• Decreasing urinary PAH metabolites and 7-methylguanine after smoking cessation.

      Ichiba, M.; Matsumoto, A.; Kondoh, T.; Horita, M.; Tomokuni, K. (2006-08)
      OBJECTIVE: Humans are exposed to various carcinogens by smoking. Urinary metabolites of polycyclic aromatic hydrocarbons (PAH), one of the major carcinogens in cigarette smoke, were measured as the environmental carcinogen exposure marker for humans. We evaluated urinary exposure markers for smoking cessation. METHOD: In this study, we measured cigarette smoke exposure markers, such as urinary cotinine, PAH exposure markers, such as urinary 1-hydroxypyrene (1-OHP), 2-naphthol (2-NP) and 1-naphthol (1-NP), as well as a methylating chemical exposure marker, 7-methylguanine (7-MeG). The before smoking cessation levels of these markers, and the after smoking cessation levels were then compared. Eighteen subjects participated in this smoking cessation program. RESULTS: Levels of all of four markers were found to have decreased by 19-54% after smoking cessation. Urinary cotinine, 1-OHP, 2-NP and 7-MeG levels were found to have significantly decreased after smoking cessation. There were positive correlations between cotinine and three urinary PAH markers and between 1-OHP, 2-NP and 7-MeG. CONCLUSION: PAH metabolites were better biomarkers of smoking cessation than 7-MeG. Analyzing urinary metabolites or urinary DNA adducts is suitable for epidemiological studies.
    • Demethylation of the pesticide methoxychlor in liver and intestine from untreated, methoxychlor-treated, and 3-methylcholanthrene-treated channel catfish (Ictalurus punctatus): evidence for roles of CYP1 and CYP3A family isozymes.

      Stuchal, Leah D.; Kleinow, Kevin M.; Stegeman, John J.; James, Margaret O. (2006-06)
      Exposure to the organochlorine pesticide methoxychlor (MXC) is associated with endocrine disruption in several species through biotransformation to mono-desmethyl-MXC (OH-MXC) and bis-desmethyl-MXC (HPTE), which interact with estrogen receptors. The biotransformation of [14C]methoxychlor was examined in channel catfish (Ictalurus punctatus), a freshwater species found in the southern United States. Hepatic microsomes formed OH-MXC and HPTE, assessed by comigration with authentic standards. The Km for OH-MXC formation by control liver microsomes was 3.8 +/- 1.3 microM (mean +/- S.D., n = 4), and Vmax was 131 +/- 53 pmol/min/mg protein. These values were similar to those of catfish pretreated with 2 mg/kg methoxychlor i.p. for 6 days (Km 3.3 +/- 0.8 microM and Vmax 99 +/- 17 pmol/min/mg) but less (p < 0.05) than the kinetic parameters for catfish treated with 3-methylcholanthrene (3-MC), which had Km of 6.0 +/- 1.1 microM and Vmax of 246 +/- 6 pmol/min/mg protein. Liver microsomes from 3-MC-treated fish produced significantly more of the secondary metabolite and more potent estrogen, HPTE. Intestinal microsomes formed OH-MXC at lower rates than liver. Methoxychlor pretreatment significantly reduced intestinal metabolite formation from 32 +/- 4 to 15 +/- 6 pmol/min/mg (mean +/- S.D., n = 4), whereas 3-MC treatment significantly increased OH-MXC production to 72 +/- 22 pmol/min/mg. Ketoconazole, clotrimazole, and alpha-naphthoflavone all decreased the production of OH-MXC in liver microsomes, whereas alpha-naphthoflavone stimulated HPTE formation, suggesting that CYP1 and CYP3 family isozymes demethylated methoxychlor. The results suggest that the formation of estrogenic metabolites from methoxychlor would be more rapid in catfish coexposed to CYP1 inducers.
    • Detection of induced male germline mutation: correlations and comparisons between traditional germline mutation assays, transgenic rodent assays and expanded simple tandem repeat instability assays.

      Singer, Timothy M.; Lambert, Iain B.; Williams, Andrew; Douglas, George R.; Yauk, Carole L. (2006-06-25)
      Several rodent assays are capable of monitoring germline mutation. These include traditional assays, such as the dominant lethal (DL) assay, the morphological specific locus (SL) test and the heritable translocation (HT) assay, and two assays that have been developed more recently--the expanded simple tandem repeat (ESTR) and transgenic rodent (TGR) mutation assays. In this paper, we have compiled the limited amount of experimental data that are currently available to make conclusions regarding the comparative ability of the more recently developed assays to detect germline mutations induced by chemical and radiological agents. The data suggest that ESTR and TGR assays are generally comparable with SL in detecting germline mutagenicity induced by alkylating agents and radiation, though TGR offered less sensitivity than ESTR in some cases. The DL and HT assays detect clastogenic events and are most susceptible to mutations arising in post-spermatogonial cells, and they may not provide the best comparisons with TGR and ESTR instability. The measurement of induced ESTR instability represents a relatively sensitive method of identifying agents causing germline mutation in rodents, and may also be useful for bio-monitoring exposed individuals in the human population. Any future use of the TGR and ESTR germline mutation assays in a regulatory testing context will entail more robust and extensive characterization of assay performance. This will require substantially more data, including experiments measuring multiple endpoints, a greatly expanded database of chemical agents and a focus on characterizing stage-specific activity of mutagens in these assays, preferably by sampling epididymal sperm exposed at defined pre-meiotic, meiotic and post-meiotic stages of development.
    • Diabetes mellitus and risk of colorectal cancer in the Singapore Chinese Health Study.

      Seow, Adeline; Yuan, Jian-Min; Koh, Woon-Puay; Lee, Hin-Peng; Yu, Mimi C. (2006-01-18)
      The incidence of colorectal cancer is highest in populations that consume an energy-dense diet, have low intakes of vegetables and fruit, or lead a sedentary lifestyle. These factors may influence colorectal carcinogenesis via insulin pathways. We examined whether diabetes mellitus was associated with colorectal cancer in Singapore Chinese, whose body type and lifestyle profiles are distinct from those of Western populations. Between April 1993 and December 1998, 63,257 Singapore Chinese men and women aged 45 to 74 years were enrolled in a prospective study of diet and cancer. Each subject provided dietary, medical, and lifestyle information through an in-person interview. As of December 31, 2002, 636 incident colorectal cancer cases had been diagnosed. A history of physician-diagnosed diabetes was statistically significantly associated with colorectal cancer risk in both men (relative risk [RR] = 1.5, 95% confidence interval [CI] = 1.2 to 2.1) and women (RR = 1.4, 95% CI = 1.0 to 1.9). In stratified analyses, this association remained statistically significant among the subset of diabetics with high total calorie intake and low physical activity levels. Our results support the hypothesis that hyperinsulinemia may play a role in colorectal carcinogenesis, even in a relatively lean population.
    • Dietary effects of soy isoflavones daidzein and genistein on 7,12-dimethylbenz[a]anthracene-induced mammary mutagenesis and carcinogenesis in ovariectomized Big Blue transgenic rats.

      Manjanatha, Mugimane; Shelton, Sharon; Bishop, Michelle; Lyn-Cook, Lascelles; Aidoo, Anane (2006-10)
      The major constituents of isoflavones daidzein (DZ) and genistein (GE) interact with the and estrogen receptors in several tissues including mammary tissues. In this study, we used ovariectomy (OVX) to model menopause and determined the effects of DZ, GE or 17beta-estradiol (E(2)) exposures on chemically induced mutagenesis and carcinogenesis in the mammary glands of female Big Blue transgenic rats. The rats were fed control diet containing the isoflavones and E(2) and treated with a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at PND50. Animals were euthanized at 16 or 20 weeks post-carcinogen treatment to assess mutant frequencies (MFs) and histopathological parameters, respectively. The isoflavones or E(2) supplementation alone resulted in the lac I MFs that were not significantly different from the MFs measured in rats fed the control diet alone. DMBA exposure, however, induced significant increases in the lac I MFs in the mammary tissues of both OVX and INT rats and Hprt MFs in spleen lymphocytes (P < 0.01). In general, feeding the isoflavones or E(2) did not cause any significant changes in DMBA-induced mutagenicity in the mammary tissues. However, feeding the isoflavone mixture (daidzein + genistein; DZG) resulted in a significant reduction in the DMBA-induced lac I MFs (P < 0.05). Cell proliferation as measured by PCNA immunohistochemistry was increased in both OVX and INT rats exposed to DMBA as compared with rats fed control diet (P < 0.05). Mammary histology indicated that hyperplasia was induced in most of the treatment groups including control. Although DMBA did not induce mammary tumors in the OVX rats, adenoma and adenocarcinoma were detected in the mammary glands of INT rats.
    • Dietary habits and stomach cancer in Mizoram, India.

      Phukan, Rup Kumar; Narain, Konwar; Zomawia, Eric; Hazarika, Nakul Chandra; Mahanta, Jagadish (2006-05)
      BACKGROUND: An extremely high prevalence of stomach cancer was observed in Mizoram (India), where the population consumes uncommon food. The relation of food habits and stomach cancer was examined in this study. METHODS: A hospital-based case-control study was conducted during 2001-2004 to determine the risk factors among 329 patients with histologically confirmed stomach cancer and 658 matched controls. Food habits were determined by personal interview. RESULTS: An elevated risk of stomach cancer was observed with frequent consumption of sa-um [odds ratio (OR) 3.4] (sa-um is fermented pork fat, a traditional food) and with frequent consumption of smoked dried salted meat (OR 2.8) and fish (OR 2.5). Soda (alkali), used as a food additive, increased the risk of stomach cancer (OR 2.9). Helicobacter pylori infection was not found to be an independent risk factor for carcinogenesis of stomach cancer in this study. However, when H. pylori infection interacted with consumption of sa-um or smoked dried meat, it showed a significant association. CONCLUSION: Peculiar food habits in Mizoram might be associated with the high prevalence of stomach cancer in Mizoram along with other factors. H. pylori infection might increase the risk of stomach cancer, or it may play a role as a promoter of stomach cancer in Mizoram.
    • Dietary patterns and risk of squamous-cell carcinoma and adenocarcinoma of the esophagus and adenocarcinoma of the gastric cardia: a population-based case-control study in Sweden.

      Bahmanyar, Shahram; Ye, Weimin (2006)
      We conducted a large population-based case-control study in Sweden to examine the association of dietary patterns and the development of cancers from the esophagus or gastroesophageal junction. In total 185 patients with esophageal adenocarcinoma, 165 with esophageal squamous-cell carcinoma, 258 with gastric cardia adenocarcinoma, and 815 randomly selected population controls underwent face-to-face interviews. Exploratory factor analysis was used to identify possible dietary patterns. Multivariate logistic regression with adjustments for age, sex, years of education, body mass index, physical activity, symptomatic gastroesophageal reflux, smoking, and total energy intake was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). We identified three major dietary patterns in this population, for example, "healthy diet" (high in vegetables, tomato, fruits, fish, and poultry), "Western diet" (high in processed meat, red meat, sweets, high-fat dairy, and high-fat gravy), and "alcohol drinker" (high in intakes of beer, liquor, and French fries). We found that a healthy diet tended to moderately decrease the risk of all three cancers under study, although none of the associations was statistically significant. A high score of Western diet was associated with increased risks of gastric cardia adenocarcinoma (high 3rd tertile vs. low 1st quartile, OR = 1.8, 95% CI = 1.1-2.9, P for trend = 0.04) and esophageal adenocarcinoma (high 3rd tertile vs. low 1st tertile, OR = 1.6, 95% CI = 0.9-3.1, P for trend = 0.13), whereas a dietary pattern characterized by high beer and liquor intake (alcohol drinker) significantly increased the risk of squamous-cell carcinoma of the esophagus (3rd tertile vs. low 1st tertile, OR = 3.5, 95% CI = 1.9-6.3, P for trend < 0.0001). Our study confirms the important role of diet in the carcinogenesis of esophageal and cardia cancer.
    • Dietary resistant starch type 3 prevents tumor induction by 1,2-dimethylhydrazine and alters proliferation, apoptosis and dedifferentiation in rat colon.

      Bauer-Marinovic, Morana; Florian, Simone; Müller-Schmehl, Katrin; Glatt, Hansruedi; Jacobasch, Gisela (2006-09)
      Some epidemiological and experimental studies suggest that consumption of resistant starch is preventive against colon cancer. Resistant starch leads to a fermentation-mediated increase in the formation of short-chain fatty acids, with a particularly high butyrate fraction in large bowel. Butyrate is considered to be protective against colon cancer because it causes growth arrest and apoptosis and regulates expression of proteins involved in cellular dedifferentiation in various tumor cell lines in culture. We sought to investigate these processes under conditions of a carcinogenicity experiment in vivo. In the present study, 1,2-dimethylhydrazine-treated Sprague-Dawley rats were fed standard diet (n=12) or diet with 10% hydrothermally modified Novelose 330, a resistant starch type 3 (RS3), replacing digestible starch (n=8). After 20 weeks tumor number, epithelial proliferation, apoptosis, immunoreactivity of carcinogenesis-related proteins [protein kinase C-delta (PKC-delta), heat shock protein 25 (HSP25) and gastrointestinal glutathione peroxidase (GI-GPx)], as well as mucin properties were evaluated in proximal and distal colon in situ. No tumors developed under RS3 diet, compared to a tumor incidence of 0.6+/-0.6 (P<0.05) under the standard diet. RS3 decreased the number of proliferating cells, the length of the proliferation zone and the total length of the crypt in the distal colon, but not proximal colon, and enhanced apoptosis in both colonic segments. It induced PKC-delta and HSP25 expression, but inhibited GI-GPx expression in the epithelium of distal colon. RS3 increased the number of predominantly acidic mucin containing goblet cells in the distal colon, but had no effect on the goblet cell count. We conclude that hydrothermally treated RS3 prevented colon carcinogenesis, and that this effect was mediated by enhanced apoptosis of damaged cells accompanied by changes in parameters of dedifferentiation in colonic mucosa.
    • Differential effects of the oxidized metabolites of oltipraz on the activation of CCAAT/enhancer binding protein-beta and NF-E2-related factor-2 for GSTA2 gene induction.

      Ko, Myong Suk; Lee, Seung Jin; Kim, Jin Wan; Lim, Jee Woong; Kim, Sang Geon (2006-08)
      Comprehensive mechanistic studies suggest that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferase (GST). Previously, we have shown that the activation of CCAAT/enhancer binding protein-beta (C/EBPbeta), promoted by oltipraz, contributes to the transcriptional induction of the GSTA2 gene. Studies also indicated that exposure of animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) with an increase in Nrf2's antioxidant response element (ARE) binding activity. Given the previous reports that C/EBPbeta activation contributes to oltipraz's induction of the GSTA2 gene and that Nrf2 activation by oltipraz was variable depending on the concentrations, this study investigated whether the major oxidized metabolites of oltipraz induce GSTA2 through the activation of C/EBPbeta and/or Nrf2. Immunoblot analysis revealed that M1 [4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one] and M2 (7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine), but not M3 (7-methyl-8-(methylsulfinyl)-6-(methylthio)H-pyrrolo[1,2-a]pyrazine) and M4 (7-methyl-6,8-bis(methylsulfinyl)H-pyrrolo[1,2-a]pyrazine), induced GSTA2 in H4IIE cells. M1 and M2 also increased the luciferase activity from pGL-1651, which contained the luciferase structural gene downstream of the -1.65-kilobase GSTA2 promoter region. Nuclear C/EBPbeta levels were enhanced by the metabolites but not by M3 or M4. Among the oxidized metabolites examined, only M2, which elicited cell death at a relatively high concentration, activated Nrf2, as indicated by nuclear accumulation of Nrf2 and its ARE binding activity. The present study provides evidence that M1 and M2, but not M3 and M4, induce GSTA2 and that M1 induces GSTA2 only via C/EBPbeta activation, whereas M2 does so by activating Nrf2 as well as C/EBPbeta. These results substantiate the differential effects of oltipraz's metabolites on C/EBPbeta- and/or Nrf2-mediated GSTA2 induction.
    • Differential expression of molecular markers in arsenic- and non-arsenic-related urothelial cancer.

      Hour, Tzyh-Chyuan; Pu, Yeong-Shiau; Lin, Chia-Chi; Huang, Shi-Wei; Chen, Jun; Chiu, Allen W.; Chen, Chien-Jen; Huang, Chao-Yuan (2009-05-15)
      BACKGROUND: Little is known about the mechanisms of arsenic-related urothelial cancer (AsUC). The aim of this study was to reveal the differential expression of molecular markers between AsUC and non-arsenic-related UC (non-AsUC). MATERIALS AND METHODS: Tissues of AsUC (n=33), non-AsUC (n=20) and normal bladder urothelia from patients with benign diseases (n=4) were examined for multiple selected molecular markers responsible for various cellular functions, includingglutathione, GST-pi, Bcl-2, p53 and c-Fos. RESULTS: The mean cellular glutathione content of normal mucosal samples (33.4 +/- 7.2 microM/mg protein) was significantly higher than either non-AsUC (22.8 +/- 1.8, p = 0.04) or AsUC (16.4 +/- 1.6, p = 0.002). The glutathione content of non-AsUC was higher than that of AsUC (p = 0.012). The expressions of Bcl-2 and c-Fos in AsUC were significantly higher than those in non-AsUC (p = 0.004 and p = 0.02, respectively). CONCLUSION: The carcinogenic pathway for AsUC is different, in part, from that of non-AsUC. Cellular glutathione contents may be down-regulated during urothelial carcinogenesis. Bcl-2 and c-Fos may play important roles in arsenic-mediated carcinogenesis of the urothelium.
    • Differential modulation of cyclooxygenase-mediated prostaglandin production by the putative cancer chemopreventive flavonoids tricin, apigenin and quercetin.

      Al-Fayez, Mohammad; Cai, Hong; Tunstall, Richard; Steward, William P.; Gescher, Andreas J. (2006-12)
      OBJECTIVES: Diet-derived flavonoids possess cancer chemopreventive properties in preclinical models. The knowledge of the pharmacology of most flavonoids is insufficient to warrant their advancement to clinical evaluation. METHODS: Here the three flavonoids tricin from rice bran, apigenin from leafy vegetables, and quercetin from onions and apples, were compared in terms of their ability to modulate cyclooxygenase- (COX-) catalyzed prostaglandin E-2 (PGE-2) generation. Specifically their effects on the following parameters were studied: (1) COX enzyme activity, (2) COX-2 expression in human-derived colon cancer cells HCA-7, which express COX-2 constitutively, (3) phorbol ester-mediated COX-2 induction in human colon epithelial cells (HCEC), and (4) PGE-2 levels in cellular incubations. RESULTS: Tricin and quercetin inhibited enzyme activity in purified COX-1 and -2 preparations with IC50 values of near 1 (tricin) and 5 microM (quercetin). Apigenin at up to 25 microM did not affect COX enzyme activity. Flavonoids were incubated with cells for 6 or 24 h and COX-2 protein expression and PGE-2 levels were assessed by Western blot and competitive immunoassay, respectively. None of the agents affected constitutive COX-2 expression in HCA-7 cells. Apigenin, but not tricin or quercetin, down-regulated inducible COX-2 expression in HCEC cells on 6 h incubation. All three flavonoids reduced cellular levels of PGE-2 in the supernatant of HCA-7 cells at both time points and of HCEC cells at 6 h. CONCLUSIONS: The results demonstrate that these structurally similar flavonoids regulate COX-mediated PGE-2 production in different fashions. Their ability to attenuate prostanoid levels may contribute to their cancer chemopreventive efficacy.
    • Distinction between hereditary and sporadic breast cancer on the basis of clinicopathological data.

      van der Groep, P.; Bouter, A.; van der Zanden, R.; Siccama, I.; Menko, F. H.; Gille, J. J. P.; van Kalken, C.; van der Wall, E.; Verheijen, R. H. M.; van Diest, P. J. (2006-06)
      BACKGROUND: About 5% of all breast cancer cases are attributable to germline mutations in BRCA1 or BRCA2 genes. BRCA mutations in suspected carriers, however, may be missed, which hampers genetic counselling. MATERIALS AND METHODS: Different clinicopathological features were compared between 22 breast cancers from carriers of proved BRCA1 mutations and 604 cancers from sporadic controls. In addition, 5 BRCA2-related breast cancers and 66 breast cancers of untested patients at intermediate risk and 19 breast cancers of untested patients at high risk of hereditary disease on the basis of family history were evaluated. RESULTS: A "probably sporadic" class (age >or=54 years and epidermal growth factor receptor (EGFR) negative; 68% of cases) with a 0% chance of BRCA1-related breast cancer containing 79% of the sporadic cases was yielded by using a decision tree with age, Ki67 and EGFR. A 75% chance of BRCA1-related breast cancer was shown by the "probably BRCA1-related" class (age <54 years and Ki67 >or=25%; 8% of cases) with 82% of the BRCA1-related cases but only 1.4% of the sporadic cases. Most cases at intermediate or high risk of hereditary disease on the basis of family history could be classified with high probability as either probably BRCA1 related or probably sporadic. CONCLUSION: Breast carcinomas can be classified with a high level of certainty as sporadic or related to BRCA1 germline mutations by using a decision tree with age, Ki67 and EGFR. This can be clinically useful in mutation analysis in families with a borderline risk of hereditary disease.
    • DNA damage induced by mutagens in plant and human cell nuclei in acellular comet assay.

      Juchimiuk, Jolanta; Gnys, Agnieszka; Maluszynska, Jolanta (2006)
      Higher plant cells have a long tradition of use in the studies on environmental mutagenesis in situ, especially in relation to human health risk determination. The studies on the response of plant and human cells to physical and chemical mutagens showed differences in their sensitivity. The differences in the presence of cell components in plants and humans could influence such response. Additionally, the level of the organization of the employed material could influence DNA-damaging effect: leukocytes are isolated cells and plant--an intact organism. To preclude these obstacles, the effects of direct treatment of isolated nuclei with genotoxic agents were determined to compare the sensitivity of plant and human cells. In the present study, we have determined the DNA-damaging effects of two chemical mutagens: maleic acid hydrazide (MH) and N-methyl-N-nitroso-urea (MNU) applied to isolated nuclei of both plant and human cells. In order to compare the sensitivity of the nuclei of Nicotiana tabacum var. xanthi and the nuclei of leukocytes, the acellular Comet assay was carried out. The results showed higher sensitivity of the nuclei of leukocytes as compared to the nuclei of plant cells to mutagenic treatment with the applied doses of MH and MNU.
    • Does butyrate protect from colorectal cancer?

      Sengupta, Shomik; Muir, Jane G.; Gibson, Peter R. (2006-01)
      Butyrate, the four-carbon fatty acid, is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber), and putatively suppresses colorectal cancer (CRC). Butyrate has diverse and apparently paradoxical effects on cellular proliferation, apoptosis and differentiation that may be either pro-neoplastic or anti-neoplastic, depending upon factors such as the level of exposure, availability of other metabolic substrate and the intracellular milieu. In humans, the relationship between luminal butyrate exposure and CRC has been examined only indirectly in case-control studies, by measuring fecal butyrate concentrations, although this may not accurately reflect effective butyrate exposure during carcinogenesis. Perhaps not surprisingly, results of these investigations have been mutually contradictory. The direct effect of butyrate on tumorigenesis has been assessed in a number of in vivo animal models, which have also yielded conflicting results. In part, this may be explained by methodological differences in the amount and route of butyrate administration, which are likely to significantly influence delivery of butyrate to the distal colon. Nonetheless, there appears to be some evidence that delivery of an adequate amount of butyrate to the appropriate site protects against early tumorigenic events. Future study of the relationship between butyrate and CRC in humans needs to focus on risk stratification and the development of feasible strategies for butyrate delivery.
    • Does growth hormone cause cancer?

      Jenkins, P. J.; Mukherjee, A.; Shalet, S. M. (2006-02)
      The ability of GH, via its mediator peptide IGF-1, to influence regulation of cellular growth has been the focus of much interest in recent years. In this review, we will explore the association between GH and cancer. Available experimental data support the suggestion that GH/IGF-1 status may influence neoplastic tissue growth. Extensive epidemiological data exist that also support a link between GH/IGF-1 status and cancer risk. Epidemiological studies of patients with acromegaly indicate an increased risk of colorectal cancer, although risk of other cancers is unproven, and a long-term follow-up study of children deficient in GH treated with pituitary-derived GH has indicated an increased risk of colorectal cancer. Conversely, extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. However, given the experimental evidence that indicates GH/IGF-1 provides an anti-apoptotic environment that may favour survival of genetically damaged cells, longer-term surveillance is necessary; over many years, even a subtle alteration in the environmental milieu in this direction, although not inducing cancer, could result in acceleration of carcinogenesis. Finally, even if GH/IGF-1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population. Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency.
    • Dosimetric challenges for residential radon epidemiology.

      Steck, Daniel J.; Field, R. William (2006-04)
      Radon concentration alone may not be an adequate surrogate to measure for lung cancer risk in all residential radon epidemiologic lung cancer studies. The dose delivered to the lungs per unit radon exposure can vary significantly with exposure conditions. These dose-effectiveness variations can be comparable to spatial and temporal factor variations in many situations. New technologies that use surface-deposited and implanted radon progeny activities make more accurate dose estimates available for future epidemiologic studies.
    • Early loss of Fhit in the respiratory tract of rodents exposed to environmental cigarette smoke.

      D'Agostini, Francesco; Izzotti, Alberto; Balansky, Roumen; Zanesi, Nicola; Croce, Carlo M.; De Flora, Silvio (2006-04-01)
      The Fhit gene, encompassing the most active common human chromosomal fragile region, FRA3B, has been shown to act as a tumor suppressor. Several studies have shown significant Fhit alterations or Fhit protein loss in lung cancers from smokers compared with lung cancers from nonsmokers. To evaluate the role of Fhit under controlled experimental conditions, we exposed rodents to environmental cigarette smoke (ECS) and evaluated Fhit expression or Fhit protein in the respiratory tract. After 14 days of exposure to ECS, loss of Fhit protein in the bronchial/bronchiolar epithelium affected half of the tested B6-129(F(1)) mice, either wild type or Fhit(+/-). After 28 days, it affected the vast majority of the tested SKH-1 hairless mice and of A/J mice and all (UL53-3 x A/J)F(1) mice, either wild type or P53(+/-). In Sprague-Dawley rats, exposure to ECS for up to 30 days caused a time-dependent loss of Fhit in pulmonary alveolar macrophages. Moreover, ECS down-regulated Fhit expression and significantly decreased Fhit protein in the rat bronchial epithelium. The oral administration of N-acetylcysteine attenuated the ECS-related loss of Fhit, whereas oltipraz, 5,6-benzoflavone, phenethyl isothiocyanate, and indole 3-carbinol, and their combinations had no significant effect. Parallel studies evaluated a variety of molecular, biochemical, and cytogenetic alterations in the respiratory tract of the same animals. In conclusion, there is unequivocal evidence that Fhit is an early, critical target in smoke-related lung carcinogenesis in rodents, and that certain chemopreventive agents can attenuate the occurrence of this gene alteration.
    • Effect of dietary apigenin on colonic ornithine decarboxylase activity, aberrant crypt foci formation, and tumorigenesis in different experimental models.

      Au, Angela; Li, Boyong; Wang, Weiqun; Roy, Hemant; Koehler, Ken; Birt, Diane (2006)
      The efficacy of dietary apigenin, a dietary flavonoid, in colon cancer prevention was investigated by evaluating the inhibition of the ornithine decarboxylase (ODC) activity and the formation of aberrant crypt foci (ACF) and by studying the ability of apigenin to block colon carcinogenesis in two mouse models. First, the activity of ODC was measured in colon cancer cells (Caco-2) and in the colon epithelium of CF-1 mice. Apigenin at 10 and 30 muM significantly inhibited the ODC activity of Caco-2 cells by 26% and 57%, respectively. Colonic ODC activity in CF-1 mice was reduced with 0.1% dietary apigenin by 42% compared with the control, but this difference was not statistically significant. Second, ACF formation was evaluated in azoxymethane (AOM)-induced CF-1 mice. Female CF-1 mice at 6 wk of age were i.p. injected with 5 mg/kg body weight (BW) AOM once to induce ACF. ACF formation in CF-1 mice was reduced by 50% (P < 0.05) with 0.1% dietary apigenin fed for 6 wk when compared with the control. Dietary apigenin inhibited ACF only in the distal region of the CF-1 mouse colon. Finally, tumorigenesis studies were conducted using two different mouse models: AOM-induced CF-1 mice and Min mice with mutant adenomatous polyposis coli (APC) gene. Female CF-1 mice at 6 wk of age were i.p. injected with 10 mg/kg BW AOM weekly for 6 (AOM Study I) or 4 (AOM Study II) wk to induce tumors. CF-1 mice were fed diets containing 0.025% or 0.1% apigenin for 23-25 wk. Female Min mice were fed diets for 10 wk beginning at 5 wk of age. In two AOM-treated mouse colon tumor studies 0.025% and 0.1% dietary apigenin modestly reduced tumors in the group fed 0.025% apigenin (25% incidence in comparison with 65% in the controls) in a non-dose response manner. Apigenin failed to inhibit adenoma formation in the Min mouse study. These results suggest that dietary apigenin showed promise in cancer prevention by reducing the ODC activity and ACF formation, however, clear evidence of cancer prevention was not obtained in mouse tumor studies. Further investigation of the potential chemopreventive effect of apigenin in carcinogenesis is warranted.
    • The effect of lifestyle factors on gynaecological cancer.

      Rieck, Gudrun; Fiander, Alison (2006-04)
      Several lifestyle factors affect a woman's risk of gynaecological cancer and-potentially-can be modified to reduce risk. This chapter summarises the evidence for the effect of lifestyle factors on the incidence of gynaecological malignancy. The incidence of obesity is increasing in the developed world such that it now contributes as much as smoking to overall cancer deaths. Women with a body mass index (BMI)>40 have a 60% higher risk of dying from all cancers than women of normal weight. They are also at increased risk from gynaecological cancer. Dietary factors significantly influence the risk of gynaecological cancer: fruit, vegetables and antioxidants reduce risk whereas high animal fat and energy intakes increase risk. Alcohol intake adversely affects breast cancer risk, possibly accounting for 4% of all breast cancers. Physical activity protects against ovarian, endometrial and postmenopausal breast cancer, independently of BMI. The oral contraceptive pill has a substantial and long-lasting effect on the prevention of ovarian and endometrial cancer and is one of the best examples of large-scale chemoprevention in the developed world. Childbearing is protective against ovarian, endometrial and breast cancer but increases the risk of cervical cancer. Smoking acts as a cofactor in cervical carcinogenesis and increases the risk of ovarian cancer, particularly mucinous tumours.
    • Effect of short-term fasting on urinary excretion of primary lipid peroxidation products and on markers of oxidative DNA damage in healthy women.

      Lee, Kyoung-Ho; Bartsch, Helmut; Nair, Jagadeesan; Yoo, Dong-Ho; Hong, Yun-Chul; Cho, Soo-Hun; Kang, Daehee (2006-07)
      The goal of this study was to determine whether short-term fasting changes in urinary biomarkers related to oxidative stress: malondialdehyde (MDA), 8-isoprostaglandin F2alpha (8-isoPGF), 8-hydroxydeoxy-guanosine (8-OHdG) and 1,N6-ethenodeoxyadenosine (epsilondA) among female volunteers participating in the short-term fasting program in South Korea. The study subjects were 52 healthy women (mean age 28, range 15-48 years old) who provided urine samples both before and after the fasting program (average 7.2, range: 3-11 days). Urinary MDA was measured by HPLC-UV and epsilondA levels were measured by immuno-affinity purification followed by HPLC-fluorescence detection. Urinary 8-OHdG and 8-isoPGF concentrations were determined by ELISA. Plasma leptin levels were also measured by radioimmunoassay. Information on demographic characteristics, personal habits (smoking and alcohol consumption) and previous medical history were collected by a self-administered questionnaire. Percent loss of body weight (average 6.3%, 4.28 +/- 0.25 kg) was significantly correlated with fasting duration (r = 0.70, n = 52, P < 0.01). The plasma leptin levels after fasting (5.89 +/- 1.10 ng/ml) were significantly lower than before fasting (6.91 +/- 1.13 ng/ml) (n = 27, P = 0.05). Urinary MDA levels after fasting (0.18 +/- 1.10 mg/g creatinine) were significantly lower than before fasting (0.37 +/- 1.11) (n = 51, P < 0.01). Urinary 8-isoPGF also were significantly reduced after fasting (n = 47, P < 0.01). However, there was no significant difference in 8-OHdG or epsilondA. There was a statistically significant correlation between % change of urinary MDA level with % change of 8-isoPGF level (partial correlation coefficient r = 0.57, n = 46, P = 0.01). The correlations between % change of 8-OHdG and plasma leptin was also significant (partial correlation coefficient r = 0.51, n = 27, P = 0.02). Our results demonstrate that the short-term fasting reduces lipid peroxidation products but does not affect oxidative stress-induced DNA damage.