beta-carotene and Mouth-Neoplasms

The systematic review and meta-analysis of published randomised controlled trials (RCTs) was conducted to review the effectiveness of current chemopreventive agents in the treatment of oral leukoplakia lesions (OPLs) and prevention of their progression to oral cancer. Material was identified through a retrospective literature search of the electronic PubMed database, Embase and Cochrane Library between 2008 and 2016.Eight RCTs were included for systematic review. The pooled estimate showed a 14% greater chance of responding for those randomised to interventions compared with placebo (Risk Ratio [RR] 1.14, 95% confidence interval [CI] 0.72 to 1.81). The CI from individual studies overlapped. The results suggested that there were no significant differences in comparing clinical responses between chemopreventive agents with placebo in treatment of OPLs. It is time to investigate new agents for oral cancer chemoprevention.

Topics: Antineoplastic Agents; beta Carotene; Chemoprevention; Erlotinib Hydrochloride; Humans; Isotretinoin; Leukoplakia, Oral; Mouth Neoplasms; Precancerous Conditions; Provitamins; Tea; Treatment Outcome; Vitamin A; Vitamins

Chemoprevention is one of the cancer prevention methods, applied for the oral squamous cell carcinoma and its main precursor lesions--leukoplakia and erythroplakia. Presently, the most extensive clinically studied group used in such cases are retinoids: vitamin A (retinol), 13-cis-retinic acid (isotretinoin), N-(4-hydroxyphenyl)retinamide (fenretinide) and precursor of vitamin A--beta-carotene. However, despite good short-time effectiveness, retinoids do not prevent recurrences of the lesions and insignificantly increase cancer-free survival. Moreover, they are also characterized by relatively high toxicity. Vitamin E, Bowman-Birkprotease inhibitor, Spirulina fusiformis and green tee extracts as well as traditional Chinese herbs known as ZengShengPing were also found as effective agents. Lack of activity was reported for cyclooxygenase inhibitors--ketorolac and celecoxib. More promising data was collected from animal experimental studies with chemically induced oral squamous cell carcinoma. Chemopreventive activity was revealed for various agents including plant-derived compounds like resveratrol, green and black tee polyphenols, as well as protocatechuic, ellagic and caffeic acids.

Topics: Animals; Antineoplastic Agents; beta Carotene; Carcinoma, Squamous Cell; Chemoprevention; Drugs, Chinese Herbal; Fenretinide; Humans; Isotretinoin; Mouth Neoplasms; Neoplasm Recurrence, Local; Phytotherapy; Precancerous Conditions; Vitamin A

We reviewed data from six cohort studies and approximately 40 case-control studies on the relation between selected aspects of diet and the risk of oral and pharyngeal cancer. Fruit and vegetables were inversely related to the risk: the pooled relative risk (RR) for high vegetable consumption was 0.65 from three cohort studies on upper aerodigestive tract cancers and 0.52 from 18 case-control studies of oral and pharyngeal cancer; corresponding RRs for high fruit consumption were 0.78 and 0.55. beta-carotene, vitamin C and selected flavonoids have been inversely related to the risk, but it is difficult to disentangle their potential effect from that of fruit and vegetables. Whole grain, but not refined grain, intake was also favorably related to oral cancer risk. The results were not consistent with reference to other foods beverages, and nutrients, but it is now possible to exclude a strong relation between these foods and oral and pharyngeal cancer risk. In western countries, selected aspects of diet may account for 20-25% of oral and pharyngeal cancer, and the population attributable risk increases to 85-95% when tobacco and alcohol consumption are also considered.

Topics: Adult; Ascorbic Acid; beta Carotene; Case-Control Studies; Cohort Studies; Diet; Edible Grain; Female; Flavonoids; Fruit; Humans; Male; Mouth Neoplasms; Pharyngeal Neoplasms; Risk; Risk Factors; Vegetables

This is an update on cultural and dietary risk factors for oral precancer and cancer. It is an overview on ethnic differences (where possible) and socio-cultural risk factors (tobacco/areca nut/betel quid, alcohol use and dietary factors) in relation to oral precancer and cancer. While studies were from Western countries, India and China, this update also attempts to include and highlight some studies conducted in the Asia-Pacific region.

Topics: Alcohol Drinking; Areca; Asia; beta Carotene; Culture; Developed Countries; Diet; Fruit; Humans; Micronutrients; Mouth Neoplasms; Pacific Islands; Plants, Medicinal; Plants, Toxic; Precancerous Conditions; Prevalence; Risk Factors; Smoking; Tobacco, Smokeless; Vegetables; Vitamins

I present evidence in support of a chemopreventive role for the so-called antioxidant nutrients, beta-carotene and vitamin E, against oral cavity cancer. This evidence is from laboratory studies, animal model systems, epidemiologic surveys, intervention trials involving reversal of premalignant changes, and prevention of malignancies in particularly high-risk subjects. Because agents proposed for disease prevention are meant to be used widely without close medical supervision, almost any toxicity is unacceptable. beta-Carotene and vitamin E fulfill this criterion for a suitable chemopreventive agent. In several epidemiologic studies, low intakes of vitamin E, carotenoids, or both have been associated with a higher cancer risk. Smoking, a major risk factor, results in lower beta-carotene concentrations in plasma and oral mucosal cells. In several laboratory and animal model systems, beta-carotene and other antioxidant nutrients are inhibitors of oral cavity carcinogenesis. beta-Carotene and vitamin E can produce clinical regression of oral leukoplakia, a premalignant lesion for oral cancer. The design and limitations of such studies in oral leukoplakia are discussed. Cancer incidence reduction trials in high-risk groups have targeted prevention of second malignancies in patients cured of a primary oral cancer. These trials are in progress. The data thus far are supportive of a significant preventive role for these nutrients in oral cancer.

Topics: Animals; Antioxidants; beta Carotene; Carotenoids; Humans; Leukoplakia, Oral; Mouth Neoplasms; Vitamin E

beta-carotene and other antioxidant nutrients, such as vitamin E, are well suited for widespread preventive use because they are nontoxic and easily given in supplement form. Intervention trials designed to show a reduction of cancer incidence in the general population are logistically and practically impossible for most types of cancer, including cancer of the oral cavity. Thus evidence for chemoprevention must be indirect, using laboratory and animal models, epidemiologic surveys, and trials showing reversal of premalignant lesions or cancer prevention in high-risk groups. In several animal models, beta-carotene and other antioxidant nutrients inhibit oral carcinogenesis. Epidemiologic studies consistently relate low intake of these nutrients with high cancer risk. Smokers have lower beta-carotene levels in plasma and oral mucosal cells than nonsmokers. Eight clinical trials have now shown that beta-carotene and vitamin E produce regression of oral leukoplakia, but chemoprevention studies in oral leukoplakia have limitations, which we review. All available evidence supports a significant role for antioxidant nutrients in preventing oral cancer.

Topics: Animals; Antioxidants; beta Carotene; Carotenoids; Clinical Trials as Topic; Humans; Leukoplakia, Oral; Mouth Neoplasms; Vitamin E

The most definitive and direct way to show that a putative chemoprevention agent actually prevents cancer would be to demonstrate a reduction in cancer incidence in a clinical trial. From a practical standpoint this approach is not feasible for most cancers. Therefore, it becomes necessary to draw conclusions on chemopreventive activity through consideration of indirect lines of evidence, one of which is activity in premalignant lesions such as leukoplakia. As a corollary, it must be emphasized that the goal of undertaking chemoprevention trials in oral leukoplakia is to develop approaches for the prevention of oral cancer. Because the risk of cancer in the usual leukoplakia lesion is low, only non-toxic agents should be tested in this setting and they should be suited for eventual use in a prevention setting. Beta-carotene and vitamin E, unlike the retinoids, fulfill the criteria for a suitable chemopreventive agent and several lines of evidence point to a preventive role for them against oral cancer. These include laboratory in vitro and animal model findings, but the strongest evidence comes from epidemiologic studies which uniformly suggest protection by beta-carotene against head and neck cancer. Much like the retinoids, but without toxicity, beta-carotene and vitamin E can produce regression of oral leukoplakia, a premalignant lesion for oral cancer, as has now been shown in eight clinical trials, five with beta-carotene alone, one with vitamin E alone and two that used these agents as part of combinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; beta Carotene; Carotenoids; Clinical Trials as Topic; Drug Combinations; Humans; Leukoplakia, Oral; Mouth Neoplasms; Vitamin E

Topics: Animals; beta Carotene; Carotenoids; Humans; Mouth Neoplasms; Neoplasm Invasiveness; Precancerous Conditions; Risk Factors

The ultimate proof that a putative chemopreventive agent does prevent cancer is a demonstration of reduced cancer incidence in a targeted population. However, because of practical and logistical considerations, such trials are virtually impossible to conduct for the majority of cancers. Therefore, a conclusion regarding the efficacy of chemopreventive activity is based on consideration of a variety of indirect lines of evidence, including laboratory studies, animal model systems, epidemiologic surveys, intervention trials involving reversal of premalignant changes, and the prevention of malignancies in particularly high risk subjects. Furthermore, the only agents worth testing are those with limited, or preferably, no toxicity, since the final use will be prevention in a generally healthy population. Beta-carotene and vitamin E both fulfill all the criteria for suitable chemopreventive agents; several lines of evidence point toward preventive roles for them in oral cancer. In numerous epidemiologic studies, low intake of beta-carotene has been associated with higher cancer risk. Both intake and supplemental use of vitamin E have been associated with a lowered risk of cancer. Smokers, whose habit is a major risk factor, have lower beta-carotene levels in oral mucosal cells when compared with non-smokers. In several laboratory and animal model systems, including the very relevant hamster cheek pouch model, these agents strongly inhibit oral cavity carcinogenesis. Beta-carotene and vitamin E produce regression of oral leukoplakia, a premalignant lesion for oral cancer. This has now been shown in seven clinical trials: five with beta-carotene alone, one with vitamin E, and one with a combination of both.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticarcinogenic Agents; beta Carotene; Carotenoids; Humans; Mouth Neoplasms; Vitamin E

The antioxidant alpha-tocopherol and the weaker antioxidant and prooxidant chemopreventative, beta-carotene have been shown to inhibit tumor cell growth in vivo and in vitro. In some epidemiologic studies their serum levels were demonstrated to be inversely related to the incidence of malignant tumor. We hypothesized two basic pathways triggered by antioxidants and prooxidants, which resulted in the control of tumor cell growth. These included changes in phosphorylation and ultimately transcription. Specifically, the prooxidant beta-carotene treatment produced an oxidative stress resulting in the selective induction of heat shock proteins (hsps). These proteins and other proteins that were possibly oxidized were associated with the increased expression of cyclins (A and D) and increased cdc2 kinase expression. An increase in expression of phosphoproteins, such as p53 (tumor suppressor form) was also discerned. The level of expression for the transcription factor c-fos was reduced. Growth factors that contribute to tumor cell growth were also reduced. Increased DNA fragmentation, depression of proliferation and intracellular calcium levels, the accumulation of tumor cells in G0-->G1, and morphologic changes, were consistent with programmed cell death. Antioxidants such as alpha-tocopherol bound to membrane-associated proteins could inhibit the development of peroxidation products (hydroxyl radicals (.OH)), which attack proteins and modify their function and promote their degradation. Some kinases such as, cdc2 may be increased in activity, which would explain the observed increased expression of tumor suppressor p53, the accumulation of the tumor cells in G1 of the cell cycle and the inhibition of tumor cell proliferation. A reduction in oxidant radicals could also reduce transcription factor products, such as c-myb. Indirectly this result may occur through changes in nuclear translocation (signaling) NF-AT or the Rel-related family of transcription factors, including NF-kB (p50 or p65) or inhibition of immunophilin-calmodulin activity. Although the data remains fragmentary there are common points for control for tumor cell growth resulting from the effects of alpha-tocopherol or beta-carotene treatment. These changes involve phosphorylation and protein expression. Ultimately there is a reduction of important transcription factor protein products, a reduction in response to growth factors, and suppression of cell proliferation, resulting in increased contr

Topics: Animals; Apoptosis; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; CDC2 Protein Kinase; Cell Division; Cricetinae; Gene Expression Regulation, Neoplastic; Genes, p53; Genes, ras; Heat-Shock Proteins; Humans; Mouth Neoplasms; Oxidation-Reduction; Proto-Oncogenes; Tumor Cells, Cultured; Vitamin E

Topics: Animals; Anticarcinogenic Agents; Antioxidants; beta Carotene; Carotenoids; Humans; Leukoplakia; Mouth Neoplasms; Precancerous Conditions; Retinoids; Vitamins

Recent data suggests that retinoids and carotenoids may be effective in reversing a putative "field cancerization" defect in the epithelium at risk for oral cancer. Animal experiments have shown that these compounds can inhibit cancer formation. Several clinical trials have demonstrated the ability of retinoids to reverse oral leukoplakia. However, toxicities associated with retinoids at the doses used in these studies limits their potential for chemoprevention. Because of its lack of toxicity, beta-carotene is a very attractive agent for chemoprevention. It suppresses micronuclei in exfoliated oral mucosal cells from subjects at risk for oral cancer and recently has been shown to be active in reversing leukoplakia. Another area under investigation is the possibility of preventing second primary tumors in patients cured of their initial cancer who have an increased risk of developing new cancers of the upper acrodigestive tract.

Topics: Animals; beta Carotene; Carotenoids; Humans; Leukoplakia, Oral; Mouth Neoplasms; Retinoids

Participants in the intervention trials were fishermen (Kerala, India), who chewed tobacco-containing betel quids daily before and throughout the study period. Frequency of oral leukoplakia, micronuclei in oral mucosal cells, and alterations in nuclear textures were used as endpoints. Administration of vitamin A (60 mg/wk) for 6-mo resulted in complete remission of leukoplakias in 57% and a reduction of micronucleated cells in 96% of tobacco-chewers. beta-carotene (2.2 mmol/wk) induced remission of leukoplakia in 14.8% and reduction of micronucleated cells in 98%. Vitamin A completely suppressed and beta-carotene suppressed by 50% formation of new leukoplakia within the 6-mo trial period. After withdrawal of vitamin A or beta-carotene treatment, oral leukoplakias reappeared, frequency of micronuclei in oral mucosa increased, and nuclear textures reverted to those present before the administration of chemo-preventive agents. The protective effect of the original treatment could be maintained for at least 8 additional months by administration of lower doses of vitamin A or beta-carotene.

Topics: Areca; beta Carotene; Carotenoids; Humans; Leukoplakia, Oral; Mouth Neoplasms; Plants, Medicinal; Plants, Toxic; Precancerous Conditions; Tobacco, Smokeless; Vitamin A

After defining chemoprevention a description is given of the phases of differentiation in normal epithelial cells and the features of proliferation in neoplasias developing in this epithelium. The latest studies on carcinogenesis indicate various types of prevention with which one can alter this transformation process. Epidemiological studies have shown that subjects with low serum levels of Vit-A or Beta carotenoids are at high risk of developing epithelial cancer. Three main categories of agents inducing cell transformation are described: a) physiological induction agents; b) non physiological induction agents; c) cytotoxic drugs. In regard to clinical use, some studies have focussed on the importance of Vit-A in chemoprevention of risk conditions (pre-cancerous lesions) and in prevention of cancer recurrence. The authors point out the increasing interest in the use of retinoids in the chemoprevention of head and neck cancer and report some personal clinical experience.

Topics: Adult; Aged; beta Carotene; Carotenoids; Cell Differentiation; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Selenious Acid; Selenium

To investigate whether retinyl palmitate (RP) alone or plus beta-carotene (BC) would be as effective and less toxic than low-dose 13-cis retinoic acid (13cRA) in treating oral premalignant lesions (OPLs) and reducing the risk of oral cancer.. Initially, patients were randomly assigned to receive low-dose 13cRA or BC plus RP for 3 years (plus 2 years follow-up). After other randomized trials established an adverse effect of BC on lung cancer incidence/mortality, BC was dropped (patients randomly assigned to 13cRA or RP alone). The primary end point was OPL clinical response at 3 months.. We randomly assigned 162 eligible patients. The 3-month clinical response rate of the combined BC plus RP and RP alone arm (32.5%) was not statistically equivalent to that of 13cRA (48.1%). The clinical response rate of RP alone (20.0%) was significantly lower than that of BC plus RP (42.9%; P = .03). Similar oral cancer-free survival rates were observed across all arms. There was no significant association between 3-month OPL response and subsequent oral cancer development (P = .11). Grades 2 and higher adverse events were more common in the 13cRA than other groups (P < .0001).. This large chemoprevention trial did not establish the equivalence of RP plus BC or RP alone with low-dose 13cRA in reducing the long-term risk of oral cancer. At present, 13cRA, BC plus RP, and RP alone cannot be recommended for chemoprevention, and new, better agents are needed in this setting. Our results did not establish short-term OPL response as a surrogate end point for oral cancer-free survival.

Topics: Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; beta Carotene; Disease-Free Survival; Diterpenes; Female; Humans; Isotretinoin; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Retinyl Esters; Treatment Outcome; Vitamin A; Vitamins

The risk of malignant transformation of oral preneoplastic lesion (OPL) is difficult to assess. DeltaNp63 is an early oncoprotein associated with mucosal tumorigenesis. The purpose of this study was to assess DeltaNp63 expression in OPL and its role as a marker of oral cancer risk.. DeltaNp63 expression was determined using immunohistochemistry in 152 OPL patients included in a clinical trial comparing retinyl palmitate alone or plus beta-carotene with low-dose 13-cis-retinoic acid. The associations between DeltaNp63 expression as well as DeltaNp63 expression with other potential risk factors for oral cancer development were analyzed.. DeltaNp63 expression was positive in 41 (27%) patients, clusters of intraepithelial inflammatory cells (EIC) were noted in 37 (26%) patients, and podoplanin (previously reported) was positive in 56 (37%) patients. Significantly more patients whose lesions were DeltaNp63 positive or exhibited EIC developed oral cancers. In the multicovariate analysis including age, treatment, and histologic status as cofactors, positive DeltaNp63 expression was associated with an increased hazard ratio of 3.308 (95% confidence interval, 1.663-6.580; P = 0.0007). Patients whose lesions showed positive DeltaNp63, podoplanin, and EIC had the highest oral cancer risk with a hazard ratio of 4.372 (95% confidence interval, 1.912-9.992; P = 0.0005) and 61% oral cancer development rate at 5 years compared with 15% of other OPL patients (P < 0.0001).. DeltaNp63 overepression in OPL is associated with increased oral cancer risk. Together, DeltaNp63, podoplanin, and EIC may be used as biomarkers to identify OPL patients with substantially high oral cancer risk.

Topics: Antineoplastic Combined Chemotherapy Protocols; beta Carotene; Biomarkers, Tumor; Carcinoma, Squamous Cell; Diterpenes; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Inflammation; Isotretinoin; Leukoplakia, Oral; Male; Membrane Glycoproteins; Middle Aged; Mouth Neoplasms; Prognosis; Retinyl Esters; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins; Up-Regulation; Vitamin A

Bowman-Birk inhibitor is a protease inhibitor derived from soybeans that has demonstrated chemopreventive activity in a number of in vitro and animal systems. We conducted a 1-month phase IIa clinical trial of Bowman-Birk inhibitor concentrate (BBIC) in patients with oral leukoplakia. BBIC was administered to 32 subjects with oral leukoplakia for 1 month. We assessed toxicity and clinical and histological response of the lesions, and oral mucosal cell protease activity (PA) and serum micronutrient levels were measured. Clinical response was determined by measurement of pre- and posttreatment individual and total lesion areas and analysis of blinded clinical judgments of photographs. On the basis of prespecified response criteria, 31% of patients achieved a clinical response (two with complete and eight with partial responses). BBIC was nontoxic in doses up to 1066 chymotrypsin inhibitory units. The mean pretreatment total lesion area decreased from 615 to 438 mm2 after BBIC treatment (P < 0.004). A linear fit of the dose-response relationship between dose of BBIC and decrease in total lesion area was suggested (P < 0.08), and analysis of blinded clinical impression from lesion photographs confirmed this relationship (P < 0.01). Overall, at all doses tested, a 24.2% decrease in total lesion area was observed following treatment (sign rank = -142; P < 0.004). High pretreatment PA was associated with greater decreases in PA after BBIC administration (P < 0.02). BBIC demonstrated clinical activity after oral administration to patients with oral leukoplakia. These results indicate that BBIC should be investigated for chemopreventive activity in a randomized clinical trial.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Dose-Response Relationship, Drug; Endopeptidases; Female; Humans; Leukoplakia; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Protease Inhibitors; Treatment Outcome; Trypsin Inhibitor, Bowman-Birk Soybean; Trypsin Inhibitors; Vitamin A; Vitamin E

To measure the beta-carotene concentration in buccal mucosal cells in smoking men who had received long-term beta-carotene (BC) supplementation in a controlled trial. To assess the association of cellular BC on the prevalence of dysplasia in oral leukoplakia.. An end-of-trial examination of a part of subjects in the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study.. 343 men who for 5-7 years had received BC (20 mg/d) or alpha-tocopherol (AT) (50 mg/d), or both of these or placebo. BC concentration of buccal mucosal cells was compared in the subjects with BC supplementation (n = 173) to that of those without it (n = 170). Oral mucosae were examined clinically and lesions showing leukoplakia histopathologically.. Mean (s.d.) BC concentration in buccal mucosal cells was 7.7 (10.3)mg/kg protein in the subjects who received BC compared to 1.1 (1.7) mg/kg protein in those who did not. The BC concentration in the cells of supplemented subjects correlated with their serum BC levels (P < 0.001). AT supplementation had no effect on BC concentration nor was daily amount of smoking statistically significantly associated with the BC concentration in buccal cells. Altogether 17 subjects showed oral leukoplakia, 7 had dysplasia. In these 7 subjects, the BC concentration in buccal mucosal cells did not differ statistically significantly compared to subjects with only hyperkeratosis (n = 10) (F-test, P = 0.74).. After long-term BC supplementation, BC concentration in oral mucosal cells was 7-fold greater than without supplementation. There was no evidence to support an association between cellular BC concentration and precancerous lesions among the few subjects having them in their oral mucosae.

Topics: Aged; beta Carotene; Humans; Leukoplakia, Oral; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Smoking

We conducted a double-blind placebo-controlled trial to evaluate the chemopreventive potential of either vitamin A alone or beta carotene alone in subjects with oral leukoplakia in Kerala, India. We randomised 160 fishermen and women with oral precancerous lesions to receive oral vitamin A (retinyl acetate 300,000 IU/week x 12 months, n = 50), or beta carotene (360 mg/week x 12 months, n = 55), or placebo (n = 55). Blood, saliva and urine samples were collected at baseline and at exit to study serum micronutrients and mutagenicity assays. Biopsies of the mucosal lesions at entry were performed for histopathological exclusion of malignancy. The subjects were examined once every 2 months to establish clinical response of lesions and toxicity, if any. The results are based on 43 complaint subjects on placebo, 42 on vitamin A and 46 on beta carotene. The complete regression rates were: 10% in the placebo arm, 52% with vitamin A and 33% with beta carotene (P < 0.0001). Homogeneous leukoplakias and smaller lesions responded better than non-homogeneous and larger lesions. No major toxicities were observed. Half of the responders with beta carotene and two thirds with vitamin A relapsed after stopping supplementation. Serum beta carotene concentration increased substantially with beta carotene administration while with vitamin A supplementation there was no change in serum retinol levels. In the vitamin A treated group there was a significant decrease in serum alpha tocopherol. Vitamin A administration resulted in a significant remission of oral leukoplakia without any side effects of prolonged vitamin A supplementation. The results of this study, as well as those from previous studies, appear to provide strong supporting evidence to justify long term trials with vitamin A in subjects with high-risk leukoplakias with oral cancer as an endpoint.

Topics: Adult; Anticarcinogenic Agents; beta Carotene; Diterpenes; Double-Blind Method; Female; Humans; Leukoplakia, Oral; Male; Micronutrients; Middle Aged; Mouth Neoplasms; Mutagenicity Tests; Retinyl Esters; Treatment Outcome; Vitamin A

The blue-green microalgae Spirulina, used in daily diets of natives in Africa and America, have been found to be a rich natural source of proteins, carotenoids, and other micronutrients. Experimental studies in animal models have demonstrated an inhibitory effect of Spirulina algae on oral carcinogenesis. Studies among preschool children in India have demonstrated Spirulina fusiformis (SF) to be an effective source of dietary vitamin A. We evaluated the chemopreventive activity of SF (1 g/day for 12 mos) in reversing oral leukoplakia in pan tobacco chewers in Kerala, India. Complete regression of lesions was observed in 20 of 44 (45%) evaluable subjects supplemented with SF, as opposed to 3 of 43 (7%) in the placebo arm (p < 0.0001). When stratified by type of leukoplakia, the response was more pronounced in homogeneous lesions: complete regression was seen in 16 of 28 (57%) subjects with homogeneous leukoplakia, 2 of 8 with erythroplakia, 2 of 4 with verrucous leukoplakia, and 0 of 4 with ulcerated and nodular lesions. Within one year of discontinuing supplements, 9 of 20 (45%) complete responders with SF developed recurrent lesions. Supplementation with SF did not result in increased serum concentration of retinol or beta-carotene, nor was it associated with toxicity. This is the first human study evaluating the chemopreventive potential of SF. More studies in different settings and different populations are needed for further evaluation.

Topics: Adult; beta Carotene; Carotenoids; Cyanobacteria; Female; Food, Fortified; Humans; India; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Remission Induction; Vitamin A

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

Recent reports have demonstrated that beta-carotene, a nontoxic carotenoid, is able to stimulate immune functions in humans. The purpose of this study is to understand the mechanisms of immunoenhancement by carotenoids in order to explain their anticancer effects. We have evaluated the clinical efficacy of beta-carotene, given 30 mg/day orally, for treatment of oral leukoplakia patients. Patients who responded to beta-carotene treatment showed increased plasma levels of TNF-alpha. Epithelial cells from these patients were characterized in vitro. These results may lead to a better understanding of the therapeutic use of beta-carotene in humans.

Topics: Adjuvants, Immunologic; beta Carotene; Carotenoids; Cell Adhesion Molecules; Cell Line; Cytotoxicity, Immunologic; Epithelium; HLA-DR Antigens; Humans; Intercellular Adhesion Molecule-1; Killer Cells, Natural; Leukoplakia; Mouth Mucosa; Mouth Neoplasms; T-Lymphocyte Subsets; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

This intervention trial carried out in Uzbekistan (former USSR) in an area with a high incidence of oral and esophageal cancer involved random allocation of 532 men, 50 to 69 years old, with oral leukoplakia and/or chronic esophagitis to one of four arms in a double-blind, two-by-two factorial design, with active arms defined by the administration of (a) riboflavin; (b) a combination of retinol, beta-carotene, and vitamin E; or (c) both. Weekly doses were 100,000 IU of retinol, 80 mg of vitamin E, and 80 mg of riboflavin. The dose of beta-carotene was 40 mg/d. Men in the trial were followed for 20 months after randomization. The aim of the trial was to determine whether treatment with these vitamins or their combination could affect the prevalence of oral leukoplakia and/or protect against progression of oral leukoplakia and esophagitis, conditions considered to be precursors of cancer of the mouth and esophagus. A significant decrease in the prevalence odds ratio (OR) of oral leukoplakia was observed after 6 months of treatment in men receiving retinol, beta-carotene, and vitamin E (OR = 0.62; 95% confidence interval (CI): 0.39 to 0.98). After 20 months of treatment, no effect of vitamin supplementation was seen when the changes in chronic esophagitis were compared in the four different treatment groups, although the risk of progression of chronic esophagitis was lower in the subjects allocated to receive retinol, beta-carotene and vitamin E (OR = 0.65; 95% CI: 0.29 to 1.48) A secondary analysis not based on the randomized design revealed a decrease in the prevalence of oral leukoplakia in men with medium (OR = 0.45; 95% CI: 0.21 to 0.96) and high (OR = 0.59; 95% CI: 0.29 to 1.20) blood concentrations of beta-carotene after 20 months of treatment. Risk of progression of chronic esophagitis was also lower in men with a high blood concentration of beta-carotene, odds ratios being 0.30 (95% CI: 0.10 to 0.89) and 0.49 (95% CI: 0.15 to 1.58) for medium and high levels, respectively. A decrease in risk, also statistically not significant, was observed for high vitamin E levels (OR = 0.39; 95% CI: 0.14 to 1.10). These results were based on levels of vitamins in blood drawn after 20 months of treatment.

Topics: Aged; beta Carotene; Carotenoids; Chronic Disease; Double-Blind Method; Esophageal Neoplasms; Esophagitis; Humans; Incidence; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Odds Ratio; Precancerous Conditions; Prevalence; Riboflavin; Risk Factors; Uzbekistan; Vitamin A; Vitamin E; Vitamins

High-dose isotretinoin therapy has been determined to be an effective treatment for leukoplakia. However, a high rate of relapses and toxic reactions led us to conduct a trial of a much lower dose of isotretinoin in the hope of maintaining a response and limiting toxicity.. In the first phase of the study, 70 patients with leukoplakia underwent induction therapy with a high dose of isotretinoin (1.5 mg per kilogram of body weight per day) for three months; in the second phase, patients with responses or stable lesions were randomly assigned to maintenance therapy with either beta carotene (30 mg per day) or a low dose of isotretinoin (0.5 mg per kilogram per day) for nine months.. In the first phase, the rate of response to high-dose induction therapy in the 66 patients who could be evaluated was 55 percent (36 patients). The lesions of seven patients progressed, and therefore they did not participate in the second phase of the trial. Of the 59 patients included in the second phase, 33 were assigned to beta carotene therapy and 26 to low-dose isotretinoin therapy; these two groups did not differ significantly in prognostic factors. Of the 53 patients who could be evaluated, 22 in the low-dose isotretinoin group and 13 in the beta carotene group responded to maintenance therapy or continued to have stable lesions (92 percent vs. 45 percent, P < 0.001). In situ carcinoma developed in one patient in each group, and invasive squamous-cell carcinoma in five patients in the beta carotene group. Toxicity was generally mild, though greater in the group given low-dose isotretinoin therapy.. When preceded by high-dose induction therapy, low-dose isotretinoin therapy was significantly more active against leukoplakia than beta carotene and was easily tolerated.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Female; Head and Neck Neoplasms; Humans; Immunologic Factors; Isotretinoin; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Remission Induction

Leukoplakia is associated with increased risk of oral cancer and is considered a premalignant lesion. Retinoids, particularly 13-cis retinoic acid, can frequently reverse leukoplakia. However, these drugs have considerable toxicity and are not suitable for large-scale use in the prevention of oral cancer. Beta-carotene is a naturally occurring, nontoxic carotenoid with biologic properties that suggest that it might be efficacious against oral leukoplakia. In 1986, we began a randomized study of 13-cis retinoic acid (1 mg/kg/d) versus beta-carotene (30 mg/d) in leukoplakia. However, owing to the marked differences in toxicity between the two compounds outlined in the consent form, 11 of the initial 16 eligible patients refused to participate unless they were "guaranteed" beta-carotene. Therefore, the study design was changed to a phase II trial of beta-carotene in which the compound was given daily for 3 months. Responding patients were continued for another 3 months of treatment. All lesions were examined histologically at entry. Responses were monitored by bidimensional measurements and photography done at entry, then monthly while on treatment and at study completion. Twenty-four evaluable patients were treated, and 17 had major responses (two complete, 15 partial), a response rate of 71% (95% confidence limits, 53% to 89%). There was no significant toxicity requiring drug discontinuation or dose reduction. These results indicate that beta-carotene has substantial activity in oral premalignancy. Because of its lack of toxicity, it is an excellent candidate for a preventive agent for oral cancer.

Topics: Aged; Antineoplastic Agents; beta Carotene; Biopsy; Carotenoids; Drug Evaluation; Female; Humans; Leukoplakia; Male; Middle Aged; Mouth; Mouth Neoplasms; Remission Induction

The frequency of micronuclei in cells scraped from inside the human cheek is a measure of chromosome breakage in earlier cell divisions, and it can be increased tenfold by carcinogenic stimuli. Supplementation for 3 months of the diet of 40 rural Filipino betel chewers with sealed capsules of retinol (100 000 IU/week) and beta-carotene (300 000 IU/week) was associated with a threefold decrease (from 4.2% to 1.4%) in the mean proportion of cells with micronuclei. This proportion decreased in 37 of the 40 supplemented subjects and no large increases were seen in any subjects. In 11 unsupplemented betel chewers in a nearby cluster of houses the mean proportion of micronuclei did not change (4.3% before and 4.8% three months later). This suggests the possibility that in this population an increase in the dietary intake of retinol and/or carotene may reduce the incidence of oral cancer, which is an important neoplasm in many parts of Asia.

Topics: Adult; Areca; beta Carotene; Carotenoids; Cell Nucleus; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Mutagenicity Tests; Mutation; Nicotiana; Philippines; Plants, Medicinal; Plants, Toxic; Vitamins

The frequency of exfoliated cells with micronuclei in buccal swabs was used to estimate the protective effect of vitamin A, beta-carotene and canthaxanthin (4,4'-diketo-beta-carotene) on the buccal mucosa of betel (areca) nut/tobacco chewers. Micronuclei were scored on exfoliated cells taken by swabbing and stained with the Feulgen reaction and fast green. The betel (areca) nut/tobacco chewers served as their own controls. Prior to the administration of vitamin A and beta-carotene, the examined betel quid chewers had elevated frequencies of micronucleated buccal mucosa cells, averaging 4.03% +/- 1.24 SD (n = 26) and 3.43% +/- 1.22 SD (n = 25), respectively. The frequency of micronucleated buccal mucosa cells in non-chewers and non-smokers was 0.51% (n = 52). Following a 9-week ingestion of vitamin A (150,000 IU/week) and beta-carotene (180 mg/week in 6 capsules), the frequency of micronucleated cells decreased significantly (p less than 0.001) to 1.70% and 1.16%, respectively. No significant shift in the frequencies of micronucleated cells was observed following the intake of canthaxanthin (180 mg/week in 6 capsules) for 9 weeks or that of a placebo. The lack of protective activity of canthaxanthin, which is a good trapper of oxygen singlets but cannot be converted into vitamin A, suggests that vitamin A and beta-carotene exert their inhibitory effect on the formation of micronuclei by a mechanism not involving the scavenging of free radicals. The efficacy of beta-carotene as an inhibitor of micronucleated cell formation, the lack of toxicity, and its availability from a multitude of dietary sources should focus attention on this carotenoid as a promising chemopreventive agent.

Topics: Adult; Areca; beta Carotene; Canthaxanthin; Carotenoids; Cell Nucleus; Cheek; Female; Humans; Male; Mouth Mucosa; Mouth Neoplasms; Mutagenicity Tests; Nicotiana; Plants, Medicinal; Plants, Toxic; Vitamin A

Cancer development is mediated by oxidative stress and inflammation, which may correlate with metabolic disorders. The aim of this study was to evaluate antioxidant vitamins status and metabolic parameters in patients with oral cancer according to tumor-node-metastasis (TNM) stages.. A total of 194 patients with oral cancer were enrolled in this study. The patients were stratified for four groups according to cancer stages and that the statistics are comparisons across these groups. The levels of antioxidant vitamins (ubiquinone, β-carotene, vitamin A and E), metabolic parameters, oxidative stress, antioxidant enzymes activity, and inflammatory markers were measured.. More than half of the subjects had high blood pressure, central obesity, hyperglycemia, and hyperlipidemia regardless of TNM stage. With regard to antioxidant vitamins status, 46 and 94% of patients had β-carotene and ubiquinone deficiency, respectively. Patients in T3 and T4 stages had significantly lower antioxidant enzyme (catalase, p = 0.03) activity and higher inflammatory markers levels (high sensitivity C-reactive protein and interleukin-6, p < 0.01) than patients in the other stages. In addition, the level of β-carotene was negatively associated with waist circumference, and ubiquinone was positively associated with the level of high-density lipoprotein cholesterol (p < 0.05). Higher β-carotene and ubiquinone levels were negatively associated with hypertriglyceridemia and the risk of metabolic syndrome (p < 0.05).. A high proportion of patients with oral cancer had ubiquinone or β-carotene deficiency and metabolic disorders. The level of ubiquinone or β-carotene was negatively associated with the risk of central obesity, hypertriglyceridemia, and metabolic syndrome. Since patients with oral cancer suffer from high oxidative stress and inflammation (particularly in the T3 and T4 stages), supplementation with antioxidant vitamins such as ubiquinone or β-carotene could be preferentially applied.

Topics: Adult; Aged; beta Carotene; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Interleukin-6; Male; Metabolic Diseases; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Oxidative Stress; Ubiquinone; Vitamin A; Vitamin E

While the protective role of antioxidant nutrients against cancer is well established, data on Asian diets in patients with oral cancer are meagre.. A total of 1029 subjects over 30 years of age were investigated on their dietary practices in the Sabaragamuwa province (Sri Lanka) in 2006-07. Data collection tools were an interviewer-administered questionnaire, a three-day food diary and an examination of the oral cavity. Subjects identified with Oral Potentially Malignant Disorders (OPMD) and disease-free controls were analysed in a case-control fashion. Among the OPMDs, those with leukoplakia were separately considered. A further subgroup analysis was undertaken for β-carotene-rich foods. The analysis was stratified by portions of fruit/vegetables consumed as five or more portions and two or more portions daily.. A low BMI (<18.5) was a significant independent risk factor for the development of OPMD. More than half of both cases and controls consumed less than two portions of fruit/vegetables per day and only 20 subjects consumed more than five portions per day. Intake of more than two portions per day of β-carotene-containing fruits/vegetables significantly reduced the risk of having an OPMD and leukoplakia (OR = 0.5; 95% CI, 0.3-0.9). The significant differences observed with BMI and fruits/vegetables were attenuated when adjusted for betel quid chewing, smoking and alcohol use.. This study discloses prevailing under-nutrition in this rural population with very low daily consumption of fruit/vegetables. Cancer preventive properties in their diets are limited and are swamped by the known carcinogenic agents associated with use of betel quid, tobacco and alcohol.

Topics: Adult; Alcohol Drinking; Areca; beta Carotene; Body Mass Index; Capsicum; Case-Control Studies; Cross-Sectional Studies; Diet; Diet Records; Female; Fruit; Humans; Leukoplakia, Oral; Male; Mouth Neoplasms; Precancerous Conditions; Recommended Dietary Allowances; Risk Factors; Rural Health; Smoking; Sri Lanka; Surveys and Questionnaires; Tea; Thinness; Vegetables; Vitamins

Oral submucous fibrosis (OSMF) is a crippling slowly progressive disease of oral cavity that predominantly affects people habit of consuming areca nut and its commercial preparations which generates high levels of reactive oxygen species (ROS) during their metabolism.. The objective of this present study is to evaluate the role of oxidative stress in causation and progression of OSMF by measuring the levels of nonenzymatic antioxidants in OSMF patients.. For this study we selected 27 newly diagnosed OSMF patients of both sex with age group between 23 to 40 years and the same number of age and sex matched healthy individuals were selected as control group. In both the groups we measured plasma non enzymatic antioxidants like vitamin A. E, C and reduced glutathione. Total antioxidant activity was also assessed in both the groups.. We observed a very low levels of plasma non-enzymatic antioxidants (p < 0.001) and at the same time a very poor antioxidant activity (p < 0.001) in OSMF patients when compared to controls. Therefore, consumption of tobacco or areca quid creates an oxidative stress environment which might plays a major role in the causation of OSMF.

Topics: Adult; Antioxidants; Areca; beta Carotene; Biomarkers; Case-Control Studies; Disease Progression; Down-Regulation; Female; Glutathione; Humans; India; Male; Mastication; Mouth Neoplasms; Nuts; Oral Submucous Fibrosis; Oxidative Stress; Precancerous Conditions; Vitamin A; Vitamin E; Young Adult

Case-control studies indicate that vitamins C, E, A and carotenoids decrease risk of oral premalignant lesions (OPLs) and oral cancer, but clinical trials have failed to find protective effects of beta-carotene and suggest that vitamin E may increase risk. The authors prospectively evaluated the association between intake of vitamins C, E, A and carotenoids and incidence of OPL. Participants were 42,340 men in the Health Professionals Follow-up Study who provided information on supplement use and diet every 2-4 years by food frequency questionnaire. The authors confirmed 207 clinically or histopathologically diagnosed OPL events occurring between 1986 and 2002 by medical record review. Multivariate-adjusted relative risks (RR) of OPL were calculated with proportional hazards models. Total intake of vitamin C, vitamin A or carotenoids was not significantly associated with OPL risk. Dietary vitamin C was significantly associated with reduced risk (quintile 5 vs. 1, RR = 0.52, 95% CI 0.31-0.85, p(trend) = 0.04), but no association with supplemental vitamin C was observed. Inverse associations were apparent for beta-cryptoxanthin and alpha-carotene intake. No clear relationship emerged with beta-carotene, lycopene or lutein/zeaxanthin. Vitamin E was associated with increased risk (quintile 5 vs. 1, RR = 1.86, 95% CI 1.06-3.19), particularly among current smokers and with supplemental intake (current-smokers, supplement dose tertile 3 vs. 1, RR = 3.07, 95% CI 1.28-7.34, p(trend) = 0.01). For current smokers, beta-carotene also increased risk. Vitamin C from dietary sources, but not supplements, was associated with a reduced risk of OPL. The observed increased risk for current smokers with high vitamin E or beta-carotene intake should be explored further.

Topics: Adult; Aged; Ascorbic Acid; beta Carotene; Carotenoids; Case-Control Studies; Cryptoxanthins; Diet; Humans; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Risk Factors; Smoking; United States; Vitamin A; Vitamin E; Vitamins; Xanthophylls

We evaluated the effects of beta-carotene, a precursor of vitamin A, on the activity of some lysosomal hydrolases and on the levels of their natural substrates in hamster major salivary glands during experimental oral 7,12-dimethylbenzanthracene (DMBA) carcinogenesis. Sixty-four hamsters (Cricetus auratus) were divided into four groups--group 1: untreated control; group 2: DMBA was painted three times a week in the left buccal pouch; group 3: beta-carotene was painted three times a week in the left buccal pouch; group 4: DMBA and beta-carotene were painted alternatively in the left buccal pouch. After 16 weeks, the animals were sacrificed and the activities of some lysosomal hydrolases and their natural substrates in the major salivary glands were measured. beta-Carotene when administered topically in DMBA treated animals (group 4) reduced the levels of the majority of enzymes and substrates closer to those of the untreated control group, thus outlining a mild protective effect of beta-carotene towards the DMBA carcinogenic stress. Nevertheless, the presence of some enzymes which responded negatively to the combined administration of DMBA and beta-carotene suggests the necessity for future studies on the effect of beta-carotene at different concentrations, the systemic administration and the possibility to combine the topical beta-carotene administration with other chemopreventive drugs.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Administration, Topical; Animals; Antioxidants; beta Carotene; Carcinogenicity Tests; Carcinogens; Cricetinae; Disease Models, Animal; Female; Hydrolases; Lysosomes; Male; Mouth Neoplasms; Salivary Glands

Cell-cell interaction via gap junctions is considered to be a key factor in tissue homeostasis, and its alteration is associated with the neoplastic phenotype. Experimental and epidemiologic data suggest that carotenoids, particularly lycopene and beta-carotene, can reduce the risk of certain cancers. The aim of this study was to assess whether lycopene and beta-carotene interfere at some stage with the carcinogenic processes in human cancer cells derived from the oral cavity. KB-1 cells, originating from a human oral cavity tumor, were incubated with different concentrations of lycopene or beta-carotene delivered via the cell culture media from stock solutions in tetrahydrofuran. Lycopene strongly and dose dependently inhibited proliferation of KB-1 human oral tumor cells. beta-Carotene was a far less effective growth inhibitor. Lycopene (3 and 7 micro mol/L) significantly upregulated both the transcription (P < 0.005) and the expression (P < 0.05) of connexin 43, a key protein in the formation of gap-junctional communication. beta-Carotene (3 micro mol/L) tended to upregulate connexin 43 expression (P = 0.07) and significantly affected transcription of connexin 43 at 7 micro mol/L (P < 0.05). Gap-junctional communication measured by scrape-loading dye transfer and electron microscopy showed that lycopene enhanced gap-junctional communication between the cancer cells, whereas beta-carotene was less effective in this regard. The pattern of cellular uptake and incorporation into cancer KB-1 cells differed significantly between the carotenoids. beta-Carotene was avidly and rapidly incorporated into KB-1 cells, whereas lycopene uptake into the cells took place after longer incubation periods and only at the highest concentrations. The results of the present study further support the hypothesis that carotenoids in general, and lycopene in particular, may be effective anticarcinogenic agents in oral carcinogenesis.

Topics: Base Sequence; beta Carotene; Carotenoids; Cell Communication; Cell Division; Connexin 43; DNA Primers; Gap Junctions; Humans; Immunohistochemistry; Lycopene; Microscopy, Electron; Mouth Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Up-Regulation

A population-based case-control study was designed for the investigation of any association between serum micronutrient levels and oral leukoplakia. Out of a total of 9536 subjects over the age of 40 years who participated in the oral mucosal screening programme in Tokoname city, 48 cases detected with oral leukoplakia (38 male:10 female) were recruited. For each case, four controls matched by age and sex were selected from the same cohort. We examined the fasting serum levels of retinol, alpha-tocopherol, zeaxanthin and lutein, cryptoxanthin, lycopene and carotenoids (alpha-carotene and beta-carotene) by high-performance liquid chromatography. Among males with leukoplakia mean serum lycopene and beta-carotene levels (0.175+/-0.202, 0.357+/-0.295 micromol/l) were significantly lower than those of controls (0.257+/-0.252, 0.555+/-0.408 micromol/l) (P<0.05, P<0.005). Logistic regression analysis with leukoplakia as the dependent variable showed that high serum levels of beta-carotene were related to low risk of oral leukoplakia (odds ratio 0.160, 95% C.I.: 0.029-0.866, P<0.05). There were no significant differences in any of the serum nutrients estimated in female subjects. Our results suggest for the first time that high serum levels of beta-carotene may provide protection against oral precancer for the Japanese male.

Topics: Adult; Analysis of Variance; Antioxidants; beta Carotene; Case-Control Studies; Female; Humans; Japan; Leukoplakia, Oral; Logistic Models; Male; Mouth Neoplasms; Smoking; Vitamin A; Vitamin E

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; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Follow-Up Studies; Head and Neck Neoplasms; Humans; Isotretinoin; Mouth Neoplasms; Time Factors; Treatment Outcome

The carotenoids beta-carotene and canthaxanthin and the retinoid 13-cis-retinoic acid (13-RA) have inhibited oral carcinogenesis in the hamster cheek pouch (16 wks, 3 times/wk at 1.4 mg/kg) induced by an 0.5% solution of 7, 12-dimethylbenz[a]anthracene (DMBA). However, 13-RA at a higher dose (> 2.0 mg/kg per treatment) increased squamous cell carcinoma growth (Eur J Cancer Clin Oncol 24, 839-850, 1988). 13-RA, beta-carotene, and canthaxanthin administered to 60 hamsters (16 wks, 3 times/wk, 10 mg/kg) altered neovascularization characterized by immunohistochemistry for transforming growth factor-alpha (TGF-alpha) and factor VIII. 13-RA + DMBA resulted in more smaller-sized tumors, with a reduced volume and tumor burden (tumor controls, 185.9; 13-RA + DMBA, 151.0). The carotenoids reduced the number and the sizes of the carcinomas formed (beta-carotene, 60 tumors, 142.3 x 10(3) mm3; canthaxanthin, 30 tumors, 116.1 x 10(3) mm3). Factor VIII and TGF-alpha were expressed in high intensity at cancer sites of the 13-RA + DMBA and DMBA groups with > 50 and > 10 cells, respectively, per x 400 field. In contrast, beta-carotene- and canthaxanthin + DMBA-treated pouches showed > 20 and 5 cells, respectively, per x 400 field for factor VIII and TGF-alpha. These results suggest that 13-RA treatment may increase vascular growth, but the carotenoids also produced enhanced levels of endothelial cell growth and TGF-alpha compared with the untreated mucosa. The carotenoids may enhance tumor growth under the appropriate carcinogenic environment.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Canthaxanthin; Carcinoma, Squamous Cell; Cheek; Cricetinae; Dose-Response Relationship, Drug; Factor VIII; Immunoenzyme Techniques; Isotretinoin; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neovascularization, Pathologic; Transforming Growth Factor alpha

In a clinical trial the effect of chemoprevention with beta-carotene, vitamin E and C on dysplastic tissue was studied. The study included 24 patients with oral leukoplakia and 24 patients after radical resection of a primary oral cancer. There was a reduction of increased cell kinetic parameters like the S-phase portion or the average number of nuclear-organizer regions (NOR) per cell nucleus, a decrease of the micronuclei portion and a normalization of the cytokeratin gene-expression. The general response was 97.5%. Stopping the alcohol and tobacco abuse the effect of the antioxidative vitamins on redifferentiation of the oral mucosa was more intense than by persistance of the alcohol and tobacco abuse, but a long term prevention seems to be ineffective.

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Biopsy; Cell Differentiation; Cohort Studies; Drug Therapy, Combination; Humans; Keratins; Leukoplakia; Mouth Mucosa; Mouth Neoplasms; Nucleolus Organizer Region; S Phase; Time Factors; Vitamin E

We conducted a follow-up study of 380 incident cases of cancer of the oral cavity, pharynx, or larynx, who had been included in a previous case-control study. Information pertaining to potential risk factors, clinical characteristics, and evolution of the tumor (vital status, metastases, and second primary tumors) was obtained. From a multivariate proportional hazard model including terms for risk factors and clinical variables, the incidence of metachronous second primary tumors occurring in the head and neck was positively associated with employment as a farmer as opposed to white collar (hazard ratio [HR] = 3.3) and with tobacco smoking before first tumor diagnosis (HR = 4.3 for heavy versus never or very light smoker). The risk of second primary tumor decreased with increasing dietary "beta-carotene" intake (HR = 0.4 for high versus low intake in tertiles). Less differentiated first primary tumors were followed more frequently by second tumors as compared to grade 1 tumors. The incidence of metastases was not associated with etiological factors of the first tumor, but with stage.

Topics: Adult; Aged; Aged, 80 and over; Alcohol Drinking; Antineoplastic Agents; beta Carotene; Carotenoids; Case-Control Studies; Cohort Studies; Female; Follow-Up Studies; Humans; Laryngeal Neoplasms; Male; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Neoplasms, Second Primary; Occupations; Pharyngeal Neoplasms; Risk Factors; Smoking

The chemopreventive effects of two xanthophylls, astaxanthin (AX) and canthaxanthin (CX) on oral carcinogenesis induced by 4-nitroquinoline 1-oxide (4-NQO) was investigated in male F344 rats. Rats were given 20 ppm of 4-NQO in their drinking water for 8 weeks to induce oral neoplasms or preneoplasms. Animals were fed diets containing 100 ppm AX or CX during the initiation or postinitiation phase of 4-NQO-induced oral carcinogenesis. The others contained the groups of rats treated with AX or CX alone and untreated. At the end of the study (week 32), the incidences of preneoplastic lesions and neoplasms in the oral cavity of rats treated with 4-NQO and AX or CX were significantly smaller than those of rats given 4-NQO alone (P < 0.001). In particular, no oral neoplasms developed in rats fed AX and CX during the 4-NQO exposure and in those given CX after the 4-NQO administration. Similarly, the incidences of oral preneoplastic lesions (hyperplasia and dysplasia) in rats treated with 4-NQO and AX or CX were significantly smaller than that of the 4-NQO-alone group (P < 0.05). In addition to such tumor inhibitory potential, dietary exposure of AX or CX decreased cell proliferation activity in the nonlesional squamous epithelium exposed to 4-NQO as revealed by measuring the silver-stained nucleolar organizer regions protein number/nucleus and 5'-bromodeoxyuridine-labeling index. Also, dietary AX and CX could reduce polyamine levels of oral mucosal tissues exposed to 4-NQO. These results indicate that AX and CX are possible chemopreventers for oral carcinogenesis, and such effects may be partly due to suppression of cell proliferation.

Topics: Animals; Anticarcinogenic Agents; beta Carotene; Bromodeoxyuridine; Canthaxanthin; Carotenoids; Male; Mouth Neoplasms; Nucleolus Organizer Region; Precancerous Conditions; Rats; Rats, Inbred F344; Xanthophylls

Screening examinations were conducted at a Chinese community health fair in Houston, Texas, to identify individuals with oral leukoplakia for a chemoprevention trial of oral-cavity squamous cell carcinoma. All 161 volunteer participants were interviewed regarding age, smoking habits, and betel-nut and alcohol use. The screening included an examination of the oral cavity, oropharynx, and neck. One participant had a 1-mm area of oral leukoplakia on the right lateral surface of the oral tongue. Eighteen participants had other head and neck abnormalities. Only 12 participants (7.5%) were active smokers, and eight (5%) reported a prior history of smoking. One participant reported prior betel-nut use. The mean age was 55 years. The authors conclude that a venue such as this has a low yield for screening and recruitment of high-risk individuals for chemoprevention of oral-cavity squamous cell carcinoma, that generally health-conscious individuals attend health fairs, and that only a small percentage volunteer for oral screening.

Topics: Adult; Aged; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; China; Female; Health Fairs; Humans; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Smoking; Texas; Vitamin A

The modifying effects of two natural products, curcumin and hesperidin, given during the initiation and postinitiation phases of oral carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats and compared with that of beta-carotene. At 6 weeks of age, rats were divided into experimental and control groups and fed the diet containing beta-carotene, hesperidin, or curcumin at a dose of 0.5 g/kg diet (500 ppm). At 7 weeks of age, all animals except those treated with each test chemical alone and control groups were given 4-NQO (20 ppm) in the drinking water for 8 weeks to induce oral cancer. Seven days after the 4-NQO exposure, groups of animals fed the diets containing test chemicals were switched to the basal diet and continued on this diet until the end of the study. Starting 1 week after the stop of 4-NQO exposure, the groups given 4-NQO and a basal diet were switched to the diets containing beta-carotene, hesperidin, and curcumin and maintained on these diets for 22 weeks. The other groups consisted of rats given 500 ppm beta-carotene, hesperidin, or curcumin alone or untreated rats. All animals were necropsied at the termination of the experiment (week 32). The incidences of tongue neoplasms and preneoplastic lesions, polyamine levels in the tongue tissue, and cell proliferation activity estimated by bromodeoxyuridine-labeling index and by morphometric analysis of silver-stained nucleolar organizer region proteins were compared among the groups. Feeding of curcumin and beta-carotene during the initiation and postinitiation phases and hesperidin at the initiation stage caused a significant reduction in the frequency of tongue carcinoma (41-91% reduction, P < 0.05) and the order of chemopreventive efficacy was curcumin > beta-carotene > hesperidin. The incidences of oral preneoplasia in rats fed the diets mixed with these compounds were also decreased (P < 0.05). There were no such lesions in rats treated with test compounds alone or those in an untreated control group. Dietary administration of these compounds significantly decreased the labeling index of bromodeoxyuridine and the number and area of silver-stained nucleolar organizer region proteins per cell nucleus that are proliferation biomarkers, of the tongue squamous epithelium (P < 0.05). In addition, polyamine levels in the oral mucosa were lowered in rats treated with 4-NQO and three test compounds when compared to those give 4-NQO alone (P < 0.05).(ABST

Topics: 4-Hydroxyaminoquinoline-1-oxide; 4-Nitroquinoline-1-oxide; Animals; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Curcumin; Hesperidin; Male; Mouth Neoplasms; Nucleolus Organizer Region; Polyamines; Precancerous Conditions; Rats; Rats, Inbred F344; Tongue; Tongue Neoplasms

Previous studies have shown that beta-carotene and alpha-tocopherol can act synergistically to inhibit the growth of experimentally induced oral cancer. The initial studies on the synergistic anticancer activity of antioxidants have been extended to include reduced glutathione and ascorbic acid. Sixty male hamsters (4-5 wks old) were divided into six equal groups. Groups 1-6 were treated with 7,12-dimethylbenz[a]anthracene (DMBA) (0.5% solution). Group 2 received a mixture containing equal amounts of beta-carotene, dl-alpha-tocopherol (vitamin E), glutathione, and l-ascorbic acid (vitamin C) (12.5 micrograms) delivered orally by pipette. Groups 3-6 were treated with beta-carotene alone (50 micrograms), vitamin E alone (50 micrograms), glutathione (50 micrograms) alone, and vitamin C alone (50 micrograms). Animals were euthanized at 12 and 14 weeks. Tumors were counted and measured, and tumor burden was calculated for each experimental group. The mixture of antioxidants significantly reduced tumor burden, whereas the beta-carotene, vitamin E, and reduced glutathione treatments also reduced tumor burden. beta-Carotene and glutathione provided greater levels of chemoprevention than vitamin E as single agents. In contrast, vitamin C treatment produced no antitumor effect but increased tumor burden by Week 14. This mixture of antioxidants produced a significant synergistic chemoprevention of oral cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Animals; Ascorbic Acid; beta Carotene; Carotenoids; Cricetinae; Drug Combinations; Drug Synergism; Glutathione; Leukoplakia; Male; Mesocricetus; Mouth Neoplasms; Vitamin E

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

To investigate the relationship between serum micronutrients and the subsequent risk of oral and pharyngeal cancer, a nested case-control study was conducted within a cohort of 25,802 adults in Washington County, MD, whose blood samples were collected in 1974 and stored at -70 degrees C for subsequent assays. The serum levels of nutrients in 28 individuals who developed oral and pharyngeal cancer during 1975 to 1990 were compared with levels in 112 matched controls. Serum levels of all individual carotenoids, particularly beta-carotene, were lower among subjects who developed oral and pharyngeal cancer. The risks of this malignancy decreased substantially with increasing serum level of each individual carotenoid. Persons in the highest tertile of total carotenoids had about one-third the cancer risk as those in the lowest tertile. High serum levels of alpha-tocopherol also were related to a low oral cancer risk in later years, but the risks were elevated significantly with increasing serum levels of gamma-tocopherol and selenium. The findings from this study are consistent with many previous epidemiological investigations of dietary factors for oral and pharyngeal cancer and provide further evidence for the potential role of carotenoids and alpha-tocopherol in the chemoprevention of these malignancies.

Topics: beta Carotene; Carotenoids; Case-Control Studies; Humans; Mouth Neoplasms; Pharyngeal Neoplasms; Risk Factors; Selenium; Smoking; Vitamin A; Vitamin E

This study compares the toxic effects of the carotenoids, beta-carotene and canthaxanthin, and alpha-tocopherol (vitamin E) on human tumor cells and their normal counterparts in vitro. Seven different malignant cell lines were examined: oral carcinoma (two cell lines), breast (two cell lines), lung carcinoma (two cell lines), and malignant melanoma. The in vitro cell culture assays showed a consistent morphologic change in the affected tumor cells following treatment with carotenoid or vitamin E. A rounding of the tumor cells and eventual lifting off the tissue culture plate were observed. These changes were apparent after 1 to 5 hours of treatment depending on the tumor cell line. Associated with these observable cellular changes were quantitative reductions in proliferation (3H-thymidine proliferation) and succinic dehydrogenase activity (MTT assay). In addition, there was a noticeable change in protein expression, with an increased expression of a 70-kD protein following treatment with beta-carotene. This protein was associated with tumor cells showing a decrease in proliferation (oral carcinoma, malignant melanoma) but not with normal keratinocytes or melanocytes. These studies substantiate a selective cytotoxic effect on human tumor cell growth by carotenoids and alpha-tocopherol in vitro, and may provide an explanation of the therapeutic activity of these agents and their possible use in the treatment of premalignancy or early oral carcinoma.

Topics: beta Carotene; Breast Neoplasms; Canthaxanthin; Carcinoma, Squamous Cell; Carotenoids; Cell Division; Cells, Cultured; Electrophoresis, Polyacrylamide Gel; Humans; Keratinocytes; Lung Neoplasms; Melanocytes; Melanoma; Mouth Neoplasms; Neoplasm Proteins; Succinate Dehydrogenase; Tumor Cells, Cultured; Vitamin E

The inhibitory effect of oral administration of betel-leaf extract (BLE) and 2 of its constituents, beta-carotene and alpha-tocopherol, as single agents or in combination with dietary turmeric on methyl(acetoxymethyl)nitrosamine (DMN-OAC)-induced oral carcinogenesis in Syrian hamsters was studied. DMN-OAC was administered twice monthly for 6 months. The chemopreventive effect of BLE or its constituents with turmeric was determined by comparing tumor incidence observed in treated groups with that seen in control animals. The apparent site-specific chemopreventive effect of BLE or its constituents was demonstrated by inhibition of tumor incidence, reduction of tumor burden, extension of the tumor latency period and regression of established, frank tumors. The inhibitory effect of BLE or its constituents combined with turmeric was higher than that of the individual constituents. The study suggests that BLE could be developed as a potential chemopreventive agent for human oral cancer.

Topics: Animals; Areca; beta Carotene; Carcinogens; Carotenoids; Cricetinae; Curcuma; Dimethylnitrosamine; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Female; Mesocricetus; Mouth Neoplasms; Plant Extracts; Plants, Medicinal; Vitamin E

The purpose of this study was to extend the knowledge of the antitumor activity of liposomes and to identify, for the first time, the antitumor effect of liposomes with the antioxidant beta-carotene. The administration of the carotenoid encapsulated in in liposomes has the advantages of quantitation, facilitation, and most importantly an increased therapeutic response, resulting in the accentuation of regression of carcinoma in the hamster pouch. Tumors induced after the application of the carcinogen 7,12-dimethylbenz[alpha]anthracene (0.5%) were injected with liposomes composed of phosphatidylcholine, phosphatidylserine, and phosphatidylethanolamine in a ratio of 1:1:1 (large unilamellar vesicles). Tumor-bearing animals were divided into four groups, each containing 10 hamsters. The group treated with the liposomes of beta-carotene exhibited a significantly lower tumor burden (approx 5,000-fold difference) than the control tumor group. Electron- and light-micrographic analyses were used to substantiate the gross observations of tumor regression. It was noted that the carcinoma cells endocytozed liposomes in increased numbers compared with normal mucosa treated with liposomes. In addition, non-tumor-bearing hamsters injected with beta-carotene liposomes or liposomes alone did not exhibit any pathological change to the normal mucosa. An inflammatory infiltrate consisting of mononuclear cells, mast cells, and some polymorphonuclear leukocytes was noted, and degranulating polymorphonuclear leukocytes and mast cells and eosinophils predominated in the tumor controls (7,12-dimethylbenz[alpha]anthracene treated only). Notably, not all areas of degenerating dysplasia or early carcinoma exhibited a dense inflammatory response adjacent to the mucosa after the injection of beta-carotene liposomes. The results demonstrate a selective nontoxic therapy to regress experimental oral cancer.

Topics: Animals; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Cheek; Chromatography, High Pressure Liquid; Cricetinae; Drug Carriers; Liposomes; Male; Mesocricetus; Mouth Neoplasms

Human keratinocytes, obtained from bioptic specimens of healthy and preneoplastic oral mucosa, and from human cell lines from oral cavity tumors (KB and SCC-25) were treated with beta-carotene (10 microM). The colony forming efficiency (CFE), the proliferation rate and the frequency of micronucleated cells were measured in these cultures. CFE was significantly reduced (p less than 0.05) by beta-carotene treatment in cells from healthy mucosa and in KB cells. Decreases (p greater than 0.05; NS) were also observed in cells from pathological mucosa and in SCC-25 cells. Cell proliferation rate was not substantially affected by beta-carotene in all cultures. Finally, a decreased frequency of micronucleated cells was found in treated cultures, but significant reductions (p less than 0.05) were only observed in cultures from oral mucosa (healthy and pathological) as well as in KB cell cultures. Our results indicate that beta-carotene is able to reduce the clonogenic activity (CFE), even if it does not seem to influence cell proliferation, and that it has a protective effect against genotoxic damage.

Topics: Adolescent; Adult; Aged; beta Carotene; Biopsy; Carcinoma, Squamous Cell; Carotenoids; Cell Division; Cells, Cultured; Female; Humans; Keratinocytes; Male; Micronucleus Tests; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Stem Cells

The hamster cheek pouch (HCP) serves as an excellent model system not only for the studies on initiation and promotion but also for the modulation of experimental oral carcinogenesis. In our studies, HCPs treated with 7,12-dimethylbenz[a]anthracene (DMBA) showed both cheek pouch and stomach papillomas. Utilizing this model system, we tested and compared the modulatory effects of snuff, retinoic acid, and beta-carotene on the incidence of tumors and the keratin expression pattern. HCPs treated with snuff, either alone or in combination with DMBA, resulted in stomach papillomas. HCPs treated with snuff showed no cheek pouch tumors, and those treated with snuff and DMBA showed only 10-15% tumor incidence. Both beta-carotene and retinoic acid showed a total inhibition of DMBA-induced carcinogenesis in the HCP as well as in the stomach. The keratin expression pattern showed alterations depending on the experimental conditions.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carotenoids; Cheek; Cricetinae; Keratins; Male; Mesocricetus; Mouth Neoplasms; Plants, Toxic; Tobacco, Smokeless; Tretinoin

In the past four years this laboratory has utilized the hamster cheek pouch tumor model to investigate the anticancer activities of antioxidants, such as beta carotene. These molecules, which have exhibited no evidence of toxicity, have been administered systemically (oral ingestion), and locally to the tumor site in the hamster cheek pouch. The results have been either the inhibition of tumor growth, or the regression of tumor. Adjacent to the degenerating tumors a dense inflammatory infiltrate was observed. Specifically, the cytokines, tumor necrosis factor alpha, and beta, have been immunohistochemically localized to the site of regressed oral carcinoma. Recently, liposomes composed of phosphaditylcholine, phosphaditylserine, and phosphodityelanolamine were combined with beta carotene and injected locally to oral squamous cell carcinoma of the hamster. The results indicated that tumor cells accumulated the liposomes and were lysed while normal mucosal cells did not demonstrate this effect. Therefore antioxidants such as beta carotene can be localized to a tumor site, without a toxic response. Future studies on the anticancer activity of the antioxidants need to focus on the cellular and molecular changes produced in the immune effectors and in the mucosal cells following administration of the antioxidants.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Cheek; Cricetinae; Drug Carriers; Immunity; Immunohistochemistry; Liposomes; Male; Mesocricetus; Mouth Neoplasms; Tumor Necrosis Factor-alpha

Beta carotene, canthaxanthin, and a carotenoid mixture from an extract of algae were shown to prevent or inhibit the gross development of squamous cell carcinoma induced in the hamster buccal pouch by 7,12-dimethylbenz(a)anthracene. The carotenoids, dissolved in mineral oil, were administered by oral ingestion on days alternate to the carcinogen. Animals fed similar amounts of canthaxanthin, beta carotene or algae extract exhibited a statistically significant reduction in the development of tumors, both in number and size. The feeding of carotenoids, besides inhibiting gross tumor development, also produced a histologically unique picture. Microscopic areas of dysplasia, carcinoma in situ histologically unique picture. Microscopic areas of dysplasia, carcinoma in situ, or early carcinoma showed areas of tumor lysis and an inflammatory infiltrate consisting of lymphocytes and histiocytes. Characterization of this infiltrate disclosed a significant increase in cytotoxic lymphocytes, and cytotoxic macrophages producing tumor necrosis factor alpha. To confirm the presence of cytotoxic lymphocytes and macrophages a 51Cr release assay was performed. The results indicate that the immune response of the hamster was directed to the developing areas of dysplasia and carcinoma and was associated with the observations of prevention and inhibition of the growth of oral squamous cell carcinoma.

Topics: Administration, Oral; Animals; beta Carotene; Canthaxanthin; Carcinoma, Squamous Cell; Carotenoids; Cheek; Cricetinae; Cytotoxicity, Immunologic; Male; Mouth Neoplasms; T-Lymphocytes, Cytotoxic; Tumor Necrosis Factor-alpha

Regression of 7,12-dimethylbenz[a]anthracene (DMBA)-induced epidermoid carcinomas of hamster buccal pouch was accomplished by local injections of beta-carotene and canthaxanthin. One-hundred male hamsters (2-3 months old) were divided into five groups of 20 animals. All animals had the right buccal pouches painted three times weekly for 14 weeks with a 0.5% solution of DMBA in mineral oil, at which time all animals exhibited gross tumors of variable size and number. Group 1 animals were then injected locally into the right buccal pouch twice weekly for 4 weeks with 250 micrograms-carotene in 0.1 ml minimal essential medium (MEM) per injection. Group 2 animals were similarly injected with 250 micrograms canthaxanthin in 0.1 ml MEM. Group 3 animals were similarly injected with 250 micrograms 13-cis-retinoic acid in 0.1 ml MEM. Group 4 animals were injected only with MEM; Group 5 animals were untreated controls. Animals were killed in a carbon dioxide chamber, and buccal pouches were photographed. Tumors were counted and measured. Tumor burden in each group was compared, and statistical significance between groups was recorded. beta-Carotene was more effective than canthaxanthin in tumor regression. 13-cis-Retinoic acid had no effect in this system.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Buccal; Animals; beta Carotene; Canthaxanthin; Carcinoma, Squamous Cell; Carotenoids; Cheek; Cricetinae; Mouth Neoplasms; Remission Induction

Topics: Adolescent; beta Carotene; Canada; Carotenoids; Female; Humans; Indians, North American; Inuit; Male; Mouth Neoplasms; Nicotiana; Nitrites; Nitrosamines; Plants, Toxic; Risk Factors; Saliva; Tobacco, Smokeless

Topics: Antineoplastic Combined Chemotherapy Protocols; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Humans; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Radiotherapy; Stomatitis

Levels of activity for gamma glutamyl transpeptidase (GGT) were studied in hamster buccal pouches developing DMBA-induced epidermoid carcinomas and in pouches in which carcinogenesis was inhibited by topical application of beta carotene. The beta carotene acted to inhibit tumor development when applied topically on days alternate to the application of 0.25% DMBA in heavy mineral oil thrice weekly for 22 weeks. Forty male young adult Syrian hamsters were divided into four equal groups. Group 1 had DMBA applied to left buccal pouches thrice weekly. Group 2 had DMBA applied as in Group 1 but also beta carotene thrice weekly on days alternate to the DMBA application. Group 3 animals were painted with only beta carotene and Group 4 animals were untreated controls. The left buccal pouches were dissected at autopsy and divided in half. One half was fixed in formalin, sectioned in paraffin and stained with hematoxylin-eosin for histologic study. The other half was prepared for the histochemical demonstration of GGT activity using epithelial whole mount preparations. GGT activity was found to be reduced in the left buccal pouches of those animals treated with both beta carotene and DMBA when compared to those animals treated with DMBA alone.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carotenoids; Cricetinae; gamma-Glutamyltransferase; Male; Mesocricetus; Mouth Neoplasms

beta-Carotene was found to significantly inhibit the formation of 7,12-dimethylbenz[a]anthracene (DMBA)-induced squamous cell carcinoma of hamster buccal pouch when applied topically on days alternate to the application of 0.25% DMBA in heavy mineral oil thrice weekly for 22 weeks. An initial experiment utilized 40 male young adult Syrian hamsters divided into four equal groups. Group 1 had DMBA applied to left buccal pouches thrice weekly. Group 2 had DMBA applied as in group 1 but also beta-carotene thrice weekly on days alternate to the DMBA application. Group 3 animals were painted with only beta-carotene and group 4 animals were untreated controls. In a second experiment with 80 animals, beta-carotene was found to inhibit oral carcinogenesis in an initiation--promotion hamster buccal pouch system using 0.1% DMBA as initiator and 40% benzoyl peroxide as promoter. beta-Carotene inhibited both initiation and promotion.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adjuvants, Immunologic; Administration, Topical; Animals; Antioxidants; beta Carotene; Carotenoids; Cricetinae; Male; Mesocricetus; Mouth Neoplasms

Beta carotene (250 micrograms/ml) dissolved in mineral oil applied either topically or injected locally (190 ng/ml dissolved in media) into DMBA (7,12-dimethylbenz(a)anthracene)-induced or HCPC-1 cell line-produced oral squamous cell carcinoma of the hamster buccal pouch was observed to result in the regression of these tumors. (p less than or equal to .005) Beta carotene application to tumor bearing pouches was observed to produce a dramatic increase in positively stained macrophages for tumor necrosis factor (TNF-alpha) as compared to macrophages in control pouches. Macrophages from hamsters with regressed tumor were shown to produce a significant increase in cytotoxicity to HCPC-1 tumor cells. Regression of the hamster oral carcinoma was correlated with the increased capacity of macrophages to lyse tumor cells, and related to the induction of tumor necrosis factor which was associated with the administration of the carotenoid, beta carotene.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Cheek; Cricetinae; Cytotoxicity, Immunologic; Glycoproteins; Macrophages; Male; Mesocricetus; Mouth Neoplasms; Neoplasm Transplantation; Tumor Necrosis Factor-alpha

Beta-carotene was estimated in exfoliated oral mucosa cells in groups of individuals at various risks for oral cancer. Approximately 4 X 10(6) exfoliated cells were collected from each subject by brushing the oral mucosa. Cell pellets were hydrolyzed with pronase and then with KOH/methanol. Beta-carotene was extracted with hexane, separated by reverse-phase HPLC, and detected at 450 nm. Mean beta-carotene levels in exfoliated cells were 0.08 ng/10(6) cells for 56 heavy consumers of alcoholic beverages (150 g or more per week), 1.36 ng/10(6) cells for 28 Seventh Day Adventists (all abstainers from alcohol, tobacco and meat consumption), 1.39 ng/10(6) cells for 55 lacto-vegetarians of the International Society for Krishna Consciousness (ISKC) (abstainers from alcohol and tobacco), and 1.08 ng/10(6) cells for 61 representatives of a "Western" life-style pattern (64% consumed the equivalent of at least one bottle of wine or 7 bottles of beer per week, and all were non-smokers). If the heavy alcohol consumers (males) are matched to non-drinking males of comparable age, the mean beta-carotene values are 0.08 ng versus 1.24 ng/10(6) cells. The possible involvement of the low levels of beta-carotene in the mucosa of heavy alcohol drinkers in increased sensitivity towards the carcinogenic and genotoxic activity of cigarette smoking plus alcohol ingestion is discussed.

Topics: Alcohol Drinking; beta Carotene; Carotenoids; Diet; Diet, Vegetarian; Humans; Mouth Mucosa; Mouth Neoplasms; Risk; Smoking

The frequency of exfoliated cells with micronuclei (MNC) was used to estimate the genotoxic effect of smokeless tobacco (snuff) on the oral mucosa and to follow the response to the administration of beta-carotene (180 mg/week, given twice weekly in 6 capsules of 30 mg each). The pilot trial was carried out with Inuits in Gjoa Haven, Northwest Territories, Canada. Their traditional diet, which is rich in caribou and seal meat and liver but low in vegetables and fruits, leads to "normal" serum levels of retinol (447 ng/ml in non-users of tobacco and 463 ng/ml in tobacco users) but low levels of beta-carotene (57 ng/ml for non-users of tobacco and 47 ng/ml for users). Prior to the twice-weekly administration of beta-carotene, the frequency of MNC was 1.87% +/- 0.92 (n = 23) in the mucosa of the lower gingival groove where the tobacco was usually kept. It decreased significantly (P less than 0.001) to 0.74% +/- 0.42 following the 10-week oral administration of beta-carotene capsules. The frequency of MNC did not change significantly in the group receiving a placebo and in snuff users who received no treatment over the 10-week trial period. The size and morphological appearance of the typical snuff-related, whitish, wrinkled patches of the mucosa where the tobacco was kept was not affected by the 10-week treatment with beta-carotene. Similarly, no reduction was observed in the frequency of anucleated, exfoliated mucosa cells. Beta-carotene appears to be an efficient inhibitor of MNC in the oral mucosa of snuff users who do not suffer from any vitamin A deficiency and who have "normal" levels of retinol.

Topics: Adolescent; Adult; Aged; beta Carotene; Carotenoids; Child; Chromatin; Humans; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Nicotiana; Plants, Toxic; Seasons; Vitamin A

The use of the micronucleus test on exfoliated cells as an approach to identify genotoxic damage in human tissues which are targets for organ-specific carcinogens and from which carcinomas will develop, is described. Chromosomal damage by carcinogens to dividing basal cells of the epithelium results in the production of micronuclei in the daughter cells which migrate up through the epithelium and are exfoliated. Exfoliated cells can be readily obtained from several tissues, including the oral buccal mucosa (scrapings of oral cells), bronchi (sputum), urinary bladder and ureter (centrifugation of urine), cervix (smears) and esophagus (imprints from biopsies). The micronucleus test on exfoliated cells has been successfully used to: (1) recognize population groups at an elevated risk for cancer of the oral cavity or urinary bladder; (2) estimate synergistic or additive effects of carcinogen exposure (cigarette smokers plus drinkers of alcoholic beverages); (3) pinpoint the site within an organ from which most carcinomas will develop (oral cancers among 'inverted' smokers in the Philippines). The possibility that this assay may also serve as a rapid monitor for chemopreventive agents is suggested by a preliminary trial on the effect of vitamin A/beta--carotene dietary supplementation among 33 betel quid chewers in the Philippines. These individuals received sealed capsules of retinol (100,000 IU/week) and beta-carotene (300,000 IU/week) for a 3-month period. At the end of this time, the frequencies of micronucleated buccal mucosa cells were reduced from an average of 4.2% to 1.4%. No changes were observed in micronucleus frequencies among 11 betel quid chewers not receiving vitamin pills. Non- chewers of betel quid in this population had a micronucleus frequency of 0.5%.

Topics: Areca; beta Carotene; Carcinogens; Carotenoids; Chromosome Aberrations; Ethnicity; Humans; Mouth Mucosa; Mouth Neoplasms; Mutagenicity Tests; Nicotiana; Philippines; Plants, Medicinal; Plants, Toxic; Racial Groups; Risk; Smoking; Vitamin A