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)

Future progress in mechanism-based cancer prevention research may be facilitated by animal models displaying specific genetic susceptibilities for cancer, such as mice deficient in 1 (+/-) or both (-/-) alleles of the p53 tumor suppressor gene. We observed in p53-/- mice that calorie restriction (CR) increased the latency of spontaneous tumor development (mostly lymphomas) by approximately 75%, decreased serum insulin-like growth factor-1 (IGF-1) and leptin levels, slowed thymocyte cell cycle traverse, and induced apoptosis in immature thymocytes. In p53+/- mice, CR and a 1 d/wk fast each delayed spontaneous tumor development (a mix of lymphomas, sarcomas, and epithelial tumors) and decreased serum IGF-1 and leptin levels, even when begun late in life. In p53+/-Wnt-1 transgenic mice, a mammary tumor model, the same interventions increased mammary tumor latency and reduced mean serum IGF-1 and leptin levels to <50% of those of control mice. We capitalized on the susceptibility of p53+/- mice to chronic, low-dose aromatic amine-induced bladder carcinogenesis to develop a useful model for evaluating bladder cancer prevention approaches. These examples clearly indicate that mice with specific (and humanlike) genetic susceptibilities for cancer are powerful models for testing interventions that may inhibit carcinogenesis in humans.
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PMID:Cancer prevention studies in p53-deficient mice. 1121 77

Chemoprevention of cancer represents a challenge for oncology during this new millennium. Substantial advances have been accomplished in the last decade, especially for primary and secondary prevention of breast cancer. In addition to tamoxifen, raloxifene and other selective estrogen receptor modulators, retinoids are among the most promising agents, given their ability to inhibit mammary carcinogenesis in preclinical models. Fenretinide, the synthetic amide of retinoic acid, inhibits cell growth mostly through the induction of apoptosis with mechanisms which may partly involve the retinoid receptors. Because it has a favourable toxicological profile, fenretinide has been extensively investigated in clinical trials. A large randomised phase III trial for secondary breast cancer prevention has been recently carried out in Italy. Results showed a reduction of second breast malignancies in premenopausal women. In addition, a significant decrease of circulating insulin-like growth factor (IGF)-1, a known risk factor for premenopausal breast cancer, was observed after 1 year of fenretinide administration in premenopausal women with breast cancer. Ongoing studies on the validation of the circulating IGF-1 as a surrogate endpoint biomarker of fenretinide activity and on the effectiveness of the combination with low dose tamoxifen may provide further insight into the future clinical application of fenretinide.
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PMID:Chemoprevention of breast cancer with fenretinide. 1143 48

Progress in mechanism-based cancer prevention research may be facilitated by the use of animal models displaying specific genetic susceptibilities for cancer such as mice deficient in the p53 tumor suppressor gene, the most frequently altered gene in human cancer. We observed in p53-knockout (p53-/-) mice that calorie restriction (CR; 60% of the control group's intake of carbohydrate energy) increased the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreased serum insulin-like growth factor (IGF)-1 and leptin levels, significantly slowed thymocyte cell cycle traverse and induced apoptosis in immature thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and 1 d/wk of food deprivation each significantly delayed spontaneous tumor development (a mix of lymphomas, sarcomas and epithelial tumors) and decreased serum IGF-1 and leptin levels even when begun late in life. We have also developed a rapid and relevant p53+/- mouse mammary tumor model by crossing p53-deficient mice with MMTV-Wnt-1 transgenic mice, and found that CR and 1 d/wk food deprivation significantly increased mammary tumor latency (greater than twofold) and reduced the mean serum IGF-1 and leptin levels to <50% of that of control mice (P < 0.0001). In addition, fluasterone, fenretinide and soy each delayed tumor development but had little effect on IGF-1 or leptin levels. We have capitalized on the susceptibility of p53+/- mice to chronic, low dose, aromatic amine-induced bladder carcinogenesis to develop a useful model for evaluating bladder cancer prevention approaches such as cyclooxygenase-2 inhibition. As demonstrated by these examples, mice with specific (and human-like) genetic susceptibilities for cancer provide powerful new tools for testing and characterizing interventions that may inhibit the process of carcinogenesis in humans.
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PMID:Diet and cancer prevention studies in p53-deficient mice. 1169 54

Insulin and insulin-like growth factor (IGF) axes are major determinants of proliferation and apoptosis and thus may influence carcinogenesis. In various animal models, modulation of insulin and IGF-1 levels through various means, including direct infusion, energy excess or restriction, genetically induced obesity, dietary quality including fatty acid and sucrose content, inhibition of normal insulin secretion and pharmacologic inhibition of IGF-1, influences colonic carcinogenesis. Human evidence also associates high levels of insulin and IGF-1 with increased risk of colon cancer. Clinical conditions associated with high levels of insulin (noninsulin-dependent diabetes mellitus and hypertriglyceridemia) and IGF-1 (acromegaly) are related to increased risk of colon cancer, and increased circulating concentrations of insulin and IGF-1 are related to a higher risk of colonic neoplasia. Determinants and markers of hyperinsulinemia (physical inactivity, high body mass index, central adiposity) and high IGF-1 levels (tall stature) are also related to higher risk. Many studies indicate that dietary patterns that stimulate insulin resistance or secretion, including high consumption of sucrose, various sources of starch, a high glycemic index and high saturated fatty acid intake, are associated with a higher risk of colon cancer. Although additional environmental and genetic factors affect colon cancer, the incidence of this malignancy was invariably low before the technological advances that rendered sedentary lifestyles and obesity common, and increased availability of highly processed carbohydrates and saturated fatty acids. Efforts to counter these patterns are likely to have the most potential to reduce colon cancer incidence, as well as cardiovascular disease and diabetes mellitus.
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PMID:Insulin, insulin-like growth factors and colon cancer: a review of the evidence. 1216 83

Discoveries of oncogenic signaling molecules lead to the comprehension of molecular mechanisms of tumor progression, as well as to the development of novel therapeutic tools for hepatocellular carcinoma. We have identified critical functions of intracellular signals transmitted from insulin-like growth factor and Wnt oncoprotein in carcinogenesis. The insulin-like growth factor system activates a number of signaling cascades resulting not only in hepatic mitogenesis, but also in cell survival. The secreted oncoprotein Wnt transforms beta-catenin potentials as a component of cell adhesion complexes with cadherins, into a transcription factor in the nucleus. Here, the important role of such signal transduction is reviewed, and we emphasize its control as a promising approach for the treatment of hepatocellular carcinoma.
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PMID:Oncogenic signal transduction and therapeutic strategy for hepatocellular carcinoma. 1182 1

The restriction of energy intake has documented beneficial effects on numerous diseases including cancer, yet the mechanism(s) that accounts for these effects is unknown. Recently, we showed that the inhibitory activity against mammary carcinogenesis mediated by energy restriction (ER) is accompanied by an increase in the secretion of adrenal cortical steroids. However, ER caused a concomitant reduction in circulating levels of insulin-like growth factor-1, which also may be involved in inhibiting carcinogenesis. To determine what cellular and molecular effects may be because of corticosterone per se, detailed mechanistic studies were performed in vitro using a mouse mammary hyperplastic cell line (TM10). The following questions were addressed: (a) is corticosterone-mediated growth inhibition accounted for by disruption of cell cycle machinery; (b) is growth inhibition accompanied by the induction of apoptosis; and (c) is growth inhibition reversible? At doses of corticosterone (50-200 micro M for 24-72 h) that resulted in inhibition (up to 76%; P < 0.001) of growth, a dose- and time-dependent G(1) arrest in cell cycle progression was observed. In the studies analyzing cell cycle regulatory molecules, corticosterone treatment of cells resulted in a strong induction (up to approximately 10-fold over control; P < 0.01) of KIP1/P27 together with a decrease (up to 98%; P < 0.01) in cyclin-dependent kinase 4 (CDK4) and cyclin D1 protein levels. Cells treated with corticosterone also showed an increased binding (up to 2.6-fold over control; P < 0.01) of KIP1/P27 with CDK4, together with a strong decrease (up to 89%; P < 0.01) in the kinase activity of the CDK4-cyclin D1 complex. Treatment of cells with KIP1/P27 antisense oligonucleotides reversed the growth inhibitory effects of corticosterone. Treatment of cells with RU 486, a glucocorticoid receptor blocker, reversed the effects of corticosterone on cell growth and KIP/P27 protein levels suggesting the involvement of the glucocorticoid receptor in accounting for these effects. Additional studies assessing the biological fate of cells after corticosterone treatment showed that corticosterone exerted reversible growth inhibitory effects with limited apoptotic cell death. Together, these findings show a reversible cytostatic effect of corticosterone via perturbations in cell cycle regulators causing a G(1) arrest in the absence of increased levels of apoptosis. These data provide evidence for a role of corticosterone on some but not all of the cellular activities associated with ER-mediated inhibition of mammary carcinogenesis.
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PMID:Mechanisms of energy restriction: effects of corticosterone on cell growth, cell cycle machinery, and apoptosis. 1223 97

Pre- and perinatal conditions and processes may affect the risk for some forms of cancer in later life, while the insulin-like growth factor (IGF) system may play a role in both early somatic growth and later carcinogenesis. Birth weight and length, and the variation of major components of the IGF system immediately after birth, were analyzed in relation to selected physiological and pathological variables. The study comprised 331 healthy full-term newborns from whom blood samples were taken during routine phlebotomy no later than the fifth day of life. Measurements of IGF-I, IGF-II and IGF-binding protein-3 concentrations were performed. Birth length and weight were measured and information on socio-economic and medical variables was recorded. The concentrations of all three proteins were lower when blood bilirubin levels were high, possibly as a result of compromised liver function and/or as a component of an activated acute phase reaction. Birth weight was significantly higher by about 46 g among children whose IGF-I was higher by one SD, while the associations of birth weight and length with other components of the IGF system were in the predicted directions, albeit only in trend. We conclude that in early life, growth is related to the IGF system, mostly IGF-I. The latter is lower in children with jaundice, possibly because of hepatic dysfunction and/or as part of an acute phase reaction. We speculate that elevations of IGF-I in early life might explain the increased risk of cancer in individuals born with a higher birth weight.
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PMID:Birth size and neonatal levels of major components of the IGF system: implications for later risk of cancer. 1250 54

Calorie restriction (CR) is the most effective and reproducible intervention for increasing lifespan in a variety of animal species, including mammals. CR is also the most potent, broadly acting cancer-prevention regimen in experimental carcinogenesis models. Translation of the knowledge gained from CR research to human chronic disease prevention and the promotion of healthy aging is critical, especially because obesity, which is an important risk factor for several chronic diseases, including many cancers, is alarmingly increasing in the Western world. This review synthesizes the key biological mechanisms underlying many of the beneficial effects of CR, with a particular focus on the insulin-like growth factor-1 pathway. We also describe some of the opportunities now available for investigations, including gene expression profiling studies, the development of pharmacological mimetics of CR, and the integration of CR regimens with targeted, mechanism-based interventions. These approaches will facilitate the translation of CR research into strategies for effective human chronic disease prevention.
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PMID:Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. 1252 70

Energy restriction (ER) results in a profound inhibition of chemically induced mammary carcinogenesis. The cancer inhibitory activity of ER has been shown to be associated with lower rates of cell proliferation during both premalignant and malignant stages of this disease process. Moreover, inhibition of carcinogenesis and suppression of cell proliferation occur in animals in which plasma concentrations of insulin-like growth factor (IGF)-I are reduced, and plasma corticosterone levels are increased concomitantly. Given the role of both hormones in signal transduction pathways that can modulate cell cycle progression, albeit via different regulatory mechanisms, we report experiments conducted to determine whether hypothesized effects of changes in plasma levels of IGF-I and corticosterone on cell cycle regulation could be detected in mammary carcinomas occurring in 40% ER rats in comparison to ad libitum fed control rats or 40% ER rats that were energy repleted for 7 days (ER-REP). As determined by appropriate combinations of immunoprecipitations, Western blots, and kinase activity assays, it was found that levels of phosphorylated retinoblastoma and E2F-1 were significantly reduced by ER (approximately 40 and 75%, respectively; P < 0.01), an effect that was partially reversed by ER-REP. Reductions in cyclin-dependent kinase (CDK)2 (82%) and CDK4 (77%) kinase activity in ER carcinomas were likely to account for the observed effects on retinoblastoma and E2F-1. Both Cip1/p21 and Kip1/p27 and levels of these proteins complexed with CDK2 were significantly elevated in ER carcinomas (P < 0.01), and levels of cyclin E were reduced. On the other hand, regulation of CDK4 kinase activity by ER was likely attributable to effects on cyclin D1 as well as increased binding of P16 and P19 to CDK4. The majority of changes induced by ER were reversed by ER-REP. These observations are consistent with the hypothesis that ER exerts its profound cancer inhibitory activity, in part, by multifaceted regulation of cell cycle machinery, possibly via concomitant changes in corticosterone and IGF-1 metabolism, although the role of other hormones and growth factors should not be dismissed.
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PMID:Effect of energy restriction on cell cycle machinery in 1-methyl-1-nitrosourea-induced mammary carcinomas in rats. 1264 81

Tyrosine kinase receptors are proteins that transduce the signal from many growth factor and cytokine ligands to produce intracellular responses. As such they can activate multiple signalling cascade pathways and influence cell division, migration and survival. Many show upregulation in certain malignancies, including those of the gastrointestinal tract, and are thought to play key roles in carcinogenesis. This makes them attractive targets for drug therapy and in recent years many inhibitors have been developed. This review discusses the current situation regarding the development of inhibitors with particular reference to the erbB family, the insulin-like growth factor receptor, the Met receptor, the receptor for vascular endothelial growth factor and the Kit receptor. The evidence will be related back to cancers of the gut lumen. Clinical effectiveness in this area seems to lie in using a combinatorial approach that inhibits multiple key signalling points, and the reasons for this will be discussed.
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PMID:The role of receptor tyrosine kinase inhibition in treating gastrointestinal malignancy. 1266 14


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