Pathogenesis of Keratinocyte Carcinomas and the Therapeutic Potential of Medicinal Plants and Phytochemicals.

Keratinocyte carcinoma (KC) is a form of skin cancer that develops in keratinocytes, which are the predominant cells present in the epidermis layer of the skin. Keratinocyte carcinoma comprises two sub-types, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This review provides a holistic literature assessment of the origin, diagnosis methods, contributing factors, and current topical treatments of KC. Additionally, it explores the increase in KC cases that occurred globally over the past ten years. One of the principal concepts highlighted in this article is the adverse effects linked to conventional treatment methods of KC and how novel treatment strategies that combine phytochemistry and transdermal drug delivery systems offer an alternative approach for treatment. However, more in vitro and in vivo studies are required to fully assess the efficacy, mechanism of action, and safety profile of these phytochemical based transdermal chemotherapeutics.

Effectiveness of Banxia Xiexin Decoction in the treatment of precancerous lesions: A protocol for systematic review and meta-analysis.

BACKGROUND: Gastric precancerous lesion (GPL) is a necessary stage in the occurrence and development of gastric cancer. At present, the incidence of gastric cancer is increasing year by year. It is important to prevent and control gastric cancer through early detection and intervention. Banxia Xiexin Decoction (BXD) has a good effect in improving symptoms, reducing inflammation, promoting the repair of gastric mucosa, reversing its atrophy and intestinal metaplasia. BXD may be a foreground choice for the treatment of GPL. METHODS: Randomized controlled trials of BXD for GPL will be searched in the relevant database, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), and Chinese Scientific Journal Database (VIP database). The studies of electronic searches will be exported to EndNote V.9.1 software. We will run meta-analyses using the Review Manager (RevMan) V.5.3 software. Any disagreement will be solved in consultation with a third reviewer. RESULTS: Our study aims to explore the efficacy of BXD for GPL and to provide up-to-date evidence for clinical of GPL. CONCLUSION: The conclusion of this study will provide evidence for the efficacy of BXD on GPL. INPLASY REGISTRATION NUMBER: INPLASY 202130102.

Ethanol-extracted propolis enhances BBN-initiated urinary bladder carcinogenesis via non-mutagenic mechanisms in rats.

Ethanol-extracted propolis (EEP) is used for medical, dietetic and cosmetic purposes. In this study, the effects of EEP on urinary bladder carcinogenesis, its underlying mechanism and in vivo genotoxicity were investigated. In experiment 1, rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 2 or 4 weeks followed by dietary administration of 0.125, 0.25, 0.5 or 1% EEP for 4 or 32 weeks, respectively. At week 6, the mRNA levels of top2a, cyclin D1 and survivin were significantly elevated in the 0.5 and 1% EEP groups. At week 36, the incidence and multiplicity of urothelial carcinomas and total tumors were markedly elevated in all EEP groups. In experiment 2, rats were fed basal diet or the 1% EEP diet for 13 weeks without carcinogen initiation. Increases in urinary precipitate, cell proliferation and incidence of simple hyperplasia were observed in the 1% EEP group. In experiment 3, dietary administration of 2.5% EEP to gpt delta rats for 13 weeks did not induce any obvious mutagenicity in the urinary bladder urothelium. Taken together, EEP enhanced BBN-initiated rat urinary bladder carcinogenesis in a non-genotoxic manner through increasing formation of urinary precipitate, enhancing cell proliferation and inhibiting apoptosis during the early stages of carcinogenesis.

YAP activation is an early event and a potential therapeutic target in liver cancer development.

BACKGROUND & AIMS: Although the growth suppressing Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its dysregulation occurs. We investigated in rat and human preneoplastic lesions whether overexpression of the transcriptional co-activator Yes-associated protein (YAP) is an early event. METHODS: The experimental model used is the resistant-hepatocyte (R-H) rat model. Gene expression was determined by qRT-PCR or immunohistochemistry. Forward genetic experiments were performed in human HCC cells and in murine oval cells. RESULTS: All foci of preneoplastic hepatocytes, generated in rats 4weeks after diethylnitrosamine (DENA) treatment, displayed YAP accumulation. This was associated with down-regulation of the ß-TRCP ligase, known to mediate YAP degradation, and of microRNA-375, targeting YAP. YAP accumulation was paralleled by the up-regulation of its target genes. Increased YAP expression was also observed in human early dysplastic nodules and adenomas. Animal treatment with verteporfin (VP), which disrupts the formation of the YAP-TEAD complex, significantly reduced preneoplastic foci and oval cell proliferation. In vitro experiments confirmed that VP-mediated YAP inhibition impaired cell growth in HCC and oval cells; notably, oval cell transduction with wild type or active YAP conferred tumorigenic properties in vitro and in vivo. CONCLUSIONS: These results suggest that (i) YAP overexpression is an early event in rat and human liver tumourigenesis; (ii) it is critical for the clonal expansion of carcinogen-initiated hepatocytes and oval cells, and (iii) VP-induced disruption of the YAP-TEAD interaction may provide an important approach for the treatment of YAP-overexpressing cancers.

Combination of sorafenib and angiotensin-II receptor blocker attenuates preneoplastic lesion development in a non-diabetic rat model of steatohepatitis.

BACKGROUND: Given the well-documented adverse side effects of sorafenib, many sorafenib-treated patients may need the reduced initial dose of the compound, and an alternative sorafenib-based therapy, which exerts similar clinical benefit, is anticipated. An angiostatic therapy with sorafenib is considered one of the promising approaches for chemoprevention of hepatocellular carcinoma. The aim of the current study was to elucidate the combination effect of low dose of sorafenib and angiotensin-II receptor blocker (ARB) on hepatocarcinogenesis, especially in conjunction with angiogenesis. METHODS: The chemopreventive effect on the development of liver preneoplastic lesions, angiogenesis, and several indices was elucidated in rats. We also performed several sets of in vitro experiments to examine the mechanisms involved. RESULTS: Using a non-diabetic rat model of steatohepatitis with choline deficient L-amino acid-defined diet, sorafenib demonstrated marked inhibition of preneoplastic lesions in a dose dependent manner. Combined treatment with ARB (losartan) at a clinically comparable dose and half dose of sorafenib resulted in the inhibitory effect equivalent to that of common dose of sorafenib along with suppression of hepatic neovascularization and potent angiogenic factor, vascular endothelial growth factor. Furthermore, similar combined inhibitory outcomes were observed in several sets of in vitro studies. CONCLUSION: Since the combinatorial treatment using low doses of sorafenib and ARB could sufficiently induce inhibitory effect on the development of preneoplastic lesions at the magnitude similar to the conventional dose of sorafenib, this regimen may provide new strategy for patients intolerant of the usual dose of sorafenib in the future.

Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: suppressing effects of EGCG on the development of liver lesions.

Non-alcoholic steatohepatitis (NASH), which involves hepatic inflammation and fibrosis, is associated with liver carcinogenesis. The activation of the renin-angiotensin system (RAS), which plays a key role in blood pressure regulation, promotes hepatic fibrogenesis. In this study, we investigated the effects of (-)-epigallocatechin-3-gallate (EGCG), a major component of green tea catechins, on the development of glutathione S-transferase placental form (GST-P)-positive (GST-P(+)) foci, a hepatic preneoplastic lesion, in SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP-ZF) obese and hypertensive rats. Male 7-week-old SHRSP-ZF rats and control non-obese and normotensive WKY rats were fed a high fat diet and received intraperitoneal injections of carbon tetrachloride twice a week for 8weeks. The rats were also provided tap water containing 0.1% EGCG during the experiment. SHRSP-ZF rats presented with obesity, insulin resistance, dyslipidemia, an imbalance of adipokines in the serum, and hepatic steatosis. The development of GST-P(+) foci and liver fibrosis was markedly accelerated in SHRSP-ZF rats compared to that in control rats. Additionally, in SHRSP-ZF rats, RAS was activated and inflammation and oxidative stress were induced. Administration of EGCG, however, inhibited the development of hepatic premalignant lesions by improving liver fibrosis, inhibiting RAS activation, and attenuating inflammation and oxidative stress in SHRSP-ZF rats. In conclusion, obese and hypertensive SHRSP-ZF rats treated with a high fat diet and carbon tetrachloride displayed the histopathological and pathophysiological characteristics of NASH and developed GST-P(+) foci hepatic premalignant lesions, suggesting the model might be useful for the evaluation of NASH-related liver tumorigenesis. EGCG might also be able to prevent NASH-related liver fibrosis and tumorigenesis.

Neglected role of hookah and opium in gastric carcinogenesis: a cohort study on risk factors and attributable fractions.

A recent study showed an association between hookah/opium use and gastric cancer but no study has investigated the relationship with gastric precancerous lesions. We examined the association between hookah/opium and gastric precancerous lesions and subsequent gastric cancer. In a population-based cohort study, 928 randomly selected, healthy, Helicobacter pylori-infected subjects in Ardabil Province, Iran, were followed for 10 years. The association between baseline precancerous lesions and lifestyle risk factors (including hookah/opium) was analyzed using logistic regression and presented as odds ratios (ORs) and 95% confidence intervals (CIs). We also calculated hazard ratios (HRs) and 95% CIs for the associations of lifestyle risk factors and endoscopic and histological parameters with incident gastric cancers using Cox regression models. Additionally, the proportion of cancers attributable to modifiable risk factors was calculated. During 9,096 person-years of follow-up, 36 new cases of gastric cancer were observed (incidence rate: 3.96/1,000 persons-years). Opium consumption was strongly associated with baseline antral (OR: 3.2; 95% CI: 1.2-9.1) and body intestinal metaplasia (OR: 7.3; 95% CI: 2.5-21.5). Opium (HR: 3.2; 95% CI: 1.4-7.7), hookah (HR: 3.4; 95% CI: 1.7-7.1) and cigarette use (HR: 3.2; 95% CI: 1.4-7.5), as well as high salt intake, family history of gastric cancer, gastric ulcer and histological atrophic gastritis and intestinal metaplasia of body were associated with higher risk of gastric cancer. The fraction of cancers attributable jointly to high salt, low fruit intake, smoking (including hookah) and opium was 93% (95% CI: 83-98). Hookah and opium use are risk factors for gastric cancer as well as for precancerous lesions. Hookah, opium, cigarette and high salt intake are important modifiable risk factors in this high-incidence gastric cancer area.

Oral submucous fibrosis: a premalignant condition in a 14-year-old Indian girl.

A 14-year-old Indian girl presented with difficulty in mouth opening and burning sensation while eating. On examination, blanching of the oral mucosa with diffuse white pigmented lesion of size 3.5 to 2 cm along with melanotic pigmentation was seen on the left buccal mucosa posteriorly. The patient was diagnosed with oral submucous fibrosis. A comprehensive treatment plan was made based on conservative management that included motivation and intense counselling of the patient and her parents so that she quits the habit of chewing areca nut and tobacco, along with systemic treatment of vitamin B complex supplements, antioxidants, multivitamins and oral physiotherapy. We present this case to highlight the difficulties faced by the clinical practitioners in providing treatment because of the taboos and myths associated with surgical treatment modality in rural population as well as to emphasise the menace of increasing consumption and availability of tobacco and areca nut to children.

Areca nut-induced buccal mucosa fibroblast contraction and its signaling: a potential role in oral submucous fibrosis--a precancer condition.

Betel quid (BQ) chewing is an oral habit that increases the risk of oral cancer and oral submucous fibrosis (OSF), a precancerous condition showing epithelial atrophy and tissue fibrosis. Persistent fibroblast contraction may induce the fibrotic contracture of tissue. In this study, we found that areca nut extract (ANE) (200-1200 µg/ml) stimulated buccal mucosa fibroblast (OMF)-populated collagen gel contraction. Arecoline but not arecaidine-two areca alkaloids, slightly induced the OMF contraction. Exogenous addition of carboxylesterase (2U/ml) prevented the arecoline- but not ANE-induced OMF contraction. OMF expressed inositol triphosphate (IP3) receptors. ANE-induced OMF (800 µg/ml) contraction was inhibited by U73122 [phospholipase C (PLC) inhibitor] and 2-aminoethoxydiphenyl borate (IP3 receptor antagonist), respectively. Ethylene glycol tetraacetic acid and verapamil, two calcium mobilization modulators, also suppressed the ANE-induced OMF contraction. ANE induced calcium/calmodulin kinase II and myosin light chain (MLC) phosphorylation in OMF. Moreover, W7 (a Ca(2+)/calmodulin inhibitor), HA1077 (Rho kinase inhibitor), ML-7 (MLC kinase inhibitor) and cytochalasin B (actin filament polymerization inhibitor) inhibited the ANE-induced OMF contraction. Although ANE elevated reactive oxygen species (ROS) level in OMF, catalase, superoxide dismutase and N-acetyl-L-cysteine showed no obvious effect on ANE-elicited OMF contraction. These results indicate that BQ chewing may affect the wound healing and fibrotic processes in OSF via inducing OMF contraction by ANE and areca alkaloids. AN components-induced OMF contraction was related to PLC/IP3/Ca(2+)/calmodulin and Rho signaling pathway as well as actin filament polymerization, but not solely due to ROS production.

Coffee and caffeine protect against liver injury induced by thioacetamide in male Wistar rats.

Coffee intake has been inversely related to the incidence of liver diseases, although there are controversies on whether these beneficial effects on human health are because of caffeine or other specific components in this popular beverage. Thus, this study evaluated the protective effects of coffee or caffeine intake on liver injury induced by repeated thioacetamide (TAA) administration in male Wistar rats. Rats were randomized into five groups: one untreated group (G1) and four groups (G2-G5) treated with the hepatotoxicant TAA (200 mg/kg b.w., i.p.) twice a week for 8 weeks. Concomitantly, rats received tap water (G1 and G2), conventional coffee (G3), decaffeinated coffee (G4) or 0.1% caffeine (G5). After 8 weeks of treatment, rats were killed and blood and liver samples were collected. Conventional and decaffeinated coffee and caffeine intake significantly reduced serum levels of alanine aminotransferase (ALT) (p < 0.001) and oxidized glutathione (p < 0.05), fibrosis/inflammation scores (p < 0.001), collagen volume fraction (p < 0.01) and transforming growth factor ß-1 (TGF-ß1) protein expression (p ≤ 0.001) in the liver from TAA-treated groups. In addition, conventional coffee and caffeine intake significantly reduced proliferating cellular nuclear antigen (PCNA) S-phase indexes (p < 0.001), but only conventional coffee reduced cleaved caspase-3 indexes (p < 0.001), active metalloproteinase 2 (p ≤ 0.004) and the number of glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions (p < 0.05) in the liver from TAA-treated groups. In conclusion, conventional coffee and 0.1% caffeine intake presented better beneficial effects than decaffeinated coffee against liver injury induced by TAA in male Wistar rats.

Effect of α-tocopherol on salivary reactive oxygen species and trace elements in oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSMF) is a chronic debilitating disease and a well-recognized, potentially malignant condition of the oral cavity associated with betel quid chewing. Betel quid chewing is a popular oral habit in India and shows strong association in the incidence of OSMF. The objective of the study was to determine the levels of trace elements, pro-oxidants and reactive oxygen species (ROS) in saliva of betel quid chewers and OSMF patients, which may help in the diagnosis of cancer progression in the oral cavity. METHODS: A total of 35 cases of OSMF and 35 cases of healthy individuals were included in the present study. The salivary status of ROS, pro-oxidants and some trace elements was studied in OSMF patients and normal healthy individuals. RESULTS: The levels of lipid peroxides (P < 0.001), conjugated dienes (P < 0.01), hydroxyl radicals (P < 0.01), superoxide dismutase (P < 0.05), copper (P < 0.05), calcium (P < 0.01), magnesium (NS), potassium (P < 0.05) and iron (P < 0.05) in OSMF patients were elevated when compared with normal healthy individuals. The levels of hydrogen peroxide (P < 0.05) and sodium (P < 0.01) in OSMF patients were found to be decreased when compared with control subjects. A significant alteration was noticed after supplementing with α-tocopherol in oral precancerous patients. CONCLUSION: These parameters may help in the detection of the severity of oral diseases.

Effect of methylxanthines (coffee/tea consumers) on oral precancer and oral cancer patients with smoking and smokeless tobacco habits.

AIM: To study, whether the consumption of regular tea/coffee (methylxanthines) increases the risk of oral cancer in patients with smoking and smokeless tobacco habits. MATERIALS AND METHODS: This study was conducted on a total of 90 oral cancer and precancerous patients, from western Maharashtra (India) males in the age group of 20 to 45 years who were with smoking and smokeless tobacco habits; also regular tea/coffee consumers were subjected to biochemical parameters such as aspartate transaminase (AST) and alanine transaminase (ALT) from saliva and serum of patients with oral precancer (submucous fibrosis, leukoplakia) and oral cancer patients and compared with 90-age and sex-matched controls. Individuals consent was taken to measure their biochemical parameters, by using Hafkenscheid method in whole saliva and serum. Statistical analysis of variance (ANOVA) with Tukey's correction for multiple group comparisons was performed using Student t-test. RESULTS: Results show, that a statistically significant increase in value (p < 0.05) in ALT, AST in both saliva and serum was observed in precancerous and oral cancer patients among the study group as compared to the control group. CONCLUSION: In the present study, there was increase in the levels of ALT, AST enzymes in both saliva and serum levels in the study group as compared to the control group which was statistically significant (p < 0.05) suggesting that long-term exposure of methylxanthines results in impairment of salivary gland antioxidant system which may affect the anticarcinogenic action of saliva. CLINICAL SIGNIFICANCE: Oral fluids may be utilized effectively to study the variations in the biochemical constituents of saliva of leukoplakia, submucous fibrosis and oral cancer patients.

Italian guidelines and therapeutic algorithm for actinic keratoses.

The prevalence of actinic keratosis (AK) continues to rise among white people throughout the world and it is necessary to increase the level of attention paid to it from a diagnostic and a preventive point of view. Today, AK must be considered an in situ squamous cell carcinoma and as such, must be managed using one of the available approved therapeutic alternatives. However, when multiple AKs develop on severely photodamaged skin, the treatment of the lesion together with that of the field of cancerization is part of an optimal strategy that aims not only to solve alterations clinically evident but also those in the surrounding skin field cancerization, that most likely hosts genetic alterations and is the site of initial gradual replacement of normal cells with tumoral cells. This paper reports the most recent evidences from a careful review of the literature's key articles of the treatment of AKs and suggests guidelines for the clinicians. The guidelines indicated by the authors have also been based on practical evaluations and their own clinical experience. The present conclusions may be modified by new findings in the field of oncologic research.

Lipid peroxidation, total antioxidant status, and total thiol levels predict overall survival in patients with oral squamous cell carcinoma.

Tobacco is the major etiological factor for oral cancer development through the generation of oxidative stress. Therefore, markers of oxidative stress such as total antioxidant status, lipid peroxidation, and total thiol levels might be useful to monitor oxidative stress and predict overall survival in oral cancer patients. The study included 140 oral cancer patients and 50 healthy controls, who were classified as with the habit of tobacco and no habit of tobacco. Adjacent normal and malignant tissue samples were collected from oral cancer patients. Plasma and tissue levels of lipid peroxidation, thiol, and total antioxidant status were assayed by spectrophotometric methods. Thiol levels were significantly lower in controls with the habit of tobacco (P= .033), oral cancer patients (P= .0001), and malignant tissues (P= .015) as compared to controls with no habit of tobacco, controls with the habit of tobacco, and adjacent normal tissues, respectively. Tobacco exposure was higher in oral cancer patients than controls with the habit of tobacco. Controls with the habit of tobacco who had lower thiol (odds ratio [OR]=10.58, P= .008) and high tobacco exposure (OR=0.251, P= .05) showed an elevated risk of oral cancer development. Patients showing a lipid peroxidation level above the cutoff level as compared to patients below the cutoff level showed poor overall survival, whereas those with thiol and total antioxidant status levels below the cutoff level as compared to their respective counterparts showed poor overall survival. In conclusion, lipid peroxidation and thiol could be useful for predicting the risk of oral carcinogenesis in healthy tobacco consumers and predicting overall survival of oral cancer patients.

Alcohol and folate consumption and risk of benign proliferative epithelial disorders of the breast.

Alcohol consumption has been associated with increased breast cancer risk and the increase in risk may be attenuated by adequate folate intake. However, their associations with the risk of benign proliferative epithelial disorders (BPEDs) of the breast, possible precursors of breast cancer, are not well understood. To investigate these associations, we conducted a cohort study among 68,132 postmenopausal women participating in the Women's Health Initiative randomized clinical trials. Women were prospectively followed and those reporting a breast procedure (open surgical biopsy or core needle biopsy) had histological sections obtained for central pathology review. A total of 1,792 women with BPED of the breast were identified over an average of 7.8 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence limits (CLs) for the associations of interest. Compared to nondrinkers, total current alcohol intake of 30 g/day or more was not associated with BPED risk (HR = 0.98, 95% CL = 0.70, 1.38). The risk of BPED was not associated with folate intake from diet (highest vs. lowest quartile: HR = 1.10, 95% CL = 0.96, 1.26), from supplements (yes vs. no: HR = 1.05, 95% CL = 0.96, 1.16) or from all sources combined (highest vs. lowest quartile: HR = 1.11, 95% CL = 0.96, 1.27). Furthermore, there was no effect modification between alcohol and folate in relation to the risk of BPED. In conclusion, we observed that alcohol consumption and folate intake were not associated with altered risk of BPED, and that there was no effect modification between them in relation to the risk of BPED.

Expression of NF-kappaB parallels COX-2 expression in oral precancer and cancer: association with smokeless tobacco.

Nuclear Factor-kappaB (NF-kappaB) activation and COX-2 overexpression have been reported in head and neck cancer, but the relationship between these proteins remains to be investigated. To determine the relationship between NF-kappaB and COX-2 in Smokeless Tobacco (ST) associated oral tumorigenesis, we performed immunohistochemistry in serial sections from 107 OSCCs, 78 oral precancerous lesions (OPLs) (58 hyperplasias, 20 dysplasias) and 15 histologically normal oral tissues and correlated with clinicopathological data. Significant increase in NF-kappaB and COX-2 immunopositivity was observed from normal oral mucosa to OPLs to OSCCs (p = 0.009 and p = 0.002 respectively). Upregulation of NF-kappaB and COX-2 was observed as early as in hyperplasia [p = 0.006; OR = 6.1 and p = 0.003; OR = 7.6, respectively]. Expression of both proteins was found to be significantly associated in OPLs (p = 0.000; OR = 12.6) and OSCCs (p = 0.001; OR = 4.0). Intriguingly, khaini consumption correlated with NF-kappaB immunopositivity in OPLs (p = 0.05, OR = 3.8) and OSCCs (p = 0.01, OR = 3.4) and with COX-2 expression in OPLs (p = 0.03; OR = 4.3). In vitro experimental system of ST associated oral carcinogenesis was used to demonstrate ST (khaini) and NNK mediated activation of NF-kappaB and COX-2, supporting the clinical data. In conclusion, this study demonstrates correlation between over expression of NF-kappaB and COX-2 in early precancerous stages of development of oral cancer and sustained elevation down the tumorigenic pathway, underscoring their potential as targets for early intervention. In vitro studies demonstrated that NNK may be one of the carcinogenic components of ST (khaini) inducing activation of NF-kappaB and COX-2 in oral precancer and cancer cells, suggesting plausible role in ST-induced oral carcinogenesis.

Enhanced estrogenic responses and sensitivity to azoxymethane following dietary soy isoflavone supplementation in older female rats.

Soy isoflavones are popular supplements among middle-aged and older women based on their potential protection against cancer and their use as alternative hormone replacement therapy. The purpose of this study was to investigate the effects of dietary soy isoflavones on early stage colon cancer in various ages of female rats. Young (1month), mature (11month) and old (22month) female Fisher 344 rats were fed either the control diet or a diet containing 0.4% soy isoflavone isolate for 1week, injected once with 20mg/kg azoxymethane (AOM) and maintained on the diets for another 15weeks. The concentration of isoflavones in the diet was 2g/kgdiet, composed of 1.2g/kg genistin, 0.7g/kg daidzin and 0.1g/kg other isoflavones including glycitin, acetylgenistin, acetyldaidzin, genistein, daidzein, and glycitein. There was no difference over all ages in the development of preneoplastic colonic aberrant crypt foci between rats fed the soy compared to the control diet, indicating that the soy diet did not provide protection against early stage colonic carcinogenesis. On the contrary, several adverse effects of soy supplementation in female AOM-treated rats were observed. Soy-supplemented rats had greater weight loss and a slower recovery of body weight following the AOM injection compared to rats fed the control diet and these changes increased with age. Five of the 21 rats fed the soy supplement died before the end of the experiment while all animals on the control diet survived to term. The density of normal crypts lining the colonic mucosa was reduced in rats fed the soy compared to control diet, indicating gastrointestinal damage. Uterine weights, serum estradiol and serum isoflavone levels were increased in mature and old female rats fed the soy-supplemented diets compared to age-matched controls, suggesting an increasing estrogenic response with age to isoflavone supplementation. These adverse effects of soy isoflavones in aged female animals need further examination because women, and particularly older women, are the prime target population for consumption of soy supplements.

Cultural and dietary risk factors of oral cancer and precancer--a brief overview.

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

Modulation of experimental colon tumorigenesis by types and amounts of dietary fatty acids.

Epidemiological studies and laboratory animal model assays suggest that a high intake of dietary fat promotes colorectal cancer. Several in vivo and in vitro studies support the hypothesis that omega-6 fatty acids promote colon tumorigenesis, whereas omega-3 fatty acids lack promoting activity. Fat intake in the United States traditionally includes high amounts (30% of total caloric intake) of saturated fat rather than omega-6 fatty acids. Therefore, the present study was designed to compare the modulatory effects of a high-fat diet containing mixed lipids (HFML), a diet rich in saturated fatty acids (the average American diet), a diet with fish oil (HFFO) that is rich in omega-3 fatty acids, and a low-fat corn oil diet (LFCO) on the formation of chemically induced colonic aberrant crypt foci (ACF) and tumors, cyclooxygenase (COX)-2 activity, and apoptosis during experimental colon carcinogenesis. At 5 weeks of age, groups of male F344 rats were fed a 5% corn oil diet (LFCO). At 7 weeks of age, rats intended for carcinogen treatment received s.c. injections of azoxymethane at a dose level of 15 mg/kg of body weight once weekly for 2 weeks. Beginning 1 day after the carcinogen treatment, groups of rats were then maintained on experimental diets containing 20% HFML or 20% HFFO. Rats were killed at 8, 23, or 38 weeks after azoxymethane treatment. Colonic ACF and tumors were evaluated histopathologically, and apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated nick end labeling method. Colonic mucosae and tumor samples harvested at week 38 were analyzed for COX-2 synthetic activity and expression. The rats fed the HFML diet showed significantly increased total colonic ACF (P < 0.001-0.0001) with a multiplicity of > or = 4 aberrant crypts/focus (P < 0.0001) compared with the effects of the HFFO or LFCO diets at week 8, 23, and 38. Interestingly, there was a 2- to 3-fold increase (> or = 4) in multicrypt foci in rats given the HFML diet as compared with such foci in rats fed the HFFO or LFCO diets. By week 23, the HFML diet had significantly increased the incidence of colonic tumors (30-60%) and their multiplicity (100-141%) when compared with the effects of the LFCO or HFFO diets. At week 38, the HFML diet had induced 100% colon tumor incidence and a 4-fold multiplicity of adenocarcinomas compared with the LFCO and HFFO diets. At weeks 23 and 38, a significantly lower percentage of apoptotic colonic epithelial cells were observed in the tumors of animals fed the HFML diet as compared with those fed the HFFO diet. The HFML diet caused significantly increased levels of COX-2 activity in colon tumors (P < 0.05-0.01), and these tumors had enhanced levels of COX-2 expression as compared with those in assays with LFCO or HFFO diets. These observations demonstrate for the first time that HFML diets containing high levels of saturated fatty acids (such as those in Western diets) promote colon carcinogenesis. Although the mechanisms involved in colon tumor promotion by a HFML diet are not fully known, our results indicate that the modulation of eicosanoid production via the influence on COX activity and the suppression of apoptosis may play a key role in HFML diet-induced colon tumorigenesis.