beta-carotene and Skin-Neoplasms

'Keratinocyte cancer' is now the preferred term for the most commonly identified skin cancers basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which were previously commonly categorised as non-melanoma skin cancers (NMSC). Keratinocyte cancer (KC) represents about 95% of malignant skin tumours. Lifestyle changes have led to increased exposure to the sun, which has, in turn, led to a significant increase of new cases of KC, with a worldwide annual incidence of between 3% and 8%. The successful use of preventive measures could mean a significant reduction in the resources used by health systems, compared with the high cost of the treatment of these conditions. At present, there is no information about the quality of the evidence for the use of these sun protection strategies with an assessment of their benefits and risks.. To assess the effects of sun protection strategies (i.e. sunscreen and barrier methods) for preventing keratinocyte cancer (that is, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) of the skin) in the general population.. We searched the following databases up to May 2016: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trial registries and the bibliographies of included studies for further references to relevant trials.. We included randomised controlled clinical trials (RCTs) of preventive strategies for keratinocyte cancer, such as physical barriers and sunscreens, in the general population (children and adults), which may provide information about benefits and adverse events related to the use of solar protection measures. We did not include trials focused on educational strategies to prevent KC or preventive strategies in high-risk groups. Our prespecified primary outcomes were BCC or cSCC confirmed clinically or by histopathology at any follow-up and adverse events.. Two review authors independently selected studies for eligibility using Early Review Organizing Software (EROS). Similarly, two review authors independently used predesigned data collection forms to extract information from the original study reports about the participants, methods of randomisation, blinding, comparisons of interest, number of participants originally randomised by arm, follow-up losses, and outcomes, and they assessed the risk of bias. We resolved any disagreement by consulting a third author and contacted trial investigators of identified trials to obtain additional information. We used standard methodological procedures expected by Cochrane.. We included one RCT (factorial design) that randomised 1621 participants.This study compared the daily application of sunscreen compared with discretionary use of sunscreen, with or without beta-carotene administration, in the general population. The study was undertaken in Australia; 55.2% of participants had fair skin, and they were monitored for 4.5 years for new cases of BCC or cSCC assessed by histopathology. We found this study to be at low risk of bias for domains such as allocation, blinding, and incomplete outcome data. However, we found multiple unclear risks related to other biases, including an unclear assessment of possible interactions between the effects of the different interventions evaluated (that is, sunscreen and beta-carotene). We found no difference in terms of the number of participants developing BCC (n = 1621; risk ratio (RR) 1.03, 95% confidence interval (CI) 0.74 to 1.43) or cSCC (n = 1621; RR 0.88, 95% CI 0.50 to 1.54) when comparing daily application of sunscreen with discretionary use, even when analyses were restricted to groups without beta-carotene supplementation. This evidence was of low quality, which means that there is some certainty that future studies may alter our confidence in this evidence.We reported adverse events in a narrative way and included skin irritation or contact allergy.We identified no studies that evaluated other sun protection measures, such as the use of sun-protective clothing, sunglasses, or hats, or seeking the shade when outdoors.. In this review, we assessed the effect of solar protection in preventing the occurrence of new cases of keratinocyte cancer. We only found one study that was suitable for inclusion. This was a study of sunscreens, so we were unable to assess any other forms of sun protection. The study addressed our prespecified primary outcomes, but not most of our secondary outcomes. We were unable to demonstrate from the available evidence whether sunscreen was effective for the prevention of basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC).Our certainty in the evidence was low because there was a lack of histopathological confirmation of BCC or cSCC in a significant percentage of cases. Amongst other sources of bias, it was not clear whether the study authors had assessed any interaction effects between the sunscreen and beta-carotene interventions. We think that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Topics: Adult; Australia; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Humans; Neoplasms, Radiation-Induced; Randomized Controlled Trials as Topic; Skin Neoplasms; Sunlight; Sunscreening Agents; Ultraviolet Rays; Vitamins

Skin cells are constantly exposed to reactive oxygen species (ROS) and oxidative stress from exogenous and endogenous sources. UV radiation is the most important environmental factor in the development of skin cancer and skin aging. The primary products caused by UV exposure are generally direct DNA oxidation or generation of free radicals which form and decompose extremely quickly but can produce effects that can last for hours, days, or even years. UV-induced generation of ROS in the skin develops oxidative stress when their formation exceeds the antioxidant defense ability. The reduction of oxidative stress can be achieved on two levels: by lowering exposure to UVR and/or by increasing levels of antioxidant defense in order to scavenge ROS. The only endogenous protection of our skin is melanin and enzymatic antioxidants. Melanin, the pigment deposited by melanocytes, is the first line of defense against DNA damage at the surface of the skin, but it cannot totally prevent skin damage. A second category of defense is repair processes, which remove the damaged biomolecules before they can accumulate and before their presence results in altered cell metabolism. Additional UV protection includes avoidance of sun exposure, usage of sunscreens, protective clothes, and antioxidant supplements.

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Glutathione; Humans; Reactive Oxygen Species; Retinoids; Skin Neoplasms; Ultraviolet Rays; Vitamin E

Mounting evidence from experimental and animal studies suggests that vitamin A may have a protective effect on melanoma, but the findings on the association of vitamin A intake with risk of melanoma have been inconsistently reported in epidemiologic studies. We attempted to elucidate the association by performing a meta-analysis.. Eligible studies were identified by searching PubMed and EMBASE databases, as well as by reviewing the references of retrieved publications. Summary odds ratios (OR) with corresponding 95% confidence interval (CI) were computed with a random-effects model. Study-specific ORs and 95% CIs for the highest vs. lowest categories of vitamin A intake were pooled.. A total of 8 case-control studies and 2 prospective studies comprising 3,328 melanoma cases and 233,295 non-case subjects were included. The summary OR for the highest compared with the lowest intake of total vitamin A, retinol and beta-carotene was 0.86 (95% CI = 0.59-1.25), 0.80 (95% CI = 0.69-0.92) and 0.87 (95%CI = 0.62-1.20), respectively. Significant heterogeneity was observed among studies on vitamin A and beta-carotene intake, but not among studies on retinol intake. Subgroup and sensitivity analyses confirmed these findings. There was no indication of publication bias.. Findings from this meta-analysis suggest that intake of retinol, rather than of total vitamin A or beta-carotene, is significantly associated with reduced risk of melanoma.

Topics: beta Carotene; Case-Control Studies; Humans; Melanoma; Prospective Studies; Skin; Skin Neoplasms; Vitamin A; Vitamins

Photodamage is known to occur in skin with exposure to sunlight, specifically ultraviolet (UV) radiation. Such damage includes inflammation, oxidative stress, breakdown of the extracellular matrix, and development of cancer in the skin. Sun exposure is considered to be one of the most important risk factors for both nonmelanoma and melanoma skin cancers. Many phytonutrients have shown promise as photoprotectants in clinical, animal and cell culture studies. In part, the actions of these phytonutrients are thought to be through their actions as antioxidants. In regard to skin health, phytonutrients of interest include vitamin E, certain flavonoids, and the carotenoids, β-carotene, lycopene and lutein.

Topics: Animals; Antioxidants; beta Carotene; Carotenoids; Flavonoids; Humans; Lutein; Lycopene; Melanoma; Mice; Oxidative Stress; Rats; Skin Neoplasms; Sunlight; Ultraviolet Rays; Vitamin E

Topics: Anticarcinogenic Agents; beta Carotene; Chemoprevention; Clinical Trials as Topic; Humans; Organ Transplantation; Retinoids; Sirolimus; Skin Neoplasms

Pro-oxidants, reactive species and free radicals, are toxic substances that can cause oxidative damage to major constituents of biological systems. In contradistinction, antioxidants are defined as any substance that significantly prevents the pro-oxidant-initiated oxidation of a substrate. Consequently, it was suggested that it might be possible to reduce free radical damage and thus cancer risk through 3 dietary changes: (1) caloric reduction, that is, lowering the level of free radical reactions arising in the course of normal metabolism; (2) minimize dietary components that increase the level of free radical reactions (eg, polyunsaturated fats); and (3) supplement the diet with one or more free radical reaction inhibitors (antioxidants). Lipid peroxidation exemplifies the type of chain reaction initiated by free radicals in (2) and (3). Both the phenolic antioxidant butylated hydroxytoluene (BHT) and the carotenoid beta-carotene can terminate such reactions and have been shown to influence ultraviolet (UV) carcinogenesis. However, there is a lack of correlation between physicochemical and patho-physiological responses in both instances. Whereas the influence on UV carcinogenesis of both antioxidants has been reported to diminish as the level of dietary fat decreases, pointing to the involvement of lipid peroxidative reactions, the mode of BHT's action in inhibiting UV carcinogenesis appears to be related to UV dose diminution through increased spectral absorbance of the stratum corneum. beta-carotene has no such effect and may actually exacerbate UV carcinogenesis under certain dietary conditions. This paradox points to the complex relationship between chemical mechanisms and biological mode of action of antioxidants. Recent clinical and experimental data suggest that antioxidant supplementation of the complex and intricately balanced natural antioxidant defense system as a cancer prevention strategy will demand extreme caution.

Topics: Animals; Antioxidants; beta Carotene; Delivery of Health Care, Integrated; Free Radicals; Humans; Lipid Peroxidation; Mice; Neoplasms; Oxidative Stress; Primary Prevention; Prognosis; Rats; Risk Factors; Skin Neoplasms; Ultraviolet Rays

An hypothesis for the role of free radicals in cancer was elaborated by D. Harman in 1962 who suggested that it might be possible to reduce the extent of damage caused by free radicals through three dietary changes: (i) caloric reduction, i.e., lowering the level of free radical reactions arising in the course of normal metabolism; (ii) minimize dietary components that tend to increase the level of free radical reactions (e.g., polyunsaturated fats); and (iii) supplement the diet with one or more free radical reaction inhibitors (anti-oxidants). With respect to (ii) and (iii), lipid peroxidation exemplifies the type of chain reaction initiated by free radicals, with unsaturated fatty acids being the primary center of free radical attack. Anti-oxidants act as free radical scavengers and are able to terminate these reactions. Indeed, the phenolic anti-oxidant butylated hydroxytoluene (BHT), and the carotenoid beta-carotene, have both been shown to influence photocarcinogenesis, although the lack of correlation between physicochemical parameters and pathophysiological responses is apparent in both instances. The bimolecular rate constant for reaction of BHT with model peroxyl radicals is low while beta-carotene is highly reactive. However, both are able to efficiently inhibit lipid peroxidation reactions in biological membranes. Indeed, the influence of photocarcinogenesis by both BHT and beta-carotene is diminished as the level of dietary fat decreases, pointing to the involvement of lipid peroxidative reactions. Nevertheless, the mode of action of BHT in inhibiting photocarcinogenesis appears to be related to dose-diminution resulting from an increased spectral absorbance of the stratum corneum. On the other hand, beta-carotene has no such effect and may actually exacerbate photocarcinogenesis under certain dietary conditions. This paradox points to the complex relationship between chemical mechanisms and biological mode of action of anti-oxidants in photocarcinogenesis. Recent clinical and experimental data also suggest that supplementation of the complex and intricately balanced natural antioxidant defense system with one or more anti-oxidants as a cancer prevention strategy will demand extreme caution.

Topics: Animals; Antioxidants; beta Carotene; Butylated Hydroxytoluene; Free Radicals; Humans; Lipid Peroxidation; Mice; Models, Chemical; Oxidants; Reactive Oxygen Species; Skin Neoplasms; Ultraviolet Rays

Cutaneous photodamage is partly mediated via oxidative pathways and there is evidence to suggest that antioxidants within the skin may have a photoprotective effect. Antioxidant activity is provided by a number of naturally occurring substances including alpha-tocopherol (vitamin E) and beta-carotene, whose effects are mediated by their capacity to quench singlet oxygen, scavenge free radicals and prevent the formation of free radicals. Beta-carotene has been used as treatment for various photosensitivity disorders for more than 30 years. The main indication for its use is in the treatment of the photosensitivity associated with erythropoietic protoporphyria. A role for beta-carotene in the prevention of non-melanoma skin cancer has yet to be demonstrated despite clinical research activity in this area. The role for alpha-tocopherol as a photoprotective agent is less clear-cut and it has yet to be established as treatment either for conditions characterized by photosensitivity or as an agent for preventing chronic photodamage or cutaneous malignancy.

Topics: Antioxidants; beta Carotene; Humans; Photosensitivity Disorders; Skin Aging; Skin Neoplasms; Vitamin E

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

Aspirin and other NSAIDs are showing promise in the chemoprevention of colorectal cancer. Ongoing trials will eventually provide still lacking information about the optimum dose and treatment duration. NSAIDs may also help to lower the risk of cancer in other organs such as the oesophagus, and possibly breast, stomach, and lung. The chemoprevention by NSAIDs should be seen not as the sole method of prevention, but as an additional tool which will be accompanied by other approaches such as stopping smoking, limiting alcohol consumption, and eating more fruits and vegetables. The chemoprevention by NSAIDs needs also to be balanced against the risks of toxicity (particularly in the stomach) and the other beneficial effects such as prevention of cardiovascular morbidity and mortality. Some of the NSAID induced gastric ulceration and bleeding will most likely be avoided by adopting the use of cyclooxygenase-2 (COX-2) selective NSAIDs, which will selectively inhibit COX-2 while sparing COX-1.

Topics: Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; beta Carotene; Case-Control Studies; Child; Cohort Studies; Colorectal Neoplasms; Cricetinae; Cyclooxygenase Inhibitors; Esophageal Neoplasms; Humans; Neoplasms; Pancreatic Neoplasms; Prospective Studies; Prostaglandin Antagonists; Prostaglandins; Randomized Controlled Trials as Topic; Skin Neoplasms; Stomach Neoplasms; Time Factors

Acute and chronic exposures to non-physiological doses of UV-light lead to a variety of changes of the skin. The most significant of these changes are a premature aging of the skin, UV-induced hyperkeratosis or atrophy, provocation of skin diseases and neoplasms of the skin. Furthermore, the local and systemic immune response can be negatively modulated. As long as society views tanned skin as a sign of beauty and success, and provided no behavioral changes occur, it will be required to emphasize prevention through education and the use of external and internal sun protection products. It is presently customary to use only sunscreens which can block UVB and UVA light to varying degrees. It could also be shown that presupplementation with beta carotene combined with topical sunscreens are more effective than sunscreen cream alone. Therefore the use of such a combination for the general health of population at risk e.g. before UV-exposure would seem advisable. There are no acceptable alternatives of protection against UV-radiation except suitable clothing and avoiding skin exposure to direct sun light.

Topics: Administration, Oral; Administration, Topical; Antioxidants; beta Carotene; Humans; Neoplasms, Radiation-Induced; Radiodermatitis; Skin Aging; Skin Neoplasms; Sunscreening Agents; Ultraviolet Rays

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

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

Topics: Antioxidants; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Combined Modality Therapy; Cryotherapy; Humans; Retinoids; Skin Neoplasms

Topics: Animals; beta Carotene; Carotenoids; Humans; Immunity; Immunity, Cellular; Killer Cells, Natural; Lymphocyte Activation; Macrophages; Neoplasms, Experimental; Skin Neoplasms; T-Lymphocytes, Helper-Inducer

Our understanding of the carcinogenic process as it relates to human skin cancer is growing rapidly. As this understanding increases, so will our ability to alter the process in a positive fashion. Presently, sun exposure is known to be the major carcinogen in human skin. The use of sunscreens is, and will continue to be, the most effective method of preventing human skin cancer. As these agents become more effective, especially against long-wave UV radiation, and as patients begin to use them more conscientiously, we should experience a decrease in skin cancer rates. In addition, a number of chemical agents are presently being investigated as anticarcinogens, especially in those patients who are at high risk for the development of skin cancers. A number of these hold promise as safe and effective chemopreventatives in reducing the morbidity and mortality of cancer in human skin.

Topics: Animals; Antioxidants; beta Carotene; Carotenoids; Diet; Humans; Immunization, Passive; Retinoids; Skin Neoplasms; Sunlight; Sunscreening Agents; Ultraviolet Rays

This paper describes the development of the use of carotenoid pigments in the treatment of light-sensitive skin diseases. It also discusses the animal and human studies involved in determining whether carotenoids have any anti-cancer activity. The possible mechanisms of carotenoid photoprotective and anti-cancer actions are briefly discussed.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adolescent; Adult; Animals; Bacteria; Bacterial Physiological Phenomena; beta Carotene; Canthaxanthin; Carotenoids; Child; Child, Preschool; Diet; Humans; Infant; Light; Neoplasms; Neoplasms, Experimental; Photochemistry; Photosensitivity Disorders; Porphyrias; Protoporphyrins; Skin Diseases; Skin Neoplasms; Sunburn; Sunlight; Ultraviolet Rays

This review deals with topical and systemic approaches for protection of human skin against the harmful effects of solar radiation. Two concerns about the deleterious effects of sun exposure involve: (1) acute effects (e.g., sunburn and drug-induced phototoxicity) and (2) potential long-term risks of repeated sun exposures leading to development of solar elastosis, keratoses, induction of both nonmelanoma and melanoma skin cancer, and alteration of immune responses and functions. Action spectra of normal and abnormal reactions of human skin to acute and chronic effects of solar radiation are presented with a view to helping the physician prescribe the appropriate sunscreens. Factors that influence acute effects of sunburn are reviewed. Various artificial methods effective in minimizing or preventing harmful effects of solar radiation, both in normal individuals and in patients with photosensitivity-related problems, are discussed. Emphasis is placed on the commercially available chemical sunscreens and their properties. Sun protection factor (SPF) values of several brand-name formulations determined with a solar simulator under indoor conditions (laboratory) and with solar radiation under natural, field conditions are presented. Factors responsible for variations of SPF values observed under indoor and outdoor conditions are reviewed. Systemic photoprotective agents and their limitations are outlined. The photobiology of melanin pigmentation (the tanning reaction) is briefly discussed, with emphasis on the dangers of using quick-tanning lotions for stimulation of the tanning reaction.

Topics: 5-Methoxypsoralen; Administration, Oral; Administration, Topical; beta Carotene; Carotenoids; Chloroquine; Dermatitis, Contact; Furocoumarins; Humans; Keratosis; Melanins; Methoxsalen; Nonprescription Drugs; Photosensitivity Disorders; Skin Neoplasms; Skin Pigmentation; Sunburn; Sunscreening Agents; Ultraviolet Rays

Topics: Aging; Animals; Antioxidants; beta Carotene; Carcinogens; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; DNA; Female; Geography; Humans; Male; Melanocytes; Melanoma; Neoplasms, Radiation-Induced; Pyrimidine Dimers; Sex Factors; Skin Neoplasms; Ultraviolet Rays; Vitamin A

Given the public health burden of skin cancer in white populations, an increase in sun protective behavior is needed. In a high-risk community, we assessed long-term sunscreen use among people who had participated in a randomized trial of daily sunscreen application for prevention of skin cancer.. In 1992, 1621 residents of the subtropical Australian township of Nambour were randomly allocated to either daily or discretionary sunscreen use until 1996. From 1997 to 2002, we monitored by questionnaires their ongoing sunscreen use.. People who had never or irregularly used sunscreen when in summer sun before the trial were more likely (P < 0.0001) to be sustaining regular application especially to their face (20% vs. 11%) and forearms (14% vs. 5%) if they had been allocated to daily, not discretionary, use of sunscreen for 5 years.. Regular voluntary sunscreen use for skin cancer prevention can be sustained by sun-sensitive people in the long term. Habit formation appears to be an important goal for sun protection programs among those living, or on vacation, in sunny places.

Topics: Adult; Aged; Analysis of Variance; Australia; beta Carotene; Follow-Up Studies; Health Behavior; Humans; Middle Aged; Skin Neoplasms; Sunburn; Sunscreening Agents; Surveys and Questionnaires; Vitamins

Topics: Adult; Aged; Aged, 80 and over; Antioxidants; beta Carotene; Carcinoma, Basal Cell; Case-Control Studies; Dietary Supplements; Humans; Male; Middle Aged; Neoplasms, Squamous Cell; Oxidative Stress; Risk Factors; Skin Neoplasms; Tocopherols; Vitamin A; Vitamin E

Although basic research provides plausible mechanisms for benefits of beta carotene supplementation on nonmelanoma skin cancer (NMSC) primarily consisting of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), observational studies are inconsistent. Randomized trial data are limited to 1 trial of secondary prevention that showed no effect of beta carotene on the incidence of NMSC after 5 years.. To test whether supplementation with beta carotene reduces the risk for development of a first NMSC, including BCC and SCC.. Randomized, double-blind, placebo-controlled trial with 12 years of beta carotene supplementation and follow-up.. Physicians' Health Study in the United States.. Apparently healthy male physicians aged 40 to 84 years in 1982 (N = 22 071).. Beta carotene, 50 mg, on alternate days.. Relative risk (RR) and 95% confidence interval (CI) for a first NMSC, BCC, and SCC.. After adjusting for age and randomized aspirin assignment, there was no effect of beta carotene on the incidence of a first NMSC (RR, 0.98; 95% CI, 0.92-1.05), BCC (RR, 0.99; 95% CI, 0.92-1.06), or SCC (RR, 0.97; 95% CI, 0.84-1.13). There was also no significant evidence of beneficial or harmful effects of beta carotene on NMSC by smoking status (current, past, or never).. This large-scale, randomized, primary prevention trial among apparently healthy well-nourished men indicates that an average of 12 years of supplementation with beta carotene does not affect the development of a first NMSC, including BCC and SCC.

Topics: Adult; Aged; Aged, 80 and over; Antioxidants; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cohort Studies; Dietary Supplements; Double-Blind Method; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Primary Prevention; Skin Neoplasms; United States

The use of sunscreens on the skin can prevent sunburn but whether long-term use can prevent skin cancer is not known. Also, there is evidence that oral betacarotene supplementation lowers skin-cancer rates in animals, but there is limited evidence of its effect in human beings.. In a community-based randomised trial with a 2 by 2 factorial design, individuals were assigned to four treatment groups: daily application of a sun protection factor 15-plus sunscreen to the head, neck, arms, and hands, and betacarotene supplementation (30 mg per day); sunscreen plus placebo tablets; betacarotene only; or placebo only. Participants were 1621 residents of Nambour in southeast Queensland, Australia. The endpoints after 4.5 years of follow-up were the incidence of basal-cell and squamous-cell carcinomas both in terms of people treated for newly diagnosed disease and in terms of the numbers of tumours that occurred. Analysis of the effect of sunscreen was based only on skin cancers that developed on sites of daily application. All analyses were by intention to treat.. 1383 participants underwent full skin examination by a dermatologist in the follow-up period. 250 of them developed 758 new skin cancers during the follow-up period. There were no significant differences in the incidence of first new skin cancers between groups randomly assigned daily sunscreen and no daily sunscreen (basal-cell carcinoma 2588 vs 2509 per 100,000; rate ratio 1.03 [95% CI 0.73-1.46]; squamous-cell carcinoma 876 vs 996 per 100,000; rate ratio 0.88 [0.50-1.56]). Similarly, there was no significant difference between the betacarotene and placebo groups in incidence of either cancer (basal-cell carcinoma 3954 vs 3806 per 100,000; 1.04 [0.73-1.27]; squamous-cell carcinoma 1508 vs 1146 per 100,000; 1.35 [0.84-2.19]). In terms of the number of tumours, there was no effect on incidence of basal-cell carcinoma by sunscreen use or by betacarotene but the incidence of squamous-cell carcinoma was significantly lower in the sunscreen group than in the no daily sunscreen group (1115 vs 1832 per 100,000; 0.61 [0.46-0.81]).. There was no harmful effect of daily use of sunscreen in this medium-term study. Cutaneous squamous-cell carcinoma, but not basal-cell carcinoma seems to be amenable to prevention through the routine use of sunscreen by adults for 4.5 years. There was no beneficial or harmful effect on the rates of either type of skin cancer, as a result of betacarotene supplementation.

Topics: Adult; Aged; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms, Radiation-Induced; Queensland; Skin Neoplasms; Sunscreening Agents

Epidemiological studies suggest that individuals with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin are more likely to develop other malignancies; however, the factors responsible for this are unknown. To clarify the risk of other cancers following the occurrence of BCC and SCC, we followed participants in a multicenter skin cancer prevention trial for subsequent malignancies. The study group consisted of 1805 BCC and SCC patients who had enrolled in a trial testing the efficacy of oral beta-carotene. Medical confirmation was sought for all cancers (other than BCC or SCC), which were reported by participants or their next-of-kin over a follow-up period of 10 years. We computed the rate ratio (RR) and 95% confidence interval (CI) of time to first new, primary cancer in relation to history of BCC and SCC, using a proportional hazards model. A total of 235 participants had a new primary invasive cancer during 13,887 person-years of follow up. The risk of other cancers was modestly elevated in patients with one or more previous SCCs compared with those who only had a history of BCC (adjusted RR, 1.37; 95% CI, 0.91-2.07). Risk of other cancers also appeared to be increased among those who had multiple prior BCCs relative to those who had only one prior BCC (adjusted RR, 1.21; 95% CI, 0.91-1.61). Further adjustment for smoking history, Quetelet index, radiotherapy, extent of actinic skin damage, treatment assignment, or baseline beta-carotene concentrations did not appreciably alter the results. Cancer of the respiratory system was most strongly related to previous SCC or multiple BCC [RRs (95% CI), 2.20 (1.05-4.62) and 2.34 (1.14-4.83), respectively]. Our data suggest that unidentified exposures or inherited risk factors may play a common etiological role in the pathogenesis of nonmelanoma skin cancer and other cancers, especially respiratory cancers, although larger studies would be necessary to exclude the role of chance in these findings.

Topics: Aged; Anticarcinogenic Agents; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Incidence; Male; Middle Aged; Neoplasms, Second Primary; Proportional Hazards Models; Risk Factors; SEER Program; Skin Neoplasms

Topics: Antioxidants; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Combined Modality Therapy; Cryotherapy; Humans; Retinoids; Skin Neoplasms

The Nambour Skin Cancer and Actinic Eye Disease Prevention Trial (the Nambour Trial) is a field trial conducted in an unselected adult population in Australia. Using a randomized 2 x 2 factorial design, the principal aim is to evaluate whether regular use of high-protection sunscreen and/or dietary supplementation with beta-carotene (30 mg daily) can alter the incidence rates of basal cell carcinomas and squamous cell carcinomas of the skin over a minimum follow-up time of 4.5 years. Changes in the incidence of solar keratoses and actinic eye disease and the rate of photoaging after intervention will also be investigated. In 1992, 1626 participants between the ages of 25 and 75 years were enrolled, all of whom had been randomly selected from residents of the southeastern Queensland township of Nambour for an earlier skin cancer prevalence survey. This paper describes the background to the trial and its design, with respect to evaluation of effects on actinic skin disease, and documents the baseline characteristics of participants recruited into the Nambour Trial.

Topics: Adult; Aged; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Cataract; Female; Humans; Male; Middle Aged; Patient Compliance; Skin Neoplasms; Sunscreening Agents; Ultraviolet Rays

Topics: Adult; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Diet; Double-Blind Method; Female; Follow-Up Studies; Humans; Life Style; Male; Middle Aged; Risk Factors; Sex Factors; Skin Neoplasms; Smoking; Surveys and Questionnaires; United States

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

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

Two series of examinations were carried out in two voluntary test groups for the purpose of elucidating the correlation between ultraviolet light load and oxidative stress as well as the way it is influenced by nutritive radical scavengers. After a 6 to 7-hour impact of sunshine on the whole body (sunbathing beach) at n = 8 a continuous progredient increase of thiobarbituric acid reactive substances could be identified in the serum (from 5.56 +/- 0.98 to 8.91 +/- 0.99 mumol/l, p < 0.001), which after new exposure to sunshine reached 11.3 +/- 2.4 mumol/l. Likewise, a 15-minute exposure to ultraviolet light at n = 24 induced increases of TBRS concentrations lasting from 1-2 days. After 14-day supplementation with beta-carotene (n = 6), D-alpha-tocopherol (n = 6), selenium (n = 6), and ginkgo biloba extract (n = 6) the extent of the oxidative stress could be inhibited during a second exposure to ultraviolet light up to the following efficiency: Se > Ginkgo > beta-carotene > vitamin E. The clastogenous effect of sunshine and ultraviolet light must be regarded as a factor for initiating and promoting cancerogenesis in the total organism. Concerning the aetiopathogenesis of malignant melanoma the paramagnetic properties of free radicals with their nonenergetic effects of the magnetic field have to be considered more carefully in scientific examinations.

Topics: Adult; beta Carotene; Carotenoids; DNA Damage; Female; Free Radical Scavengers; Ginkgo biloba; Humans; Male; Malondialdehyde; Melanoma; Neoplasms, Radiation-Induced; Plant Extracts; Selenium; Skin Neoplasms; Sunlight; Ultraviolet Rays; Vitamin E

The primary aims of this study were to assess risk of subsequent basal and squamous cell skin cancer among patients with a prior history of these tumors and to examine these risks in relation to patient characteristics and life-style factors.. Follow-up of participants in a randomized trial of betacarotene as a possible skin cancer preventive agent.. Clinical centers in Los Angeles, Calif, San Francisco, Calif, Minneapolis, Minn, and Hanover, NH.. Patients (n = 1805) who were diagnosed as having a basal or squamous cell skin cancer between January 1980 and February 1986 and were free of skin cancer at study entry.. Time from study entry to first new occurrence of basal and squamous cell skin cancer.. The estimated risk of developing one or more new skin cancers was 35% at 3 years and 50% at 5 years. New skin cancers tended to be of the same cell type as the previous skin cancers. For both basal and squamous cell skin cancer, risk was higher among patients who were male, were over the age of 60 years, had more prior skin cancers, had severe actinic skin damage, or who burned easily with sun exposure. Compared with those who had never smoked, the rate of subsequent squamous cell skin cancer was higher among current smokers (rate ratio, 2.01; 95% confidence interval, 1.21 to 3.34) and former smokers (rate ratio, 1.62; 95% confidence interval, 1.07 to 2.47) and increased with both duration and amount smoked. There was no clear relationship between smoking and basal cell skin cancer; the rate appeared lower among heavy smokers but was unrelated to duration of smoking.. Persons with a prior nonmelanoma skin cancer had a substantial 5-year risk of developing another tumor of the same histologic type. Number of previous skin cancers, solar damage, and skin sensitivity to sun exposure were particularly related to this risk. The increased risk of squamous cell skin cancer associated with cigarette smoking merits further study.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Probability; Risk Factors; Sex Factors; Skin Neoplasms; Smoking

Previous studies suggest that chronic oral administration of retinol and other retinoids causes elevation of plasma triglyceride concentrations. The effects of chronic oral administration of beta-carotene, a carotenoid partially metabolized to retinol, on plasma lipid concentrations have not been well studied; therefore, we studied 61 subjects over 12 mo while they were enrolled in a skin-cancer-prevention study in which patients were randomly assigned to receive either placebo (n = 30) or 50 mg beta-carotene/d orally (n = 31). At study entry and 1 y later, fasting blood samples were obtained for measurement of triglycerides, total cholesterol, HDL cholesterol, retinol, and beta-carotene. Retinol concentrations changed minimally in both groups; beta-carotene concentration increased an average of 12.1 +/- 47 nmol/L in the placebo group and 4279 +/- 657 nmol/L in the active-treatment group. Both groups experienced similar small increases in triglyceride and total cholesterol concentrations and small decreases in HDL cholesterol. Daily oral administration of 50 mg beta-carotene/d did not affect plasma lipid concentrations.

Topics: Administration, Oral; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Cholesterol; Cholesterol, HDL; Humans; Lipids; Skin Neoplasms; Triglycerides; Vitamin A

We studied the relationship between eight variables, including age, sex, baseline plasma beta-carotene (BC) concentration, and smoking status and the increase in plasma BC in 582 subjects receiving oral supplementation with 50 mg BC/d. Median plasma BC concentrations after 1 y of supplementation increased from 335 nmol/L at entry to 3163 nmol/L. Changes in plasma BC concentrations ranged widely from -313 to 16,090 nmol/L (median 2721 nmol/L). Multivariate analysis revealed that the subject's plasma BC concentration before supplementation was the most important indicator of the amount of increase after supplementation. Nonsmokers, women, and leaner subjects all had larger increases in plasma concentrations although the statistical model could account for relatively little of the variability in subjects' plasma response to BC supplementation (R2 = 0.14). We conclude that between-subject variability in response to daily supplementation with oral BC is very large and that the best predictor of this response is the initial plasma BC concentration.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; beta Carotene; Body Constitution; Body Weight; Carotenoids; Female; Humans; Male; Middle Aged; Regression Analysis; Sex Factors; Skin Neoplasms; Smoking

Beta carotene has been associated with a decreased risk of human cancer in many studies employing dietary questionnaires or blood measurements, and it has had protective effects in some animal models of carcinogenesis.. We tested the possible cancer-preventing effects of beta carotene by randomly assigning 1805 patients who had had a recent nonmelanoma skin cancer to receive either 50 mg of beta carotene or placebo per day and by conducting annual skin examinations to determine the occurrence of new nonmelanoma skin cancer.. Adherence to the prescribed treatment was good, and after one year the actively treated group's median plasma beta carotene level (3021 nmol per liter) was much higher than that of the control group (354 nmol per liter). After five years of follow-up, however, there was no difference between the groups in the rate of occurrence of the first new nonmelanoma skin cancer (relative rate, 1.05; 95 percent confidence interval, 0.91 to 1.22). In subgroup analyses, active treatment showed no efficacy either in the patients whose initial plasma beta carotene level was in the lowest quartile or in those who currently smoked. There was also no significant difference between treated and control groups in the mean number of new nonmelanoma skin cancers per patient-year.. In persons with a previous nonmelanoma skin cancer, treatment with beta carotene does not reduce the occurrence of new skin cancers over a five-year period of treatment and observation.

Topics: Aged; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Drug Evaluation; Female; Follow-Up Studies; Humans; Male; Patient Compliance; Randomized Controlled Trials as Topic; Recurrence; Skin Neoplasms

We describe a randomized clinical trial of oral beta-carotene (50 mg/day) for preventing nonmelanoma skin cancer. It is a multicenter study conducted at sites in California, Minnesota, and New Hampshire. This report describes the design of the study, baseline characteristics of the 1805 randomized patients, changes in their plasma beta-carotene and retinol levels after 1 year of treatment, and plans for statistical analyses. Important features of this study are (1) a high proportion of potential subjects were found to be ineligible or chose not to enter the study, (2) the study agent is readily available over the counter and in common foods, and (3) nonmelanoma skin cancer is a relatively minor health concern for most patients. These considerations necessitated intensive efforts to encourage compliance with the study regimen. There are also some unusual statistical features of the study. One is that the study outcome is routinely assessed only at annual examinations, so the precise time of failure cannot be identified. Also, a secondary goal of the study is to determine whether beta-carotene decreases the average number of new skin cancers per patient per year, and there are no established statistical methods for analysis of data in this situation. Alternative approaches to the analysis are discussed.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Clinical Trials as Topic; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Random Allocation; Risk Factors; Skin Neoplasms; Time Factors

The associations of retinol and beta-carotene plasma concentrations with eight personal variables and the use of seven classes of cardiovascular drugs were studied in over 1,750 patients with nonmelanoma skin cancer enrolled at four American study centers in a cancer prevention clinical trial. Dietary carotene and female sex were positively related to beta-carotene levels, while cigarette smoking and Quetelet index were negatively related. Use of vitamins, beta blockers, or other antihypertensive drugs were also related to beta-carotene levels, but were associated with much smaller changes in these levels. Age and use of other types of cardiovascular drugs were not associated with beta-carotene levels to a statistically significant extent. There was no statistically significant interaction of smoking and dietary carotene in predicting plasma beta-carotene levels. The multiple correlation coefficient between log plasma beta-carotene and the full model was R = 0.50. Retinol levels were positively related to male sex and use of vitamins, diuretics, beta blockers, other cardiovascular drugs, and menopausal estrogens, and negatively related to current cigarette smoking and use of nitrates. The multiple correlation coefficient between plasma retinol and the full model was R = 0.33. These findings confirm the importance of several previously reported predictors of plasma retinol and beta-carotene levels. They also identify several new predictors of these micronutrient levels.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; beta Carotene; Carotenoids; Clinical Trials as Topic; Humans; Male; Middle Aged; Skin Neoplasms; Smoking; Vitamin A

Mucopermeating nanoformulations can enhance mucosal penetration of poorly soluble drugs at their target site. In this work, thiolated chitosan (TCS)-lithocholic acid (LA) nanomicelles loaded with β-carotene, a safe phytochemical with anticancer properties, were designed to improve the pharmaceutical and pharmacological drug profile. The TCS-LA nanomicelles were characterized by FTIR to confirm the presence of the thiol group that favors skin adhesion, and to corroborate the conjugation of hydrophobic LA with hydrophilic CS to form an amphiphilic polymer derivative. Their crystalline nature and thermal behavior were investigated by XRD and DSC analyses, respectively. According to DLS and TEM, their average size was <300 nm, and their surface charge was +27.0 mV. β-carotene entrapment and loading efficiencies were 64 % and 58 %, respectively. In vitro mucoadhesion and ex vivo mucopenetration analyses further corroborated the potential of the nanoformulation to deliver the drug in a sustained manner under conditions mimicking cancer micro-environment. Anticancer studies in mice demonstrated that the loaded nanomicelles delayed skin cancer growth, as revealed by both morphological and biochemical parameters. Based on the results obtained herein, it can be concluded that drug-loaded TCS-LA is a novel, stable, effective and safe mucoadhesive formulation of β-carotene for the potential treatment of skin cancer.

Topics: Animals; beta Carotene; Chitosan; Mice; Mucous Membrane; Nanoparticles; Polymers; Skin Neoplasms; Tumor Microenvironment

Low-molecular-weight antioxidants are some of the most efficient agents of the skin defense mechanism against environmental factors, such as cosmic rays, smoke, and pollutants. The total skin concentrations of hydrophilic ascorbic and uric acids, as well as lipophilic α-tocopherol, β-carotene, and ubiquinol-10 antioxidants were determined by an HPLC-EC detector from 18 biopsies of human nonmelanoma skin carcinomas and 18 biopsies from skin areas adjacent to carcinomas. No significant differences in the concentrations of lipophilic antioxidants in both carcinomas and normal-looking skin areas adjacent to carcinomas were observed. On the contrary, ascorbic and uric acid concentrations were found to be 18 and 36% lower in carcinomas than in normal-looking skin areas, respectively. No statistical significance was observed between antioxidant concentrations and age, sex, phototype, profession, site of tumor, frequency, and time of UV light exposure either. Accordingly the antioxidant concentrations in both cancerous skin and adjacent normal-looking areas were found to be much higher than in normal skin, in contrast to literature data.

Topics: Adult; Aged; Aged, 80 and over; alpha-Tocopherol; Antioxidants; Ascorbic Acid; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Male; Middle Aged; Molecular Weight; Skin; Skin Neoplasms; Ubiquinone; Uric Acid

Two-part regression models are frequently used to analyze longitudinal count data with excess zeros, where the same set of subjects is repeatedly observed over time. In this context, several sources of heterogeneity may arise at individual level that affect the observed process. Further, longitudinal studies often suffer from missing values: individuals dropout of the study before its completion, and thus present incomplete data records. In this paper, we propose a finite mixture of hurdle models to face the heterogeneity problem, which is handled by introducing random effects with a discrete distribution; a pattern-mixture approach is specified to deal with non-ignorable missing values. This approach helps us to consider overdispersed counts, while allowing for association between the two parts of the model, and for non-ignorable dropouts. The effectiveness of the proposal is tested through a simulation study. Finally, an application to real data on skin cancer is provided.

Topics: beta Carotene; Female; Humans; Longitudinal Studies; Male; Models, Theoretical; Pattern Recognition, Automated; Skin Neoplasms; Statistics as Topic

Analysis of longitudinal data with excessive zeros has gained increasing attention in recent years; however, current approaches to the analysis of longitudinal data with excessive zeros have primarily focused on balanced data. Dropouts are common in longitudinal studies; therefore, the analysis of the resulting unbalanced data is complicated by the missing mechanism. Our study is motivated by the analysis of longitudinal skin cancer count data presented by Greenberg, Baron, Stukel, Stevens, Mandel, Spencer, Elias, Lowe, Nierenberg, Bayrd, Vance, Freeman, Clendenning, Kwan, and the Skin Cancer Prevention Study Group[New England Journal of Medicine 323, 789-795]. The data consist of a large number of zero responses (83% of the observations) as well as a substantial amount of dropout (about 52% of the observations). To account for both excessive zeros and dropout patterns, we propose a pattern-mixture zero-inflated model with compound Poisson random effects for the unbalanced longitudinal skin cancer data. We also incorporate an autoregressive of order 1 correlation structure in the model to capture longitudinal correlation of the count responses. A quasi-likelihood approach has been developed in the estimation of our model. We illustrated the method with analysis of the longitudinal skin cancer data.

Topics: Aged; Antioxidants; beta Carotene; Bias; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Data Interpretation, Statistical; Drug Evaluation; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Male; Patient Compliance; Randomized Controlled Trials as Topic; Recurrence; Skin Neoplasms

Thirteen cucurbitane-type triterpene glycosides, including eight new compounds named charantosides I (6), II (7), III (10), IV (11), V (12), VI (13), VII (16), and VIII (17), and five known compounds, 8, 9, 14, 15, and 18, were isolated from a methanol extract of the fruits of Japanese Momordica charantia. The structures of the new compounds were determined on the basis of spectroscopic methods. On evaluation of these triterpene glycosides and five other cucurbitane-type triterpenes, 1-5, also isolated from the extract of M. charantia fruits, for their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, these compounds showed inhibitory effects on EBV-EA induction with IC(50) values of 200-409 mol ratio/32 pmol TPA. In addition, upon evaluation of compounds 1-5 for inhibitory effects against activation of (+/-)-(E)-methyl-2[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitrogen oxide (NO) donor, compounds 1-3 showed moderate inhibitory effects. Compounds 1 and 2 exhibited marked inhibitory effects in both 7,12-dimethylbenz[a]anthracene (DMBA)- and peroxynitrite (ONOO-; PN)-induced mouse skin carcinogenesis tests.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antigens, Viral; Fruit; Glycosides; Humans; Inhibitory Concentration 50; Mice; Molecular Structure; Momordica charantia; Nitric Oxide Donors; Peroxynitrous Acid; Plants, Medicinal; Skin Neoplasms; Tetradecanoylphorbol Acetate; Triterpenes

Experimental studies have consistently shown a protective effect of nonsteroidal antiinflammatory drugs (NSAIDs) against nonmelanoma skin cancers (NMSC). However, little human epidemiological research has been done in this regard. We used data from the Skin Cancer Chemoprevention Study to explore the association of NSAID use and with the risk of basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC). 1,805 subjects with a recent history of NMSC were randomized to placebo or 50 mg of daily beta-carotene. Participants were asked about their use of over-the-counter and prescription medications at baseline and every 4 months during the trial. Skin follow-up examinations were scheduled annually with a study dermatologist; confirmed lesions were the endpoints in the study. We used a risk set approach to the analysis of grouped times survival data and unconditional logistic regression to compute odds ratios [ORs] for various exposures to NSAIDs. The use of NSAIDs was reported in over 50% of questionnaires. For BCC, NSAIDs exhibited a weak protective effect in crude analyses, which attenuated markedly after adjustment. For SCC, the use of NSAIDs in the year previous to diagnosis reduced the odds by almost 30% (adjusted OR=0.71, 95% CI 0.48-1.04). When we accounted for frequency of use, results for BCC were not striking, and there were inconsistent suggestions of an inverse association with SCC. There were some indications of a modest, nonsignificant reduction on the number of BCCs and SCCs with NSAID use. Our data suggest a weak and inconsistent chemopreventive effect of NSAIDs on BCC and SCC.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antioxidants; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Odds Ratio; Randomized Controlled Trials as Topic; Regression Analysis; Risk Factors; Skin Neoplasms; Surveys and Questionnaires

A study of the chemical constituents of the stems of Derris trifoliata Lour. (Leguminosae) led to the isolation and identification of one new rotenoid, 6aalpha,12aalpha-12a-hydroxyelliptone ( 3), together with five other known rotenoids. In a search for novel cancer chemopreventive agents (anti-tumor promoters), we carried out a primary screening of five of the rotenoids isolated from the plant for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12- O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells. The inhibitory activity of 3 was found to be equivalent to that of beta-carotene without any cytotoxicity. Deguelin ( 4) and alpha-toxicarol ( 5) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. This investigation indicated that rotenoids might be valuable anti-tumor promoters.

Topics: Animals; Antigens, Viral; Antineoplastic Agents, Phytogenic; Benzopyrans; beta Carotene; Cell Line; Fabaceae; Female; Herpesvirus 4, Human; Humans; Mice; Mice, Inbred ICR; Papilloma; Phytotherapy; Plant Extracts; Plant Stems; Rotenone; Skin Neoplasms; Virus Activation

The effects of ethyl alcohol and synthetic beta-carotene have been studied on two models of carcinogenesis in mice BALB/c. Lung tumours were induced with organotropically acting urethane (given by i.p. injections, total dose--100 mg/mouse) subcutaneous tumours were induced with locally acting benzo(a)pyrene (single injection, 2 mg/mouse) beta-Carotene was given 3 times per week 0.4 mg/mouse by gastric intubations and 10% ethanol was given instead of drinking water until the end of experiments (4-6 months). Results showed that beta-carotene did not significantly inhibit lung adenomogenesis and may moderately delay subcutaneous tumours occurence. In ourstudies chronic ethanol intake did notshow significant influence on this delay.

Topics: Animals; Benzo(a)pyrene; beta Carotene; Carcinogens; Ethanol; Liver; Lung Neoplasms; Mice; Mice, Inbred BALB C; Models, Animal; Skin Neoplasms; Urethane

The induction of pre-cancerous squamous metaplasia in lungs of ferrets by high doses of dietary beta-carotene (BC) and cigarette smoke is compared with and contrasted to the different effects of high doses of dietary BC on skin papilloma and carcinoma induction by the two-stage carcinogenesis protocol. Whereas high dietary BC can inhibit the conversion of skin papillomas to carcinomas, such treatment would not be expected to inhibit smoke-induced lung tumors.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carcinogens; Dose-Response Relationship, Drug; Ferrets; Lung Neoplasms; Mice; Nicotiana; Papilloma; Precancerous Conditions; Skin Neoplasms; Smoke; Tetradecanoylphorbol Acetate

Topics: Animals; Animals, Laboratory; beta Carotene; Carcinogens; Disease Models, Animal; Ferrets; Liver Neoplasms; Lung Neoplasms; Marmota; Mice; Mutation; Neoplasms; Phenotype; Sciuridae; Skin Neoplasms; Zebrafish

Clinical trials have shown a significant increase in incidence of lung cancer among smokers and asbestos workers supplemented with beta-carotene, suggesting a tumor-promoting activity for this agent. We set out to test possible tumor-promoting and chemopreventive activities of dietary and topical beta-carotene in the two-stage 7,12-dimethylbenz[a]anthracene-12-O-tetradecanoylphorbol 13-acetate (TPA) model of mouse skin carcinogenesis. In the first study, the effects of three levels of dietary beta-carotene (6, 60, and 600 micrograms/g purified diet containing no other retinoid or carotenoid) were assessed over a period of 42 weeks. Carcinoma yield was reduced by approximately 50% in the 600 micrograms/g diet group (mean 0.22 carcinomas/mouse) compared with the 6 micrograms/g diet group (mean 0.44 carcinomas/mouse, p = 0.003). The 60 micrograms/g diet group showed a pattern of inhibition similar to the 600 micrograms/g diet group. A protective effect (25% reduction) of beta-carotene (in the 600 micrograms/g diet group) on papilloma formation was also found. However, the intermediate 60 micrograms/g diet group showed the same incidence as the low 6 micrograms/g diet group. This points to a lack of correlation between papilloma and carcinoma incidence, as we also found in previous work on dietary retinoids and carotenoids. The purpose of the second study was to assess whether topical beta-carotene (2 micrograms) has tumor-promoting or chemopreventive activity in the two-stage protocol. In the absence of TPA, beta-carotene had no significant tumor-promoting activity. Instead, papilloma yield induced by TPA was decreased by topical beta-carotene from an average of 20 to approximately 10 papillomas/mouse (p = 2.5 x 10(-7)). The effect of topical beta-carotene persisted beyond the treatment period (Week 24) until the termination of the study at Week 42. Western blot analysis of mouse skin extracts showed that topical beta-carotene upregulated retinoic acid receptor-alpha and -gamma expression in the dorsal skin. This finding suggests that beta-carotene may work as a chemopreventive agent by upregulating the expression of retinoid receptors in mouse skin. In conclusion, our data show that beta-carotene prevents skin carcinoma formation, induces retinoic acid receptor expression, and fails to act as a tumor promoter in the two-stage model of skin tumorigenesis.

Topics: Administration, Topical; Animals; beta Carotene; Blotting, Western; Carcinogens; Carcinoma; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred SENCAR; Papilloma; Pregnancy; Receptors, Retinoic Acid; Skin; Skin Neoplasms; Time Factors; Up-Regulation

Topics: Adult; Aged; Antioxidants; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dietary Supplements; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Skin Neoplasms; Sunscreening Agents

Seven labdane-type diterpenoids from the stem bark of Thuja standishii (Gord.) Carr. (Cupressaceae) and their analogues showed strong inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among these compounds, 15,16-bisnor-13-oxolabda-8(17), 11E-dien-19-oic acid was revealed to have the strongest inhibitory effect on the EBV-EA activation, being stronger than that of beta-carotene which has been intensively studied in cancer prevention using animal models. 15,16-bisnor-13-Oxolabda-8(17), 11E-dien-19-oic acid was also found to exhibit the excellent anti-tumor promoting activity in two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene and TPA.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antigens, Viral; beta Carotene; Carboxylic Acids; Carcinogens; Diterpenes; Female; Humans; Mice; Mice, Inbred ICR; Naphthalenes; Nasopharyngeal Neoplasms; Neoplasms; Papilloma; Plant Extracts; Plant Stems; Skin Neoplasms; Tetradecanoylphorbol Acetate; Trees

The role of beta-carotene as an anticancer agent has been questioned as a result of clinical trials in which the incidence of nonmelanoma skin cancer was unchanged in patients receiving a beta-carotene supplement and in beta-carotene-supplemented smokers who suffered a significant increase in lung cancer occurrence. In laboratory studies, beta-carotene-supplemented semidefined diets, in contrast to earlier studies employing commercial closed-formula diets, not only failed to provide a protective effect to ultraviolet (UV) carcinogenesis but resulted in significant exacerbation. A rationale for this distinct carcinogenic response to beta-carotene rests with the stability of the carotenoid radical cation, believed to be dependent on the presence of other antioxidants for rapid repair, and suggests that response to beta-carotene depends on the presence and interaction with other dietary factors. Here, we report that diet potentiates beta-carotene-mediated exacerbation of UV carcinogenesis. Although the dietary factor(s) responsible for this effect is unidentified, these studies underscore the potential risk of beta-carotene supplementation in free-living populations where dietary status is widely varied.

Topics: Animals; Anticarcinogenic Agents; beta Carotene; Diet; Dietary Supplements; Epidermis; Female; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Random Allocation; Skin Neoplasms; Time Factors; Ultraviolet Rays

Various natural carotenoids were proven to have anticarcinogenic activity. Epidemiological investigations have shown that cancer risk is inversely related to the consumption of green and yellow vegetables and fruits. Since beta-carotene is present in abundance in these vegetables and fruits, it has been investigated extensively as possible cancer preventive agent. However, various carotenoids which co-exist with beta-carotene in vegetables and fruits also have anti-carcinogenic activity. And some of them, such as alpha-carotene, showed higher potency than beta-carotene to suppress experimental carcinogenesis. Thus, we have carried out more extensive studies on cancer preventive activities of natural carotenoids in foods; i.e., lutein, lycopene, zeaxanthin and beta-cryptoxanthin. Analysis of the action mechanism of these natural carotenoids is now in progress, and some interesting results have already obtained; for example, beta-cryptoxanthin was suggested to stimulate the expression of RB gene, an anti-oncogene, and p73 gene, which is known as one of the p53-related genes. Based on these results, multi-carotenoids (mixture of natural carotenoids) seems to be of interest to evaluate its usefulness for practice in human cancer prevention.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; beta Carotene; Carotenoids; Colonic Neoplasms; Cryptoxanthins; Disease Models, Animal; Fruit; Humans; Lutein; Lycopene; Methylnitrosourea; Mice; Rats; Rats, Inbred F344; Skin Neoplasms; Tetradecanoylphorbol Acetate; Vegetables; Xanthophylls; Zeaxanthins

We explore the effects of measurement error in a time-varying covariate for a mixed model applied to a longitudinal study of plasma levels and dietary intake of beta-carotene. We derive a simple expression for the bias of large sample estimates of the variance of random effects in a longitudinal model for plasma levels when dietary intake is treated as a time-varying covariate subject to measurement error. In general, estimates for these variances made without consideration of measurement error are biased positively, unlike estimates for the slope coefficients which tend to be 'attenuated'. If we can assume that the residuals from a longitudinal fit for the time-varying covariate behave like measurement errors, we can estimate the original parameters without the need for additional validation or reliability studies. We propose a method to test this assumption and show that the assumption is reasonable for the example data. We then use a likelihood-based method of estimation that involves a simple extension of existing methods for fitting mixed models. Simulations illustrate the properties estimators.

Topics: Analysis of Variance; beta Carotene; Bias; Humans; Likelihood Functions; Longitudinal Studies; Models, Statistical; Nutritional Requirements; Skin Neoplasms

Studies employing time-resolved techniques have shown that beta-carotene, astaxanthin, and lycopene behave quite distinctly with respect to radical quenching and stability, lycopene being the least stable. These results are compatible with the relative effects of the various carotenoids on ultraviolet (UV)-mediated carcinogenesis in mice in which a statistically significant exacerbation by beta-carotene and astaxanthin, but not by lycopene, was observed. Interactions between these carotenoids and vitamin C and E radicals not only provide a chemical basis to explain the failure of beta-carotene to provide benefit in recent clinical trials but suggest that future carotenoid supplementation studies should proceed with caution until carotenoid interactions and radical repair mechanism(s) are elucidated.

Topics: Animals; Anticarcinogenic Agents; beta Carotene; Carcinogenicity Tests; Carotenoids; Dietary Supplements; Female; Free Radicals; Lycopene; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Random Allocation; Skin Neoplasms; Ultraviolet Rays; Xanthophylls

We conducted a nested case-control study of squamous cell skin cancer (SCC) to determine whether risk was related to plasma concentrations of selenium, alpha-tocopherol, beta-carotene, and retinol. We derived the study sample from participants in our Skin Cancer Prevention Study, all of whom had at least one basal cell or squamous cell skin cancer before study entry. Those who developed a new squamous cell skin cancer during the 3-5-year follow-up period were selected as cases (n = 132). Controls (n = 264) were chosen at random, with matching by age, sex, and study center, from among those who did not develop SCC but were being followed actively at the time the SCC case was diagnosed. Prediagnostic plasma samples were analyzed for alpha-tocopherol, beta-carotene, and retinol using high-performance liquid chromatography. Selenium determinations were made using instrumental neutron activation analysis. Odds ratios were computed using conditional logistic regression for matched samples. We found no consistent pattern of SCC risk associated with any of the nutrients examined. The odds ratios (95% confidence intervals) for the highest versus the lowest quartiles of beta-carotene, retinol, alpha-tocopherol, and selenium were 0.73 (0.38-1.41), 1.43 (0.77-2.64), 0.89 (0.43-1.85), and 0.86 (0.47-1.58), respectively. Thus, our data add to the growing body of evidence that these nutrients, at the concentrations we evaluated, are not related strongly to SCC risk.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Biomarkers, Tumor; Carcinoma, Squamous Cell; Case-Control Studies; Female; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Risk Factors; Selenium; Skin Neoplasms; Vitamin A; Vitamin E

To elucidate the associations of arsenic-induced skin cancer with serum beta-carotene level and arsenic methylation capability, a total of 654 residents of age 30 or older were recruited from three arseniasis-hyperendemic villages in Taiwan and regularly examined for skin lesions during the follow-up period. There were 33 cases affected with newly diagnosed skin cancer during the follow-up, giving an incidence of 14.74 per 1000 person-years. Although most study subjects had stopped consuming high-arsenic artesian well water more than 20 years ago, the risk of skin cancer was found to increase significantly with cumulative arsenic exposure before the cessation of drinking artesian well water in a dose-response relationship. Frozen serum samples collected at the recruitment from newly developed skin cancer cases and matched controls were tested for beta-carotene levels by high-performance liquid chromatography. Frozen urine samples of these subjects were examined by high-performance liquid chromatography to speciate arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMA), and dimethylarsinic acid and then quantitated by hydride generator combined with atomic absorption spectrometry. Skin cancer cases had a significantly lower serum level of beta-carotene than matched healthy controls. Although the primary methylation capability indexed by the ratio of MMA/(AsIII + AsV) was greater in cases than in controls, the secondary methylation capability indexed by the ratio of dimethylarsinic acid/MMA was lower in cases than in controls. An elevated proportion of MMA in total urinary arsenic level was associated with an increased risk of skin cancer. Subjects with a cumulative arsenic exposure of > or = 20.0 mg/liter-year and a proportion of MMA in total urinary arsenic level >26.7% had a multivariate-adjusted odds ratio of developing skin cancer as high as 20.91 (95% confidence interval, 2.63-166.5) compared wih those who had a cumulative arsenic exposure of <20.0 mg/liter-year and a MMA percentage of < or = 26.7%. Whether the association with capability of inorganic methylation is also applied to cancers of internal organs, including lung, liver, and urinary bladder, remains to be elucidated.

Topics: Adult; Aged; Arsenic; Arsenicals; beta Carotene; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Female; Humans; Incidence; Male; Methylation; Middle Aged; Skin Neoplasms; Structure-Activity Relationship; Taiwan; Teratogens; Water Pollutants, Chemical

Using mouse skin papilloma as a model system, we examined whether the antitumorigenic activity of carotenoids was related to their provitamin A activity. Oral administration of canthaxanthin (CX) or beta-carotene at 200 mg/kg/day for 14 days significantly reduced the cumulative size of papillomas induced on the skin by 9,10-dimethyl-1,2-benzanthracene (p < 0.05), after the accumulation of these carotenoids in the tumors. The levels of a protooncogene, c-myc, were simultaneously suppressed in papillomas in carotenoid-treated mice. Because CX cannot be converted metabolically to retinoids, these results suggested that CX directly inhibited the growth of papillomas. Neither the accumulation of retinoids nor the expression of a retinoic acid-inducible gene, retinoic acid receptor-beta, was found in papillomas of CX- and beta-carotene-treated mice, suggesting that, like CX, beta-carotene might exert the tumor-suppressing effect without being converted to retinoids. Thus a certain antitumorigenic activity of carotenoids appears not necessarily to require their provitamin A activity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Canthaxanthin; Female; Gene Expression; Mice; Papilloma; Proto-Oncogene Proteins c-myc; Receptors, Retinoic Acid; RNA, Messenger; Skin Neoplasms; Tretinoin

Solar radiations (UV A and B) can cause epidermis photoaging and skin cancers. These frequently irreversible effects result from the in situ generation of free radicals. However, it has been noted that nutritional factors can modulate photochemical damage, in particular the common carotenoids present in food, which can be considered as potential prophylactic agents against carcinogenesis. We investigated the effect of UV A and B radiations on the skin of the SKH1 hairless mouse fed a diet either lacking in vitamin A or supplemented with retinol, beta-carotene or astaxanthin. The latter is an oxygenated carotenoid (like canthaxanthin) without provitamin A activity and with strong singlet oxygen quenching ability. After analysing of vitamin status of each group (plasma retinol concentrations and hepatic reserves), we searched for UV-induced modifications of polyamine metabolism by measuring epidermal ornithine decarboxylase (ODC) activity and free polyamines concentration (putrescine, spermidine and spermine). In the basal state without irradiation, differences in ODC activity between groups were nonsignificant; but after UV stimulation, ODC increased markedly in the skin of vitamin A-deficient animals, much more than in other groups. Curiously, the addition of astaxanthin or beta-carotene to the regimen containing retinol reduced the protective effect of retinol alone. Regarding polyamines after irradiation, putrescine was significantly increased in the skin of deficient animals, in parallel with ODC activity. However, astaxanthin had a stronger inhibitory effect on putrescine accumulation than retinol, and decreased spermidine and spermine concentrations: this suggests a specific action on transglutaminases.

Topics: Animals; beta Carotene; Carotenoids; Epidermis; Female; Food, Fortified; Liver; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Nutritional Status; Ornithine Decarboxylase; Polyamines; Putrescine; Random Allocation; Skin; Skin Neoplasms; Spermidine; Spermine; Ultraviolet Rays; Vitamin A; Vitamin A Deficiency; Xanthophylls

A number of lifestyle factors are important in the etiology of basal cell carcinoma. Previous studies have investigated smoking, alcohol, diet, and sun exposure as possible contributing factors. No previous studies have investigated case-controlled lifestyle influences in basal cell carcinomas referred for Mohs micrographic surgery.. Cases were obtained from Mohs-referred basal cell carcinoma patients. Matched controls were selected from a busy dermatology clinic. The only criteria for selection of controls was never having had cancer previously. Cases and controls were surveyed regarding lifestyle characteristics.. Forty-six age, sex, and skintype-matched controls were compared. Sun exposure, alcohol, and smoking were not significant factors. Dietary fat, fiber, and the vitamins A, C, and beta carotene, as well as selenium showed important, but not significant differences. Caffeine consumption was higher in the cancer group.. Our findings agree with previously published studies in regard to antioxidant consumption as a protective factor for basal cell carcinoma. Caffeine consumption was higher in the cancer patients.

Topics: Aged; Alcohol Drinking; Ascorbic Acid; beta Carotene; Caffeine; Carcinoma, Basal Cell; Carotenoids; Case-Control Studies; Female; Humans; Life Style; Male; Middle Aged; Mohs Surgery; Risk Factors; Selenium; Skin Neoplasms; Smoking; Vitamin E

Anticarcinogenic action of beta-carotene was analyzed with determination of ornithine decarboxylase (ODC) activity induced by TPA and a two-stage model of skin papilloma-genesis in mice. Results showed increase of ODC activity induced by TPA could be significantly inhibited, onset of tumor postponed, and number of tumor foci decreased by beta-carotene. It suggested beta-carotene had an obvious chemoprophylactic effect on tumor.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; beta Carotene; Carotenoids; Female; Mice; Ornithine Decarboxylase; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate

Using 7,12-dimethylbenz[a]anthracene as the initiator and 12-O-tetradecanoyl-13-acetate as the tumor promoter on the dorsal skin of Sencar mice, we previously showed that pharmacological dietary all-trans-retinoic acid and beta-carotene inhibit the conversion of papillomas to carcinomas in a two-stage system of chemical carcinogenesis. The purpose of this study was to determine the influence of dietary retinoic acid and beta-carotene on retinoid and beta-carotene concentrations in skin and other tissues. We were unable to measure tissue retinoic acid because of the relatively limited amount of tissue available for analysis and the fast rate of metabolism. Different dietary levels of retinoic acid or beta-carotene did not influence total retinol of skin, papilloma, and carcinoma tissues, which all showed a concentration of approximately 1 +/- 0.5 microgram/g wet wt. Equally refractory to dietary retinoic acid or beta-carotene was serum retinol concentration. In contrast, dietary retinoic acid protected loss of liver retinol and retinyl palmitate, and beta-carotene caused an increase in beta-carotene and retinyl palmitate in liver but did not affect serum and liver retinol. We further investigated metabolic and functional aspects of retinoic acid in cultured mouse epidermal keratinocytes (LC-8 cells) and found that these cells actively metabolized [10,11-14C]retinoic acid to polar compounds. Isomers of retinoic acid were a minor product in the presence of cells and the major product when incubated in serum-containing medium in the absence of cells. From the functional point of view, exposure of LC-8 cells to 3 x 10(-6) M all-trans-retinoic acid (RA) caused a 75-fold induction in tissue transglutaminase and an approximately 9-fold induction in 10(-6) M RA at three days of culture. We conclude that retinoic acid spares endogenous retinol and that beta-carotene greatly enhances liver retinyl palmitate levels. Moreover we show that although mouse epidermal cells metabolize retinoic acid at a very high rate, they respond functionally by induction of tissue transglutaminase activity. Because this enzyme has been suggested to be involved in programmed cell death, we are presently investigating the possibility that it may be involved in the inhibition of carcinogenesis in mice fed pharmacological doses of RA.

Topics: Animals; beta Carotene; Carcinoma; Carotenoids; Cell Division; Chromatography, High Pressure Liquid; Diet; Female; Keratinocytes; Liver; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Papilloma; Skin; Skin Neoplasms; Transglutaminases; Tretinoin; Tumor Cells, Cultured; Vitamin A

In the past several years there has been a great deal of interest in the antioxidant beta-carotene and other micronutrients for their protective potential against various toxic insults. Two studies concerning the protective effects of beta-carotene, which were conducted in our laboratory, are reported here. The first involved the role of beta-carotene in modifying two-stage skin tumorigenesis initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by phorbol 12-myristate 13-acetate (PMA, TPA). In this study, the protective effects of two types of dietary beta-carotene, a beadlet formulation and crystalline beta-carotene, were compared in two strains of mice (Skh:HR-1 and CR:ORL Sencar). Mice were maintained on food fortified with 3% beta-carotene or on control diets. Mice receiving the beta-carotene-supplemented diets had fewer tumours than mice in the control groups. However, only in the Skh strain of mice was this difference statistically significant. In the second study, an in vitro experiment, BALBc 3T3 mouse fibroblasts were used to determine beta-carotene's accumulation in cells and the ability of these cells to metabolize beta-carotene to vitamin A. This in vitro model was also used to show a beta-carotene protective effect towards 8-MOP phototoxicity. These studies contributed to the increasing evidence of in vivo and in vitro protection by beta-carotene against chemically induced toxicity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animal Feed; Animals; beta Carotene; Carotenoids; Cell Line; Diet; Fibroblasts; Mice; Skin Neoplasms; Tetradecanoylphorbol Acetate

Various epidemiological and experimental studies have indicated that beta-carotene and vitamin E protect against a variety of cancers. This investigation determined whether a synergistic protective effect could be observed against chemically induced skin tumorigenesis in Skh mice by combining these two antioxidants in the diet. Forty-five mice were used in each of four diet groups. Control animals were fed standard mouse chow. Three other groups received the chow supplemented with one of the following: 0.5% beta-carotene, 0.12% vitamin E (added as d-alpha-tocopheryl succinate), or 0.5% beta-carotene + 0.12% vitamin E. Mice were topically treated with a single application of the initiator 7,12-dimethylbenz[a]anthracene and promoted with multiple applications of phorbol 12-myristate 13-acetate. Mice were observed for tumors each week for 27 weeks after initiation. The protective effect of each diet was determined by the decrease in the number of skin tumors in supplemented diet groups compared with that of the control diet group. Decreases in the number of cumulative tumors at Week 27 were 32% for beta-carotene-, 25% for vitamin E-, and 21% for beta-carotene+vitamin E-supplemented diet groups. However, differences in the number of tumors among the three groups supplemented with beta-carotene and/or vitamin E were not statistically significant. Thus, although protection was provided by the individual supplements, there was no synergistic effect for a decrease in the number of chemically induced skin tumors by the simultaneous dietary administration of beta-carotene and vitamin E.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Body Weight; Carotenoids; Female; Food, Fortified; Mice; Mice, Hairless; Prospective Studies; Skin Neoplasms; Trace Elements; Vitamin E

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; beta Carotene; Carotenoids; Diet; Drug Synergism; Mice; Mice, Inbred Strains; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Vitamin E

SENCAR mice were used to determine the effects of the provitamin A compound beta-carotene on papilloma formation and the conversion of papillomas to carcinomas in a two-stage protocol with one application of the initiator 7,12-dimethylbenz[a]anthracene (DMBA, 20 micrograms) and 20 weekly applications of the promotor 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 micrograms). A purified vitamin A-free diet was supplemented with beta-carotene at four levels (0.6, 6, 60 and 600 micrograms/g of diet) for female mice and two levels (60 and 600 micrograms/g) for male mice. Dietary supplementations of beta-carotene did not result in significant changes in body weight and survival of female and male mice. However, papillomas developed more rapidly and papilloma incidence (% mice with papillomas) reached its maximum (100%) sooner in male mice fed 600 micrograms of beta-carotene/g of diet than those fed 60 micrograms/g. There were smaller differences in papilloma incidence among the dietary groups in female mice, but the papilloma incidence again reached 100% sooner in mice fed 600 micrograms of beta-carotene/g of diet. Female and male mice fed 600 micrograms of beta-carotene/g of diet had significantly higher papilloma yields (average number of papillomas/mouse) than other dietary groups and a very low percentage of these papillomas converted to carcinomas in these mice. Thus, beta-carotene at 600 micrograms/g inhibited the conversion of papillomas to carcinomas in both sexes. In addition, papilloma yields were higher in female mice and these papillomas regressed more quickly than those in the corresponding groups of male mice. In conclusion, dietary beta-carotene caused differential effects on papilloma and carcinoma yields and sex-dependent differences in papilloma formation in female and male SENCAR mice treated with DMBA and TPA in a two-stage carcinogenesis protocol.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carcinoma; Carotenoids; Cocarcinogenesis; Dose-Response Relationship, Drug; Female; Incidence; Male; Mice; Neoplasms, Multiple Primary; Papilloma; Pregnancy; Sex Factors; Skin Neoplasms; Tetradecanoylphorbol Acetate

A case-control study was conducted in Melbourne, Australia of 88 consecutive males admitted for the surgical removal of a nonmelanocytic skin cancer (histologically confirmed basal cell carcinoma and squamous cell carcinoma) and of 88 male control patients admitted for small elective surgical procedures. In both cases and controls, previous diet, alcohol consumption, and smoking habit were investigated and serum beta-carotene and vitamin A levels were measured. A statistically significant inverse relationship was found between the risk of skin cancer and a high intake of fish (p = 0.05); vegetables in general (p < 0.001); beans, lentils, or peas (p < 0.001), carrots, silverbeet (Swiss chard), or pumpkin (p < 0.001); cruciferous vegetables (cabbage, brussel sprouts, or broccoli) (p < 0.001); and beta-carotene- and vitamin C-containing foods (p = 0.004). Cases had a lower mean serum level of beta-carotene (p < 0.001) and vitamin A (p = 0.02) than controls. The incidence of skin cancer in the study was inversely related to the level of serum beta-carotene (p < 0.0001). The correlation coefficient between dietary beta-carotene/vitamin C and serum beta-carotene was 0.22 (p = 0.04). Smoking and alcohol consumption showed no statistically significant association with the risk of nonmelanocytic skin cancer. The results were similar for both cell types. A high intake of vegetables including cruciferous vegetables, beta-carotene- and vitamin C-containing foods, and fish appears to be protective for nonmelanocytic skin cancer, and this deserves further study, as does the possible etiologic relevance of the low serum levels of beta-carotene and vitamin A.

Topics: Aged; Alcohol Drinking; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Case-Control Studies; Diet; Humans; Incidence; Male; Middle Aged; Skin Neoplasms; Smoking; Vitamin A

Vitamin E (alpha-tocopherol) is the major lipid-soluble chain-breaking antioxidant of membranes. Its UV-absorbance spectrum (lambda max 295 nm) extends well into the solar spectrum. We hypothesize that in skin alpha-tocopherol may absorb solar UV light and generate tocopheroxyl radicals. Reduction of tocopheroxyl radicals by other antioxidants (e.g. ascorbate, thiols) will regenerate (recycle) vitamin E at the expense of their own depletion. Hence, vitamin E in skin may act in two conflicting manners upon solar illumination: in addition to its antioxidant function as a peroxyl radical scavenger, it may act as an endogenous photosensitizer, enhancing light-induced oxidative damage. To test this hypothesis, we have illuminated various systems (methanol-buffer dispersions, liposomes and skin homogenates) containing alpha-tocopherol or its homologue with a shorter 6-carbon side chain, chromanol-alpha-C6 with UV light closely matching solar UV light, in the presence or absence of endogenous or exogenous reductants. We found that: (i) alpha-tocopheroxyl (chromanoxyl) radicals are directly generated by solar UV light in model systems (methanol-water dispersions, liposomes) and in skin homogenates; (ii) reducing antioxidants (ascorbate, ascorbate+dihydrolipoic acid) can donate electrons to alpha-tocopheroxyl (chromanoxyl) radicals providing for vitamin E (chromanol-alpha-C6) recycling; (iii) recycling of UV-induced alpha-tocopheroxyl radicals depletes endogenous antioxidant pools (accelerates ascorbate oxidation); (iv) beta-carotene, a non-reducing antioxidant, is not active in alpha-tocopherol recycling, and its UV-dependent depletion is unaffected by vitamin E.

Topics: Animals; Antioxidants; Ascorbic Acid; beta Carotene; Carotenoids; Electron Spin Resonance Spectroscopy; Free Radicals; Liposomes; Methanol; Mice; Mice, Hairless; Models, Biological; Neoplasms, Radiation-Induced; Oxygen; Phosphatidylcholines; Radiation Tolerance; Skin; Skin Neoplasms; Suspensions; Thioctic Acid; Ultraviolet Rays; Vitamin E; Water

Although beta-carotene has been considered to be a key cancer preventive agent in green and yellow vegetables, other types of carotenoids, such as alpha-carotene, may also contribute to anticarcinogenic action, since these carotenoids usually coexist with beta-carotene and are detectable in human blood and tissues. In this study, we compared the inhibitory effect of natural alpha-carotene, obtained from palm oil, with that of beta-carotene on spontaneous liver carcinogenesis in C3H/He male mice. The mean number of hepatomas per mouse was significantly decreased by alpha-carotene supplementation (per os administration in drinking water at a concentration of 0.05%, ad libitum) as compared with that in the control group (P < 0.001, Student's t test). On the other hand, beta-carotene, at the same dose as alpha-carotene, did not show any such significant difference from the control group. Furthermore, we also compared the antitumor-promoting activity of alpha-carotene with that of beta-carotene against two-stage mouse lung carcinogenesis (initiator, 4-nitroquinoline 1-oxide; promoter, glycerol). alpha-Carotene, but not beta-carotene, reduced the number of lung tumors per mouse to about 30% of that in the control group (P < 0.001, Student's t test). The higher potency of the antitumor-promoting action of alpha-carotene compared to beta-carotene was confirmed in other experimental systems; e.g., alpha-carotene was also found to have a stronger effect than beta-carotene in suppressing the promoting activity of 12-O-tetradecanoylphorbol-13-acetate on skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated mice. These results suggest that not only beta-carotene, but also other types of carotenoids, such as alpha-carotene, may play an important role in cancer prevention.

Topics: 4-Nitroquinoline-1-oxide; 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Animals; beta Carotene; Carotenoids; Drug Screening Assays, Antitumor; Humans; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred C3H; Ornithine Decarboxylase; Papilloma; Skin Neoplasms; Specific Pathogen-Free Organisms; Tetradecanoylphorbol Acetate

Topics: Anticarcinogenic Agents; beta Carotene; Carcinoma, Basal Cell; Carotenoids; Humans; Isotretinoin; Skin Neoplasms

Beta-carotene, administered orally to mice, caused a decrease in angiogenesis evoked by HPV-transformed tumorigenic cell lines (SKv-t, HeLa). It did not affect angiogenesis induced by the non-tumorigenic SKv (not-t) cell line, and increased lymphocyte-induced immune angiogenesis. We suggest that the anti-cancerogenic effect of beta-carotene may be due, at least in part, to its inhibitory effect on formation of new blood vessels within the tumour mass.

Topics: Animals; beta Carotene; Carotenoids; Cell Line; HeLa Cells; Humans; Mice; Mice, Hairless; Neovascularization, Pathologic; Skin; Skin Neoplasms

Topics: beta Carotene; Carotenoids; Diet; Humans; Isotretinoin; Skin Neoplasms

In order to evaluate the role of beta-carotene as an inhibitor of skin carcinogenesis, hairless female HRA/Skh mice were treated with the initiator 7,12-dimethylbenz[a]anthracene (DMBA) and with the promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), and were fed a balanced diet free from vitamin A either with or without gavage-administered beta-carotene. There was no evidence of avitaminosis A or differences in body weight in mice deprived of beta-carotene and vitamin A, compared with those given 290 or 1430 IU beta-carotene/kg per day. Mice fed with normal animal feed pellets displayed a significantly higher body weight (28.5 +/- 1.95 g) compared with mice on the special diet (25.7 +/- 1.9 g), and also displayed a higher papilloma yield. However animals on the special diet, fed with beta-carotene from weaning, displayed significantly lower numbers of papillomas per mouse. This lower papilloma yield was evident particularly between 12-24 weeks after commencement of the study, which coincided with the period of maximum tumor yield in DMBA/TPA-treated mice. The characteristic regression of papillomas after that time points to the reversibility of many earlier papillomas, and their dependence on continued TPA administration. Evaluation of carcinomas in mice on the various dietary regimes showed there was no significant difference between any group, including those fed with beta-carotene continuously from weaning. The present results demonstrate that a sustained dietary intake of beta-carotene from 3 weeks of age partially suppressed the growth of papillomas, but did not affect the course of malignant progression in DMBA/TPA-treated HRA/Skh mice. It is evident that beta-carotene predominantly affects TPA-dependent papillomas, which possess reversible properties and have a low probability of progression to form carcinomas.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Body Weight; Carotenoids; Diet; Female; Mice; Mice, Hairless; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate

There is currently a great interest in the protective potential of beta-carotene and other micronutrients against carcinogenesis. We investigated the role of beta-carotene in modifying 7,12-dimethylbenz[a]anthracene (DMBA)-initiated, 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted, two-stage skin carcinogenesis. We were interested in comparing the protective effects of two types of dietary beta-carotene, a beadlet formulation and crystalline beta-carotene, in two strains of mice (Skh:HR-1 and CR:ORL Sencar). Mice were maintained throughout the study on one of these 3% beta-carotene-fortified diets or on control diets. In Week 11 after the start of the diets, the DMBA/TPA treatment regimen was begun. The resulting skin tumors were counted weekly. In addition, serum and skin levels were monitored for beta-carotene at the time of chemical initiation and at the termination of the study. A decrease in the number of cumulative tumors in the beta-carotene-fed animals compared with the appropriate control groups was observed in both strains of mice. However, statistical evaluation of the data revealed that the decrease was significant only in Skh mice. This phenomenon might be explained by the inherent sensitivity of Sencar mice to the two-stage carcinogenesis treatment regimen. The mechanism of the protective effect found in this study is still not clear. Recent data suggest that a vitamin A pathway is not probable but that a direct 1O2 and/or radical-quenching property of the parent beta-carotene molecule may be involved. This study also demonstrates that two-stage-induced skin tumorigenesis can be modified by both types of beta-carotene-fortified diets.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Body Weight; Carotenoids; Diet; Female; Food, Fortified; Mice; Mice, Inbred Strains; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate

Beta-carotene and canthaxanthin at concentrations of 70 or 300 microM were shown to inhibit the proliferation of cultured human squamous cells (SK-MES lung carcinoma and SCC-25 oral carcinoma) in a 5 hr cell density assay. Responses were similar for both tumor cell lines, ranging from 71-84% inhibition. In contrast, equimolar concentrations of alpha-tocopherol gave only 19-36% inhibition of SCC-25, but 50-75% inhibition of SK-MES cell density. Equimolar reduced glutathione resulted in 4-15% stimulation of SCC-25 and 22-25% inhibition of SK-MES cell proliferation. With cultured normal keratinocytes, treated final cell densities did not differ significantly from those of controls. Two additional assays measuring the metabolic generation of formazan (MTT assay) and [5-3H]thymidine incorporation were in substantial agreement with the growth inhibition pattern. Thus both continuous and cyclic cellular processes are involved in the tumor-specific response. Onset of the response to beta-carotene alone or in combination with alpha-tocopherol is signalled within 1-2 hours of treatment by the appearance of a unique 70 kD heat-shock protein.

Topics: beta Carotene; Canthaxanthin; Carcinoma, Squamous Cell; Carotenoids; Cell Division; Cell Survival; Glutathione; Humans; In Vitro Techniques; Keratinocytes; Liposomes; Molecular Weight; Proteins; Skin Neoplasms; Tumor Cells, Cultured; Vitamin E

Retinoids have chemopreventive activity for epithelial tumors in a variety of systems, including the two-stage tumorigenesis system of mouse skin in which only the promotion stage is inhibited. We asked whether dietary vitamin A deficiency could affect the skin tumorigenic response, prior to major changes in body weight or general health of the animals. Two regimens were tested to induce vitamin A deficiency. SENCAR mice were either (a) fed a vitamin A-deficient diet from 4 or 9 weeks of age or (b) their mothers were fed the diet from the time of birth of the experimental animals which were then weaned on the same diet. The latter regimen produced typical symptoms of vitamin A deficiency in the offspring by Weeks 12-14 and all the mice died by Week 19; the former regimen permitted sufficient accumulation of retinol and its esters to sustain life for up to 45 and 75 weeks, respectively, in the majority of mice. For our experiments, vitamin A depletion was produced by placing the mothers on the deficient diet at birth of the experimental animals. A single topical dose of 20 micrograms of 7,12-dimethylbenz(a)anthracene (DMBA) was used as the initiator at 3 weeks of age and 1 to 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) once weekly as the tumor promoter for 10 weeks (from Week 4 through 13 of the experiment). Fifty-five % of mice (n = 40) on Purina laboratory chow (mean body weight, 31.4 g) developed skin tumors (2.58 per mouse) at 12 weeks, versus 2.5% (0.05 papillomas per mouse) of mice (n = 40) kept on the purified vitamin A-deficient diet (mean body weight, 30.3 g), a 98% decrease in tumor/mouse. Retinoic acid (RA) (1-3 micrograms/g diet) supplementation after Week 12 caused a rapid tumorigenic response in 95% of the mice by week 22. This tumor response occurred to a reduced extent in the absence of continued TPA treatment up to Week 13. Even though tumor incidence increased within 1 week of RA and 95% of the mice showed the tumorigenic response, the number of tumors per mouse was about 50% of that observed in mice maintained on standard Purina diet. This was confirmed in an experiment in which the mice were maintained for life either on Purina or on the RA (3 micrograms/g) containing purified diet, the latter being the control group for the effect of vitamin A deficiency on skin tumorigenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carotenoids; Cocarcinogenesis; Diet; Female; Liver; Male; Mice; Neoplasms, Experimental; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Vitamin A Deficiency; Weight Loss

Beta-carotene (BC) and canthaxanthine (CX), two carotenoids with and without pro-vitamin A activity, respectively, were found to help to prevent benzo[a]pyrene (BP)-induced skin carcinogenesis in the dark and BP photocarcinogenesis (UV 300-400 nm) when given as an oral supplement to female Swiss albino mice. The same experimental procedure was adapted to 8-methoxypsoralen (8-MOP) photoinduction of mammary carcinomas in mice. Here also, the two carotenoids were strongly antitumorigenic. Indeed, 8-MOP photomutagenesis, tested in S. typhimurium TA 102, appeared to depend on a two-step reaction, namely an oxygen-independent DNA-8-MOP photoadduct, followed by an oxygen-dependent second step, sensitive to carotenoids. This result suggests that dietary carotenoids (powerful antioxidant molecules) might prevent the carcinogenic risk caused by substances that are transformed into ultimate carcinogens by oxidative processes which are indirectly carcinogenic. Finally, to verify whether supplemental carotenoids can affect carcinogenesis where neither light excitation nor oxidative metabolic processes are involved, an experimental attempt was made on gastric carcinogenesis induced in rats by the direct carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The results demonstrate that supplemental carotenoids do not affect initiation and progression stages, but do prevent the progression stage of dysplasias to infiltrating gastric carcinomas. Thus, this provides strong presumptive evidence for oxygen radical involvement in the later stages of this neoplastic development, as recently reported in the literature. As far as mutagenicity in S. typhimurium is concerned, carotenoids do not exert, as expected, any protective effect on MNNG mutagenic activity. The above experimental data suggest that supplemental carotenoids, instead of sunscreen preparations, can be adopted by outdoor workers to prevent skin cancer. Accordingly, such natural antioxidants may be useful in human chemoprevention against neoplasias of the lung, breast, urinary bladder, and colon and rectum even after radical surgery.

Topics: Animals; Benzo(a)pyrene; beta Carotene; Canthaxanthin; Carcinogens; Carotenoids; Diet; Female; Free Radicals; Methoxsalen; Methylnitronitrosoguanidine; Mice; Mutagenicity Tests; Neoplasms, Experimental; PUVA Therapy; Skin Neoplasms

Topics: Animals; beta Carotene; Canthaxanthin; Carotenoids; Female; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Skin Neoplasms; Ultraviolet Rays

Topics: Animals; beta Carotene; Carotenoids; Dietary Fats; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Skin Neoplasms; Ultraviolet Rays

Topics: beta Carotene; Canthaxanthin; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Etretinate; Humans; Keratosis; Male; Skin Neoplasms; Xeroderma Pigmentosum

The carotenoids beta-carotene (C) and canthaxanthine (CX), with and without pro-vitamin A activity, respectively, when perorally administered to mice, markedly prevent benzo(a)pyrene photocarcinogenic enhancement (BP-PCE), continue to block such BP-PCE and protect significantly against BP carcinogenesis in mice maintained in the dark. These results appear relevant to both the pathogenesis of chemical carcinogenesis and rational programs of skin cancer prevention in humans.

Topics: Animals; Benzo(a)pyrene; Benzopyrenes; beta Carotene; Canthaxanthin; Carotenoids; Darkness; Diet; Female; Mice; Photochemistry; Skin Neoplasms; Ultraviolet Rays

Mice were given either beta-carotene or either of two carotenoids with no vitamin A activity--canthaxanthin or phytoene--or placebo. Skin tumors were induced in each group by each of three methods: (1) UV-B (290--320 nm); (2) dimethylbenz(a)anthracene (DMBA)/croton oil applications; (3) DMBA followed by low-dose UV-B. For tumors induced by UV-B alone, beta-carotene-phytoene- and canthaxanthin-treated mice developed fewer tumors per mouse, with a delay in tumor appearance, than did control mice. For tumors induced by DMBA/croton oil or DMBA/UV-B, mice receiving beta-carotene showed a significant difference in tumor numbers and appearance time from placebo mice; phytoene and canthaxanthin treatment had no effect.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Canthaxanthin; Carcinoma, Squamous Cell; Carotenoids; Croton Oil; Female; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Papilloma; Skin Neoplasms; Ultraviolet Rays

Topics: Adult; Animals; Benzo(a)pyrene; Benzopyrenes; beta Carotene; Biotransformation; Canthaxanthin; Carotenoids; Female; Humans; Photic Stimulation; Skin Neoplasms