beta-carotene and Cell-Transformation--Neoplastic

Pancreatic cancer has a poor prognosis and is often diagnosed at an advanced stage, which makes it difficult to treat. The low survival rate of patients with pancreatic cancer points towards an increased need for novel therapeutic and chemopreventive strategies and also early detection of this disease. Increased consumption of fruits and vegetables has been associated with a reduced risk of pancreatic cancer. Synthetic and natural, diet-derived bioactive compounds have been evaluated as pancreatic cancer chemopreventive agents and have demonstrated various degrees of efficacy in cellular and in vivo animal models. Some chemopreventive agents (for example, curcumin or resveratrol) have also been reported to sensitize pancreatic cancer cells to standard chemotherapeutic drugs (for example, gemcitabine or erlotinib), which suggests that chemopreventive agents could potentially be used as potentiators of standard chemotherapy. Few clinical trials of pancreatic cancer chemopreventive agents have been completed and some are in early phases. Further development of pancreatic cancer chemopreventive agents may prove to be tremendously valuable for individuals at high risk of developing pancreatic cancer and patients who present with premalignant lesions. This Review discusses the current state of the pancreatic cancer chemoprevention field and highlights the challenges ahead.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; beta Carotene; Camellia sinensis; Celecoxib; Cell Transformation, Neoplastic; Chemoprevention; Curcumin; Cyclooxygenase 2 Inhibitors; Deoxycytidine; Disease Models, Animal; Down-Regulation; Drug Synergism; Gemcitabine; Humans; Isothiocyanates; Pancreatic Neoplasms; Phototherapy; Pyrazoles; Sulfonamides; Tea; Vitamin D; Vitamin E

Oral leukoplakia is a relatively common oral lesion that, in a varying proportion of cases, undergoes malignant transformation. The aim of this review was to assess the effectiveness of treatments for leukoplakia. Randomized controlled trials (RCTs) enrolling patients with a diagnosis of oral leukoplakia were identified by searching biomedical databases, hand-searching relevant oral medicine journals, and contacting oral medicine experts through a European mailing list. The methodological quality of included studies was assessed on the basis of the method of allocation concealment, blindness of the study, and loss of participants. Data were analyzed by calculating relative risk. Malignant transformation of leukoplakia, demonstrated by histopathological examination, was the main outcome considered. Secondary outcomes included clinical resolution of the lesion and variation in dysplasia severity. Six RCTs were included in the review. Vitamin A and retinoids were tested in four RCTs; the other agents tested were bleomycin, mixed tea, and beta carotene. Malignant transformation was recorded in just two studies: none of the treatments tested showed a benefit when compared with placebo. Treatment with beta carotene and vitamin A or retinoids was associated with better rates of clinical remission, compared with placebo or absence of treatment. Whenever reported, a high rate of relapse was a common finding. Side effects of variable severity were often described; however, interventions were well accepted by patients since drop-out rates were similar between treatment and control groups. It is noteworthy that the possible effectiveness of surgical interventions, including laser therapy and cryotherapy, has apparently never been studied by means of an RCT. To date, in conclusion, there is no evidence of effective treatment in preventing malignant transformation of leukoplakia. Treatments may be effective in the resolution of lesion; however, relapses and adverse effects are common.

Topics: Antineoplastic Agents; beta Carotene; Bleomycin; Cell Transformation, Neoplastic; Humans; Leukoplakia, Oral; Meta-Analysis as Topic; Neoplasm Recurrence, Local; Outcome Assessment, Health Care; Phytotherapy; Randomized Controlled Trials as Topic; Research Design; Retinoids; Tea

Topics: Anticarcinogenic Agents; Antioxidants; beta Carotene; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Chemoprevention; Head and Neck Neoplasms; Humans; Leukoplakia, Oral; Retinoids; Tea

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antioxidants; beta Carotene; Cell Transformation, Neoplastic; Clinical Trials as Topic; Endpoint Determination; Genes, Tumor Suppressor; Humans; Lung Neoplasms; Proto-Oncogenes; Retinoids; Risk Factors

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; beta Carotene; Carotenoids; Case-Control Studies; Cell Transformation, Neoplastic; Diet; Free Radicals; Guinea Pigs; Humans; Incidence; Lung Neoplasms; Melanoma; Mice; Mice, Hairless; Models, Chemical; Neoplasms; Neoplasms, Radiation-Induced; Oxygen; Partial Pressure; Prospective Studies; Reactive Oxygen Species; Retrospective Studies; Selenium; Singlet Oxygen; Skin Neoplasms; Smoking; Structure-Activity Relationship; Ultraviolet Rays; Vegetables; Vitamin E

The safety of beta-carotene was reassessed by evaluating the relevant literature on the beneficial and adverse effects of beta-carotene on cancer and, in particular, by evaluating the results of toxicity studies. Beta-carotene appeared neither genotoxic nor reprotoxic or teratogenic, and no signs of organ toxicity have been found in subacute, subchronic, or chronic oral toxicity studies in experimental animals receiving doses of up to 1000 mg/day beta-carotene per kg body weight via the diet. Synthetic beta-carotene did not exert any carcinogenic effect in Sprague-Dawley rats or in CD1 mice. An enhanced risk of lung cancer was found in two human intervention studies. Although dose and (timing of) exposure, smoking status, and imbalance of antioxidant defense have been recognized as potential factors accounting for the outcome of these studies, a conclusive explanation has not yet been found. It is concluded that exposure to beta-carotene resulting in mean plasma concentrations of no more than 2.2 micromol/l (1.2 microg/ml) is safe to the general population. By contrast, in heavy smokers higher plasma concentrations may be associated with a higher lung cancer risk.

Topics: Absorption; Animals; Antioxidants; beta Carotene; Cell Transformation, Neoplastic; Chemoprevention; Drug Interactions; Humans; Lung Neoplasms; Mice; Rats; Rats, Sprague-Dawley; Skin Neoplasms; Smoking

Topics: Animals; Antioxidants; Ascorbic Acid; beta Carotene; Carcinogens; Carotenoids; Cell Transformation, Neoplastic; DNA, Neoplasm; Drug Synergism; Humans; Neoplasms, Experimental; Tumor Cells, Cultured; Vitamin E

Vitamins A (retinol, retinoids), beta-carotene (provitamin A), E (alpha-tocopherol), and C (ascorbic acid) are used in experimental, clinical and epidemiological studies for cancer chemoprevention and treatment. The cellular and metabolic effects are depending on the dose used, duration of exposure, and cancer cell type. Despite recent advances, the anticarcinogenic mechanisms remain as yet unknown. Studies regarding the role of vitamins A, beta-carotene, E and C in cancer cell biology and metabolism are of critical importance for their use in cancer treatment. Autoradiographic, ultrastructural and cell surface studies demonstrated that vitamins A, E and C are strong regulator factors of cancer cell differentiation, cell regression, membrane biogenesis, DNA, RNA, protein, and collagen synthesis, as well as transformation of precancer cells into cancer cells. These vitamins exert cytotoxic and cytostatic effects, and may reverse the cancer cell to the normal phenotype. Interrelation of vitamins A, E and C with oncogenes and growth factors play an important role in cancer cell biology. The data presented in this review can provide new insights for the understanding of anticarcinogenic mechanisms, and a rationale for the use of vitamins A, E and C in cancer chemo-prevention and treatment.

Topics: Animals; Anticarcinogenic Agents; Ascorbic Acid; beta Carotene; Carotenoids; Cell Transformation, Neoplastic; Humans; Neoplasms; Vitamin A; Vitamin E

Epidemiological studies have shown that diets rich in one or more antioxidant nutrients may reduce the risk of cancers of the lung, uterine cervix, mouth, and gastrointestinal tract. Study of premalignant lesions offers a comparatively expedient approach to identifying and evaluating the efficacy of the cancer chemopreventive components of foods. Some recent findings suggest roles for beta-carotene and/or vitamin C in reversing or reducing the risk of cervical dysplasia and oral leukoplakia. There are some indications that vitamin C and beta-carotene may reduce the risk of atrophic gastritis and gastric cancer. Additional epidemiological and molecular biology studies and clinical intervention trials using premalignant lesions as the marker of specific cancer risks should become an important component of future research in the area of cancer chemoprevention.

Topics: Ascorbic Acid; beta Carotene; Carotenoids; Cell Transformation, Neoplastic; Diet; Female; Humans; Neoplasms; Precancerous Conditions; Vitamin E

Management of oral leukoplakia-a potentially malignant disorder-is currently not evidence-based. Of the few randomized trials that have been reported, most have negative data. Therefore, a multi-centre, randomized, double-blind controlled trial (RCT) was undertaken to evaluate the use of low-dose beta-carotene combined with vitamin C supplements for the treatment and to prevent malignant transformation of oral leukoplakia. 46 Japanese participants with oral leukoplakia were allocated randomly either to an experimental arm (10 mg day(-1) of beta-carotene and 500 mg day(-1) of vitamin C) or placebo arm (50 mg day(-1) of vitamin C). Current or ex-smokers within 3 months of cessation were excluded. The supplements were continued over a period of 1 year. The primary endpoint was clinical remission at 1-year and the likelihood of malignant transformation during a 5-year follow-up period as a secondary endpoint. The overall clinical response rate in the experimental arm was 17.4% (4/23) and 4.3% (1/23) in the placebo arm (p = 0.346). During the median 60-month follow-up period, two subjects in the experimental arm and three in the control arm developed oral cancer. Under the intention-to-treat principle, relative risk by supplementing with beta-carotene and vitamin C was 0.77 (95%CI: 0.28-1.89) (p = 0.580) by the Cox proportional hazards model. No unfavorable side-effects were noted. Beta-carotene (10 mg day(-1) ) and vitamin C were neither effective for clinical remission, nor for protection against the development of cancer. Data from this RCT does not support the hypothesis that chemoprevention with this treatment is effective for oral leukoplakia.

Topics: Adult; Aged; Ascorbic Acid; beta Carotene; Cell Transformation, Neoplastic; Dietary Supplements; Disease Progression; Female; Follow-Up Studies; Humans; Leukoplakia, Oral; Male; Middle Aged; Risk Factors; Treatment Outcome

High intakes of carotenoid-rich fruits and vegetables are associated with a reduced risk of various cancers including colon cancer. A human intervention study with carrot and tomato juice should show whether a diet rich in carotenoids, especially high in beta-carotene and lycopene, can modify luminal processes relevant to colon carcinogenesis. In a randomised cross-over trial, twenty-two healthy young men on a low-carotenoid diet consumed 330 ml tomato or carrot juice per d for 2 weeks. Intervention periods were preceded by 2-week depletion phases. At the end of each study period, faeces of twelve volunteers were collected for chemical analyses and use in cell-culture systems. Consumption of carrot juice led to a marked increase of beta-carotene and alpha-carotene in faeces and faecal water, as did lycopene after consumption of tomato juice. In the succeeding depletion phases, carotenoid contents in faeces and faecal water returned to their initial values. Faecal water showed high dose-dependent cytotoxic and anti-proliferative effects on colon adenocarcinoma cells (HT29). These effects were not markedly changed by carrot and tomato juice consumption. Neither bile acid concentrations nor activities of the bacterial enzymes beta-glucosidase and beta-glucuronidase in faecal water changed after carrot and tomato juice consumption. Faecal water pH decreased only after carrot juice consumption. SCFA were probably not responsible for this effect, as SCFA concentrations and profiles did not change significantly. In summary, in the present study, 2-week interventions with carotenoid-rich juices led only to minor changes in investigated luminal biomarkers relevant to colon carcinogenesis.

Topics: Adult; beta Carotene; Beverages; Biomarkers, Tumor; Carotenoids; Cell Death; Cell Proliferation; Cell Transformation, Neoplastic; Colonic Neoplasms; Cross-Over Studies; Daucus carota; Feces; Humans; Lycopene; Male; Solanum lycopersicum; Tumor Cells, Cultured; Water

Gastric cancer is one of the most common malignancies worldwide. Histopathologic studies have identified a sequence of changes in the gastric mucosa that mark the slow progression from normal tissue to carcinoma. Epidemiologic evidence suggests that a diet rich in fresh fruit and vegetables could be a protective factor against this disease. This effect may be mediated through antioxidant vitamins.. A randomized, double-blind chemoprevention trial was conducted among 1980 subjects in Tachira State, Venezuela (whose population is at high risk for gastric cancer), to determine the effect of dietary supplementation with vitamin C, vitamin E, and beta-carotene on the progression and regression of precancerous gastric lesions. Subjects were randomly assigned to receive either a combination of vitamin C (750 mg/day), vitamin E (600 mg/day), and beta-carotene (18 mg/day) or placebo for 3 years. Changes in the gastric mucosa were determined by histologic diagnosis based on five biopsies taken from prespecified areas of the stomach at baseline and annually for 3 years. All biopsies were reviewed by a single expert pathologist. Progression rates (and regression rates) were calculated by comparing the first and last available gastroscopies for each subject and dividing the number of subjects whose diagnoses increased (decreased) in severity by the total follow-up time. Overall rate ratios were calculated by Poisson regression, controlling for baseline diagnosis. All statistical tests were two-sided.. Median plasma vitamin levels were increased in the treatment group between baseline and 1 year after randomization from 0.43 micromol/L (interquartile range [IQR] = 0.26-0.69) to 2.89 micromol/L (IQR = 1.76-4.22) for beta-carotene, from 26.7 micromol/L (IQR = 23.1-31.2) to 54.9 micromol/L (IQR = 42.8-67.6) for alpha-tocopherol, and from 47.70 micromol/L (IQR = 36.9-58.5) to 61.9 micromol/L (IQR = 52.2-72.7) for vitamin C. Overall progression rates per 100 person-years were 74.3 in the placebo group and 67.8 in the group randomly assigned to vitamins. Overall regression rates were 109.4 in the placebo group and 116.5 in the group randomly assigned to vitamins. There was no statistically significant difference in progression rate (rate ratio = 0.92, 95% confidence interval [CI] = 0.74 to 1.15) or regression rate (rate ratio = 1.09, 95% CI = 0.90 to 1.33) between vitamin and placebo groups.. Supplementation with antioxidant micronutrients is not an effective tool for gastric cancer control in this high-risk population. The results of this trial are consistent with previous findings on the lack of effect of nutritional supplementation on precancerous gastric lesions.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; beta Carotene; Cell Transformation, Neoplastic; Disease Progression; Double-Blind Method; Female; Gastric Mucosa; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Logistic Models; Male; Middle Aged; Patient Selection; Precancerous Conditions; Risk Assessment; Sample Size; Smoking; Stomach Neoplasms; Treatment Failure; Venezuela; Vitamin E; Vitamins

Previous research has identified a high risk of gastric carcinoma as well as a high prevalence of cancer precursor lesions in rural populations living in the province of Nariño, Colombia, in the Andes Mountains.. A randomized, controlled chemoprevention trial was conducted in subjects with confirmed histologic diagnoses of multifocal nonmetaplastic atrophy and/or intestinal metaplasia, two precancerous lesions. Individuals were assigned to receive anti-Helicobacter pylori triple therapy and/or dietary supplementation with ascorbic acid, beta-carotene, or their corresponding placebos. Gastric biopsy specimens taken at baseline were compared with those taken at 72 months. Relative risks of progression, no change, and regression from multifocal nonmetaplastic atrophy and intestinal metaplasia were analyzed with multivariate polytomous logistic regression models to estimate treatment effects. All statistical tests were two-sided.. All three basic interventions resulted in statistically significant increases in the rates of regression: Relative risks were 4.8 (95% confidence interval [CI] = 1.6-14.2) for anti-H. pylori treatment, 5. 1 (95% CI = 1.7-15.0) for beta-carotene treatment, and 5.0 (95% CI = 1.7-14.4) for ascorbic acid treatment in subjects with atrophy. Corresponding relative risks of regression in subjects with intestinal metaplasia were 3.1 (95% CI = 1.0-9.3), 3.4 (95% CI = 1.1-9.8), and 3.3 (95% CI = 1.1-9.5). Combinations of treatments did not statistically significantly increase the regression rates. Curing the H. pylori infection (which occurred in 74% of the treated subjects) produced a marked and statistically significant increase in the rate of regression of the precursor lesions (relative risks = 8.7 [95% CI = 2.7-28.2] for subjects with atrophy and 5.4 [95% CI = 1.7-17.6] for subjects with intestinal metaplasia).. In the very high-risk population studied, effective anti-H. pylori treatment and dietary supplementation with antioxidant micronutrients may interfere with the precancerous process, mostly by increasing the rate of regression of cancer precursor lesions, and may be an effective strategy to prevent gastric carcinoma.

Topics: Adult; Aged; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; beta Carotene; Biopsy; Cell Transformation, Neoplastic; Disease Progression; Drug Therapy, Combination; Female; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Logistic Models; Male; Middle Aged; Precancerous Conditions; Remission, Spontaneous; Risk; Stomach; Stomach Neoplasms; Treatment Outcome

Biomarkers are being sought that could serve as surrogate end points for chemoprevention trials. Micronuclei, cytoplasmic fragments of DNA, have been proposed as a biomarker and studied in oral pre-malignancy. This study evaluated micronuclei frequency in a randomized chemoprevention trial of oral pre-malignancy. A recent clinical trial evaluated the responses of pre-malignant oral lesions to 3 months of therapy with isotretinoin followed by 9 months of either low-dose isotretinoin or beta-carotene. For 57 study participants, micronuclei were counted in mucosal scrapings of the lesion and in normal-appearing mucosa at baseline and following 3 months and 12 months of therapy. Micronuclei counts were higher in scrapings from the lesion than in the normal-appearing mucosa. Following 3 months of isotretinoin, the micronuclei counts in scrapings of the lesion were significantly reduced. With treatment, the mean micronuclei count declined at 3 months. In a randomized comparison, both isotretinoin and beta-carotene maintained the suppression of micronuclei. The change in micronuclei count was not associated with the clinical or histological response to treatment. Chemoprevention treatment with isotretinoin led to a reduction in frequency of micronuclei, a marker of recent DNA injury, which was then maintained by both isotretinoin and beta-carotene.

Topics: beta Carotene; Biomarkers, Tumor; Carotenoids; Cell Transformation, Neoplastic; Female; Humans; Isotretinoin; Leukoplakia, Oral; Male; Micronuclei, Chromosome-Defective; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Precancerous Conditions; Remission Induction; Statistics, Nonparametric

A randomized nutrition intervention trial was conducted among 29,584 adult residents of Linxian, China, to examine the effects of vitamin/mineral supplementation on the occurrence of esophageal/gastric cardia cancer in this high-risk population. A fractional factorial study design allowed evaluations of four different combinations of nutrients: (A) retinol and zinc; (B) riboflavin and niacin; (C) vitamin C and molybdenum; and (D) beta-carotene, vitamin E, and selenium. During the 5.25-year intervention, significant reductions in total mortality, total cancer mortality, and stomach cancer mortality occurred among those receiving beta-carotene, vitamin E, and selenium. At the end of intervention, an endoscopic survey was carried out in a sample of subjects to see if the nutritional supplements had affected the prevalence of clinically silent precancerous lesions and early invasive cancers of the esophagus or stomach. Endoscopy was performed on 391 individuals from two study villages. The prevalences of esophageal and gastric dysplasia and cancer were compared by nutrient factor. Cancer or dysplasia was diagnosed in 15% of the participants. No statistically significant reductions in the prevalence of esophageal or gastric dysplasia or cancer were seen for any of the four vitamin/mineral combinations. The greatest reduction in risk (odds ratio, 0.38; P = 0.09) was seen for the effect of retinol and zinc on the prevalence of gastric cancer. Although no significant protective effects were seen in this endoscopic survey, there was a suggestion that supplementation with retinol and zinc may protect against the development of gastric neoplasia in this high-risk population. Additional studies with larger numbers of endpoints will be needed to further evaluate this possibility.

Topics: Adenocarcinoma; Adult; Aged; Ascorbic Acid; beta Carotene; Carotenoids; Cell Transformation, Neoplastic; China; Cross-Cultural Comparison; Cross-Sectional Studies; Double-Blind Method; Endoscopy, Gastrointestinal; Esophageal Neoplasms; Esophagus; Female; Gastric Mucosa; Humans; Incidence; Male; Middle Aged; Minerals; Molybdenum; Niacin; Precancerous Conditions; Riboflavin; Rural Population; Selenium; Stomach Neoplasms; Survival Rate; Vitamin A; Vitamin E; Vitamins; Zinc

Linxian, China has some of the highest rates of esophageal/gastric cardia cancer in the world, and epidemiological evidence suggests that chronically low intake of micronutrients may contribute to these high cancer rates. To examine whether supplementation with multiple vitamins and minerals can affect the occurrence of esophageal/gastric cardia cancer in this population, a two-arm randomized nutrition intervention trial was conducted among 3318 Linxian residents with cytological evidence of esophageal dysplasia. During the 6-year intervention, esophageal/gastric cardia cancer mortality was 8% lower among those receiving the active supplements. After 30 and 72 months of intervention, endoscopic surveys were carried out to see if the nutritional supplements had affected the prevalence of clinically silent precancerous lesions and early invasive cancers of the esophagus and stomach. In the first survey, in 1987, 833 subjects were endoscoped; in the second survey, in 1991, 396 subjects were examined. The histological diagnoses from each survey were compared by treatment group. Cancer or dysplasia was diagnosed in 28% of the subjects endoscoped in 1987 and 24% of those examined in 1991. The odds ratio for subjects in the treatment group (versus those in the placebo group) having esophageal or gastric dysplasia or cancer was 0.84 (95% confidence interval, 0.61-1.15) in 1987 and 0.86 (0.54-1.38) in 1991. Although modest protective effects on worst overall diagnosis were seen in the supplemented group in both surveys, none of the results was statistically significant, and the findings must be considered inconclusive.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Adult; Aged; Ascorbic Acid; beta Carotene; Carotenoids; Cell Transformation, Neoplastic; Cross-Cultural Comparison; Double-Blind Method; Endoscopy, Gastrointestinal; Esophageal Neoplasms; Esophagus; Female; Follow-Up Studies; Gastric Mucosa; Humans; Male; Middle Aged; Minerals; Molybdenum; Niacin; Precancerous Conditions; Riboflavin; Rural Population; Selenium; Stomach Neoplasms; Survival Rate; Vitamin A; Vitamin E; Vitamins; Zinc

The goal of this study was to investigate the effects of beta-carotene and astaxanthin (ASX) - carotenoid without provitamin A activity on the proliferation and differentiation of rat oval cells (OC) in vitro. Oval cells were isolated from two groups of animals: I - partial hepatectomised (PH) and II- diethylnitrosamine (DEN) treated rats. At various time points cell lysates were separated by PAGE. For immunodetection primary antibodies against CD-34, Ck19 and albumin were used. Medium concentration of fibrinogen and haptoglobin was measured. Mitochondrial competence of cells was expressed as the proliferation index. In comparison to HP- and DEN-obtained oval cells cultured without carotenoids, the addition of beta-carotene and ASX increased albumin expression during the experimental period. The same condition didn't reveal CK19 expression. CD34 expressed by oval cells was detected up to the 5(th) week of beta-carotene and ASX absence in the medium. beta-carotene addition resulted in a decrease of the proliferative activity of OC, with significant changes in 48 h, the 5(th) and 15(th) week of incubation. ASX (p < or = 0.05) inhibited the proliferation, especially in 24h and 5(th) week of cell culture. In respect to haptoglobin concentration, its maximum value after the 10(th) week was observed. The fibrinogen level obtained from DEN-oval cells incubated with beta-carotene elevated from 480+/-6.87 microg/ml after 24h to 5520+/-34,56 microg/ml after the 15(th) week. In a condition without carotenoids fibrinogen concentration did not exceed 2280+/-31.5 microg/ml after the 15(th) week of cell culture.

Topics: Animals; Anticarcinogenic Agents; beta Carotene; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic; Diethylnitrosamine; Female; Fibrinogen; Haptoglobins; Hepatectomy; Liver; Liver Neoplasms, Experimental; Rats; Rats, Wistar; Tumor Cells, Cultured; Xanthophylls

Carotenoids have been implicated in numerous epidemiological studies as being protective against cancer at many sites, and their chemopreventive properties have been confirmed in laboratory studies. Astaxanthin (AST), primarily a carotenoid of marine origin, responsible for the pink coloration of salmon, shrimp and lobster, has received relatively little attention. As with other carotenoids, its highly lipophilic properties complicate delivery to model systems. To overcome this issue we have synthesized a novel tetrasodium diphosphate astaxanthin (pAST) derivative with aqueous dispersibility of 25.21 mg/ml. pAST was delivered to C3H/10T1/2 cells in an aqueous/ethanol solution and compared with non-esterified AST dissolved in tetrahydrofuran. We show pAST to (i) upregulate connexin 43 (Cx43) protein expression; (ii) increase the formation of Cx43 immunoreactive plaques; (iii) upregulate gap junctional intercellular communication (GJIC); and (iv) cause 100% inhibition of methylcholanthrene-induced neoplastic transformation at 10(-6) M. In all these assays, pAST was superior to non-esterified AST itself; in fact, pAST exceeded the potency of all other previously tested carotenoids in this model system. Cleavage of pAST to non-esterified (free) AST and uptake into cells was also verified by HPLC; however, levels of free AST were approximately 100-fold lower than in cells treated with AST itself, suggesting that pAST possesses intrinsic activity. The dual properties of water dispersibility (enabling parenteral administration in vivo) and increased potency should prove extremely useful in the future development of cancer chemopreventive agents.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Benzoates; beta Carotene; Carotenoids; Cell Line; Cell Transformation, Neoplastic; Fibroblasts; Gap Junctions; Mice; Mice, Inbred C3H; Retinoids; Xanthophylls

In order to study the protection of beta-carotene and vitamin C against the transformation of human lung fibroblasts (HLF) cell induced by nickel sesquioxide, HLF cells were treated repeatedly by different concentrations of Ni2O3 in vitro. beta-carotene (5.4 mg/L) and vitamin C(1.8 mg/L) were added into the media containing Ni2O3(1.0 mg/L) respectively. The identification of malignancy of the transformation of HLF cell was carried out by the tests of ConA and the growth on semisolid agar culture. The results showed that Ni2O3 could induce the malignant transformation of HLF cell. The transformed cell proliferated rapidly. The transformed colonies exhibited in extensively random orientation and the cells were crossingover. The frequency of transformation showed a dose-response relation at the experimental concentrations. The transformed cell could be agglutinated by lower concentration of ConA and could grow in semisolid agar. The frequencies of transformation of HLF cell exposed to beta-carotene and vitamin C were decreased significantly. The cells could not be agglutinated by ConA and not grow in semisolid agar. It was concluded that Ni2O3 could induce strongly the malignant transformation of HLF cell and might be carcinogenic to human. The protection of beta-carotene and vitamin C on the transformation of HLF cell induced by Ni2O3 was observed. The increase of foods riched in beta-carotene and vitamin C was suggested for workers exposed to nickel.

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Cell Transformation, Neoplastic; Cells, Cultured; Fibroblasts; Lung; Nickel

We previously found that beta-carotene (betaCT) can act as a co-carcinogenic agent enhancing the cell transforming activity of powerful carcinogens such as benzo(a)pyrene (B(a)P) and cigarette-smoke condensate (TAR) in an in vitro medium-term ( approximately 8 weeks) experimental model utilizing BALB/c 3T3 cells (Mutat. Res. 440 (1999) 83-90). Here, we investigated whether vitamin E (VitE) and alpha-naphthoflavone (alphaNF) are able to affect the co-carcinogenic activity of betaCT in terms of inhibiting B(a)P and TAR cell transforming potential. The following experimental schedules were performed: (i) cultures treated for 72 h with chemicals in various experimental combinations (acute treatment); (ii) cultures grown in presence of tester agents for the whole period of the assay (chronic treatment) to more closely mimic human exposure. While the co-carcinogenic potential of betaCT was confirmed on both B(a)P and TAR, the latter being ineffective by itself, we found in repeated experiments that the presence of VitE or alphaNF significantly reduced the betaCT's enhancing effect in the formation of transformation foci by B(a)P and TAR. The mechanism of the inhibition could be explained by the known ability of alphaNF to inhibit cytochrome P450-linked B(a)P-bioactivating monooxygenases, while VitE may contrast the prooxidant activity of betaCT (e.g., oxygen radicals overgeneration). While highlighting the importance of increasing knowledge of the role of single provitamins, vitamins and micronutrients, our findings also underline the potential advantages of combining several dietary supplements in in vitro preventive investigations.

Topics: 3T3 Cells; Animals; Benzo(a)pyrene; Benzoflavones; beta Carotene; Biotransformation; Carcinogens; Cell Transformation, Neoplastic; Cocarcinogenesis; Drug Interactions; Humans; Mice; Nicotiana; Plants, Toxic; Smoke; Vitamin E

8-Hydroxy-2'-deoxyguanosine (OH8dG) is one of the most prevalent oxidative DNA modifications found in eukaryotic cells. Previous studies have suggested an association between OH8dG formation and carcinogenesis. However, it is unclear whether OH8dG formation results in the necessary genotoxic events for cancer development. In the present study, the formation of OH8dG and its ability to transform Syrian hamster embryo (SHE) cells was examined. Methylene blue, a photosensitizer that in the presence of light can generate singlet oxygen by a type II mechanism, was used to produce oxidative DNA damage (predominantly OH8dG) in SHE cells. Photoactivated methylene blue produced a dose-dependent increase in OH8dG as well as a dose-dependent increase in morphological transformation in SHE cells. SHE cells transfected with DNA that contained increasing concentrations of OH8dG displayed a dose-dependent increase in morphological transformation. Treatment with beta-carotene (a singlet oxygen quencher) inhibited both the formation of OH8dG and the induction of morphological transformation in photoactivated methylene blue-treated SHE cells. These results suggest that formation of OH8dG can induce morphological transformation and provide further support for a role of OH8dG formation in the carcinogenesis process.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; beta Carotene; Cell Transformation, Neoplastic; Cricetinae; Deoxyguanosine; Dose-Response Relationship, Drug; Embryo, Mammalian; Free Radical Scavengers; Mesocricetus; Methylene Blue; Transfection

9-cis beta-Carotene was extracted from a commercial extract of the algae Dunaliella salina (Betatene), and its actions on proliferation and gene expression were examined in murine 10T1/2 cells and human HaCaT keratinocytes. The 9-cis isomer was less active than all-trans beta-carotene in reducing proliferation and in upregulating expression of connexin 43 in 10T1/2 cells. However, it had comparable ability to suppress carcinogen-induced neoplastic transformation. When tested in HaCaT cells in organotypic culture, it was less active in inducing connexin 43 expression and suppressing expression of keratin K1. In this assay the all-trans isomer was highly active at 10(-6) M, whereas 10(-5) M 9-cis beta-carotene was required to produce a comparable effect. Only small reductions in expression of the basal keratin 5 were seen. All-trans and 9-cis retinoic acids, potential metabolites of beta-carotene isomers, were studied in the same systems. In contrast to the carotenoids, the 9-cis isomer of retinoic acid was approximately 10-fold more active in suppressing neoplastic transformation and inducing connexin 43 expression in both cell types than the all-trans isomer. The retinoic acid isomers were about equipotent in suppressing K1 expression. Cellular levels of 9-cis beta-carotene were approximately 3.5-fold lower than levels of all-trans beta-carotene, suggesting that part, but not all, of this decreased activity of the 9-cis isomer was due to decreased cell uptake. Thus 9-cis beta-carotene is consistently less active than the all-trans isomer; that 9-cis retinoic acid is, in general, much more potent than the all-trans isomer suggests little or no conversion from the carotenoid to the retinoid under these culture conditions.

Topics: Animals; beta Carotene; Cell Division; Cell Line; Cell Transformation, Neoplastic; Chlorophyta; Chromatography, High Pressure Liquid; Connexin 43; Gene Expression; Humans; Immunoblotting; Isomerism; Keratinocytes; Keratins; Kinetics; Mice; Tumor Cells, Cultured

We report the ability of beta-carotene (betaC) to affect the cell transforming activity of 3-methylcholanthrene (3-MCA), benzo(a)pyrene (B(a)P) and cigarette-smoke condensate (TAR) in an in vitro medium-term (approximately 8 weeks) experimental model utilizing BALB/c 3T3 cells. Different experimental schedules were performed either in the presence or absence of betaC: (i) cultures treated for 72 h with each chemical (acute treatment), (ii) cultures grown in presence of each chemical for the whole period of the experiment (chronic treatment). These procedures suggested a possible cocarcinogenic potential of the carotenoid following interactions with other chemicals mimicking continuous human exposition to several xenobiotics. Although the pigment did not show any cell transforming potential when tested alone either in acute or chronic treatment, it did augment that of other tested agents. Induction of cell transformation by B(a)P was markedly enhanced by the presence of this carotenoid in either acute or chronic treatment. Only in presence of betaC, was TAR able to significantly act as a cell transforming agent in prolonged, chronic treatment of cultures. Enhanced cell transformation activity could be due to the boosting effect of betaC on P450 apparatus. Indeed, elsewhere we have found that the latter increased the ratio of formation of diol epoxide carcinogenic metabolites of B(a)P as well as other carcinogens present in TAR. By contrast, no differences of cell transforming activity of 3-MCA, an ultimate carcinogen, were seen either in the presence or absence of betaC under the various experimental conditions. These data, which are in keeping with the cocarcinogenic potential of betaC, may help to explain the unexpected lung cancer increases obtained in chemoprevention trials in heavy smokers supplemented with the isoprenoid. Our findings also highlight the potential risk to humans derived from interactions among xenobiotics present in the environment.

Topics: 3T3 Cells; Animals; Benzo(a)pyrene; beta Carotene; Carcinogens; Cell Survival; Cell Transformation, Neoplastic; Clone Cells; Cocarcinogenesis; Drug Synergism; Methylcholanthrene; Mice; Mice, Inbred BALB C; Smoke

In vitro changes of normal human keratinocytes (NHKs) derived from the oral mucosa after treatment with the chemical carcinogen 7,12 dimethylbenz[a]anthracene (DMBA; 5, 50, 200 ng/10 ml) were evaluated. NHKs were also treated with chemopreventive nutrient agents that previously had enhanced growth of epidermal and oral keratinocytes or suppressed growth of oral squamous cell carcinoma. These agents included the carotenoids beta-carotene and canthaxanthin and the retinoid retinyl palmitate (60 microM). Plating efficiency, growth in agarose (independent growth), viability [tetrazolium salt (MTT) assay], and proliferation ([3H]thymidine labeling) defined the growth of NHKs. The number of cornified cells and keratin expression (high-molecular-weight keratin) defined differentiation. gamma-Glutamyl transpeptidase, p53 expression, and tumorigenesis in mice defined oxidation and malignant transformation. Treatment with DMBA (50 ng/10 ml) was detected by autofluorescence; it produced an increase in pleomorphism and multinucleation and enhanced plating efficiency and the number of colonies grown in agarose. Chemopreventive treatment enhanced the number of colonies grown in agarose, but the MTT levels and [3H]thymidine incorporation-proliferation (24 h) were reduced. Chemopreventives also increased differentiation defined by the number of cornified cells and the expression of high-molecular-weight keratin-positive cells. Malignant transformation potential was depressed by reducing gamma-glutamyl transpeptidase and mutant p53 expression, whereas tumor suppressor p53 was enhanced. NHKs treated with DMBA and injected into nude mice (nu/nu: 1 x 10(6) cells/0.25 ml) produced tumor masses (3 of 3 animals), whereas the nutrient and DMBA groups produced smaller tumor masses, some with central ulcers (2 of 3 animals). Mock injection of untreated or nutrient-treated NHKs without DMBA treatment did not produce a tumor mass (0 of 3 animals). beta-Carotene, retinyl palmitate, and canthaxanthin increased differentiation and reduced transformation induced by DMBA in oral NHKs.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adult; Animals; Anticarcinogenic Agents; beta Carotene; Canthaxanthin; Carcinogens; Cell Division; Cell Transformation, Neoplastic; Chromatography, High Pressure Liquid; Diterpenes; Flow Cytometry; Gene Expression Regulation; Humans; Immunohistochemistry; Keratinocytes; Male; Mice; Mice, Nude; Mouth Mucosa; Mouth Neoplasms; Retinyl Esters; Vitamin A

Topics: Anticarcinogenic Agents; beta Carotene; Carotenoids; Cell Transformation, Neoplastic; Humans; Lycopene; Male; Prostatic Neoplasms; Risk Factors; Vitamin A; Vitamin E

Although cigarette smoking is one major determinant of lung carcinogenesis, not all smokers develop cancer. This phenomenon is due to individual variation in genetic susceptibility to carcinogens, nutrition, and lifestyle. Previous studies have shown that genetic polymorphism of metabolic enzymes and plasma micronutrients are associated with lung cancer risk. DNA adducts may serve as a molecular dosimeter for exposure to carcinogens. In this cross-sectional study, we analyzed the blood samples of 158 subjects to evaluate the effects of polymorphisms of cytochrome P450 1A1 (CYP1A1), glutathione S-transferase M1 (GSTM1), T (GSTT), N-acetytransferase 2 (NAT2), and aldehyde dehydrogenase 2 (ALDH2) as well as the effects of plasma beta-carotene and alpha-tocopherol on lymphocyte DNA adducts measured by 32P-postlabeling analysis. The DNA adduct level of smokers (mean +/- SD, 1.26 +/- 0.79/10(8) nucleotides) was significantly higher than that of nonsmokers (0.87 +/- 0.33, P = 0.007). Smokers with CYP1A1 minor homozygotes and GSTM1 null genotypes had a significantly higher level of DNA adducts than those without (P = 0.027 for homozygotes, P = 0.049 for heterozygotes). Smokers with NAT2 minor homozygotes also tended to have a higher DNA adduct level than those with heterozygotes and wild alleles, but the difference was not statistically significant. The DNA adduct level of smokers with ALDH2 heterozygotes was significantly higher than that of smokers with minor homozygotes (P = 0.045). When smokers were divided into "high" and "low" groups according to mean level of plasma beta-carotene or alpha-tocopherol, in the low beta-carotene group, the subjects with CYP1A1 minor homozygotes had higher DNA adduct levels than those with other CYP1A1 genotypes. Smokers with GSTT null genotype and high beta-carotene tended to have a higher DNA adduct level than those with GSTT present and high beta-carotene (P = 0.07), and those with GSTT null genotype and low beta-carotene (P = 0.07). There was weak correlation between DNA adduct level and number of cigarettes smoked per day in the low plasma beta-carotene group (r = 0.28, n = 36, p < 0.1). These results suggested that polymorphisms of CYP1A1, GSTM1, T, NAT2, and ALDH2, and plasma beta-carotene may modulate the level of DNA adducts.

Topics: Adolescent; Adult; beta Carotene; Cell Transformation, Neoplastic; Cross-Sectional Studies; DNA Adducts; Enzymes; Humans; Life Style; Lung Neoplasms; Lymphocytes; Male; Middle Aged; Nutritional Status; Polymorphism, Genetic; Smoking; Vitamin E

Topics: Anticarcinogenic Agents; beta Carotene; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Follow-Up Studies; Head and Neck Neoplasms; Humans; Isotretinoin; Mouth Neoplasms; Time Factors; Treatment Outcome

We compared the ability of all-transretinoic acid (RA), all-trans-retinoyl-beta-D-glucuronide (RAGL), and all-trans-beta-carotene (BC) to inhibit growth and to induce differentiation of the human promyelocytic leukemia cell line HL-60 into morphologically mature granulocytes. BC was made water-soluble by the solutol-solvent-system. RA (1 microM) could induce differentiation of 85% of the HL-60 cells after a total incubation time of 180 hours, RAGL (5 microM) induced 64% of the cells, whereas 33% of the HL-60 cells were differentiated after incubation with BC (10 microM), which was determined by assessing cell functional capacity to reduce nitroblue tetrazolium dye in response to phorbolesters. The absence of RA in RAG and BC treated cells gives strong evidence that RAG and BC exert intrinsic biological effects.

Topics: Antioxidants; beta Carotene; Cell Division; Cell Survival; Cell Transformation, Neoplastic; HL-60 Cells; Humans; Time Factors; Tretinoin

Topics: beta Carotene; Carcinogens; Cell Transformation, Neoplastic; Chemoprevention; Environmental Exposure; Humans; Imidazoles; Mutagens; Neoplasms; Neoplasms, Unknown Primary; Precancerous Conditions; Primary Prevention; Quinoxalines; Risk Factors

Liarozole has been reported to inhibit P450 enzymes responsible for the catabolism of retinoic acid. This suggests that it may increase the effectiveness of cancer chemopreventive agents, such as retinoic acid, and pro-vitamin A carotenoids, such as beta-carotene, which may yield retinoids. To test this we have utilized the 10T1/2 cell assay system of neoplastic transformation. Simultaneous treatment with Liarozole (10(-5) M) potentiated by a factor of 1000 the ability of low concentrations of retinoic acid (10(-10) M) to inhibit carcinogen-induced neoplastic transformation, to up-regulate gap junctional communication and to increase connexin43 expression. When tested under conventional culture conditions, Liarozole itself partially suppressed neoplastic transformation and up-regulated gap junctional communication; this ability appears due to the presence of retinol in the serum component of cell culture medium. When assays for junctional communication and of connexin43 expression were performed under defined conditions, in the absence of serum, Liarozole was ineffective alone, yet still augmented the effects of retinoic acid. HPLC analysis of cell culture medium demonstrated that Liarozole (10(-5) M) completely protected retinoic acid (10(-6) M) from catabolism over a 48 h period. Potential effects of Liarozole on the activities of carotenoids were also examined. Inhibition of neoplastic transformation by the pro-vitamin A carotenoid beta-carotene, but not by the non-pro-vitamin A carotenoid canthaxanthin, was moderately potentiated by Liarozole. The augmentation of response to beta-carotene was more apparent when tested under defined conditions; here Liarozole strongly increased junctional communication and Cx43 expression. In contrast, Liarozole did not potentiate the activity of canthaxanthin under defined conditions, while increasing the activity of 4-keto retinoic acid, a likely metabolite. Liarozole also elevated connexin43 expression in early passage human fibroblasts. These data indicate that rapid catabolism of retinoic acid limits its in vitro activities, that a portion of the action of beta-carotene as a cancer preventive agent is due to its conversion to retinoic acid and that canthaxathin exerts its chemopreventive action largely independent of conversion to 4-keto retinoic acid.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; beta Carotene; Carotenoids; Cell Communication; Cell Transformation, Neoplastic; Cells, Cultured; Connexin 43; Drug Synergism; Fibroblasts; Gap Junctions; Humans; Imidazoles; Mice; Mice, Inbred C3H; Skin; Tretinoin; Up-Regulation

Topics: Antineoplastic Agents; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Cell Transformation, Neoplastic; Humans; Incidence; Lung Neoplasms

We observed that various retinoids (including all-trans-retinoic acid, 13-cis-retinoic acid, and the synthetic retinoid Ro-11-1430) have approximately the same ability to suppress ultraviolet light-induced transformation of C3H10T1/2 cells in vitro. Retinoids also suppress X-ray induced transformation in vitro. Ro-11-1430 has no effect when present for only 1 day after the X-ray exposure but does have a suppressive effect on radiation transformation when present for 5 or 10 days after irradiation. Ro-11-1430 has its major suppressive effect on X-ray transformation when present in irradiated cultures in the confluent stationary phase of growth. Natural beta-carotene (type IV) from carrots, but not synthetic beta-carotene, has the ability to suppress radiation (X-ray)-induced transformation when present for the entire transformation assay period. Natural beta-carotene is without effect on the transformation process when present in irradiated cultures only during confluence. For these retinoids, as well as beta-carotene and canthaxanthin, there is a highly significant suppressive effect on radiation transformation and radiation transformation enhanced by 12-O-tetradecanoylphorbol-13-acetate when the compounds are present at toxic levels; when nontoxic levels are utilized, these compounds have the ability to suppress the yield of transformed cells to approximately one-half of that observed in irradiated cultures in the absence of these compounds. A selective toxicity for transformed cells appeared to exist for the beta-carotene-treated F-17 cells. This apparent selective toxicity was not observed in another line of transformed cells. Cl 16 cells, or in human cells. We observed different uptake patterns of beta-carotene by nontransformed C3H10T1/2 cells, F-17 cells, and Cl 16 cells that may account for the observed apparent selective toxicity of one line of transformed cells (F-17 cells) to beta-carotene.

Topics: Animals; Antineoplastic Agents; beta Carotene; Canthaxanthin; Carotenoids; Cell Transformation, Neoplastic; Cells, Cultured; Mice; Mice, Inbred C3H; Retinoids; Tetradecanoylphorbol Acetate; Time Factors; Ultraviolet Rays; X-Rays

Topics: beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Cell Transformation, Neoplastic; Head and Neck Neoplasms; Humans; Immunologic Factors; Isotretinoin; Leukoplakia, Oral; Mouth Neoplasms

Topics: Animals; Anticarcinogenic Agents; beta Carotene; Carotenoids; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Furans; Indicators and Reagents; Methylcholanthrene; Mice; Mice, Inbred C3H; Solvents

The influence of beta-carotene on the formation of DNA-adducts induced by 7,12-dimethylbenz(a)anthracene (DMBA) and 7-hydroxymethyl-12-methylbenz(a)anthracene (7-OHM-12-MBA) during transformation of mouse mammary cells in organ culture was analysed. Treatment with beta-carotene (10(-8)-10(-5) mol/l) caused inhibition (48.8-94.4%) of an adduct (VI), which was detectable in DNA samples from DMBA-treated mammary glands. Out of six adducts, derived from further analysis of DNA samples from 7-OHM-12-MBA-treated glands, adduct f eluted in the same fraction as adduct (VI), indicating these adducts were analogous. Likewise, adduct f was also inhibited by beta-carotene. Boronate chromatographic analysis revealed this particular adduct was a syn-dihydrodiol epoxide product. Adduct inhibition was detectable both at the start and after DMBA treatment. alpha-Tocopherol and canthaxanthin were ineffective in inhibiting adducts. It is reasonable to conclude that beta-carotene-mediated modification of adducts is associated with the inhibition of a syn-adduct, which is derived from further metabolism of a 7-OHM-12-MBA intermediate.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carotenoids; Cell Transformation, Neoplastic; Chromatography, High Pressure Liquid; DNA; DNA Adducts; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C

We have previously demonstrated that diverse carotenoids inhibit chemically induced neoplastic transformation in 10T1/2 cells. To address their mechanism of action, the effects of six diverse carotenoids, with or without provitamin A activity, on gap junctional communication and lipid peroxidation have been investigated. beta-Carotene, canthaxanthin, lutein, lycopene and alpha-carotene increased gap junctional intercellular communication in a dose-dependent manner in the above order of potency, whereas m-bixin was inactive at concentrations up to 10(-5) M. alpha-Tocopherol, a potent chain-breaking antioxidant, caused a marginal enhancement of junctional communication. The enhancement of junctional communication by diverse carotenoids showed a strong statistical correlation with their previously determined ability to inhibit methylcholanthrene-induced neoplastic transformation (r = -0.75). All carotenoids tested inhibited lipid peroxidation, but with differing potencies. alpha-Tocopherol was the most active inhibitor followed by m-bixin. The capacity of carotenoids or alpha-tocopherol to inhibit lipid peroxidation was neither consistent with their ability to inhibit neoplastic transformation (r = 0.30) nor to increase junctional communication (r = 0.12). Since junctional communication appears to play an important role in cell growth control and carcinogenesis, we propose that in this system carotenoid-enhanced intercellular communication provides a mechanistic basis for the cancer chemopreventive action of carotenoids. These data also imply that carotenoids function in a manner analogous to retinoids in the 10T1/2 assay system. Interestingly this activity appears independent of their provitamin A status.

Topics: Animals; beta Carotene; Canthaxanthin; Carotenoids; Cell Communication; Cell Transformation, Neoplastic; Lipid Peroxidation; Lutein; Lycopene; Mice; Vitamin E

We have studied the effects of beta-carotene (beta-C), a vitamin A precursor of plant origin, and canthaxanthin (CTX), a non-provitamin A carotenoid, on the neoplastic transformation of C3H/10T1/2 murine fibroblast cells. Chemical transformation in this well-characterized cell system has previously been shown to be reversibly inhibited by retinoids, compounds with vitamin A-like activity. Here we show that both beta-C and CTX inhibit 3-methylcholanthrene (MCA)-induced transformation with ED50s of 9 x 10(-7) M and 2 x 10(-7) M, respectively. Both carotenoids failed to inhibit X-ray-induced transformation when the cells were treated prior to and during irradiation. However, when the drugs were added 1 week after X-irradiation and maintained in the medium thereafter, as in the chemical transformation protocol, both carotenoids inhibited subsequent development of transformed foci in a dose-dependent manner. Again, CTX was more effective than beta-C, such that 3 x 10(-6) M completely inhibited radiogenically-induced foci. Similar to the previously described action of retinoids, the inhibition of MCA-induced transformation was reversible; upon removal of the drug, transformed foci developed within 2 weeks, indicating that the carotenoids were not specifically toxic to initiated cells. Although both carotenoids caused a small dose-dependent decrease in the growth rate of both parental and initiated 10T1/2 cells, they did not markedly affect colony size or number when the cells were treated as in the transformation assays, nor did they influence the expression of neoplasia of two transformed cell lines. Although the actions of beta-C and CTX are similar to those of retinoids in the 10T1/2 system, we suggest that the carotenoids act via a different mechanism, since CTX cannot be converted to active retinoids in mammalian cells, and there is no evidence that 10T1/2 cells can convert beta-C to vitamin A. We suggest that the carotenoids' lipid anti-oxidant properties may be responsible for their inhibitory actions on transformation.

Topics: Animals; beta Carotene; Canthaxanthin; Carotenoids; Cell Division; Cell Line; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Lipid Peroxides; Methylcholanthrene; Mice; X-Rays

The purpose of the present studies was to determine the influence of the chemopreventive agents selenium, 4-(hydroxyphenyl)-retinamide (4-HPR) and beta-carotene, on functional differentiation (lactogenesis) of the mouse mammary gland cells. The hormone-induced expression of the milk-protein genes, beta-casein, epsilon-casein and the whey acidic protein (WAP) was used as molecular marker of differentiation of the mammary cells in organ culture medium containing insulin, prolactin, aldosterone and hydrocortisone. Quantitative determination of the cellular concentration of the respective mRNA was ascertained by molecular hybridization of RNA to the specific cloned cDNA probes using both the solution and the filter hybridization methods. Selenium at 100 nm concentration caused a pronounced inhibition of accumulation of the respective mRNAs. The retinoid, 4-HPR, also caused a dose-dependent inhibition of expression of these mRNA sequences. In contrast, concentrations of the 3 mRNAs in beta-carotene-treated glands remained similar to those observed in glands cultured in medium containing the hormones and hexane (the latter being the solvent for beta-carotene). The significant antagonistic action of selenium and 4-HPR, however, was reversible after removal of the chemicals from the culture medium. Thus, among the 3 chemicals tested, selenium and retinoid can cause an adverse effect on functional differentiation (lactogenesis) of the mammary cells. This inhibitory effect, however, was reversible. beta-Carotene, on the other hand, caused no apparent antagonistic effect on expression of the milk-protein genes in the isolated whole mammary organ in culture.

Topics: Actins; Animals; beta Carotene; Carotenoids; Cell Transformation, Neoplastic; Female; Fenretinide; Hormones; In Vitro Techniques; Mammary Glands, Animal; Mice; Milk Proteins; RNA, Messenger; Selenium; Tretinoin

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carotenoids; Cell Transformation, Neoplastic; DNA; Furocoumarins; Humans; Neoplasms; Skin; Ultraviolet Rays; Vegetables

Present studies in the mammary epithelial cell transformation model in organ culture showed that presence of beta-carotene during the 24 hr treatment (initiation stage) of the glands with the carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA), N-nitrosodiethylamine (DENA) and N-methylnitrosourea (MNU), caused a highly significant (P less than 0.001-0.01) reduction of SCE induced by the same carcinogens. In contrast, 4-hydroxyphenyl retinamide (4-HPR) which is known to act at the promotional stage of carcinogenesis did not show any significant reduction of SCE. Thus findings suggest that beta-carotene can modify the DNA damaging effect of the carcinogens and thereby may also prevent the initiation of the carcinogenic process.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carcinogens; Carotenoids; Cell Transformation, Neoplastic; Diethylnitrosamine; Female; Fenretinide; Mammary Glands, Animal; Methylnitrosourea; Mice; Organ Culture Techniques; Retinoids; Sister Chromatid Exchange; Tretinoin

The chemopreventive action of beta-carotene during chemically-induced transformation of the epithelial cells in organ culture of the whole mammary glands from BALB/c female mice was studied. The mammary epithelial cells in the whole mammary organ in a hormone supplemented, serum-free medium were transformed after 24 h exposure to 7.8 microM 7,12-dimethylbenz[a]anthracene (DMBA) between 3rd and 4th day of a total 10 day culture period. The transformation process was associated with appearance of nodule-like alveolar lesions (NLAL) in glands in vitro. The epithelial cells transformed by DMBA are potentially neoplastic, and NLAL serves as a morphological marker of preneoplasia in the glands in vitro. Treatment with beta-carotene (10(-6) M) during DMBA exposure (3rd-4th day) caused 68% inhibition in the number of glands with incidence of NLAL. A 49% inhibition of NLAL was evident when the glands were incubated with beta-carotene (days 4-10) after exposure to DMBA. Results indicate that beta-carotene inhibits DMBA-induced transformation of the mammary glands in vitro acting both at the initiation and the promotional stages. This inhibitory effect is likely due to the action of beta-carotene itself since no accumulation of retinol, the metabolic derivative of the vitamin A precursor, was detectable in the mammary glands during the 10 day culture period.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carotenoids; Cell Transformation, Neoplastic; Epithelium; Female; In Vitro Techniques; Mammary Glands, Animal; Mice; Mice, Inbred BALB C

Topics: Adult; beta Carotene; Canthaxanthin; Carotenoids; Cell Transformation, Neoplastic; Child; Child, Preschool; Electrosurgery; Eye Diseases; Female; Humans; Infant; Male; Neurologic Manifestations; Skin Diseases; Tretinoin; Xeroderma Pigmentosum