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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Globally, oral cancer is one of the ten common cancers. In some parts of the world, including the Indian subcontinent, oral cancer is a major cancer problem. Tobacco use is the most important risk factor for oral cancer. The most common form of tobacco use, cigarette smoking, demonstrates a very high relative risk--in a recent cohort study (CPS II), even higher than lung cancer. In areas where tobacco is used in a smokeless form, oral cancer incidence is generally high. In the West, especially in the U.S. and Scandinavia, smokeless tobacco use consists of oral use of snuff. In Central, South, and Southeast Asia smokeless tobacco use encompasses nass, naswar, khaini, mawa, mishri, gudakhu, and betel quid. In India tobacco is smoked in many ways; the most common is bidi, others being chutta, including reverse smoking, hooka, and clay pipe. A voluminous body of research data implicating most of these forms of tobacco use emanates from the Indian subcontinent. These studies encompass case and case-series reports, and case-control, cohort, and intervention studies. Collectively, the evidence fulfills the epidemiological criteria of causality: strength, consistency, temporality, and coherence. The biological plausibility is provided by the identification of several carcinogens in tobacco, the most abundant and strongest being tobacco-specific N-nitrosamines such as N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These are formed by N-nitrosation of nicotine, the major alkaloid responsible for addiction to tobacco. The etiological relationship between tobacco use and oral cancer has provided us with a comprehensive model for understanding carcinogenesis.
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PMID:Epidemiology of cancer by tobacco products and the significance of TSNA. 868 60

Although nicotine has been implicated as a potential factor in the pathogenesis of human lung cancer, its mechanism of action in the development of this cancer remains largely unknown. The present study provides evidence that nicotine (a) activates the mitogen-activated protein (MAP) kinase signalling pathway in lung cancer cells, specifically extracellular signal-regulated kinase (ERK2), resulting in increased expression of the bcl-2 protein and inhibition of apoptosis in these cells; and (b) blocks the inhibition of protein kinase C (PKC) and ERK2 activity in lung cancer cells by anti-cancer agents, such as therapeutic opioid drugs, and thus can adversely affect cancer therapy. Nicotine appears to have no effect on the activities of c-jun NH2-terminal protein kinase (JNK) and p38 MAP kinases, which have also been shown to be involved in apoptosis. While exposure to nicotine can result in the activation of the two major signalling pathways (MAP kinase and PKC) that are known to inhibit apoptosis, nicotine regulation of MAP (ERK2) kinase activity is not dependent on PKC. These effects of nicotine occur at concentrations of 1 microM or less, that are generally found in the blood of smokers, and could lead to disruption of the critical balance between cell death and proliferation, resulting in the unregulated growth of cells. The findings suggest caution in the use of smokeless tobacco products to treat smoking addiction, as they could have a potentially deleterious effect in patients with undetectable early tumour development.
Carcinogenesis 1998 Apr
PMID:Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells. 960 Mar 37

The therapeutic opioid methadone, used to treat cancer pain and opioid addiction, is also a potent inducer of apoptosis in human lung cancer cells, thereby inhibiting their growth. However, in contrast to its central nervous system (CNS) actions, this effect appears to be mediated through a non-opioid mechanism involving bombesin, an autocrine growth-stimulatory factor that plays a central role in the early events of pulmonary carcinogenesis. Exposure of 'variant' small cell lung carcinoma (SCLC) and non-SCLC cells, which secrete low concentrations (< 0.01 pmol/mg protein) of bombesin, to nanomolar concentrations of methadone resulted in increased levels of mitogen-activated protein (MAP) kinase phosphatases and inactivation of MAP kinase, suppression of the bcl-2 protein, and induction of apoptosis. These effects of methadone were reversed by the addition of bombesin to the culture medium, at concentrations of < 1 microM, and 'classic' SCLC cells, which secrete high concentrations of bioactive bombesin (> 6 pmol/mg protein), were found not to respond to methadone. Thus, methadone's effectiveness is dependent upon the concentration of bioactive bombesin secreted by lung cancer cells. Methadone treatment suggests a novel therapeutic approach for patients presenting 'variant' SCLC and non-SCLC morphologies, since they respond less to conventional therapy.
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PMID:Effects of bombesin on methadone-induced apoptosis of human lung cancer cells. 1035 47

The multistage process of carcinogenesis involves the progressive acquisition of mutations, and epigenetic abnormalities in the expression, of multiple genes that have highly diverse functions. An important group of these genes are involved in cell cycle control. Thus, cyclin D1 is frequently overexpressed in a varety of human cancers. Cylin D1 plays a critical role in carcinogenesis because (i) overexpression enhances cell transformation and tumorigenesis, and enhances the amplification of other genes, and (ii) an antisense cyclin D1 cDNA reverts the malignant phenotype of carcinoma cells. Therefore, cyclin D1 may be a useful biomarker in molecular epidemiology studies, and inhibitors of its function may be useful in both cancer chemoprevention and therapy. We discovered a paradoxical increase in the cell cycle inhibitors protein p27(Kip1) in a subset of human cancers, and obtained evidence for homeostatic feedback loops between cyclins D1 or E and p27(Kip1). Furthermore, derivatives of HT29 colon cancer cells with increased levels of p27(Kip1) showed increased sensitivity to induction of differentiation. This may explain why decreased p27(Kip1) in a subset of human cancers is associated with a high grade (poorly differentiated) histology and poor prognosis. Agents that increase cellular levels of p27(Kip1) may, therefore, also be useful in cancer therapy. Using an antisense Rb oligonucleotide we obtained evidence that the paradoxical increase in pRb often seen in human colon cancers protects these cells from growth inhibition and apopotosis. On the basis of these, and other findings, we hypothesize that homeostatic feedback mechanisms play a critical role in multistage carcinogenesis. Furthermore, because of their bizarre circuitry, cancer cells suffer from 'gene addiction' and 'gene hypersensitivity' disorders that might be exploited in both cancer prevention and chemotherapy.
Carcinogenesis 2000 May
PMID:Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. 1078 4

Tobacco smoking is a worldwide epidemic. Tobacco smoke is an established human carcinogen that contains more than 50 carcinogens, among the most potent of which are polycyclic aromatic hydrocarbons (PAHs) and tobacco- specific nitrosamines (TSNs). Over the last 40 years, the level of tar and nicotine in cigarettes has decreased, along with the level of PAHs, but the level of TSNs has increased. Also, decreases in nicotine content can lead to an attendant increase in smoking in order for an individual to maintain his or her blood nicotine levels. Several factors determine the biologically effective dose of carcinogens, including the number of cigarettes smoked per day, type of cigarette, smoking topography, carcinogen metabolism, and DNA repair. Many studies have shown a relationship between tobacco smoke exposure, carcinogen-DNA adduct formation, tumor specific mutations (eg, p53 mutational spectra), and cancer risk. Genetically determined host capacity can influence these outcomes and the risk for tobacco addiction. Current areas of interest include determining whether women are indeed at greater risk of lung cancer compared with men, and if blacks are at higher risk than women. Also, newer methods can probably clarify the role of environmental tobacco smoke in carcinogenesis.
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PMID:Epidemiology of tobacco carcinogenesis. 1112 51

There are many gaps in our knowledge of the molecular basis of alcohol toxicity and addiction. Metabolism affords mainly acetic acid via acetaldehyde. A minor metabolite, diacetyl (an alpha-dicarbonyl), arises from the aldehyde. We propose that this C(4) entity and/or its iminium derivatives from condensation with protein amino groups plays important roles in bioresponses. A review of the literature reveals substantial support for this premise. Reduction potentials for diacetyl and its iminium derivatives fall in the range favorable for catalytic electron transfer in vivo, which can generate oxidative stress via reactive oxygen species due to redox cycling. Oxidative stress and reactive oxygen species are linked to toxicity associated with major organs by alcohol. The alpha-dicarbonyl moiety in related substances is believed to induce various toxic responses, such as Alzheimer's disease, mutagenesis, and carcinogenesis. In addition to discussion of addiction and computational studies, potential applications for health improvement are suggested.
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PMID:Role of diacetyl metabolite in alcohol toxicity and addiction via electron transfer and oxidative stress. 1565 7

Carcinogenesis and cancer therapy are two sides of the same coin, such that the same cytotoxic agent can cause cancer and be used to treat cancer. This review links carcinogenesis, chemoprevention and cancer therapy in one process driven by cytotoxic agents (carcinoagents) that select either for or against cells with oncogenic alterations. By unifying therapy and cancer promotion and by distinguishing nononcogenic and oncogenic mechanisms of resistance, I discuss anticancer- and chemopreventive agent-induced carcinogenesis and tumor progression and, vice versa, carcinogens as anticancer drugs, anticancer drugs as chemopreventive agents and exploiting oncogene-addiction and drug resistance for chemoprevention and cancer therapy.
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PMID:Carcinogenesis, cancer therapy and chemoprevention. 1581

Strong epidemiologic evidence links smoking and cancer. An increased understanding of the molecular biology of tobacco-related cancers could advance progress toward improving smoking cessation and patient management. Knowledge gaps between tobacco addiction, tumorigenesis, and cancer brought an interdisciplinary group of investigators together to discuss "The Biology of Nicotine and Tobacco: Bench to Bedside." Presentations on the signaling pathways and pathogenesis in tobacco-related cancers, mouse models of addiction, imaging and regulation of nicotinic receptors, the genetic basis for tobacco carcinogenesis and development of lung cancer, and molecular mechanisms of carcinogenesis were heard. Importantly, new opportunities to use molecular biology to identify and abrogate tobacco-mediated carcinogenesis and to identify high-risk individuals were recognized.
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PMID:The biology of tobacco and nicotine: bench to bedside. 1582 40

1,4-Butanediol is an industrial chemical used primarily as an intermediate in the manufacture of other organic chemicals. It has recently been associated with deaths, addiction and withdrawal related to its promotion and use as a dietary supplement. The rapid absorption and conversion of 1,4-butanediol to gamma-hydroxybutyric acid (GHB, or date rape drug) in animals and humans is well documented and is the basis for its abuse potential. A disposition and metabolism study conducted in F344 rats by the National Toxicology Program (NTP) confirmed the rapid conversion of 1-(14)C-1,4-butanediol to (14)CO2. Because of this, the toxicological profile of 1,4-butanediol resembles that of gamma-hydroxybutyric acid. Gamma-hydroxybutyric acid occurs naturally in the brain and peripheral tissues and is converted to succinate and metabolized through the TCA cycle. Although the function of gamma-hydroxybutyric acid in peripheral tissues is not known, the presence of specific high affinity receptors for gamma-hydroxybutyric acid suggests that it functions as a neuromodulator in the brain and neuronal tissue. Gamma-hydroxybutyric acid readily crosses the blood-brain barrier and elicits characteristic neuropharmacologic responses after oral, i.p., or i.v. administration. The same responses are observed after administration of 1,4-butanediol. The cyclic lactone of gamma-hydroxybutyric acid, gamma-butyrolactone, is also rapidly converted to gamma-hydroxybutyric acid by enzymes in the blood and liver in animals and humans, and produces pharmacological effects identical to those produced by 1,4-butanediol and gamma-hydroxybutyric acid. Gamma-butyrolactone was previously evaluated by the NTP in 14-day and 13-week prechronic toxicology studies and in 2-year chronic toxicology and carcinogenesis studies in F344 rats and B6C3F1 mice. No organ specific toxicity occurred. In the carcinogenesis studies there was an equivocal response in male mice based on a marginal increase in the incidence of pheochromocytomas of the adrenal medulla. Because the absence of chronic toxicity and significant carcinogenicity of gamma-hydroxybutyric acid were established in NTP prechronic and chronic studies with gamma-butyrolactone, it is concluded that similar results would be obtained in a 2-year study with 1,4-butanediol, and that 1,4-butanediol is not a carcinogen.
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PMID:A review of evidence leading to the prediction that 1,4-butanediol is not a carcinogen. 1619 34

Indole-3-carbinol (I3C), a dietary chemopreventive compound, induced marked reduction in epidermal growth factor receptor (EGFR) prior to cell death in cells representing three breast cancer subtypes. Signalling pathways, linking these events were investigated in detail. I3C modulated tyrosine phosphorylation from 30 min in four cell lines. In MDA-MB-468 and HBL100 cells, it induced Src activation after 5 h. In MDA-MB-468 cells, I3C induced signalling between 4.5 and 7 h, which involved sequential activation of Src, EGFR, STAT-1 and STAT-3, followed by EGFR degradation. It also induced physical association between activated Src and EGFR. In MCF7 and MDA-MB-231 cells, I3C modulated expression of cell cycle-related proteins, p21Cip1, p27Kip1, cyclin E, cyclin D1 and CDK6, with upregulation of p21Cip1 and cyclin E being dependent on Src. Inhibition of EGFR by specific inhibitors PD153035 or ZD1839 increased susceptibility to I3C-induced apoptosis of MCF7, MDA-MB-468 and MDA-MB-231 cells. Inhibition of Src sensitized MDA-MB-468 and MDA-MB-231 cells to I3C, whereas overexpression of c-Src increased resistance to I3C in MDA-MB-468 and HBL100 cells. Modulation of Src in MDA-MB-468 cells influenced the basal level of EGFR expression and cell viability; the latter being positively correlated with EGFR activation levels. Therefore, EGFR and Src activities are essential for I3C-induced cell cycle arrest and death; however, I3C-induced pathways depend on specific features of breast cancer cells. The cancer types, which rely on 'EGFR addiction' or Src deregulation, are likely to be susceptible to I3C.
Carcinogenesis 2007 Feb
PMID:EGFR and Src are involved in indole-3-carbinol-induced death and cell cycle arrest of human breast cancer cells. 1695 7


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