Carcinogenesis Research Research Articles

Viruses and Oral Cancer: Crossreactivity as a Potential Link.

Oral cancer (OC) is a common and aggressive cancer with poor survival rate. Recent research has investigated in detail the complex network of chemical, viral, and (epi)genetic factors associated with oral carcinogenesis. However, the causal factors that trigger the oral carcinogenesis process and the molecular mechanisms that underlie the tumor progression, and metastasis of OC have not been clarified. The present study analyses the hypothesis that immune reactions following viral infections may crossreact with tumor suppressor action proteins involved in OC. Using proteome databases and epitope catalogue resources together with data derived from an ample scientific-clinical literature, potential peptide crossreactions between HCV, HPV16, EBV, and CMV pathogens and human p53 and CSMD tumor suppressor proteins are detailed. The present study might contribute to understand the molecular basis of oral carcinogenesis and open new therapeutic research perspectives.

Establishment of a new OSCC cell line derived from OLK and identification of malignant transformation-related proteins by differential proteomics approach.

Oral squamous cell carcinoma (OSCC) is usually preceded by the oral premalignant lesions, mainly oral leukoplakia (OLK) after repeated insults of carcinogens, tobacco. B(a)P and DMBA are key carcinogens in tobacco smoke. In the present study, for the first time we established the cancerous cell line OSCC-BD induced by B(a)P/DMBA mixture and transformed from dysplastic oral leukoplakia cell line DOK. Cell morphology, proliferation ability, migration ability, colony formation, and tumorigenicity were studied and confirmed the malignant characteristics of OSCC-BD cells. We further identified the differential proteins between DOK and OSCC-BD cells by stable isotope dimethyl labeling based quantitative proteomic method, which showed 18 proteins up-regulated and 16 proteins down-regulated with RSD < 8%. Differential proteins are mainly related to cell cycle, cell proliferation, DNA replication, RNA splicing and apoptosis. Abberant binding function, catalysis activity and transportor activity of differential proteins might contribute to the malignant transformation of OLK. Of the 34 identified differential proteins with RSD < 8%, 13 novel cancer-related proteins were reported in the present study. This study might provide a new insight into the mechanism of OLK malignant transformation and the potent biomarkers for early diagnosis, meanwhile further facilitate the application of the quantification proteomics to carcinogenesis research.

Role of pregnane X receptor and aryl hydrocarbon receptor in transcriptional regulation of pxr, CYP2, and CYP3 genes in developing zebrafish.

Ligand-activated receptors regulate numerous genes, and mediate effects of a broad set of endogenous and exogenous chemicals in vertebrates. Understanding the roles of these transcription factors in zebrafish (Danio rerio) is important to the use of this non-mammalian model in toxicological, pharmacological, and carcinogenesis research. Response to a potential agonist for the pregnane X receptor (Pxr) [pregnenolone (PN)] was examined in developing zebrafish, to assess involvement of Pxr in regulation of selected genes, including genes in cytochrome P450 subfamilies CYP2 and CYP3. We also examined interaction of Pxr and the aryl hydrocarbon receptor (Ahr) signaling pathways. Pregnenolone caused a dose-dependent increase in mRNA levels of pxr, ahr2, CYP1A, CYP2AA1, CYP2AA12, CYP3A65, and CYP3C1, most of which peaked at 3 µM PN. The well-known Ahr agonist 3,3',4,4',5-pentachlorobiphenyl (PCB126) also upregulated expression of pxr, ahr2, CYP1A, CYP2AA12, CYP3A65, and CYP3C1 in a dose-dependent manner. Inhibition of pxr translation by morpholino antisense oligonucleotides (MO) suppressed PN-induced expression of pxr, ahr2, CYP3A65, and CYP3C1 genes. Levels of CYP2AA1 and CYP2AA12 mRNA were increased in the control-MO group exposed to PN; this was prevented by knocking down Pxr. Similarly, Ahr2-MO treatment blocked PCB126-induced mRNA expression of pxr, CYP1A, CYP2AA12, CYP3A65, and CYP3C1. The present study shows self-regulation of pxr by PN in developing zebrafish. Selected zebrafish CYP1, CYP2 (including several CYP2AAs) and CYP3 genes appear to be under the regulation of both Pxr and Ahr2.

Personalized Quantification of Imaging Doses to Children and Adults Scanned by Standard Thoracic Cone Beam CT in Radiation Therapy

Personalized Quantification of Imaging Doses to Children and Adults Scanned by Standard Thoracic Cone Beam CT in Radiation Therapy Y. Zhang, H. Wu, Z. Chen, J.P. Knisely, R. Nath, H. Yue, Z. Feng, S. Bao, and J. Deng; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Radiotherapy, Peking University Cancer Hospital & Institute, Beijing, China, Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, Department of Radiation Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, Beijing Key Lab of Medical Physics and Engineering, Peking University, Beijing, China

Circulating soluble advanced glycation end product is inversely associated with the significant risk of developing cancer: evidence from a meta-analysis.

Currently, advanced glycation end product (RAGE) is receiving much attention in carcinogenesis research due to its involvement in cancer progression and metastasis. We therefore sought to examine the association of circulating soluble RAGE (sRAGE) with all types of cancer by a meta-analysis. The PubMed and EMBASE databases were searched before March 1, 2014. Data and study quality were assessed in duplicate. Effect estimates were expressed as weighted mean difference (WMD) and its 95 % confidence interval (CI). Altogether, nine eligible articles including 1,337 cancer patients and 1,839 controls were analyzed. The overall analysis indicated that circulating sRAGE was remarkably reduced by 222.07 pg/ml in cancer patients compared with controls (95 % CI: -373.77 to -70.37; P = 0.004), with heterogeneity and without publication bias. In subgroup analyses, this reduction was weakened yet still significant in prospective studies (WMD = -87.62; 95 % CI: -138.60 to -36.63; P = 0.001) with improved heterogeneity (I (2) = 56.5 %; P = 0.056). Restricting analyses to the large studies (total number of subjects ≥200) identified significant reduction of circulating sRAGE in cancer patients relative to controls (WMD = -231.34; 95 % CI: -450.10 to -12.58; P = 0.038). Further meta-regression analysis showed that smoking status explained some part of heterogeneity for the association of circulating sRAGE with cancer risk (regression coefficient: -67.02; P = 0.046). Our findings demonstrate a protective role of circulating sRAGE in the development of cancer, especially in patients without diabetes mellitus or with normal renal function.

Fifty years of tobacco carcinogenesis research: from mechanisms to early detection and prevention of lung cancer.

The recognition of the link between cigarette smoking and lung cancer in the 1964 Surgeon General's Report initiated definitive and comprehensive research on the identification of carcinogens in tobacco products and the relevant mechanisms of carcinogenesis. The resultant comprehensive data clearly illustrate established pathways of cancer induction involving carcinogen exposure, metabolic activation, DNA adduct formation, and consequent mutation of critical genes along with the exacerbating influences of inflammation, cocarcinogenesis, and tumor promotion. This mechanistic understanding has provided a framework for the regulation of tobacco products and for the development of relevant tobacco carcinogen and toxicant biomarkers that can be applied in cancer prevention. Simultaneously, the recognition of the link between smoking and lung cancer paved the way for two additional critical approaches to cancer prevention that are discussed here: detection of lung cancer at an early, curable stage, and chemoprevention of lung cancer. Recent successes in more precisely identifying at-risk populations and in decreasing lung cancer mortality with helical computed tomography screening are notable, and progress in chemoprevention continues, although challenges with respect to bringing these approaches to the general population exist. Collectively, research performed since the 1964 Report demonstrates unequivocally that the majority of deaths from lung cancer are preventable.

Differentiation and adaptation epigenetic networks: Translational research in gastric carcinogenesis

There are several kinds of epigenetic networks in the human body including the cell differentiation epigenetic network (DiEN) and the host adaptation epigenetic network (AdEN). DiEN networks are static and cell/tissue-specific. AdEN networks are variable and dependent upon environmental factors. DiEN and AdEN alterations can respectively serve as biomarkers for different kinds of diseases. Cancer is a consequence of accumulated pathophysiological adaptations of tissue stem cells to exposure of environmental carcinogens. Cancer cells are de-differentiated cells that obtain the capacity of unrestricted proliferation, local invasion, and distant migration/metastasis. Both DiEN and AdEN changes can be observed in cancer tissues. Alterations of DNA methylation are the most stable epigenetic modifications and can be sensitively detected in a small cell population. These advantages make DNA methylation the optimal biomarkers for detection of initiated cells in precancerous lesions and metastasis stem cells in cancer tissues. It has been proven that p16 methylation can be used as a diagnostic biomarker to determine malignant potential of epithelium dysplasia in many organs including the stomach. In a large-scale validation study on the DNA methylome of gastric carcinomas (GC), the methylation status of more than 90 CpG islands has been analyzed by DHPLC. Furthermore, GFRA1 demethylation and methylation of SRF and ZNF382 are frequent events during gastric carcinogenesis and consistently correlate to GC metastasis and overall survival of GC patients from China, Japan, and Korea, respectively. In a population study, it has been demonstrated that gradual increasing of plasma miR-211 and other miRNA levels may be an early risk predictor for GC development.

From Pathology to Chemistry and Back: James W. Cook and Early Chemical Carcinogenesis Research

During the 1920s, concerns over occupational cancers in the tar, coal-gas and synthetic dye industries stimulated investigations into the responsible carcinogenic agents. Chemical pathologist Ernest L. Kennaway and organic chemist James W. Cook at London’s Cancer Hospital Research Institute were the first to identify pure carcinogenic coal-tar polyaromatic hydrocarbons. Cook, who joined Kennaway in 1929, synthesised and tested hundreds of compounds, seeking to identify the exact relationship between chemical constitution and cancer. This paper reviews Cook’s research programme until the early 1940s, and the attempt of his collaborator, Cambridge biochemist Joseph Needham, to identify the biological basis of carcinogenesis. In this, they drew upon structural and functional analogies between recently discovered hormones and carcinogens. Cook established novel ways of studying chemical carcinogenesis, although conflicting empirical results and understandings of cancerous growth militated against the development of a coherent mechanistic theory.

Cancer Risk at Ultra-low Dose: Lessons Learned from 40,000-animal Cancer Dose-response Studies

There continues to be a shortage of ultra-low dose/response animal data on which to conduct modeling of human cancer risk. We have conducted two large-scale cancer and biomarker dose-response studies, one with dibenzo[def,p]chrysene (DBC, formerly called dibenzo[a,l]pyrene DBP) and a more recent study with aflatoxin B1 (AFB1), to address this need. These experiments used rainbow trout (Oncorhyncus mykiss), an animal model well suited to ultra low-dose carcinogenesis research, to explore dose-response down to a targeted 10 excess liver tumors per 10,000 animals (ED001). In study one, 40,800 trout were fed 0-225 ppm DBC for four weeks, sampled for biomarker analyses, and returned to control diet for nine months prior to gross and histologic examination. Suspect tumors were confirmed by pathology, and resulting incidences were modeled and compared to the default EPA LED10 linear extrapolation method. The study provided observed incidence data down to 2 above-background liver tumors per 10,000 animals at lowest dose (that is, an un-modeled ED0002 measurement). Among nine statistical models explored, three were determined to fit the liver data well—linear probit, quadratic logit, and Ryzin-Rai. None of these fitted models is compatible with the LED10 default assumption, and all fell increasingly below the default extrapolation with decreasing DBC dose. Low-dose tumor response was also not predictable from hepatic DBC-DNA adduct biomarkers, which accumulated as a power function of dose (adducts=100*DBC1.31). Two-order extrapolations below the modeled liver tumor data predicted DBC doses producing one excess cancer per million individuals (ED10−6) that were 500-1500-fold higher than that predicted by the five-order LED10 extrapolation. Study two was of similar design, but using AFB1. Analysis of the results is underway, and complicated by several differences from study 1, especially presence in some quartiles and treatment groups of a fatty liver syndrome. Preliminary logistic regression analysis excluding fish with this syndrome did not support the EPA linear default assumption (i.e., logistic slope 1.0), rather indicated a sublinear dose-response with slope of 1.42 (95% CI 1.23-1.61), and an extrapolated ED10−6 that is 32-fold greater than the LED10 default extrapolation. Inclusion of all fish also yielded a sublinear dose-response, with slope 1.31 (95%CI 1.13-1.50), and an extrapolated ED10−6 17-fold greater than the LED10 default extrapolation. Thus two genotoxins with differing biological properties yielded ultra-low dose-response curves in the same animal model that are statistically incompatible with the linear default assumption. These results are considered specific to the animal model, carcinogens, and protocols used. They provide the first experimental estimations in any model of the degree of conservatism that may exist for the EPA default linear assumption for a genotoxic carcinogen.

VI. DNA microarray technology. Principles and application to the analysis of malignant tumours (with special emphasis on lymphoma)

The human genome sequence is now available, virtually complete. Why should oncologists bother about this data bank? Until now most research in molecular carcinogenesis has been directed at discovering and characterizing single ‘cancer’ genes. Virtually all established diagnostic techniques in molecular cancer pathology suffer from the limitation that they only tell us what we are specifically looking for. It may well be that a chosen molecular marker may be less relevant than another one which was not ordered by the clinician, or was not considered by the pathologist. Colon cancer is a nice example to illustrate this issue. For example, patients with stage III colon cancer seem to derive more benefit from adjuvant therapy if their tumours retain a wild-type K-ras sequence [1, 2]. Interestingly, colon cancer with a wild-type K-ras status will also derive particular benefit from epidermal growth factor receptor (EGFR)-targeted treatment. Colon cancers with microsatellite instability may be less aggressive than tumours with stable microsatellites. Retention of 18q alleles in microsatellite-stable tumours, and mutations of the gene for type II TGF-b1 receptor in node-positive microsatellite-instable colon cancers both point to a more favourable prognosis after adjuvant chemotherapy. A glance at this literature shows that in most papers the molecular marker of interest was carefully studied, and one or the other additional gene included in the analysis, but no such study provided an overall appraisal of all molecular markers of potential clinical value in this cancer. The established molecular diagnostic techniques are mostly too laborious to permit the comprehensive screening of a tumour biopsy sample for all possible types of genetic marker. A new approach would be to screen cancer specimens for all possible ‘gene’ problems, i.e. to obtain individual comprehensive cancer gene expression profiles, at the RNA expression level (also known as ‘signatures’). This is now possible with microarray gene profiling [3, 4]. In contrast to the study of single genes and their proteins, molecular tumour profiling is a large-scale analysis of gene expression in a tumour using DNA microarrays (Figure 1). DNA microarrays typically consist of rows and rows of oligonucleotide sequence strands, or cDNA sequences lined up in dots on a silicon chip or glass slide [3–6]. Oligonucleotide sequences or cDNAs on the chip permit specific hybridization to labelled mRNAs of interest extracted from a biopsy. Arrays can accommodate up to 30 000 specific sequences on a single chip, either chosen randomly or deliberately ‘biased’ to represent theme parks of genes typically expressed in a cell type of interest, e.g. ‘lymphoid genes’ in B cells (‘Lymphochip’) [6]. The Lymphochip is a cDNA microarray containing selected genes preferentially expressed in lymphoid cells [7, 8]. Analysis of gene expression in various lymphoid malignancies yields an orderly picture of gene expression patterns in particular types of lymphoma, reflecting lineage characteristics, stage of maturation of lymphoid cells and proliferation signatures. Diffuse large B-cell lymphoma (DLBCL, a clinically heterogeneous group of lymphomas despite their morphological similarity) can be split into subtypes with gene expression profiles typical either of germinal centre B cells, or of activated B cells. DLBCL expression signatures differ markedly between patients who were cured, and those who eventually relapsed [8]. The promise is that such expression profiles or ‘signatures’ offer more precise prognostic information than established prognostic factors, such as the International Prognostic Index in NHL (Figure 2), and eventually translate into concepts of refined differentially targeted therapy. Likewise, one invasive ductal breast cancer specimen may look deceptively similar to another one on histology, but the fate of the two women may be totally different. This is due to inherent biological differences of the two tumours hidden in their genome, which may be elusive to morphological examination. Variation in gene transcription programmes governed by specific somatic gene alterations accounts for much of the biological diversity in human tumours. The study of gene expression patterns in human breast cancer specimens displays distinct molecular portraits, or gene expression profiles providing molecular ‘fingerprints’ [9]. Tumours may be clustered by sharing gene expression patterns, and it is likely that such subgroups comprise clinically distinct subtypes or entities of breast cancer. It also turns out that the overall gene expression pattern of a breast cancer case is by and large retained in its metastases. Figure 2 shows an analysis where T1– 2 N0 tumours that had or had not relapsed within 5 years after diagnosis and primary treatment, show clearly distinct gene expression profiles, respectively. Breast cancers of the basal-like cell type, which often express neither hormone receptors nor

Abstract 2121: High-resolution melting for detection of KRAS and EGFR mutations in tumors of the alimentary system

Abstract The EGFR/Ras/Raf/MAPK pathway is one of the most important signal transduction pathways in cells. Dysregulation of this pathway is a common event in many cancers, including cancers of the alimentary system. EGFR and KRAS are two common genes in which mutations caused abnormal activation of the pathway. EGFR mutations are closely associated with a favorable response to treatment with tyrosine kinase inhibitors. KRAS mutations are associated with unresponsiveness to EGFR inhibitors. EGFR and KRAS mutation detection is important for carcinogenesis research and clinical therapy. Tumor tissue samples included 13 esophagus cancer, 52 gastric cancer and 67 colon cancer from a Chinese population. These were obtained from Dalian Medical University collection. High resolution melting (on a LightScanner™) was used to scan the mutations of KRAS exon 2, EGFR exon 19 and exon 21. All mutations detected by HRM were sequenced to identify the genotype. We found KRAS mutations in 5 (9.6%) patients with gastric cancer (2 with G12D; 1 with G12V; 2 with G13D) and 19 (28.4%) patients with colon cancers (11 with G12D, 3 with G12V, 4 with G13D; 1 with G13V). No KRAS mutations were found in esophagus cancer patients. The frequency of KRAS mutations in colon cancer was significantly higher than those in esophagus and gastric cancer (P&amp;lt;0.01). In 19 colon cancer patients with KRAS mutations, there were 6 (20.7%, 6/29) cases in the right colon (ascending colon and proximal 2/3 transverse colon) and 13 (34.2%, 13/38) cases in the left colon (distal 1/3 transverse colon, sigmoid colon and rectum). There is no significant difference in KRAS mutation frequencies between the right and the left colon. KRAS mutations were not associated with genders, ages, the invasive depth, lymph node metastasis and histopathological types in gastric and colon cancers. There were no EGFR exon 19 mutations found in any cases. EGFR exon 21 mutations were found in 2 gastric cancer patients (1 with L858R; 1 with G863D). In cancers of the alimentary system, KRAS mutations were more common than EGFR mutations, and KRAS mutations could be associated with the original tissues in the embryonic development. Namely, KRAS mutations were more common in cancers of organs from the midgut and hintgut than of those from the foregut, while EGFR mutations were all found in organs from the foregut. High resolution melting was a valuable method both in research and clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2121.

Comparative proteomic analysis of human gallbladder carcinoma

To find out potential molecular targets for gallbladder carcinoma diagnosis and treatment by analyzing and comparing the proteins expressed in human gallbladder carcinoma tissue and benign gallbladder tissue. Proteomic analysis of 6 human gallbladder carcinoma tissues and 6 benign gallbladder tissues was carried out. Total proteins of the carcinoma tissue and benign gallbladder tissue were separated by two-dimensional gel electrophoresis (2-DE). The differentially expressed proteins were analyzed and identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Immunohistochemistry was used to examine the expression of PEBP1 protein in an independent series of samples. Protein extracts of individual samples in each type of tissues were separated on two-dimensional gels. There were forty six differentially expressed proteins in the gallbladder carcinom tissues. Seventeen proteins were successfully identified by MS, in which nine proteins were overexpressed in tumors while the other eight proteins were underexpressed. The increased level of PEBP1 protein in gallbladder carcinoma was further confirmed by immunohistochemical analysis. Seventeen differentially expressed proteins were successfully characterized by comparative proteomic analysis. Those results may provide scientific foundation for screening the molecular biomarkers which can be used in diagnosis and treatment of gallbladder carcinoma, as well as to improve its prognosis and provide a new clue for carcinogenesis research of gallbladder carcinoma.

Defective TPA signalling compromises HaCat cells as a human in vitro skin carcinogenesis model

HaCat cells, a human keratinocyte line, are commonly utilised as an in vitro cell model for toxicity testing and the discernment of processes of chemically induced skin carcinogenesis. Here, as part of an ongoing program of carcinogenesis research, we tested the genomic transcriptional response of two keratinocyte cell lines HaCat (human) and Pam212 (mouse) to 12-O-tetradecanoylphorbol 13-acetate (TPA), one of the most studied skin carcinoma promoting agents, and compared this with the response in primary keratinocytes. Differences in the genomic response profile indicated an insufficiency in the MEK/ERK pathway signalling in HaCat but not Pam212 cells compared to primary keratinocytes. TPA can also activate NFκB and so we tested whether this was also deficient in the HaCat cells using TNFα which signals directly to NFκB. By this method NFκB was found to be equally active in both HaCat and Pam212 cells. Analysis of ERK phosphorylation showed that while TPA mediated ERK phosphorylation occurred in both cell lines it was more robust and difficult to inhibit in Pam212 cells suggesting that there may be an insufficiency in this step in HaCat cells leading to a reduced response. Overall these data indicate that caution should be employed when using HaCat cells as an in vitro skin model for biochemical research or toxicological evaluation.

Conference Report: Seventh Annual AACR International Conference on Frontiers in Cancer Prevention Research

In November, 2008 the AACR held the Seventh Annual Frontiers in Cancer Prevention Research meeting in Washington, DC. At this meeting, a wide range of cutting-edge cancer prevention research was presented. This summary highlights some of the most impactful presentations with a focus on the interaction between inflammation, infections, the immune system, and tumor microenvironment in promoting cancer. Several of these presentations described targeting host-tumor interactions as a means for cancer prevention. As discussed below, this meeting continues to represent all phases of cancer prevention research including epidemiologic studies, behavioral and lifestyle interventions, carcinogenesis research, preclinical studies testing novel preventive interventions, and the results of early- and late-phase cancer prevention trials. Major advances presented at the 2008 meeting included studies showing that immune cells can be either protumorigenic or antitumorigenic, efforts to develop more comprehensive human papillomavirus vaccines to more effectively prevent cervical cancer and other human papillomavirus-related cancers, controversial studies of vitamin D and cancer risk, and studies of single-nucleotide polymorphisms to better assess cancer risk. These and the other presentations at this meeting continue to provide strong support for the concept that cancer will be most effectively controlled by applying modern cancer prevention strategies.

Nonlinear Cancer Response at Ultralow Dose: A 40800-Animal ED001 Tumor and Biomarker Study

Assessment of human cancer risk from animal carcinogen studies is severely limited by inadequate experimental data at environmentally relevant exposures and by procedures requiring modeled extrapolations many orders of magnitude below observable data. We used rainbow trout, an animal model well-suited to ultralow-dose carcinogenesis research, to explore dose-response down to a targeted 10 excess liver tumors per 10000 animals (ED(001)). A total of 40800 trout were fed 0-225 ppm dibenzo[a,l]pyrene (DBP) for 4 weeks, sampled for biomarker analyses, and returned to control diet for 9 months prior to gross and histologic examination. Suspect tumors were confirmed by pathology, and resulting incidences were modeled and compared to the default EPA LED(10) linear extrapolation method. The study provided observed incidence data down to two above-background liver tumors per 10000 animals at the lowest dose (that is, an unmodeled ED(0002) measurement). Among nine statistical models explored, three were determined to fit the liver data well-linear probit, quadratic logit, and Ryzin-Rai. None of these fitted models is compatible with the LED(10) default assumption, and all fell increasingly below the default extrapolation with decreasing DBP dose. Low-dose tumor response was also not predictable from hepatic DBP-DNA adduct biomarkers, which accumulated as a power function of dose (adducts = 100 x DBP(1.31)). Two-order extrapolations below the modeled tumor data predicted DBP doses producing one excess cancer per million individuals (ED(10)(-6)) that were 500-1500-fold higher than that predicted by the five-order LED(10) extrapolation. These results are considered specific to the animal model, carcinogen, and protocol used. They provide the first experimental estimation in any model of the degree of conservatism that may exist for the EPA default linear assumption for a genotoxic carcinogen.

Advances in chemical carcinogenesis: a historical review and prospective.

The American Association for Cancer Research has been the citadel for communicating research on chemical carcinogens for over a century. It therefore seems appropriate that a review of chemical carcinogenesis inaugurates a series of articles highlighting advances in understanding, treating, and

Online toxicology resources in support of risk assessment from the U.S. National Library of Medicine

The U.S. National Library of Medicine (NLM), a component of the National Institutes of Health (NIH), is the world’s largest biomedical library. NLM’s Specialized Information Services division houses the Toxicology and Environmental Health Information Program (TEHIP), established in 1967, pre-dating the U.S. Environmental Protection Agency. TEHIP builds databases related to toxicology and makes them, and others created external to NLM, available on the Web. It creates other Web-based resources and tools, collaborates with government agencies, universities, and NGOs, and has active public training and outreach programs. TEHIP and its databases are accessible on the Web at http://sis.nlm.nih.gov/enviro.html. Although, historically, TEHIP’s services were geared strictly to the scientific community, they have expanded to include a spectrum of users from the technically oriented professional to the general public. These users include toxicologists and other researchers and scientists, health care professionals, lawyers and regulators, journalists, environmental advocates, librarians and other information science professionals, emergency responders, students, and educators. Increasingly, projects are being geared to the international community. TEHIP’s primary suite of databases is known at TOXNET. These include ChemIDplus, an extensive chemical dictionary/directory; HSDB (Hazardous Substances Data Bank), a peer-reviewed databank of over 4000 chemicals with some 150 fields of data in areas such as chemical/physical properties, human and animal toxicity, environmental fate, emergency medical treatment etc.; CCRIS (Chemical Carcinogenesis Research Information System); GENE-TOX (on genetic toxicology); LactMed (on drugs and lactation); TOXLINE (a bibliographic file of over three and one-half million citations to the technical literature); Household Products database; databases on toxic releases to the environment (TRI) and occupational safety and health and (HazMap). More recently, a Dietary Supplements Labels database and a Drug Information Portal have been released. Other TEHIP resources include WISER (Wireless Information System for Emergency Response), REMM (Radiation Event Medical Management), TOXSEEK (a meta search engine and clustering tool), ToxTown and ToxMystery (designed for kids), and online toxicology tutorial, a glossary of terms used in toxicology, and more. Although a number of the above resources, particularly HSDB and TOXLINE are especially relevant to risk assessment, the following additional TOXNET databases focus on the topic: IRIS (Integrated Risk Information System) is the U.S. EPA’s (Environmental Protection Agency) database on official government risk values and includes oral and inhalation risk values (as well as summaries and references used to derive them) for carcinogens and non-carcinogens.; ITER (International Toxicity Estimates for Risk) is a product of the Cincinnati-based TERA (Toxicology Excellence for Risk Assessment), and presents, in tabular form, peer-reviewed, risk values from EPA’s IRIS, as well as other groups, including Health Canada, ATSDR (Agency for Toxic Substances and Disease Registry), IARC (International Agency for Research on Cancer), the Dutch RIVM (its National Institute of Public Health and the Environment), NSF International, values derived via TERA’s own ITER Peer Review Process, and Independently Reviewed Peer Review Values derived by independent parties and outside the TERA peer review process. ITER thus provides a one-stop agency by agency comparison of risk values. NLM is also a partner in the newly formed ARA (Alliance for Risk Assessment), and an NLM representative serves on its Steering Committee. ARA is a collaborative effort of organizations dedicated to supporting public health protection by improving the process and efficiency of risk assessment, and increasing the capacity for developing risk information to meet growing demand. In the near future, in collaboration with ARA, NLM will be adding the RiskIE (Risk Information Exchange) database to its risk assessment arsenal, to supplement IRIS and ITER. The RiskIE system will coordinate work on chemical risk value and methodology documents that are under development or revision. It will provide a platform for notification of human health risk assessment projects. Identification of groups working on a chemical or issue of interest will allow stakeholders (e.g., other States, provinces, tribes, industry, public interest groups, or Federal agency stakeholders) an opportunity to provide input on ongoing assessments or develop collaborations with document authors More online resources with potential application to toxicology and risk assessment are under development at NLM. Work is progressing on a database to be known as TOXREF, which will contain data on therapeutic/normal, toxic, and lethal levels of chemicals in biological samples. Finally, the World Library of Toxicology, Chemical Safety, and Environmental Health (WLT), is being created by a network of Country Correspondents and is designed to link to multi-lingual global resources at both the individual country and multi-lateral levels.

Molecular analysis of rat mammary carcinogenesis: an approach from carcinogenesis research to cancer prevention

A rat strain carrying the human c-Ha-ras proto-oncogene is highly susceptible to chemically induced mammary carcinogenesis. All the transgenic rats develop preneoplastic mammary lesions within 20 days of an injection of N-methyl-N-nitrosourea, and mammary carcinomas appear within 8 weeks of treatment with a variety of chemical carcinogens. In this review, we summarize molecular aspects of mammary carcinogenesis in transgenic rats and the potential application of this model for studies of breast cancer prevention.

Cancer treatment with retinoids and their receptors : a paradigm for the convergence of nutrition, molecular biology and carcinogenesis research to fight cancer

Cancer treatment with retinoids and their receptors : a paradigm for the convergence of nutrition, molecular biology and carcinogenesis research to fight cancer

Toxicological Information Resources at the National Library of Medicine

TOXicology Data NETwork (TOXNET) 〈www.toxnet. nlm.nih.gov〉, is a web-based information system that provides access to information regarding the medical, occupational, pharmacokinetic, toxicological, and environmental effects of biological and chemical substances. TOXNET is maintained by the National Library of Medicine’s Division of Specialized Information Services, a part of the National Institutes of Health within the U.S. Department of Health and Human Services. TOXNET includes bibliographic, factual, and dictionary data banks. One factual data bank is the Hazardous Substances Data Bank (HSDB) 〈www.toxnet.nlm.nih.gov/cgibin/sis/htmlgen?HSDB〉, which contains more than 5,000 comprehensive records for unique chemical compounds. The data covered in this resource include the following: chemical identification, chemical and physical properties, safety and handling, human and nonhuman toxicity data, pharmacology, metabolism, environmental fate, monitoring and analysis, and regulatory information. HSDB files are peer-reviewed by a group of nationally and internationally recognized scientists and physicians. Another factual data bank is Haz-Map 〈www.hazmap.nlm.nih.gov/〉, which provides information about occupational exposures to chemical substances. Haz-Map also contains acute human toxicity information. Another data bank, Household Products Database 〈www.hpd.nlm.nih.gov/〉, contains data derived from material safety data sheets and product labels for items commonly purchased in grocery stores and hardware shops. The Toxics Release Information (TRI) 〈www.toxnet. nlm.nih.gov/cgi-bin/sis/htmlgen?TRI〉 provides data reported to EPA on the amount of specified (regulated) chemicals that industrial and governmental organizations release into the environment (air, water, soil), as well as data on the amounts removed from a particular facility. ToxMap (Environmental Health e-Maps) 〈www.toxmap.nlm. nih.gov/toxmap/main/index.jsp〉 is a data bank that provides geographic representation of TRI data, showing chemical plants and facilities releasing selected hazardous substances to the environment Information can be retrieved by locality (name of state, county, zip code), as well as by chemical name or other identifier or facility name. Another TOXNET data bank, the Chemical Carcinogenesis Research Information System (CCRIS) 〈www.toxnet. nlm.nih.gov/cgi-bin/sis/htmlgen?CCRIS〉, provides data on carcinogenesis, mutagenesis, and tumor promotion studies. The content of the file is reviewed by experts at the National Cancer Institute. Meanwhile, the GENETOX data bank 〈www.toxnet.nlm.nih.gov/cgi-bin/sis/ htmlgen?GENETOX〉, reviewed by EPA scientific experts, contains citations and test results from mutagenicity studies. The Integrated Risk Information System (IRIS) 〈www. toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?IRIS〉 is a TOXNET data bank built by the EPA. IRIS contains data on animal and human risk calculations for selected chemicals. By contrast, the ITER data bank 〈www.toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?iter〉 built by Toxicology Excellence for Risk Assessment (TERA), contains over 600 chemical records, including risk assessment information based on noncancer oral, cancer oral, non-cancer inhalation, and cancer inhalation endpoints. Central to TOXNET is ChemIDplus 〈www.chem.sis.nlm. nih.gov/chemidplus/〉, a dictionary-type data bank for nearly 400,000 compounds. ChemIDplus provides synonyms, pointers to other NLM files containing information on the chemical selected, and pointers to non-NLM sources, including links to the Agency for Toxic Substances Disease Registry, the American Council of Governmental and Industrial Hygienists (ACGIH), the International Agency for Research on Cancer (IARC), the EPA, the Food and Drug Administration (FDA), the National Institute of Occupational Safety and Health (NIOSH), the Occupational Safety and Health Administration (OSHA), and the World Health Organization (WHO). TOXLINE 〈www.toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen? TOXLINE〉 on TOXNET is a bibliographic toxicology information set, with citations and abstracts from various resources, including standard journal literature, technical reports, and other special collections. TOXLINE records can be searched using chemical name, CAS registry number, synonyms, and index terms or keywords. Developmental and Reproductive Toxicology (DART) 〈www.toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?DARTETIC〉 is another bibliographic