed between higher prediagnostic plasma retinol concentration and a lower risk of colon cancer (IRR for highest quartile = 0.63, 95% CI: 0.46, 0.87, p for trend = 0.01), most notably proximal colon cancer (IRR for highest quartile = 0.46, 95% CI: 0.27, 0.77, p for trend = 0.01). Additionally, inverse associations for dietary β-carotene and dietary vitamins C and E with (distal) colon cancer were observed. Although other associations were suggested, there seems little evidence for a role of these selected compounds in preventing CRC through their antioxidative properties.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Body Mass Index; Carotenoids; Case-Control Studies; Colonic Neoplasms; Diet; Europe; Female; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Oxidative Stress; Rectal Neoplasms; Risk Factors; Surveys and Questionnaires; Vitamin A; Vitamin E

Based on the previous result, several naringenin derivatives modified at position 7 with bulky substituents were designed and synthesized, and their inhibitory effects on HCT116 human colon cancer cells were tested using a clonogenic assay. The half maximal inhibitory concentrations (IC(50)) of five naringenin derivatives ranged between 1.20 μM and 20.01 μM which are much better than naringenin used as a control. In addition, new structural modification at C-4 of flavanone results in improving both the anti-cancer effect and anti-oxidative effect. In vitro cyclin dependent kinase 2 (CDK2) binding assay was carried out based on the previous results. To elucidate the possible interaction between naringenin derivatives and CDK2, in silico docking study was performed. This result demonstrates the rationale for the different inhibitory activities of the naringenin derivatives. These findings could be used for designing cancer therapeutic or preventive flavanone-derived agents.

Topics: Binding Sites; Cell Survival; Colonic Neoplasms; Cyclin-Dependent Kinase 2; Drug Design; Flavanones; HCT116 Cells; Humans; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary

Chemoprotection refers to the use of specific natural or synthetic chemical agents to suppress or prevent the progression to cancer. The purpose of this study is to assess the protective effect of aspirin, vitamin C or zinc in a dimethyl hydrazine (DMH) colon carcinoma model in rats and to investigate the effect of these supplements on changes associated with colonic zinc status. Rats were randomly divided into three groups, group 1 (aspirin), group 2 (vitamin C) and group 3 (zinc), each being subdivided into two groups and given subcutaneous injection of DMH (30 mg/kg body wt) twice a week for 3 months and sacrificed at 4 months (A-precancer model) and 6 months (B-cancer model). Groups 1, 2, 3 were simultaneously given aspirin, vitamin C, or zinc supplement respectively from the beginning till the end of the study. It was observed that 87.5% of rats co-treated with aspirin or vitamin C showed normal colonic histology, along with a significant decrease in colonic tissue zinc at both time points. Rats co-treated with zinc showed 100% reduction in tumor incidence with no significant change in colonic tissue zinc. Plasma zinc, colonic CuZnSOD (copper-zinc superoxide dismutase) and alkaline phosphatase activity showed no significant changes in all 3 cotreated groups. These results suggest that aspirin, vitamin C or zinc given separately, exert a chemoprotective effect against chemically induced DMH colonic preneoplastic progression and colonic carcinogenesis in rats. The inhibitory effects are associated with maintaining the colonic tissue zinc levels and zinc enzymes at near normal without significant changes.

Topics: 1,2-Dimethylhydrazine; Alkaline Phosphatase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Ascorbic Acid; Aspirin; Blotting, Western; Carcinogens; Cell Proliferation; Colonic Neoplasms; Dietary Supplements; Disease Models, Animal; Precancerous Conditions; Rats; Rats, Wistar; Superoxide Dismutase; Trace Elements; Zinc

To investigate the mechanisms underlying the biological activity of piceatannol (PCT), a hydroxystilbene natural product that has anti-colitic properties, we examined whether PCT could modulate hypoxia-inducible factor (HIF)-1 activity in human colon carcinoma cells. PCT induced HIF-1α protein, leading to induction of its target gene products, vascular endothelial growth factor and heme oxygenase-1, which are involved in amelioration of colitis. PCT induction of HIF-1α resulted from HIF-1α protein stabilization, which occurred through inhibition of HIF-prolyl hydroxylase-2 (HPH-2). PCT inhibition of HPH-2 was reversed by addition of ascorbate, a cofactor of HPH-2, but not the cosubstrate, 2-ketoglutarate, to the reaction mixture of an in vitro von Hippel-Lindau (VHL) capture assay, and pretreatment with ascorbate abrogated PCT induction of cellular HIF-1α. Moreover, PCT prevented hydroxylation of cellular HIF-1α and attenuated coimmunoprecipitation of Flag-VHL protein and HA-HIF-1α over-expressed in human embryonic kidney 293 cells. Structural analysis using derivatives of PCT revealed that the catechol moiety in PCT was required for the stabilization of HIF-1α protein. Taken together, PCT activation of HIF-1 resulting from inhibition of HPH-2 may be a molecular mechanism for an anti-colitic effect of the natural product.

Topics: Ascorbic Acid; Cell Line, Tumor; Colitis; Colonic Neoplasms; HEK293 Cells; Heme Oxygenase-1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Procollagen-Proline Dioxygenase; Stilbenes; Vascular Endothelial Growth Factor A

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Ascorbic Acid; Colonic Neoplasms; Humans

Oxidative stress has become widely viewed as an underlying condition in diseases such as ischemia/reperfusion disorders, central nervous system disorders, cardiovascular disease, cancer, diabetes, etc. The role that antioxidants play in the process of carcinogenesis has recently gained considerable attention. β-Sitosterol, a naturally occurring sterol molecule, is a relatively mild to moderate antioxidant and exerts beneficial effects in vitro by decreasing the level of reactive oxygen species. The present study evaluated the antioxidant potential of β-sitosterol in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. The enzymatic and nonenzymatic antioxidants and lipid peroxides in colonic and hepatic tissues were evaluated. Generation of reactive oxygen species, beyond the body's endogenous antioxidant capacity, causes a severe imbalance of cellular antioxidant defense mechanisms. Elevated levels of liver lipid peroxides by DMH induction were effectively decreased by β-sitosterol supplementation. β-Sitosterol also exhibited a protective action against DMH-induced depletion of antioxidants such as catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, and reduced glutathione in colonic and hepatic tissues of experimental animals. Supplementation with β-sitosterol restored the levels of nonenzymatic antioxidants (vitamin C, vitamin E, and glutathione). Histopathological alterations in DMH-induced animals were restored to near normal in rats treated with β-sitosterol. Thus, β-sitosterol by virtue of its antioxidant potential may be used as an effective agent to reduce DMH-induced oxidative stress in Wistar rats and may be an effective chemopreventive drug for colon carcinogenesis.

Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Catalase; Colon; Colonic Neoplasms; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Sitosterols; Superoxide Dismutase; Vitamin E

Ascorbic acid (vitamin C) inhibits cancer cell growth, and there is a controversy regarding the cancer chemoprotective effects of pharmacologic doses of this compound that exhibits prooxidant activity. We hypothesized that the anticancer activity of pharmacologic doses of ascorbic acid (<5 mM) is due, in part, to reactive oxygen species-dependent downregulation of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and Sp-regulated genes. In this study, ascorbic acid (1-3 mM) decreased RKO and SW480 colon cancer cell proliferation and induced apoptosis and necrosis, and this was accompanied by downregulation of Sp1, Sp3, and Sp4 proteins. In addition, ascorbic acid decreased expression of several Sp-regulated genes that are involved in cancer cell proliferation [hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor and cyclin D1], survival (survivin and bcl-2), and angiogenesis [vascular endothelial growth factor (VEGF) and its receptors (VEGFR1 and VEGFR2)]. Other prooxidants such as hydrogen peroxide exhibited similar activities in colon cancer cells, and cotreatment with glutathione inhibited these responses. This study demonstrates for the first time that the anticancer activities of ascorbic acid are due, in part, to ROS-dependent repression of Sp transcription factors.

Topics: Anticarcinogenic Agents; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Colon; Colonic Neoplasms; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Proto-Oncogene Proteins c-met; Reactive Oxygen Species; Sp1 Transcription Factor; Sp3 Transcription Factor; Sp4 Transcription Factor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Three series of novel pyrazole derivatives 2b-d, 4a-d and 6a-d were synthesized via two step procedure that utilizes hydrazonoyl chlorides 1a-d and enaminones 3a-d and 5a-d, respectively as starting materials. The structures of all the newly synthesized products have been established on the basis of analytical and spectral data. Moreover, some of the products 2-6 were tested against HCV and Subacute Sclerosing Panencephalitis (SSPE). In addition, compounds 2-6 were also tested for the inhibition of peroxynitrite-induced tyrosine nitration and antioxidant activity. The tested compounds are highly effective at very low concentration as anti-HCV, SSPE antioxidant and anticancer in the following ascending order 2d, 4c, 6b, 3b, 6c, 4d, 2b, 2c, 2a, 6a, 5b, 5a, 3a, 4b and 5c. It is worth to mention that all tested compounds are more potent than the reference standards used for comparing activity. All the measurements revealed that the mechanism of action of the anti cancer activities of all the tested compounds is topoisomerase I inhibitor.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; Colonic Neoplasms; Cricetinae; Drug Screening Assays, Antitumor; Female; Hepacivirus; Mice; Mice, Inbred C57BL; Molecular Structure; Pyrazoles; Subacute Sclerosing Panencephalitis

Colon cancer is a major cause of morbidity and mortality in developed and developing countries and its etiology is known to be a combination of hereditary, environmental, dietary factors and lack of physical activity. Chemoprevention offers a novel approach to control the incidence of colon cancer. Gallic acid (GA) is a polyphenol widely present in tea and other plants which is popularly used in the traditional medicine of China. The present study was to evaluate the efficacy of GA supplementation on tissue lipid peroxidation and antioxidant defense system in 1,2-dimethyhydrazine (DMH) induced colon carcinogenesis in male Wistar rats. The rats were assorted into six groups, viz., group1 control rats received modified pellet diet; group 2 rats received GA (50 mg/kg body weight) orally along with modified pellet diet; group 3 rats received DMH (20 mg/kg body weight) subcutaneously once a week for the first 15 weeks; groups 4, 5 and 6 rats received GA along with DMH during the initiation, post- initiation stages and the entire period of study respectively. All the rats were sacrificed at the end of 30 weeks and the tissues were evaluated biochemically. We observed decreased lipid peroxidation (LPO) products such as thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dienes (CD) and diminished levels of antioxidants such as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione reductase (GR) and glutathione peroxidase (GPx) in the tissues of DMH treated rats, which were elevated significantly on GA supplementation. Moreover, enhanced activity of ascorbic acid and alpha-tocopherol levels were also observed in DMH alone treated rats which were significantly reduced on GA supplementation. Our results suggest that GA could exert a significant chemopreventive effect on DMH induced colon carcinogenesis.

Topics: 1,2-Dimethylhydrazine; alpha-Tocopherol; Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Colonic Neoplasms; Drug Screening Assays, Antitumor; Gallic Acid; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar

Our previous studies have demonstrated the oxidative stress properties of sodium ascorbate (SAA) and its benzaldehyde derivative (SBA) on cancer cell lines, but the molecular mechanisms mediating their cytotoxicity remain unclear. In this study, we treated human colon cancer HT-29 cells with SAA and SBA, and found a significant exposure time-dependent increase of cytotoxicity in both treatments, with a higher cytotoxicity for 24 h with SAA (IC(50) = 5 mM) than SBA (IC(50) = 10 mM). A short-term treatment of cells with 10 mM SAA for 2 h revealed a destabilization of the lysosomes and subsequent induction of cell death, whereas 10 mM SBA triggered a remarkable production of reactive oxidative species, phosphorylation of survival kinase AKT, expression of cyclin kinase-dependent inhibitor p21, and induction of transient growth arrest. The crucial role of p21 mediating this cytotoxicity was confirmed by isogenic derivatives of the human colon carcinoma HCT116 cell lines (p21(+/+) and p21(-/-)), and immunoprecipitation studies with p21 antibody. The SAA cytotoxicity was blocked by co-incubation with catalase, whereas the SBA cytotoxicity and its subsequent growth arrest were abolished by N-acetyl-L-cysteine (NAC), but was not affected by PI3K phosphorylation inhibitor LY294002, or catalase, suggesting two separated oxidative stress pathways were mediated by these two ascorbates. In addition, neither active caspase 3 nor apoptotic bodies but autophagic vacuoles associated with increased LC3-II were found in SBA-treated HT-29 cells; implicating that SBA induced AKT phosphorylation-autophagy and p21-growth arrest in colon cancer HT-29 cells through an NAC-inhibitable oxidative stress pathway.

Topics: Antineoplastic Agents; Antioxidants; Ascorbic Acid; Autophagy; Benzylidene Compounds; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Humans; Oxidative Stress; Proto-Oncogene Proteins c-akt; Time Factors

Berries and berry extracts possess properties that make them important in the prevention of cancer. The high antioxidant levels of these extracts play a role, but components of the berries can have other effects on cell replication and survival. We chose to test the hypothesis that (i) although the antioxidant capacity of raspberry extracts is important for inhibiting the proliferation of tumor cells, other characteristics of the berry extracts are responsible for a major part of their antiproliferative activity, and that (ii) the relative importance of the antioxidant effect can depend on the cell type being studied. The aim of this study was to assess the relative roles of low pH and high antioxidant levels in the killing of 3 cell types by an aqueous extract from Meeker red raspberries. Stomach, colon, and breast cancer cells were treated with berry extract and with HCl and ascorbic acid solutions of the same pH. A dilution of 7.5% ascorbic acid solution, of the same pH and slightly higher antioxidant concentration than the berry extract, killed less than 10% of the stomach and colon cancer cells. In contrast, the berry extract at this same dilution killed more than 90% of these cells. Antioxidants played a more significant role in the killing of breast cancer cells, however. For these cells, approximately 50% of the killing could be attributed to antioxidant effects. We conclude that the antioxidant effect plays a minor role in the killing of 2 gastrointestinal cell types, but its role in inactivating a breast cancer cell line is much more significant. No evidence of apoptosis was observed, and caspase activation did not contribute to cell killing by the extract.

Topics: Adenocarcinoma; Antioxidants; Ascorbic Acid; Breast Neoplasms; Caspases; Cell Division; Cell Line, Tumor; Colonic Neoplasms; Fruit; Humans; Phytotherapy; Plant Extracts; Stomach Neoplasms

We reported previously that 7beta-hydroxysitosterol and 7beta-hydroxycholesterol induced apoptosis in Caco-2 cells. Apoptosis caused by 7beta-hydroxysitosterol but not by 7beta-hydroxycholesterol was related to a caspase-dependent process. In the present report, we compared the effects of both compounds on mitochondria integrity and on various modulators of apoptosis. When Caco-2 cells were exposed to both hydroxysterols, no changes in Bcl-2 and Bax expressions were detected indicating a Bcl-2/Bax-independent cell death pathway, whereas loss of mitochondrial membrane potential and cytochrome c release were observed. Endonuclease G expression and enhanced production of reactive oxygen species were detected in 7beta-hydroxycholesterol treated cells, but not with 7beta-hydroxysitosterol. Loss of mitochondrial membrane potential and cell death produced by both hydroxysterols were prevented by vitamin C. Lysosomal membrane integrity was altered with both hydroxysterols, but 7beta-hydroxysitosterol was significantly more active on than 7beta-hydroxycholesterol. Both hydroxysterols induced apoptosis by mitochondrial membrane permeabilization. However, 7beta-hydroxycholesterol exhibited a specific enhancement of oxidative stress and of endonuclease G expression despite its closely related chemical structure with 7beta-hydroxysitosterol. The two hydroxysterols exhibit different lipophilic properties which may explain their different biological effects.

Topics: Apoptosis; Ascorbic Acid; bcl-2-Associated X Protein; Caco-2 Cells; Colonic Neoplasms; Cytochromes c; Endodeoxyribonucleases; Humans; Hydroxycholesterols; Lysosomes; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Sitosterols

The aim was to investigate mechanisms contributing to quercetin's previously described effects on cell-proliferation and -differentiation, which contradicted its proposed anticarcinogenic potency. In a 10-day experiment, 40 microM quercetin stabilized by 1 mM ascorbate reduced Caco-2 differentiation up to 50% (p < 0.001). Caco-2 RNA from days 5 and 10, hybridized on HG-U133A2.0 Affymetrix GeneChips(R), showed 1,743 affected genes on both days (p < 0.01). All 14 Caco-2 differentiation-associated genes showed decreased expression (p < 0.01), including intestinal alkaline phosphatase, that was confirmed technically (qRT-PCR) and functionally (enzyme-activity). The 1,743 genes contributed to 27 pathways (p < 0.05) categorized under six gene ontology (GO) processes, including apoptosis and cell-cycle. Genes within these GO-processes showed fold changes that suggest increased cell-survival and -proliferation. Furthermore, quercetin down-regulated expression of genes involved in tumor-suppression and phase II metabolism, and up-regulated oncogenes. Gene expression changes mediated by ascorbate-stabilized quercetin were concordant with those occurring in human colorectal carcinogenesis ( approximately 80-90%), but were opposite to those previously described for Caco-2 cells exposed to quercetin without ascorbate ( approximately 75-90%). In conclusion, gene expression among Caco-2 cells exposed to ascorbate-stabilized quercetin showed mechanisms contrary to what is expected for a cancer-preventive agent. Whether this unexpected in vitro effect is relevant in vivo, remains to be elucidated.

Topics: Ascorbic Acid; Caco-2 Cells; Cell Differentiation; Cell Division; Colonic Neoplasms; Drug Stability; Gene Expression; Humans; Oligonucleotide Array Sequence Analysis; Quercetin

Colon cancer is a leading cause of cancer death and its prevention is of great interest throughout the world. This study was conducted to examine the efficacy of different doses of dietary caraway (Carum carvi L.) on tissue lipid peroxidation (LPO) and antioxidant profile in rat colon carcinogenesis. Wistar male rats were divided into 6 groups and were fed a modified pellet diet for the whole of 30 weeks. To induce colon cancer, rats were given a weekly subcutaneous injection of 1,2-dimethylhydrazine (DMH) at a dose of 20 mg kg(-1) (based on body weight) for the first 15 weeks. Caraway was supplemented every day orally at doses of 30, 60 and 90 mg kg(-1) for different groups of rats for the total period of 30 weeks. All rats were sacrificed at the end of 30 weeks, the colons were examined visually for masses and were subsequently evaluated histologically. The results showed diminished levels of intestinal, colonic and caecal LPO products, such as conjugated dienes (CD), lipid hydroperoxides (LOOH) and thiobarbituric acid reactive substances (TBARS) and also the antioxidants superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione reductase (GR) in DMH treated rats, which were significantly reversed (P<0.05) on caraway supplementation. Moreover, enhanced activity of intestinal, colonic and caecal glutathione peroxidase (GPx), glutathione S-transferase (GST) and colonic ascorbic acid and alpha-tocopherol levels were observed in carcinogen-treated rats, which were significantly (P<0.05) reduced on caraway supplementation. Thus, our study showed that caraway supplementation at a dose of 60 mg kg(-1) had a modulatory role on tissue LPO, antioxidant profile and prevented DMH-induced histopathological lesions in colon cancer rats.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Ascorbic Acid; Carcinogens; Carum; Catalase; Colon; Colonic Neoplasms; Diet; Glutathione; Lipid Peroxidation; Male; Plant Extracts; Rats; Rats, Wistar; Superoxide Dismutase; Suspensions; Thiobarbituric Acid Reactive Substances; Vitamin E

Colorectal cancer is the second most deadly cancer in the United States. When diagnosed early, current treatments bring a limited success; however, once metastasis occurs, radiation and chemotherapy are generally ineffective. Structural changes in the ECM are necessary for cell migration during tissue remodeling. Matrix metalloproteinases (MMPs), VEGF, Ki-67 (proliferative protein), and constituents of ECM, such as fibronectin, play a critical role in angiogenesis and are thus crucial in neoplastic invasion and metastasis. Based on antitumor properties of certain nutrients, we investigated the effect of a diet containing lysine, proline, arginine, ascorbic acid, and green tea extract (NM) on the growth of tumors, induced by implanting human colon HCT 116 cancer cells in athymic nude mice, and the expression of MMPs, VEGF, Ki-67 and fibronectin in these tumors, as well as the production of mucin (by PAS staining). After one week of isolation, 5 to 6 week-old athymic male nude mice (n=12) were inoculated with 3x10(6) colon cancer HCT 116 cells. After injection, the mice were randomly divided into 2 groups; group A was fed a regular diet and group B was fed a regular diet supplemented with 0.5% NM. The mice were sacrificed 4 weeks later, and their tumors were excised, weighed, and processed for histology. Results showed that the nutrient mixture (NM) inhibited growth and reduced the size of tumors in nude mice. Furthermore, histological evaluation revealed increased mitotic index, MMP-9 and VEGF secretion and reduced basement membrane in the control group tissues. Nutrient supplementation strongly suppressed the growth of tumors without any adverse effects in nude mice, suggesting the nutrient combination has potential as an anticancer agent. Histological studies supported these findings by showing inhibition of MMP-9 and VEGF secretion and mitotic index, which are critical parameters for cancer control and prevention.

Topics: Animals; Antioxidants; Ascorbic Acid; Colonic Neoplasms; Diet; Disease Progression; Immunohistochemistry; Ki-67 Antigen; Lysine; Male; Matrix Metalloproteinases; Mice; Mice, Nude; Mucins; Neoplasms, Experimental; Proline; Tea; Transplantation, Heterologous; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Vitamin C interferes with assays involving the redox-reaction. However, the interference of Vitamin C with electrolytes has not been reported. In the present case, we describe a 61-year-old lady with severe electrolyte abnormalities after administration of high doses of vitamin C. This patient, who had terminal colon cancer, presented to hospital with anuria. Her electrolytes were extremely abnormal (determined on the Beckman Synchron LX20): serum sodium 200 mmol/L, potassium 7.0 mmol/L, and chloride 50 mmol/L. Repeated measurements showed similar abnormalities. However, these critical abnormalities did not fit her clinical picture, as she was alert with normal vital signs. One of the specimens was also run on both the ABL700 and the Bayer644 analyzers, and the electrolytes appeared normal. Pooled serum from healthy individuals to which various amounts of vitamin C was added then was analyzed on Beckman Synchron LX20 for electrolytes, demonstrating the interference of vitamin C consistent with the initial finding. Thus, we eventually figured out that the aberrant results were due to the vitamin C caused analytical interference.

Topics: Ascorbic Acid; Colonic Neoplasms; Electrolytes; Female; Humans; Medical Laboratory Science; Middle Aged; Reproducibility of Results

Colon cancer is the third most common cancer and second leading cause of cancer-related death in the United States. A number of recent articles demonstrate the importance of natural products as cancer chemopreventive agents. In this study, we evaluated the chemopreventive efficacy of luteolin, a flavonoid, on tissue lipid peroxidation and antioxidant status, which are used as biomarkers in DMH-induced experimental colon carcinogenesis. Rats were given a weekly subcutaneous injection of DMH at a dose of 20 mg/kg body weight for 15 weeks. Luteolin (0.2 mg/kg body weight/everyday p.o.) was given to the DMH-treated rats at the initiation and post-initiation stages of carcinogenesis. The animals were killed after 30 weeks. After a total experimental period of 32 weeks (including 2 weeks of acclimatization), tumor incidence was 100% in DMH-treated rats. In those DMH-treated rats that had received luteolin during the initiation or post-initiation stages of colon carcinogenesis, the incidence of cancer and the colon tumor size was significantly reduced as compared to that for DMH-treated rats not receiving luteolin. In the presence of DMH, relative to the results for the control rats, there were decreased levels of lipid peroxidation, as denoted by thiobarbituric acid reactive substances (TBARS), conjugated dienes and lipid hydroperoxides, decreased activities of the enzymic antioxidants superoxide dismutase (SOD) and catalase (CAT), and elevated levels of glutathione and the glutathione-dependent enzymes reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR), and of the non-enzymic antioxidants vitamin C and vitamin E. Our study shows that intragastric administration of luteolin inhibits colon carcinogenesis, not only by modulating lipid peroxidation and antioxidant status, but also by preventing DMH-induced histopathological changes. Our results thus indicate that luteolin could act as a potent chemopreventive agent for colon carcinogenesis.

Topics: 1,2-Dimethylhydrazine; Animals; Ascorbic Acid; Carcinogens; Catalase; Colon; Colonic Neoplasms; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Humans; Lipid Peroxidation; Lipid Peroxides; Luteolin; Male; Molecular Structure; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Time Factors; Vitamin E

Nitric oxide-mediated signals have been suggested to regulate the activity of caspases negatively, yet literature has provided little direct evidence. We show in this paper that cytokines and nitric-oxide synthase (NOS) inhibitors regulate S-nitrosation of an initiator caspase, procaspase-9, in a human colon adenocarcinoma cell line, HT-29. A NOS inhibitor, N(G)-methyl-l-arginine, enhanced the tumor necrosis factor-alpha (TNF-alpha)-induced cleavage of procaspase-9, procaspase-3, and poly-(ADP-ribose) polymerase, as well as the level of apoptosis. N(G)-Methyl-l-arginine, however, did not affect the cleavage of procaspase-8. These results suggest that nitric oxide regulates the cleavage of procaspase-9 and its downstream proteins and, subsequently, apoptosis in HT-29 cells. Labeling S-nitrosated cysteines with a biotin tag enabled us to reveal S-nitrosation of endogenous procaspase-9 that was immunoprecipitated from the HT-29 cell extracts. Furthermore, the treatment with TNF-alpha, as well as NOS inhibitors, decreased interferon-gamma-induced S-nitrosation in procaspase-9. Our results show that S-nitrosation of endogenous procaspase-9 occurs in the HT-29 cells under normal conditions and that denitrosation of procaspase-9 enhances its cleavage and consequent apoptosis. We, therefore, suggest that S-nitrosation regulates activation of endogenous procaspase-9 in HT-29 cells.

Topics: Apoptosis; Ascorbic Acid; Biotin; Blotting, Western; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Death; Colonic Neoplasms; Cysteine; DNA; Enzyme Activation; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; HT29 Cells; Humans; Interferon-gamma; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Nitrosation; Precipitin Tests; Time Factors; Tumor Necrosis Factor-alpha

Although a high alimentary intake of antioxidant vitamins such as ascorbic acid may play an important role in cancer prevention, a high level of antioxidants may have quite different effects at different stages of the transformation process. In cancer development, the resistance of cells to apoptosis is one of the most crucial steps. We have tested the effects of ascorbic acid on apoptosis in HT-29 human colon carcinoma cells when induced by two potent apoptosis inducers, the classical antitumor drug camptothecin or the flavonoid flavone. Apoptosis was assessed based on caspase-3-like activity, plasma membrane disintegration and finally nuclear fragmentation and chromatin condensation. Ascorbic acid dose-dependently inhibited the apoptotic response of cells to camptothecin and flavone. RT-PCR analysis and western blot analysis revealed that ascorbic acid specifically blocked the decrease of bcl-X(L) by camptothecin or flavone. An increased generation of mitochondrial O(2)(-.) precedes the down-regulation of bcl-X(L) by camptothecin and flavone and ascorbic acid at a concentration of 1 mM prevented the generation of this reactive oxygen species. In conclusion, ascorbic acid functions as a potent antioxidant in mitochondria of human colon cancer cells and thereby blocks drug-mediated apoptosis induction allowing cancer cells to become insensitive to chemotherapeutics.

Topics: Antioxidants; Apoptosis; Ascorbic Acid; bcl-X Protein; Camptothecin; Caspase 3; Caspases; Colonic Neoplasms; Down-Regulation; Flavones; Flavonoids; Free Radical Scavengers; HT29 Cells; Humans; Hydroxyl Radical; Immunoblotting; Mitochondria; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; Superoxides

African Americans have the highest incidence of colon cancer among United States racial/ethnic groups, but these disparities are largely unexplained. This report describes associations of micronutrients with colon cancer risk in African Americans and whites using data from a case-control study in North Carolina. Incident cases of histologically confirmed colon cancer, age 40-80 years (n = 613), and matched controls (n = 996) were interviewed in person to elicit information on potential colon cancer risk factors. A previously validated food frequency questionnaire adapted to include regional foods was used to assess diet over the year prior to diagnosis or interview date. Micronutrient exposure included food sources and dietary supplements. Multivariate logistic regression models estimated energy-adjusted and non-energy-adjusted odds ratios (ORs). African Americans reported lower mean micronutrient intakes than whites, primarily due to larger contributions from dietary supplements in whites. Controls generally reported higher micronutrient intakes than cases; however, these differences were only statistically significant for whites. In whites, high beta-carotene, vitamin C, and calcium intakes were associated with 40-60% reductions in colon cancer risk when contrasting highest to lowest quartiles in both energy-adjusted and non-energy-adjusted models, e.g., OR = 0.4 (95% confidence interval, 0.3-0.6) for the highest quartile of calcium in the energy-adjusted model. In African Americans, vitamins C and E were strongly inversely associated using both statistical approaches: high vitamin E intake was associated with a 70% reduced risk for colon cancer, and the OR comparing the highest to lowest quartiles of vitamin C was 0.5 (95% confidence interval, 0.3-0.8). Folate and lutein were not statistically significantly associated with colon cancer risk in either racial group. These results suggest that at high intakes, micronutrients commonly found in plant and other foods (in particular, beta-carotene, vitamin C, and calcium in whites and vitamins C and E in African Americans) exhibit independent associations consistent with 30-70% reductions in colon cancer risk.

Topics: Adult; Aged; Ascorbic Acid; beta Carotene; Black or African American; Calcium, Dietary; Colonic Neoplasms; Dietary Supplements; Feeding Behavior; Female; Humans; Logistic Models; Male; Micronutrients; Middle Aged; North Carolina; Risk Factors; Vitamin E; White People

We examine whether the level of 8-oxo-2'-deoxyguanosine (8-oxodGuo) in lymphocytes DNA is higher in colon cancer when compared to the control group. Factors that may influence oxidative stress such as antioxidant vitamins and uric acid were also determined. Blood samples were obtained from a control group of 55 healthy persons and 43 colon cancers. 8-OxodGuo level and the vitamins concentration were measured by high-performance liquid chromatography. The levels of 8-oxodGuo were significantly higher whereas the concentrations of the vitamins and uric acid were significantly lower in colon cancer patients than in control group. Therefore, the decreased concentration of antioxidant vitamins together with lower amount of uric acid may be responsible for the formation of pro-oxidative environment in blood of colorectal carcinoma patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Ascorbic Acid; Chromatography, High Pressure Liquid; Colonic Neoplasms; Deoxyguanosine; DNA; Female; Humans; Lymphocytes; Male; Middle Aged; Oxidative Stress; Uric Acid; Vitamin A; Vitamin E

Alkaline phosphatase (ALP) refers to a group of nonspecific phosphomonoesterases located primarily in cell plasma membrane. It has been described in different cell lines that ecto-ALP is directly or indirectly involved in the modulation of organic cation transport. We aimed to investigate, in Caco-2 cells, a putative modulation of 1-methyl-4-phenylpyridinium (MPP(+)) apical uptake by an ecto-ALP activity. Ecto-ALP activity and (3)H-MPP(+) uptake were evaluated in intact Caco-2 cells (human colon adenocarcinoma cell line), in the absence and presence of a series of drugs. The activity of membrane-bound ecto-ALP expressed on the apical surface of Caco-2 cells was studied at physiological pH using p-nitrophenylphosphate as substrate. The results showed that Caco-2 cells express ALP activity, characterized by an ecto-oriented active site functional at physiological pH. Genistein (250 micro M), 3-isobutyl-1-methylxanthine (1 mM), verapamil (100 micro M), and ascorbic acid (1 mM) significantly increased ecto-ALP activity and decreased (3)H-MPP(+) apical transport in this cell line. Orthovanadate (100 micro M) showed no effect on (3)H-MPP(+) transport and on ecto-ALP activity. On the other hand, okadaic acid (310 nM) and all trans-retinoic acid (1 micro M) significantly increased (3)H-MPP(+) uptake and inhibited ecto-ALP activity. There is a negative correlation between the effect of drugs upon ecto-ALP activity and (3)H-MPP(+) apical transport (r = -0.9; P = 0.0014). We suggest that apical uptake of organic cations in Caco-2 cells is affected by phosphorylation/dephosphorylation mechanisms, and that ecto-ALP activity may be involved in this process.

Topics: Adenocarcinoma; Alkaline Phosphatase; Antioxidants; Ascorbic Acid; Caco-2 Cells; Cations; Cell Membrane; Colonic Neoplasms; Dose-Response Relationship, Drug; Humans; Phosphoric Monoester Hydrolases; Protein Transport; Tretinoin; Tumor Cells, Cultured; Up-Regulation; Vanadates

We conducted a prospective study on the association between supplemental vitamin E and colon cancer in 87,998 females from the Nurses' Health Study and 47, 344 males from the Health Professionals Follow-up Study. There was some suggestion that men with supplemental vitamin E intake of 300 IU/day or more may be at lower risk for colon cancer when compared with never users [multivariate relative risk (RR), 300-500 IU/day versus never users, 0.73 (95% confidence interval (CI), 0.52-1.03); >or=600 IU/day versus never users = 0.70 (95% CI = 0.38-1.29)], but CIs included 1. In women, there was no evidence for an inverse association between vitamin E supplementation and risk of colon cancer. Our findings do not provide consistent support for an inverse association between supplemental vitamin E and colon cancer risk. Considering the paucity of epidemiological data on this association, further studies of vitamin E and colon cancer are warranted.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Carotenoids; Cohort Studies; Colonic Neoplasms; Dietary Supplements; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Menopause; Middle Aged; Multivariate Analysis; Prospective Studies; Risk Factors; Treatment Outcome; United States; Vitamin D; Vitamin E

The mechanisms underlying the frequent development of carcinomas associated with ulcerative colitis (UC) are not understood. Cellular antioxidants play a crucial role in protection against neoplastic disease. The purpose of this study is to investigate a critical balance between free radical activity and the antioxidant defense system in carcinogenesis associated with UC, using a model of experimental colitis induced in mice by dextran sulfate sodium (DSS) treatment.. Chronic colitis was induced by feeding the mice for 7 days with 4% DSS, followed by drinking water alone for the subsequent 14 days. Animals were sacrificed after one, two, three, or four cycles of DSS administration. Development of dysplastic epithelium and invasive carcinoma was histologically examined. Lipid peroxide level was estimated by measuring malondialdehyde (MDA) content. Alterations in MDA content and superoxide dismutase (SOD) activity in colonic tissues together with production of serum tumor necrosis factor (TNF)-alpha were determined.. Colonic neoplasms including dysplastic epithelium and invasive carcinoma developed in 28.6 and 25.0% of the animals at the end of the third and fourth cycles, respectively. In accordance with elevation of serum TNF-alpha level, there was a substantial increase in MDA in the colonic mucosa, while tissue SOD activity tended to be suppressed during the DSS treatment periods. Dysplastic epithelium and invasive carcinoma revealed significantly lower SOD levels compared with colonic colitis, although MDA levels were not statistically different among these colonic diseases.. The results obtained in this experimental model suggest that an impaired antioxidant defense system might be critical for cancer development associated with UC.

Topics: Animals; Anticoagulants; Antioxidants; Ascorbic Acid; Chronic Disease; Colitis; Colonic Neoplasms; Dextran Sulfate; Female; Free Radicals; Intestinal Mucosa; Lipid Peroxides; Malondialdehyde; Mice; Mice, Inbred Strains; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Vitamin C (ascorbate) is toxic to tumour cells, and has been suggested as an adjuvant cancer treatment. Our goal was to determine if ascorbate, in combination with other antioxidants, could kill cells in the SW620 hollow fibre in vitro solid tumour model at clinically achievable concentrations. Ascorbate anti-cancer efficacy, alone or in combination with lipoic acid, vitamin K3, phenyl ascorbate, or doxorubicin, was assessed using annexin V staining and standard survival assays. 2-day treatments with 10 mM ascorbate increased the percentage of apoptotic cells in SW620 hollow fibre tumours. Lipoic acid synergistically enhanced ascorbate cytotoxicity, reducing the 2-day LC(50)in hollow fibre tumours from 34 mM to 4 mM. Lipoic acid, unlike ascorbate, was equally effective against proliferating and non-proliferating cells. Ascorbate levels in human blood plasma were measured during and after intravenous ascorbate infusions. Infusions of 60 g produced peak plasma concentrations exceeding 20 mM with an area under the curve (24 h) of 76 mM h. Thus, tumoricidal concentrations may be achievable in vivo. Ascorbate efficacy was enhanced in an additive fashion by phenyl ascorbate or vitamin K3. The effect of ascorbate on doxorubicin efficacy was concentration dependent; low doses were protective while high doses increased cell killing.

Topics: Antioxidants; Apoptosis; Ascorbic Acid; Carcinoma; Colonic Neoplasms; Dose-Response Relationship, Drug; Doxorubicin; Drug Interactions; Humans; Necrosis; Thioctic Acid; Tumor Cells, Cultured

Genomic instability associated with deficiencies in mismatch repair (MMR) plays a critical role in tumorigenesis. Here we have investigated the contribution of oxidative damage to this instability in MMR-defective cells. Treatment with H(2)O(2) produced less cytotoxicity in MMR-deficient cells than in those proficient in MMR, supporting a role for MMR in the recognition and/or processing of oxidative damage. Additionally, growth of MMR-defective cells in the presence of the antioxidant ascorbate (500 microM) reduced the spontaneous mutation rate at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus by up to 50% and reduced microsatellite instability by 30%. Induction of HPRT mutants by exogenously added H(2)O(2) was also significantly suppressed by ascorbate. Collectively, these results suggest that (i) oxidative damage contributes significantly to the spontaneous mutator phenotype in MMR-defective cells, (ii) this damage may select for MMR-deficient cells due to their increased resistance to cell killing and (iii) dietary antioxidants may help to suppress the mutator phenotype and resulting carcinogenesis in individuals with compromised MMR.

Topics: Antimetabolites, Antineoplastic; Antioxidants; Ascorbic Acid; Base Pair Mismatch; Cell Survival; Chromosomes, Human, Pair 3; Colonic Neoplasms; DNA Repair; Free Radical Scavengers; Humans; Hydrogen Peroxide; Hypoxanthine Phosphoribosyltransferase; Microsatellite Repeats; Mutagenesis; Mutagenicity Tests; Mutation; Neoplasm Proteins; Thioguanine; Tumor Cells, Cultured

Our purpose was to determine whether the administration of anti-oxidant vitamins could reduce dose-limiting toxicity from radio-immunotherapy (RAIT) and thereby allow higher escalation of RAIT doses. Lipophilic vitamins A and E were administered i.p. and hydrophilic vitamin C was administered i.m. for 14 days (3 days pre-RAIT through 11 days post-RAIT) alone or with bone marrow transplantation (BMT) to either BALB/c mice for toxicity studies or to nude mice bearing s.c. GW-39 human colonic cancer xenografts for therapy studies. The maximal tolerated dose (MTD) of RAIT ((131)I-MN14 anti-CEA IgG) that results in no lethality was determined for mice that did not receive vitamins or BMT and those that did receive one or both interventions. Body weight, peripheral white blood cell (pWBC) and platelet (PLT) counts and tumor growth were also measured. Administration of vitamins (equivalent of 3.5 IU/day vitamin A, 0.107 IU/day vitamin E and 4.0 mg/day ascorbic acid) to mice along with BMT increased the MTD by 42% and reduced body weight loss associated with RAIT. Vitamins also reduced the magnitude of RAIT-induced myelosuppression. As early as day 7 after RAIT, vitamins increased WBC counts following both a 400 microCi and a 500 microCi dose. On day 14 after the 400 microCi dose of RAIT (day 7 post-BMT), the additive effect of BMT and vitamin could be detected. Tumor growth was not adversely affected by vitamin administration.

Topics: Animals; Antioxidants; Ascorbic Acid; Body Weight; Bone Marrow Diseases; Bone Marrow Transplantation; Colonic Neoplasms; Humans; Intestinal Diseases; Leukocyte Count; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Platelet Count; Radioimmunotherapy; Vitamin A; Vitamin E

We determined whether intakes of the main dietary carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein plus zeaxanthin, and lycopene) and of vitamins A, C, and E were associated with the prevalence of colorectal adenomas among male and female members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy (n = 488 matched pairs). Participants, ages 50-74 years, completed a 126-item semiquantitative food-frequency questionnaire and a non-dietary questionnaire from 1991 to 1993. In the univariate-matched analysis, alpha-carotene, beta-carotene (with and without supplements), beta-cryptoxanthin, lutein plus zeaxanthin, vitamin A (with and without supplements), and vitamin C (with and without supplements) were associated with a decreased prevalence of colorectal adenomas. After adjustment for intake of calories, saturated fat, folate, fiber, and alcohol, and for current smoking status, body mass index, race, physical activity, and use of nonsteroidal anti-inflammatory drugs, only beta-carotene including supplements was inversely associated with adenomas (odds ratio (OR), 0.6; 95% confidence interval (CI), 0.41.1; trend, P= 0.04; ORs compare highest to lowest quartiles0; vitamin C showed a weaker inverse association (OR, 0.8; 95% CI, 0.5-1.5; trend, P = 0.08); and the remaining compounds were no longer clearly associated with risk. After including beta-carotene with supplements and vitamin C simultaneously in the mutivariate model, the association of beta-carotene with supplements with adenomas was weakened (OR, 0.8; 95% CI, 0.5-1.3; trend P = 0.15), and vitamin C was no longer associated with risk. These data provide only modest support for a protective association of beta-carotene with colorectal adenomatous polyps.

Topics: Adenoma; Aged; Anticarcinogenic Agents; Ascorbic Acid; beta Carotene; Carotenoids; Case-Control Studies; Colonic Neoplasms; Cryptoxanthins; Diet; Feeding Behavior; Female; Humans; Los Angeles; Lutein; Lycopene; Male; Middle Aged; Multivariate Analysis; Prevalence; Rectal Neoplasms; Risk Factors; Sigmoidoscopy; Vitamin A; Vitamin E; Xanthophylls; Zeaxanthins

CBA female mice treated with 1,2-dimethylhydrazine (DMH) alone or in combination with oestradiol dipropionate (EP) or ascorbic acid (AA) developed, as expected, a high incidence of uterine sarcomas. In addition, sarcomatous lesions at unusual sites (mainly in the forestomach) were evident. The incidence of sarcomatous lesions at other sites was 53/220 in mice having uterine sarcomas and 0/186 in mice treated with DMH but without uterine sarcomas. The difference between the two groups was highly statistically significant (P < 0.001) and demonstrates non-coincidental association of the above sarcomatous lesions with uterine sarcomas. Uterine sarcomas which presented in association with lesions at other sites were of a larger size than those found in isolation, and the difference in weights in three out of four groups was statistically significant (P = 0.008, 0.035 and 0.011). Histologically, sarcomatous lesions were similar in structure to those of uterine sarcomas, i.e. were of a fibroblastic-histiocytic nature with admixture of giant cells. On the basis of the above data the sarcomatous lesions described appear to represent uterine sarcoma metastases rather than independent primary tumours. AA did not have any influence on carcinogenesis induced by DMH alone but inhibited the growth of uterine sarcomas (whether or not they were associated with other sarcomatous lesions) induced by DMH combined with oestradiol dipropionate.

Topics: 1,2-Dimethylhydrazine; Animals; Ascorbic Acid; Carcinogens; Colonic Neoplasms; Dimethylhydrazines; Estradiol; Female; Incidence; Mice; Mice, Inbred CBA; Mutagens; Sarcoma; Stomach Neoplasms; Uterine Neoplasms

Topics: Antioxidants; Ascorbic Acid; Colonic Neoplasms; Humans; Vitamin A; Vitamin E

High consumption of fruits and vegetables which are abundant in dietary antioxidants has been linked to a reduced incidence of colorectal cancer. A potential mechanism of dietary anticarcinogenesis involves the induction of detoxifying phase II enzymes, including NAD(P)H:quinone reductase (QR) and glutathione-S-transferase (GST). This study therefore examined the ability of the dietary antioxidant vitamins beta-carotene, alpha-tocopherol and ascorbic acid to induce cellular expression of QR and GST activities in human colon cancer cells. Colo205 cells were cultured in the presence or absence of various concentrations (10(-10) to 10(-5) M) of each antioxidative micronutrient, then assessed for cytosolic QR and GST activities and cell growth. beta-Carotene, alpha-tocopherol and ascorbic acid each resulted in dose-dependent increases in QR activity, without adverse effects upon cell proliferation. To investigate whether the ability of beta-carotene to induce QR may be attributable to its conversion to vitamin A and/or to its antioxidant capacity as a carotenoid, retinol, retinoic acid, and lycopene were similarly tested for their capacity for enzyme induction. Although retinol and retinoic acid were both noted to be antiproliferative at higher concentrations (10(-6) to 10(-5) M), both retinoids stimulated QR at physiological concentrations. Lycopene, a carotenoid which is not converted to vitamin A, was devoid of biologic activity. By contrast with the effects upon QR, GST activity was unaffected by treatment with any of the micronutrients tested in this in vitro model. The results support a hypothesis that a high dietary consumption of vitamins A, E and C may confer partial protection against colorectal cancer by the induction of specific detoxifying enzymes. The antioxidant capacity of beta-carotene appears to have less biologic impact vis-a-vis QR induction than its function as a non-toxic reservoir of vitamin A. Measurements of QR activity within the colorectal mucosa may provide an index of cancer susceptibility, and may be an appropriate surrogate endpoint biomarker for colorectal cancer prevention studies involving diet modification or specific relevant micronutrients.

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Carotenoids; Colonic Neoplasms; Enzyme Induction; Glutathione Transferase; Humans; Lycopene; Micronutrients; NAD(P)H Dehydrogenase (Quinone); Tumor Cells, Cultured; Vitamin A; Vitamin E

Caco-2 cells were used as a model of human intestinal epithelium to investigate the role of redox systems in transepithelial transport of 59Fe3+. The cells reduced Fe3+ present in the apical medium; the reduction was 50% inhibited by adriamycin and p-chloromercuribenzoate. Addition of [14C]ascorbate to the basolateral medium resulted in accumulation of 14C radioactivity in both cells and apical medium; apical radioactivity increased with time and was probably caused by paracellular flux. The cells provided Fe3+ reduction capacity to the apical incubation medium. Addition of ascorbate to the basolateral medium increased this reduction capacity 2-fold and the cellular uptake of 59Fe3+ 1.8-fold. Adriamycin significantly inhibited both cellular 59Fe uptake and Fe transport into the basolateral side. The results indicate that Caco-2 cells reduce apical Fe3+ by two parallel mechanisms: by a plasma membrane ferrireductase and by the secretion of reductants of either cellular or basolateral origin. The data support a model for Fe3+ intestinal absorption in which cell-mediated Fe3+ reduction occurs before cellular Fe uptake.

Topics: Ascorbic Acid; Biological Transport; Colonic Neoplasms; Humans; Intestinal Absorption; Iron; Oxidation-Reduction; Tumor Cells, Cultured

Topics: Ascorbic Acid; Carcinogens; Colonic Neoplasms; Feeding Behavior; Humans; Neoplasms; Vitamin A; Vitamin D; Vitamin E

Topics: Adenocarcinoma; Ascorbic Acid; Colonic Neoplasms; Colonic Polyps; Diet; Dietary Fiber; Risk Factors; Triticum; Vitamin E

A case-control study was conducted in Utah between July 1979 and June 1983 in which 231 cases of colon cancer identified through the Utah Cancer Registry and 391 controls identified through random digit dialing were interviewed. Odds ratios (OR) were calculated comparing the highest exposure categories with the lowest exposure categories. The highest quintile of body mass index (weight (kg)/height (m)2 for males; weight (kg)/height (m)1.5 for females) was associated with increased risk in both males (OR = 2.1) and females (OR = 2.3). In females, total dietary fat (OR = 1.9) and energy intake (OR = 1.5) were associated with an increased colon cancer risk after adjusting for age, body mass index, and crude fiber. Fiber was protective in females (OR = 0.5) after adjusting for age, body mass index, and energy intake, as was beta-carotene (OR = 0.5) after also adjusting for crude fiber. Adjusted risk estimates in males were 2.0 for total dietary fat, 3.8 for polyunsaturated fat, 2.1 for monounsaturated fat, 2.1 for energy intake, 2.5 for protein, 0.3 for fiber, 0.4 for beta-carotene, and 0.3 for cruciferous vegetables. Risk estimates differed by site of cancer within the colon. In males, protein (OR = 3.8) was a risk factor for cancer of the descending colon, while fats (OR = 2.7-8.8) increased the risk of cancer of the ascending colon. The hypotheses that dietary fat increases colon cancer risk while dietary fiber decreases colon cancer risk and that fat and protein may be independently associated with colon cancer risk are supported.

Topics: Aged; Ascorbic Acid; Body Constitution; Case-Control Studies; Colonic Neoplasms; Data Collection; Data Interpretation, Statistical; Diet; Dietary Fats; Dietary Fiber; Dietary Proteins; Energy Intake; Female; Humans; Male; Middle Aged; Odds Ratio; Random Allocation; Risk Factors; Sex Factors; Utah; Vegetables; Vitamin A

Topics: Adult; Aged; Ascorbic Acid; beta Carotene; Bronchial Neoplasms; Carotenoids; Colonic Neoplasms; Humans; Lipids; Middle Aged; Neoplasms; Prospective Studies; Risk Factors; Stomach Neoplasms; Vitamin A; Vitamin E

With the assumption of the validity of the Hardin Jones principle that the death rate of members of a homogeneous cohort of cancer patients is constant, three criteria for the validity of clinical trials of cancer treatments are formulated. These criteria are satisfied by most published clinical trials, but one trial was found to violate all three, rendering the validity of its reported results uncertain.

Topics: Ascorbic Acid; Clinical Trials as Topic; Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Double-Blind Method; Humans; Models, Statistical; Neoplasms

As part of a large-scale investigation of colorectal cancer (CRC) incidence, etiology, and survival, a case-control study was conducted to identify dietary factors associated with the risk of CRC. The study compared 715 cases with 727 age- and sex-matched community controls. A quantitative diet history, assessed to be the most representative of the previous 20 years, was obtained from each subject and analyzed for both food groups and nutrients. The combination of a high-fiber and high-vegetable intake was found to be protective against large bowel cancer. Cruciferous vegetable intake was also found, although with less certainty, to be protective. Dietary vitamin C was protective for estimated intakes greater than 230 mg/day. Dietary Beta-carotene had no separate association with the risk of CRC. Beef intake was a risk factor in males but not in females. Fat intake was a risk factor for both males and females. A low intake of milk drinks was a risk for both males and females. A high intake of pork and fish was protective. The use of vitamin supplements was highly protective. A risk score, which was calculated as the number of risk factors an individual has in his or her diet, showed an increasing monotonic relationship with risk of CRC. The effects of the dietary variables were similar for colon and rectal cancer and, with the exception of beef, were similar for males and females.

Topics: Age Factors; Animals; Ascorbic Acid; Australia; Cattle; Colonic Neoplasms; Diet; Diet Surveys; Dietary Fats; Dietary Fiber; Female; Humans; Interviews as Topic; Male; Meat; Milk; Rectal Neoplasms; Risk; Sex Factors; Vegetables; Vitamins

A case-control study was conducted to assess the role of diet in the etiology of colon cancer. Diet was measured by means of a comprehensive quantifiable food frequency history instrument in 246 cases and 484 controls drawn from the general population of Utah. Each subject's diet was described by major nutrient groups and total energy based on the nutritional content of foods reported. Cases reported higher daily food intake 5 years preceding diagnosis than controls [men, rate ratio (RR) = 2.5; women, RR = 3.6], as measured by total energy content of the diet. Higher risk of colon cancer with increasing energy intake was independent of stage of disease at diagnosis and obesity, as measured by body mass. Fat, protein, and carbohydrate intake all had elevated RRs but could not be assessed as risk factors independent of energy intake because of their strong correlations with total calories. Due to the higher energy intake of the cases, odds ratios for the daily intake of dietary fiber and vitamins A and C were also greater than 1. However, adjusting for caloric intake removed this effect, and dietary fiber showed a weak protective effect. Total energy intake must be evaluated before attempting to assign a causal role to any food or nutrient that may be postulated to play a role in colon cancer.

Topics: Adult; Aged; Ascorbic Acid; Colonic Neoplasms; Dietary Fiber; Energy Intake; Female; Humans; Male; Mental Recall; Middle Aged; Nutritional Physiological Phenomena; Regression Analysis; Risk; Vitamin A

Topics: Aged; Ascorbic Acid; beta Carotene; Carotenoids; Colonic Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Prospective Studies; Rectal Neoplasms; Smoking; Stomach Neoplasms; Switzerland; Vitamin A; Vitamin E

Relatively low concentrations of ascorbic acid inhibited the binding of the alpha-1 adrenergic antagonist [125I]HEAT [DL-[beta(3-iodo-4-hydroxyphenyl)-ethyl-aminomethyl]-tetralone) in rat submandibular gland and rat aorta. However, no inhibition was observed with this ligand in several other tissues, nor with several other ligands in these tissues. The inhibition observed was dependent on the concentration of both the ascorbic acid and the tissue. Maximal inhibition of [125I]HEAT occurred in submandibular gland at 10 microM ascorbic acid with Bmax values reduced 65% and no change in affinity. Ascorbic acid had a greater effect in assays in which less tissue was used, causing a 22% decrease in binding at 46 micrograms/ml, but a 48% decrease in binding at a tissue concentration of 12 micrograms/ml. EDTA prevented the loss of binding normally seen with ascorbic acid at a tissue concentration of 17 micrograms/ml. We suggest that, if an antioxidant is thought to be necessary in an assay system, its effects be carefully examined before routine use.

Topics: Adrenergic alpha-Antagonists; Animals; Aorta; Ascorbic Acid; Binding, Competitive; Blood Platelets; Cell Line; Cerebral Cortex; Colonic Neoplasms; Dogs; Edetic Acid; Female; Humans; In Vitro Techniques; Male; Phenethylamines; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Submandibular Gland; Tetralones

In 1979-81, 419 patients with incident cases of colon and rectal cancer and 732 controls were questioned regarding diet and alcohol. Cancer cases were a population-based series reported to the South Australian Central Cancer Registry, were 30-74 years of age, and were residing in Metropolitan Adelaide. Controls were selected from the electoral roll and individually age- and sex-matched to cancer cases. The most consistent risk factor for colorectal cancer was dietary protein, which was associated with a twofold-to-threefold relative risk for colon cancer and for rectal cancer in women for all levels of consumption above the base line (i.e., the lowest consumption quintile). For male colon cancer the corresponding relative risk was similar; but for male rectal cancer, risk was elevated only at old ages. Total energy intake and, less clearly, meal frequency were also positively associated with increased risk. Total alcohol intake (but not specifically beer) was associated with increased risk of both colon and rectal cancer in women; in both sexes, there was an increased risk of colon and rectal cancer associated with spirits consumption. A reduced risk of rectal cancer was associated with vitamin C but not with vitamin A. The increased risk associated with high protein and total energy was confined to those consuming a low fiber diet, particularly among women; but some other aspects of the relationship between fiber consumption and risk of colorectal cancer were more complex. Some modifications and extensions of the current fat-to-bile acid-to-fiber theory of bowel carcinogenesis were suggested.

Topics: Adult; Age Factors; Aged; Alcohol Drinking; Animals; Ascorbic Acid; Beer; Bile Acids and Salts; Colonic Neoplasms; Diet; Dietary Fats; Dietary Fiber; Dietary Proteins; Energy Intake; Female; Humans; Male; Middle Aged; Rats; Rectal Neoplasms; Risk; Sex Factors; Vitamin A

The organospecific, 1,2-dimethylhydrazine-induced rat tumor model was used to test tumor formation in groups of animals receiving regular chow, powdered chow with 7%/wt ascorbic acid supplement, pelleted chow with 1%/wt beta-carotene supplement, and pelleted chow with placebo beadlets. Following a 16-week induction period, animals were killed and tumor formation was recorded. Tumor formation in the ascorbic acid supplement group was found to be significantly less than the control group. The beta-carotene group showed no difference in tumor formation compared with the placebo-beadlet control group. Tumor incidence was generally the same between the two control groups, and the ascorbic acid group had significantly fewer tumors than the beta-carotene group. In sum, ascorbic acid supplements in high doses significantly decreased tumor formation, whereas beta-carotene supplements in moderately high doses had no effect on tumor formation in this model.

Topics: 1,2-Dimethylhydrazine; Animals; Ascorbic Acid; beta Carotene; Body Weight; Carotenoids; Colonic Neoplasms; Diet; Dimethylhydrazines; Male; Rats; Rectal Neoplasms

Topics: Ascorbic Acid; beta Carotene; Blood Pressure; Body Composition; Carotenoids; Colonic Neoplasms; Diet; Female; Humans; Life Style; Lipids; Lung Neoplasms; Male; Neoplasms; Prospective Studies; Risk; Smoking; Stomach Neoplasms; Vitamin B Complex; Vitamin E; Vitamins

The effects of antioxidants given in the post initiation phase of colon tumor development were investigated in male F344 rats treated with 1,2-dimethylhydrazine (DMH). Animals (20/group) were given s.c. injections of DMH at a dose of 20 mg/kg once a week for four consecutive weeks. One week after the last injection, rats were fed diet containing 5% sodium L-ascorbate (SA), 0.5% butylated hydroxyanisole (BHA), 0.8% ethoxyquin (EQ), 1.0% propyl gallate or 0.5% butylated hydroxytoluene (BHT) for 36 weeks. A control group was fed the basal diet not containing antioxidants. The experiment was terminated 40 weeks after the first injection of DMH and all intestinal tumors were confirmed histologically. SA significantly increased the incidence of adenomas and the number of tumors per rat of the colon (especially of the distal colon). Although EQ and BHT did not affect the number of rats with colon tumors, the number of tumors per rat occurring in the distal colon was significantly increased by EQ while being decreased by BHT. No modification of tumor development was observed with BHA or PG. Thus, modification of tumor development by SA, EQ and BHT was apparent, mainly in the distal colon.

Topics: 1,2-Dimethylhydrazine; Adenoma; Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carcinoma; Colonic Neoplasms; Dimethylhydrazines; Ethoxyquin; Male; Propyl Gallate; Rats; Rats, Inbred F344

The relationship between dietary factors and mortality from colon cancer was explored by an analysis of the correlation between age-adjusted colon cancer death rates for men in 38 countries and estimates of the availability of a number of dietary components. Cereals were the only source of fiber found to be negatively associated with colon cancer mortality after adjustment for the availability of total or animal fats, or total or red meats, foods that were themselves positively associated with mortality. The estimate of dietary fiber from cereals was more closely associated with mortality than that of crude fiber. The previously postulated protective effects of vitamins C and A and of cruciferous vegetables were not supported by the international data; we found no evidence of a negative association between colon cancer mortality and availability of these dietary factors. The positive association previously reported between colon cancer and beer consumption disappeared following adjustment for animal fat.

Topics: Ascorbic Acid; Colonic Neoplasms; Dairy Products; Diet; Dietary Fats; Dietary Fiber; Edible Grain; Geography; Humans; Meat; Vitamin A

p-Hydroxyphenyl lactic acid (PHA) in a concentration of 5 . 10(-5) M produced a significant inhibition of cell proliferation in response to alloantigens in a one-way mixed lymphocyte culture (MLC) in colonic cancer patients and in blast transformation in response to suboptimal doses of Con A. Multiple administration of ascorbic acid in an optimal concentration to the culture increased the proliferative response of lymphocytes to alloantigens and Con A. PHA and ascorbic acid did not exhibit any immunomodulating action during the use of healthy donors' lymphocytes or lymphocytes from colonic cancer patients, transformed with optimal mitogen doses. PHA did not affect the production of cytotoxic T lymphocytes in the MLC of the spleens of allogeneic mice but inhibited lymphocyte proliferation in response to alloantigens in the MLC of the spleens obtained from B6 and vitamin A deficient animals.

Topics: Ascorbic Acid; Cell Division; Colonic Neoplasms; Humans; In Vitro Techniques; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Lymphocytes; Phenylpropionates

Human large bowel neoplasia seems to be caused by environmental carcinogens. The experimental carcinogen, 1,2-dimethylhydrazine (DMH), must be oxidized in the body to have effect. The antioxidants, butylated hydroxyanisole (BHA) and ascorbic acid, were tested for efficacy in prevention of experimental large bowel neoplasia. Carcinogenesis was induced in female CF-1 mice by administering DMH, 20 mg/kg, sq for 24 weekly doses. Test animals received varying doses of ascorbic acid, BHA, or both agents together. Animals were sacrificed when moribund or at 35 weeks. All colons were totally embedded and analyzed histologically. Ascorbic acid demonstrated no effects on incidence or density of large bowel tumors. Ascorbic acid did increase the ratio of adenomas to adenocarcinomas. BHA decreased the incidence and density of large bowel tumors. The lowest incidence was obtained in the group receiving both agents combined. It is concluded that BHA is effective in the chemoprevention of DMH-induced large bowel neoplasms. Ascorbic acid demonstrates only modest effect. The greatest effect on tumor incidence is seen when ascorbic acid and BHA are administered together.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Adenoma; Administration, Oral; Animals; Anisoles; Ascorbic Acid; Butylated Hydroxyanisole; Colonic Neoplasms; Diet; Dimethylhydrazines; Female; Mice

It is now recognized that screening for fecal occult blood is useful to alert the clinician to possible colon cancer in an early stage. The guaiac impregnated card is not widely used because patients must maintain strict diets omitting red meat, peroxidase-containing foods, iron supplements, and ascorbic acid. The Hemo-matic Analyzer uses a special filter to adsorb fecal Hb which is then automatically washed free of interfering substances and quantitatively identified. The filter electrostatically binds Hb and not pepsinized blood or substances that interfere with occult blood testing. We evaluated the sensitivity of this device and compared it to the Hemoccult II test in vivo and in vitro. It was approximately six times more sensitive than Hemoccult II and was not influenced by the presence of ascorbic acid, plant peroxidase, or ingestion of a large quantity of rare red meat. In addition, the samples remained positive more than 10 wk after preparation. The Hemo-matic Analyzer is a useful new device that offers many advantages over Hemoccult card testing for screening for colon cancer.

Topics: Adult; Animals; Ascorbic Acid; Cattle; Colonic Neoplasms; Evaluation Studies as Topic; Hemoglobins; Horseradish Peroxidase; Humans; Male; Meat; Occult Blood; Reagent Strips

Blood plasma retinol level in normal donors and patients with colonic carcinoma was measured by high-pressure liquid chromatography and the concentration of p-hydroxyphenyl lactic and homogentizine acids by Gas Chromatograph Mass Spectrometer MAT-311A using 2H4-p-hydroxyphenylacetic acid as internal reference. The functional activity of lymphocytes was estimated from the proliferative response to alloantigens in a one-way mixed lymphocyte culture and in blast transformation reaction to Con A and pokeweed mitogen. After systematic intake of retinyl acetate and ascorbic acid in optimally high doses, the patients manifested an increase in vitamin C level in plasma and lymphocytes and a lowering of p-hydroxyphenyl lactic acid excretion. Blood plasma retinol remained unchanged. Daily intake of retinyl acetate and ascorbic acid for 8-12 days produced a significant increase of lymphocyte proliferation in response to alloantigens in mixed lymphocyte culture and blast transformation reaction to suboptimal mitogen doses.

Topics: Adult; Aged; Ascorbic Acid; Colonic Neoplasms; Diterpenes; Homogentisic Acid; Humans; Lymphocyte Activation; Middle Aged; Phenylpropionates; Retinyl Esters; Vitamin A

The possible inhibitory effect of vitamin C (sodium ascorbate) on metastases from two transplantable murine tumors was studied. The first murine tumor, colon carcinoma CA-51, was subcutaneously transplanted into male Balb/c mice. Immediately after tumor implantation, the mice were given either 1.0% sodium ascorbate or tap water. Subcutaneous tumors were surgically removed from one half of the animals in each group when the tumors reached a size of 1.5 cm. Results indicated no differences in survival, in the number of mice with metastases, or in the size of metastases between treated and untreated groups. The second murine tumor, lymphosarcoma 6C3HED, was subcutaneously implanted into C3H male and female mice. Sodium ascorbate (1.0% or 3.0%) was administered as above, but surgery was not performed. Again, no significant differences in the number of mice with metastases were observed between treated and untreated groups, with the exception of brain and regional lymph node metastases (enhanced, in males, by ascorbate).

Topics: Animals; Ascorbic Acid; Carcinoma; Colonic Neoplasms; Female; Lymphoma, Non-Hodgkin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Neoplasm Metastasis; Neoplasms, Experimental

The biological mode of action of tumor promoters, exemplified by the phorbol esters, is a subject of intensive study in a number of laboratories. A few investigators have recently begun to examine the role of dietary nutrients in tumor promotion, but the available data are sparse and interpretation difficult. A few examples are provided to indicate that some nutrients may be important in the promotion of cancer. However, the fine dividing line between effects on initiation or on promotion, so clearly shown in the mouse two-stage skin cancer model, is not so clear as yet in models used for studies in nutritional carcinogenesis. The animal models for these studies have been primarily rats, mice and hamsters. These have shown that nutrients which appear to have promotion activity are zinc deficiency and 13-cis-retinoic acid for the esophagus; vitamin A deficiency and lipotrope deficiency for the forestomach, unsaturated fat and vitamin A deficiency for liver and colon, lipotrope deficiency for the liver; selenium for the liver. It is probably more correct at this early stage of investigation to consider the effects of nutrients acting either during the time of exposure to the carcinogen, or, after such exposure and when no detectable carcinogen is found in the animals tissues, rather than as promoters in the strict sense.

Topics: Animals; Ascorbic Acid; Carcinogens; Cocarcinogenesis; Colonic Neoplasms; Cricetinae; Diet; Disease Models, Animal; Esophageal Neoplasms; Gastrointestinal Neoplasms; Liver Neoplasms; Mice; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Stomach Neoplasms; Zinc

The effect of dietary sodium ascorbate (SA) on colon carcinogenesis evoked by 1,2-dimethylhydrazine (DMH) or N-methyl-N-nitrosourea (MNU) was studied in female F344 rats. Animals were fed diets containing 0, 0.25 and 1% of SA and given s.c. a single dose of 150 mg DMH/kg body wt., 10 weekly s.c. injections of 20 mg DMH/kg body wt. or intra-rectal administration of 2 mg MNU, twice a week for 2 weeks. The incidence of colon and kidney tumors was lower in rats fed the 0.25 or 1% SA and treated with a single dose of DMH than in the animals fed the diet without SA; however, the tumour incidences did not differ between the SA- and control diet-fed animals and treated with multiple doses of DMH or MNU.

Topics: 1,2-Dimethylhydrazine; Animals; Ascorbic Acid; Colonic Neoplasms; Diet; Dimethylhydrazines; Female; Methylhydrazines; Methylnitrosourea; Neoplasms, Experimental; Nitrosourea Compounds; Rats

Topics: Ascorbic Acid; Citrus; Colonic Neoplasms; Cyclic AMP; Diet; DNA; Humans; Models, Biological; Polyps; United States

Topics: Adult; Ascorbic Acid; Colonic Neoplasms; Dietary Fats; Female; Humans; Intestinal Polyps; Middle Aged; Rectal Neoplasms

Traditional methods for prevention of large bowel cancer rely on surveillance of patients with known precursors of bowel cancer, namely ulcerative colitis and those genetically linked polyposis syndromes that have malignant potential. Identification of heritable bowel cancer families and solitary polyp--cancer families provide additional populations that merit intensive scrutiny. Persuasive, if circumstantial, evidence suggests that maintaining patients free of large bowel polyps reduces the risk of developing large bowel cancer. Prospects for prevention of large bowel cancer are extended by recognition that a diet low in fat may reduce the risk of large bowel cancer. Furthermore, there is considerable evidence in animals that a variety of antioxidants limit large bowel carcinogenesis and preliminary evidence in man that these agents may control large bowel neoplasia.

Topics: Adenoma; Ascorbic Acid; Colitis, Ulcerative; Colonic Neoplasms; Diet; Humans; Polyps; Precancerous Conditions

Ascorbic acid metabolism is associated with a number of mechanisms known to be involved in host resistance to malignant disease. Cancer patients are significantly depleted of ascorbic acid, and in our opinion this demonstrable biochemical characteristic indicates a substantially increased requirement and utilization of this substance to potentiate these various host resistance factors. The results of a clinical trial are presented in which 100 terminal cancer patients were given supplemental ascorbate as part of their routine management. Their progress is compared to that of 1000 similar patients treated identically, but who received no supplemental ascorbate. The mean survival time is more than 4.2 times as great for the ascorbate subjects (more than 210 days) as for the controls (50 days). Analysis of the survival-time curves indicates that deaths occur for about 90% of the ascorbate-treated patients at one-third the rate for the controls and that the other 10% have a much greater survival time, averaging more than 20 times that for the controls. The results clearly indicate that this simple and safe form of medication is of definite value in the treatment of patients with advanced cancer.

Topics: Adult; Aged; Ascorbic Acid; Breast Neoplasms; Bronchial Neoplasms; Colonic Neoplasms; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Rectal Neoplasms; Stomach Neoplasms; Terminal Care; Urinary Bladder Neoplasms

In a study of the vitamin C status of 50 patients with malignant disease, 46 had leucocyte levels less than the lower limit of the normal range (18-50,μg/10(8) W.B.C.) and of these 30 had very low levels (< 12.5 μg/10(8) W.B.C.). Physical signs compatible with subclinical scurvy were frequently recorded and there was a significant decrease in capillary fragility in those with the lowest levels. Most patients had an inadequate dietary intake of ascorbic acid-containing foods and this was felt to be the major factor in producing the vitamin depletion.

Topics: Adult; Ascorbic Acid; Ascorbic Acid Deficiency; Bronchial Neoplasms; Capillary Fragility; Colonic Neoplasms; Diet; Humans; Leukocytes; Lymphatic Diseases; Neoplasms; Rectal Neoplasms; Scurvy; Stomach Neoplasms

Topics: Administration, Oral; Ascorbic Acid; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Evaluation; Drug Stability; Female; Fibrosarcoma; Humans; Injections, Intravenous; Neoplasms; Papilloma; Rectal Neoplasms; Stomach Neoplasms; Time Factors; Urinary Bladder Neoplasms