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

Retinoblastoma (RB) and the familial adenomatous polyposis/colorectal cancer (FAP/CRC) complex provide well-characterised examples of multistage carcinogenesis and inheritance of a predisposition to cancer. Retinoblastoma appears to conform to the simple two-step model first proposed by Knudson. The gene responsible for RB, now called Rb1, has been located in chromosome region 13q14. The Rb1 gene has been cloned and subjected to extensive analysis. It is probable that the Rb1 gene product has a role in the regulation of transcription. The familial form of RB occurs as the result of a germline mutation of one of the copies of the Rb1 gene. Colorectal cancer, in contrast, appears to be the result of four or five steps involving both activation of oncogenes and inactivation of antioncogenes. The FAP gene has been located in chromosome region 5q21 by genetic linkage, and a candidate gene, MCC (mutated in colon cancer), has been cloned. Other mutations in previously-identified genes that have been identified as important in the genesis of CRC include the activation of p53 and of Ki-ras. A gene lying in chromosome region 18q which is deleted in colorectal cancer, and hence named DCC has been cloned. Its protein product has sequence homology to neural cell adhesion molecules and other related cell-surface glycoproteins. Delineation of the genes involved in the development of tumours such as RB and CRC provides insight into the mechanisms by which sequential mutations result in carcinogenesis.
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PMID:Multistage carcinogenesis in paediatric and adult cancers. 131 30

Di-n-octyl phthalate (DOP) is the straight chain isomer of di(2-ethylhexyl) phthalate (DEHP) which is a widely used plasticizer and an environmental contaminant. DEHP is a strong inducer of peroxisome proliferation in rat liver. This is significant since other compounds which are strong inducers of peroxisome proliferation have been reported to be weak carcinogens (Reddy, J.K. and Lalwani, N.D., CRC Crit. Rev. Toxicol., 12 (1983) 1). In contrast to DEHP, DOP causes little or no induction of liver peroxisomes (Mann, A.H. et al., Toxicol. Appl. Pharmacol., 77 (1985) 116, and Gray, T.J.B. et al., Toxicology, 28 (1983) 167). In the current study the ability of 1% DOP to promote the development of putative preneoplastic lesions was evaluated. The effect of feeding 0.5% DEHP as well as equimolar amounts of its 2 major metabolites, mono(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol (2-EH) were also investigated. GGT+ foci were initiated in the livers of Sprague--Dawley male rats with a single dose of diethylnitrosamine (DEN) following partial hepatectomy. The control group of rats was fed a semipurified diet (Co) for 10 weeks while the experimental groups received the semipurified diet containing the respective compounds. Induction of peroxisome proliferation was monitored by carnitine acetyltransferase (CAT) levels. DOP treatment resulted in a 6-fold increase in the number of GGT+ foci (20.8 +/- 4.0 vs. 3.5 +/- 1.3; P less than 0.05). This was accompanied by no change in liver weight and only a slight increase in CAT activity when compared with control animals. In contrast to DOP, 2-EH produced essentially no effect with regard to number of foci, peroxisome proliferation or liver weight. DEHP and MEHP induced significant peroxisome proliferation and hepatomegaly but the number of foci were significantly lower than in 2-EH-treated rats. The mechanism for the promoting ability of DOP is not clear but would not appear to be related to peroxisome proliferation. Because of the close similarity of chemical structure and metabolism between DOP and DEHP, it is possible that studies to define the mechanism of DOP induced promotion might also serve to further clarify the mechanism of DEHP induced carcinogenesis.
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PMID:Di-n-octyl phthalate (DOP), a relatively ineffective peroxisome inducing straight chain isomer of the environmental contaminant di(2-ethylhexyl)phthalate (DEHP), enhances the development of putative preneoplastic lesions in rat liver. 287 11

This paper outlines the aims and potential scope of experimental research for risk identification and assessment in industrial carcinogenesis (environmental and occupational). It then reviews the basic, general, and specific requisites of a rigorously scientific nature that are required to render experiments to be more appropriate and better geared to the information they seek. A range of experimental approaches to risk assessment are illustrated by results achieved in the Cancer Research Centre of the Ramazzini Foundation (CRC/RF). The paper ends with a call for closer relations and integration among experimental, epidemiologic, and biostatistical studies.
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PMID:The scientific and methodological bases of experimental studies for detecting and quantifying carcinogenic risks. 1067 6

Considering the various stages of carcinogenesis and the numerous tumor types and available chemoprevention agents, knowledge of the etiology and the type of cancer to be treated, or possibly prevented, and understanding of the mechanisms by which agents exert their chemoprevention benefits may provide for improved strategy in designing therapeutic regimens. Because cancer usually develops over a 10- to 20-year period, it may be necessary for some agents to be provided before or early in the initiation steps of carcinogenesis to have beneficial effects. On the other hand, some agents may be more suitable for CRC prevention if provided at a later stage of carcinogenesis. Gene array, genomics, and proteomics are useful tools in advancing our understanding of the molecular events involved in carcinogenesis and in identifying markers of risk and surrogate end-points for colorectal cancer progression. These techniques may also serve for screening, identifying, and providing treatment targets for high-risk patients populations. Treatment could be developed depending on a patient's individual needs and genomic tumor profile. Clinical markers and surrogate end-points should be considered, together with molecular measurements, to more accurately assess risk. NSAIDs and COXIBs are clinically recognized as chemoprevention agents, and clinical trials evaluating their efficacy are ongoing. Treatment protocols, including dose and timing, remain to be determined, however. DFMO may best be used in combination with other chemoprevention agents. Dietary fiber and calcium supplements, as part of an overall low-fat diet, may decrease CRC risk. Long-term compliance with this regimen may be necessary to effect a beneficial outcome. Folate holds promise but needs further investigation, especially because its beneficial effects may depend on cancer type. Phytochemicals have been identified as strong candidates for use as agents to prevent colorectal cancer in cell culture and in rodent models of carcinogenesis. Their potential as chemoprevention agents must be demonstrated in clinical trials. In vitro and animal studies indicated that combination therapy may be a promising strategy over the monotherapy approach; clinical trials addressing the safety and efficacy of some combinations (DFMO/sulindac, fiber/calcium) are underway. The gastrointestinal tract and other organs are constantly exposed to a mixture of potentially toxic compounds and molecules considered favorable to health. Homeostasis between stress-mediated by toxic compounds and defensive mechanisms, is key for the maintenance of health and the prevention of disease. Whereas aggressive pharmacologic treatment may be necessary for patients at high risk for cancer, dietary supplements may be useful for populations at normal risk. The message for cancer prevention in the general population may well remain: keep a balanced healthy diet, eating a variety from all food groups, as part of a healthy lifestyle that includes moderate exercise.
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PMID:Primary prevention: phytoprevention and chemoprevention of colorectal cancer. 1241 50

CRC, the second-leading cause of cancer death in the United States, is a highly preventable disease. Ironically, available and effective screening technologies are not consistently applied, even as new ones are developed. This discordance between preventive opportunity and practice conveys a sobering message regarding nontechnologic issues that must be addressed if the promise of CRC prevention is to be realized. Our response to this message will determine the public health impact of cancer prevention. In the 1980s, cancer chemoprevention was regarded as scientific speculation. Within the last decade, however, cancer has been recognized as a late, nonobligate stage of carcinogenesis, a chronic process that provides time and targets for preventive intervention. Further advances are emerging out of rigorous clinical testing, which remains the limiting factor in transforming ingenious concepts into useful tools for the prevention of CRC. The challenges and rewards of participation in chemoprevention research--both as patients and health care providers-have never been greater.
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PMID:Epidemiology and prevention of colorectal cancer. 1250

The cyclooxygenase-2 (COX-2) enzyme has a fundamental role in the carcinogenesis of colorectal cancer. The anticarcinogenic mechanisms of NSAIDs are not completely understood and appear to be only partially dependent on inhibition tumoral COX-2. Moreover, the mechanisms of NSAIDs depend on the concentration. In experimental setting, at low levels NSAIDs downregulate the COX-2 gene in colorectal cancer cells, whereas at clinical relevant concentrations the production of prostaglandin E2 by enzymatic activity of COX-2 is diminished resulting in inhibition of the tumor angiogenesis. At higher levels NSAIDs and especially some selective COX-2 inhibitors are capable of COX-2 independent effects, such as apoptosis induction of tumor cells. In animal models, NSAIDs administration results in inhibition of angiogenesis and proliferation, induction apoptosis and prevention of metastasis. In clinical setting, NSAIDs and selective COX-2 inhibitors have the capacity to prevent the development of colorectal adenomas. We have summarized data regarding the role of COX-2 in CRC and discuss the multiple targets of NSAIDs in their anticarcinogenic action. However, the translation of these anticarcinogenic effects of NSAIDs to its clinical application as adjuvant therapy in CRC is hampered by a lack of randomized clinical trials with long-term follow-up.
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PMID:COX-2 inhibition as a tool to treat and prevent colorectal cancer. 1550 Oct 74

The APC gene plays an important role in colorectal carcinogenesis. The impact of APC mutations on the clinical features in sporadic CRC remains to be uncovered. The APC gene was screened for mutations with systematic analysis techniques including DHPLC, PTT, MLPA and DNA sequencing in 43 Chinese sporadic CRC patients. Twenty nine somatic mutations (in 17 different types) in APC gene were found in 18 of 43 sporadic CRC patients. Of those, nine were novel mutations. Higher frequency of somatic APC mutations was found in younger CRC patients than that in elder ones. The biallelic somatic mutations of APC gene were identified in four CRC patients whose tumors had more invasive clinical features. The nonsense mutation Arg1114X in APC gene was found in five of 43 CRC tumor tissues. A higher cancer metastasis rate was uncovered in CRC patients with this mutation. The somatic mutations of APC gene may influence the clinical features of sporadic CRC. Arg1114X in APC gene, as a hot spot mutation in Chinese CRC, may predispose to the cancer metastasis of sporadic CRC.
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PMID:May the APC gene somatic mutations in tumor tissues influence the clinical features of Chinese sporadic colorectal cancers? 1765 97

Aberrant crypt foci (ACF) originally described in rodents treated with colon-specific carcinogens have been identified also in humans at high risk of colon cancer (CRC) and are extensively used as cancer biomarkers. However, studies documenting the heterogeneity of ACF have questioned their precancerous nature. Recently, we described dysplastic foci depleted of mucins (MDF) in the colon of rats treated with colon-specific carcinogens. Like colon tumors, MDFs show activation of Wnt signaling driven by mutations in the beta-catenin gene and Apc, a key gene in colorectal carcinogenesis. Because MDFs have been identified thus far only in rodents, we wanted to search for similar lesions in humans. Familial adenomatous polyposis (FAP) subjects, carrying germ-line mutations in the APC gene, are at high risk of CRC. Therefore, we first searched for MDF-like lesions in unsectioned colon samples from FAP patients and then in patients with sporadic CRC. MDFs were present in the colon of FAP patients (average of 0.0577 lesions/cm(2)) and at a much lower density in CRC patients (average of 0.0006 lesions/cm(2)). ACFs were also observed in all patients. Histologic preparations of all the MDFs identified in FAP and CRC consisted of microadenomas at variable grades of dysplasia. The occurrence of MDF-like lesions in high-risk patients provides evidence that these lesions have a counterpart in human pathology and, as observed in rodents, may represent the very early stages of CRC.
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PMID:Identification of mucin depleted foci in the human colon. 1913 6

CD74 (major histocompatibility complex (MHC) Class II invariant chain) has recently been identified as the cell-surface receptor for the pro-tumorigenic cytokine macrophage migration inhibitory factor (MIF). Therefore, we investigated CD74 gene expression in intestinal adenomas in Apc(Min/+) mice and humans. CD74 mRNA (p31 and p41 splice variants) and immunoreactive CD74 protein levels were significantly lower in small intestinal and colonic Apc(Min/+) mouse adenomas compared with histologically normal mucosa. These findings were mirrored by a reduction in MHC Class II expression and Class II trans-activator type IV transcripts. Conversely, CD74 protein levels were actually increased in dysplastic epithelial cells in 47/55 (85%) human colorectal adenomas, with CD74 and MIF protein levels together predicting increasing dysplasia in individual adenomas (P=0.003). Down-regulation of CD74 during Apc(Min/+) mouse intestinal tumorigenesis does not model increased CD74 expression at the early, benign stages of human colorectal carcinogenesis. Epithelial cell CD74 represents a valid target for anti-CRC therapy.
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PMID:Differential CD74 (major histocompatibility complex Class II invariant chain) expression in mouse and human intestinal adenomas. 1926 7

Pharmacological intervention to reduce CRC mortality entails the use of oral agents that can avert carcinogenesis. Silibinin, a major component of silymarin isolated from Silybum marianum (L.) was found to possess attractive remedial features. An in vivo study was designed to elucidate the effect of silibinin on the formation of 1, 2 dimethylhydrazine (DMH) induced aberrant crypt foci (ACF), tissue lipid peroxidation (LPO) and enzymic antioxidants status during different phases of experimental colon cancer. DMH alone treated rats showed significantly (p < 0.05) increased size and number of ACF, accompanied by decreased LPO and enzymic antioxidant activities. Administration of silibinin to DMH treated rats inhibited mean colonic ACF and multi-crypt AC/foci and also improved the levels of enzymic antioxidants in a time dependent manner. Histologically no obvious sign of neoplasia was observed in silibinin supplemented DMH treated rats during the various stages of carcinogenesis. Our results show that silibinin possesses potent chemopreventive activity against colon carcinogenesis.
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PMID:Silibinin ameliorates oxidative stress induced aberrant crypt foci and lipid peroxidation in 1, 2 dimethylhydrazine induced rat colon cancer. 1927 40


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