Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic dietary treatment of rodents with the fungicide chlorothalonil causes an increased incidence of papillomas and carcinomas of the forestomach squamous epithelium (rats and mice, both sexes) and adenomas and carcinomas of the renal proximal tubule epithelium (rats, both sexes; mice, males only); the product elicits no tumorigenic response in dogs. As a result, chlorothalonil is classified by EPA as a Group B2 "probable human carcinogen." However, chlorothalonil is not genotoxic and there is strong evidence that both the forestomach and renal tumors observed in rodents result from cytotoxicity followed by compensatory cell proliferation and hyperplasia. In the case of the forestomach, cytotoxicity results from sustained irritation of the squamous epithelium by chlorothalonil leading to inflammation, ulceration, and restorative hyperplasia. Cytotoxicity in the renal tubular epithelium is associated with formation of di- and trithiols that arise through the action of renal beta-lyase on cysteine S-conjugates derived from the corresponding glutathione conjugates of chlorothalonil. Renal cytotoxicity and cell necrosis in rodents result from the ability of the di- and trithiols to inhibit kidney mitochondrial respiration and disrupt cellular integrity. There is strong evidence that this mechanism is not operative in other species such as dogs and monkeys. The progression from cytotoxicity to hyperplasia to neoplasia is becoming increasingly well-recognized as a threshold-based mechanism of carcinogenesis. Unless exposure is excessively prolonged or intense, the cytotoxic effects will be fully reversible. Furthermore, the effects observed in rodents are not appropriate for evaluating the potential human cancer risk from chlorothalonil. Humans do not possess an organ equivalent to the rodent forestomach and the rat is a poor model for evaluating potential human risk for the renal tumorigenicity of chlorothalonil. Humans are likely to be very much less sensitive than rats to the nephrotoxic effects of chlorothalonil. In view of the fact that the tumorigenic effects of chlorothalonil are mediated through a well-understood, nongenotoxic, threshold-based mechanism of little or no relevance to humans, chlorothalonil should be a prime candidate for re-review under EPA's new risk assessment guidelines. Expert committees in both Europe and Canada have concluded that human risks to chlorothalonil should be evaluated by means of the NOEL/safety factor approach usually employed for noncarcinogenic materials.
 ...
PMID:A mechanistic interpretation of the oncogenicity of chlorothalonil in rodents and an assessment of human relevance. 892 47

A workshop entitled "Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data" was held in Anaheim, California, in 1996 at the 35th Annual Meeting of the Society of Toxicology (SOT). This workshop was jointly sponsored by the Carcinogenesis, Risk Assessment, and Veterinary Specialty Sections of the SOT. The thrust of the workshop was to discuss the scientific basis for the revisions to the EPA Guidelines for cancer assessment and EPA's plans for their implementation. This is the first revision to the original EPA guidelines which have been in use by EPA since 1986. The principal revisions are intended to provide a framework for an increased ability to incorporate biological data into the risk assessment process. Two cases were presented, for chloroform and triclioroethylene, that demonstrated the use of the revised guidelines for specific cancer risk assessments. Using these new guidelines, nonlinear margin of exposure analyses were proposed for these chemicals instead of the linearized multistage model previously used by the EPA as the default method. The workshop participants generally applauded the planned revisions to the EPA guidelines. For the most part, they considered that the revised guidelines represented a positive step which should allow for and encourage the use of biological information in the conduct of cancer risk assessments. Several participants cautioned however that the major problem with cancer risk assessments would continue to be the inadequacy of available data on which to conduct more scientific risk assessments.
 ...
PMID:Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data. 919 20

This review covers new mechanistic information spanning the past 10 years relevant to normal and abnormal thyroid growth and function that may assist in the risk assessment of chemicals inducing thyroid follicular cell neoplasia. Recent studies have shown that thyroid regulation occurs via a complex interactive network mediated through several different messenger systems. Increased thyroid-stimulating hormone (TSH) levels activate the signal transduction pathways to stimulate growth and differentiation of the follicular cell. The important role of TSH in growth as well as in function helps to explain how disruptions in the thyroid-pituitary axis may influence thyroid neoplasia in rodents. New investigations that couple mechanistic studies with information from animal cancer bioassays (e. g., sulfamethazine studies) confirm the linkage between prolonged disruption of the thyroid-pituitary axis and thyroid neoplasia. New initiation/promotion studies in rodents also support the concept that chronic stimulation of the thyroid induced by goitrogens can result in thyroid tumors. Some of these studies confirm previous suggestions regarding the importance of chemically induced thyroid peroxidase inhibition and the inhibition of 3,3',5, 5'-tetraiodothyronine (T4, thyroxine) deiodinases on disruption of the thyroid-pituitary axis leading to thyroid neoplasia. Some comparative physiologic and mechanistic data highlight certain differences between rodents and humans that could be expected to confer an increased vulnerability of rodents to chronic hypersecretion of TSH. New data from epidemiologic and molecular genetic studies in humans contribute further to an understanding of thyroid neoplasia. Acute exposure to ionizing radiation, especially in childhood, remains the only verified cause of thyroid carcinogenesis in humans. Iodine deficiency studies as a whole remain inconclusive, even though several new studies in humans examine the role of dietary iodine deficiency in thyroid cancer. Specific alterations in gene expression have been identified in human thyroid neoplasia, linked to tumor phenotype, and thus oncogene activation and tumor-suppressor gene inactivation may also be factors in the development and progression of thyroid cancer in humans. An analysis by the U.S. EPA Risk Assessment Forum, prepared as a draft report in 1988 and completed in 1997, focused on the use of a threshold for risk assessment of thyroid follicular tumors. New studies, involving several chemicals, provide further support that there will be no antithyroid activity until critical intracellular concentrations are reached. Thus, for chemically induced thyroid neoplasia linked to disruptions in the thyroid-pituitary axis, a practical threshold for thyroid cancer would be expected. More information on thyroid autoregulation, the role of oncogene mutations and growth factors, and studies directly linking persistently high TSH levels with the sequential cellular development of thyroid follicular cell neoplasia would provide further confirmation.
 ...
PMID:Recent developments in the investigation of thyroid regulation and thyroid carcinogenesis. 968 69

The effect of dietary fish oil on colonic crypt cell apoptosis and proliferation was examined in male Wistar rats, 24 and 48 h after administration of 1,2-dimethylhydrazine (DMH), and its influence on the induction of aberrant crypt foci (ACF) in the distal colon was assessed. Rats (125-150 g) fed a high-fat semi-synthetic diet containing corn oil (CO) were given DMH (30 mg/kg body wt) or a sham injection of EDTA/NaCl. Animals were then fed either the CO diet or a diet in which fish oil (EPA 18.7%; DHA 8%) was substituted for corn oil. Subgroups of rats (n = 5) were killed after 24 and 48 h, and crypt cell apoptosis and proliferation were quantified by morphological criteria in isolated intact crypts from the mid and distal colon. Consumption of the fish oil diet (FO) was associated with increased apoptotic cell death (P < 0.001) and suppression of proliferation (P < 0.05) in colonic crypts both 24 and 48 h after DMH. In a second experiment, animals were given three injections of DMH or sham injections of carrier at weekly intervals. For 48 h after each injection animals were fed either the CO or FO diet, but otherwise maintained on the CO throughout. The number and crypt multiplicity of ACF in the distal colon were determined after 18 weeks, and animals given the FO diet for the 48 h period following carcinogen administration were found to have significantly fewer ACF than rats fed the CO diet (P < 0.05). The data demonstrate that the fatty acid composition of the diet is an important determinant in the induction of carcinogenesis by DMH. The proliferative and apoptotic response of the colonic crypt to carcinogen and fish oil, coupled with the reduced incidence of ACF, suggest n-3 PUFA can protect against the carcinogenic effects of DMH by mediating changes in the balance proliferation and cell death.
Carcinogenesis 1999 Apr
PMID:Dietary n-3 PUFA increases the apoptotic response to 1,2-dimethylhydrazine, reduces mitosis and suppresses the induction of carcinogenesis in the rat colon. 1022 94

In 1969, the International Agency for Research on Cancer (IARC) initiated the Monographs Programme to evaluate the carcinogenic risk of chemicals to humans. Results from short-term mutagenicity tests were first included in the IARC Monographs in the mid-1970s based on the observation that most carcinogens are also mutagens, although not all mutagens are carcinogens. Experimental evidence at that time showed a strong correlation between mutagenicity and carcinogenicity and indicated that short-term mutagenicity tests are useful for predicting carcinogenicity. Although the strength of these correlations has diminished over the past 20 years with the identification of putative nongenotoxic carcinogens, such tests provide vital information for identifying potential human carcinogens and understanding mechanisms of carcinogenesis. The short-term test results for agents compiled in the EPA/IARC Genetic Activity Profile (GAP) database over nearly 15 years are summarized and reviewed here with regard to their IARC carcinogenicity classifications. The evidence of mutagenicity or nonmutagenicity based on a 'defining set' of test results from three genetic endpoints (gene mutation, chromosomal aberrations, and aneuploidy) is examined. Recommendations are made for assessing chemicals based on the strength of evidence from short-term tests, and the implications of this approach in identifying mutational mechanisms of carcinogenesis are discussed. The role of short-term test data in influencing the overall classification of specific compounds in recent Monograph volumes is discussed, particularly with reference to studies in human populations. Ethylene oxide is cited as an example.
 ...
PMID:Genetic toxicology data in the evaluation of potential human environmental carcinogens. 1042 88

Studies have shown effects of dietary lipids on carcinogenesis and tumour progression. Different mechanisms for the inhibitory effect of n-3 fatty acids (FA) have been proposed. The inhibition of the growth of subcutaneously transplanted A427 lung adenocarcinoma cells in athymic nude mice may occur due to an increased level of lipid peroxidation products and is the object of this study. The nude mice were fed diets supplemented with corn oil (CO), olive oil (OO) or K85, a mixture of ethyl esters of n-3 FAs, mainly eicosapentaenoic acid (EPA, 20:5, n-3) and docosahexaenoic acid (DHA, 22:6, n-3). Tumours of the n-3 FA group showed reduced growth. Peroxidation products measured by the thiobarbituric acid reactive substances (TBARS) test showed higher levels in tumours from n-3 FA fed mice than in the other diet groups. The growth inhibitory effects and the elevated level of TBARS in the n-3 FA diet group were counteracted by vitamin E supplement in the diet. Cu/Zn-superoxide dismutase (SOD) activity in liver did not differ greatly among the diet groups. The Ki-67 labelling index (LI), indicating cell proliferation rate was significantly lower in the K85 diet group compared to the other diet groups.
 ...
PMID:Growth of human lung adenocarcinoma in nude mice is influenced by various types of dietary fat and vitamin E. 1047 96

This reevaluation of the current U.S. EPA cancer potency factor for toxaphene is based upon a review of toxaphene carcinogenesis bioassays in mice conducted by Litton Bionetics (unpublished report, 1978) and the National Cancer Institute (NCI) (Technical Report Series No. 37, conducted by Gulf South Research Institute, 1979). The mechanistic data available for toxaphene, including consideration of the potential of the compound to induce genotoxicity, was examined with an emphasis on whether this information supports a change in the cancer potency factor. If a quantitative dose-response assessment for toxaphene is to be performed, the data from both the NCI and Litton cancer bioassays should be used. Additionally, liver tumor results from female mice, rather than male mice, should be used for estimating potential human cancer risk because the background rate of liver tumors in females is lower and less variable than that exhibited by males. An ED(10) was estimated as the point of departure. The mechanistic data were not sufficient to fully support a margin of exposure approach. Therefore, we believe that applying a linear extrapolation from the ED(10) to the origin is an appropriate means to estimate risk at low doses. This is a highly conservative approach and, when it is applied, we conclude that the current EPA cancer potency factor should be reduced from 1.1 (mg/kg/day)(-1) to 0.1 (mg/kg/day)(-1).
 ...
PMID:Reevaluation of the cancer potency factor of toxaphene: recommendations from a peer review panel. 1109 53

According to a multiplicative model for prediction of cancer risk for genotoxic agents the incremental cancer risk is, for low-intermediate exposures, proportional to target doses of the genotoxic substance and to the background risk in control groups. This model has been applied to evaluate cancer tests of acrylamide in rodents. Because of its reactivity toward DNA, glycidamide is assumed to be the causative genotoxic metabolite of acrylamide. Evaluation of experimental data according to the multiplicative model shows that mice, compared with rats, are of the order of 10 times more sensitive per administered dose of acrylamide. The US EPA procedure would, however, generally predict rats to be about twice as sensitive as mice to carcinogenic chemicals, because their estimates are based on scaling of the dose per square meter body surface area, as a surrogate for metabolic differences between the species. The comparison of rats and mice with respect to observed cancer incidence is at a key position in the evaluation of the usefulness of risk models for extrapolation between species. In the present study mice and rats were compared, with respect to in vivo doses of acrylamide and the metabolite glycidamide, after exposure to acrylamide. The relative in vivo doses were inferred from levels of hemoglobin adducts. The adduct levels from glycidamide were, per administered dose of acrylamide, approximately 3-10 times higher in mice than in rats. In combination with the above mentioned higher sensitivity of mice than rats in cancer tests of acrylamide this is compatible with the concept that glycidamide is the key genotoxic factor in acrylamide exposure. Furthermore, it is shown that the multiplicative, i.e. relative, risk model and measurements of the dose of the genotoxic factor give good prediction of the observed risk from acrylamide in cancer tests with rats and mice.
Carcinogenesis 2001 May
PMID:The multiplicative model for cancer risk assessment: applicability to acrylamide. 1132 3

Organotropic chemopreventive effects of n-3 unsaturated fatty acids were studied using a multi-organ carcinogenesis model in male rats. Rats were treated with diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-4-hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and dihydroxy-di-n-propylnitrosamine (DHPN) during the first 7 weeks, and then given unsaturated fatty acid (UFAs), docosahexaenoic acid (n-3, C(22:6)) (DHA), eicosapentaenoic acid (n-3, C(20:5)) (EPA), linoleic acid (n-6, C(18:2)) (LA) or oleic acid (n-9, C(18:1)) (OA) at a dose of 1.0 ml/rat, 3 times a week by gavage for the consecutive 30 weeks. All rats were fed a low LA basal diet throughout the experiment and a calorie-restricted basal diet during the period of UFAs feeding administration. DHA significantly reduced tumor size and numbers in the large intestine as compared to OA treatment. Furthermore, DHA showed a tendency to inhibit carcinogenesis in the small intestine and lung. EPA also showed a tendency to inhibit intestinal carcinogenesis. On the other hand, LA showed a tendency to inhibit lung carcinogenesis, but to promote large intestinal carcinogenesis. However these UFAs did not influence preneoplastic and neoplastic lesion development in the liver, kidney, and urinary bladder. Levels of the administered fatty acids were clearly increased in the serum and organs. In contrast, arachidonic acid (AA) levels in the large and small intestines and liver were markedly decreased by treatment with DHA and EPA. Decreased levels of AA in the large intestine correlated well with tumor incidence, although the number of glutathione S-transferase-positive (GST-P(+)) foci showed an inverse correlation with AA levels. The data thus provide evidence that an organotropism exists with regard to the influence of UFAs on carcinogenesis, which correlates with reduction of tissue AA levels in the target organs.
 ...
PMID:Organotropic chemopreventive effects of n-3 unsaturated fatty acids in a rat multi-organ carcinogenesis model. 1171 41

Linoleic and alpha-linolenic acids, obtained from plant material in the diet are the precursors in tissues of two families with opposing effects which are referred to as "essential fatty acids" (EFA): arachidonic acid (AA) and pentaene (eicosapentaenoic acid: EPA) and hexaene (docosahexaenoic acid: DHA) acids. The role of EFA is crucial, without a source of AA or compounds which can be converted into AA, synthesis of prostaglandins (PGs) by a cyclooxygenase (COX) enzyme would be compromised, and this would seriously affect many normal metabolic processes. COX, also known as prostaglandin endoperoxide synthase (Pghs) or as prostaglandin G/H synthase, is a key membrane bound enzyme responsible for the oxidation of AA to PGs. Two COX isoforms have been identified, COX-1 and COX-2 that form PGH2, a common precursor for the biosynthesis of thromboxane A2 (TxA2), prostacyclin (PGI2) and PGs (PGD2, PGE2, PGF2alpha. COX-1 enzyme is expressed constitutively in most cells and tissues. Its expression remains constant under either physiological or pathological conditions controlling synthesis of those PGs primarily involved in the regulation of homeostatic functions. In contrast, COX-2 is an intermediate response gene that encodes a 71-kDa protein. COX-2 is normally absent from most cells but highly inducible in certain cells in response to inflammatory stimuli resulting in enhanced PG release. PGs formed by COX-2 primarily mediate pain and inflammation but have multiple effects that can favour tumorigenesis. They are more abundant in cancers than in normal tissues from which the cancers arise. COX-2 is a participant in the pathway of colon carcinogenesis, especially when mutation of the APC (Adenomatous Polyposis Coli) tumour suppressor gene is the initiating event. In addition, COX-2 up-regulation and elevated PGE2 levels are involved in breast carcinogenesis. It seems that there is a correlation between COX-2 level of expression and the size of the tumours and their propensity to invade underlying tissue. Inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) of COX enzymes which significantly suppress PGE2 levels, reduced breast cancer incidence and protected against colorectal cancer. Therefore it is suggested that consumption of a diet enriched in n-3 PUFA (specifically EPA and DHA) and inhibition of COX-2 by NSAIDs may confer cardioprotective effects and provide a significant mechanism for the prevention and treatment of human cancers.
 ...
PMID:Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. 1219 20


<< Previous 1 2 3 4 5 Next >>