Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-alpha (TGF-alpha) is a polypeptide growth factor that binds to the epidermal growth factor receptor and is though to stimulate cell proliferation. It has been believed to play a role in tumor initiation by inducing the reversible transformed phenotype; overexpression of TGF-alpha may be important for tumor progression via autocrine stimulation and oncogene overexpression. Expression of TGF-alpha and the epidermal growth factor receptor has been documented in several nontumorous tissues and in a variety of tumors. This study used immunohistochemistry to localize TGF-alpha expression in normal and neoplastic endocrine tissues. Transforming growth factor-alpha was found in nontumorous hypothalamus, pituitary, thyroid, parathyroid, adrenal cortex and medulla, and pancreatic islets. Immunoreactivity was detected in most benign and malignant tumors of these tissues, as well as in endocrine neoplasms of the lung and gastrointestinal tract. Hypothalamic gangliocytomas, pheochromocytomas, and adrenal cortical carcinomas showed consistently greater immunoreactivity than their normal counterpart, but there was no correlation between degree of reactivity and tumor grade, stage, or hormone content. These results suggest that in endocrine tissues, TGF-alpha is unlikely to prove useful as a tumor marker but that the growth factor may play a role in both normal physiology and tumorigenesis.
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PMID:Transforming growth factor-alpha in normal and neoplastic human endocrine tissues. 146 72

The role of free radicals and active states of oxygen in human cancer is as yet unresolved. Various lines of evidence provide strong but inferential evidence that free radical reactions can be of crucial importance in certain carcinogenic mechanisms. A central point in considering free radical reactions in carcinogenesis is that human cancer is really a group of highly diverse diseases for which the initial causation and the progression to clinical disease occur through a wide variety of mechanisms. Furthermore, for many human cancers it appears that there are alternate pathways capable of tumor initiation and tumor progression. While for certain of these pathways free radical reactions appear necessary, it is unlikely that there are human cancers for which free radicals, or any other mechanism, are sufficient for the entire process beginning with the genetic alteration leading to a somatic mutation and eventually resulting in clinically overt disease. It is crucial that we view free radical reactions as among a panoply of mechanisms leading to human cancer, and consider research about the role of free radicals in cancer as opportunities to prevent the initiation or progression of human cancer.
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PMID:Free radicals and carcinogenesis. 207 48

In the past decades a large number of DNA adducts induced in the intact animal by alkylating agents have been identified. The formation and repair of these adducts are important determinants, not only of mutagenesis, tumor initiation and DNA-mediated toxicity but probably also of tumor progression. Most studies on in vivo DNA modification have been performed on isolated bulk DNA. More recently, methods have been developed to study the distribution of DNA adducts at the level of either the individual gene or the individual cell. This paper reviews immunocytochemical methods to study the formation and repair of DNA adducts and other DNA modifications at the level of the individual cell. DNA modifications induced by alkylating agents and a variety of other agents including ultraviolet radiation, aromatic amines, polycyclic aromatic hydrocarbons and platinum anti-cancer drugs will be discussed. Up to now, immunocytochemical analysis of in vivo modified DNA has largely concentrated on experimental animals. These studies have revealed striking heterogeneities with regard to formation and/or repair of DNA adducts in tissues from rat, hamster and mouse. Immunocytochemical adduct analysis can be used to identify in a convenient, fast and detailed way cell types, cell stages and sites in which biological effects of the adducts might be expressed. More recently, immunocytochemical analysis of DNA adducts also proved to be feasible on in situ exposed human samples. A number of existing and potential applications in the field of chemical carcinogenesis, experimental chemotherapy and molecular epidemiology are discussed.
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PMID:Immunocytochemical analysis of in vivo DNA modification. 223 8

The two-step initiation-promotion protocol for the induction of skin tumors in mice is a convenient model to elucidate what molecular events are involved in the multistage process of carcinogenesis and how they can be modulated. The current theories concerning the mechanisms of skin tumor initiation, stages 1 and 2 of tumor promotion, and tumor progression are reviewed. Because chemical carcinogens and tumor promoters may, directly or indirectly, generate reactive oxygen species (ROS) and because various antioxidants inhibit effectively some of the biochemical and biological events linked to tumor initiation, promotion and/or progression, it is conceivable that different sequences and levels of free radical-induced macromolecule damage may contribute to the evolution of the epidermal target cells from the preneoplastic stage to the malignant stage.
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PMID:Antioxidants and multistage carcinogenesis in mouse skin. 269 40

From experimental and epidemiological evidence, radiation-induced cancers appear to arise as multistage, monoclonal growths, which are elicited through various mechanisms, depending on the neoplasm in question and the conditions of exposure. At the molecular level, the process of carcinogenesis may involve the activation of oncogenes and/or the inactivation or loss of anti-oncogenes, through chromosomal rearrangements, point mutations, and other effects of radiation on DNA. In contrast to these mechanisms of carcinogenesis, which result from the absorption of radiation by the tumor-forming cells themselves, abscopal effects resulting from irradiation of other cells may contribute to carcinogenesis under certain conditions, e.g. in the induction of tumors of endocrine target cells through radiation-induced disturbances of hormonal balance. Effects of the latter type, which require the killing of substantial numbers of cells, are not elicited at low doses, thus contrasting with effects of the former type, which may be presumed to have no thresholds. Because radiation carcinogenesis may be mediated through a diversity of effects, the relationship between incidence and dose can vary accordingly. The relationship between the incidence of radiation-induced tumors and the time elapsing after irradiation also varies, depending on the type of tumor in question, species, age at irradiation, exposure conditions, and other factors. Although the variations with dose and time are consistent with multistage models of tumor initiation, tumor promotion, and tumor progression, the precise nature of the successive steps that are involved remains to be determined. The tendency for the tumors to resemble their spontaneous counterparts in age-distribution points to interactions between radiation and other carcinogenic risk factors which are as yet poorly understood. Also poorly understood are species- and organ-differences in susceptibility to radiation carcinogenesis, which bear no consistent relationship to corresponding 'spontaneous' cancer rates.
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PMID:Evolving perspectives on the biology and mechanisms of carcinogenesis. 373 8

The effects of various conditions on tumor initiation by 7,12-dimethylbenz(a) anthracene (DMBA) and promotion by retinyl acetate (RA), both in dimethylsulfoxide, were studied by topical application in hamster cheek pouch. The variables studied were: initiation and promotion time and schedule (alternate vs consecutive day paintings), concentration of DMBA used for initiation, and cytotoxicity. Spontaneous tumor progression followed by regression was observed in control animals which had been initiated for 4 weeks with 0.2% DMBA, but not given subsequent promotion treatment. Spontaneous progression was not observed in control animals which had been given only 2 weeks of initiation treatment, although RA both promoted new tumors and caused progression of benign hyperplastic lesions (BHLs) to advanced tumors. The approximate optimal conditions for obtaining acceptable tumor yields from promotion while minimizing associated errors and time periods were: 2 weeks of initiation with 0.2% DMBA and 4 weeks of promotion with 0.05 M RA, both with alternate day painting schedules. Reducing the initiation period but painting on consecutive days caused intolerable cytotoxicity and lowered tumor yields although the total dose of DMBA was kept constant. Increasing initiation time increased tumor yield in unpromoted controls as well as promoted groups, thus increasing errors in net yield from promotion. Similar results were obtained from doubling concentration of DMBA and halving initiation time. Reducing promotion time to below 4 weeks lowered tumor yield due to insufficient time for tumor development. Increasing promotion time to 6 weeks lowered tumor yield in both control and promoted groups, possibly due to spontaneous regression. Cytotoxicity enhanced progression to advanced tumors all of which were inflamed polypoid fibrovascular lesions. The cytotoxicity of DMBA was far greater than that of RA. Evidence is presented that tumor promotion by RA is not due to cytotoxicity. The hamster pouch system may afford an excellent short term mammalian screening test for tumor initiating and promotion agents.
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PMID:Hamster cheek pouch as a bioassay system in short term screening for tumor initiating and promoting agents. Optimization of parameters and observations of effects of cytotoxicity on tumor promotion by retinyl acetate. 644 Sep 77

This subject was particularly important to discuss in the presence of Werner Kalow, 77 years young, who is considered as one of the grandfathers of this unique combination of medical research fields. It has become increasingly appreciated that dozens of human drug metabolism polymorphisms exist. The interindividual variabilities in drug metabolism discussed at this symposium do not represent small differences such as 50% or 3-fold but, rather, represent 10- to greater than 1000-fold differences. When attributed to a single gene, dramatic differences can be seen among family members, just as blue and brown eyes can occur in siblings. These differences can result in acute drug toxicity. In addition, there are chronic effects: over one's lifetime, striking differences in the metabolism of drugs, occupationally hazardous chemicals, and other environmental pollutants can lead to interindividual differences in the buildup of DNA damage (e.g., mutations, chromosomal breaks, rearrangements) leading to toxicity and tumor initiation, as well as leading to a buildup in nongenotoxic signals (signal transduction pathways without DNA damage) important for toxicity, tumor promotion, and tumor progression. The human UDP glucuronosyltransferase (UGT superfamily is known to comprise more than 10 genes in humans, and probably in other mammalian species. Breakthroughs in UGT gene mutations responsible for the Crigler-Najjar syndrome and Gilbert's disease have recently been reported. The human cytochrome P450 termed CYP3A4 is a major P450 enzyme in the liver and gastrointestinal tract, and the full impact of the CYP3A4 polymorphism has yet to be fully appreciated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacogenetics in clinical pharmacology and toxicology. 764 12

Protein tyrosine kinases have been implicated in tumor initiation and progression. Here we used Northern blotting to study expression of their genes in cultured normal melanocytes and 19 melanoma cell lines from different stages of tumor progression. We detected transcripts for 2 cytoplasmic (ABL and FES) and 6 receptor (ECK, ERB-B2, FGF-R4, IGFI-R, KDR and TIE) kinases but not for receptors RET or TRK-A. Genes for ECK, FGF-R4 and TIE were expressed ectopically in melanomas (not in normal melanocytes). Similarly, ECK protein was detected by immunoblotting in metastatic melanomas but not in normal melanocytes. ECK mRNA levels tended to increase again during late melanoma progression. ECK and TIE mRNAs were also detected in highly metastatic variant cells but not in the corresponding poorly metastatic parental lines. Conversely, FES and KDR gene expression was lost in most advanced primary and metastatic melanomas. These findings suggest positive and negative roles for specific tyrosine kinases during progression.
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PMID:Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. 781 45

Cancer cytogenetics is a valuable tool for the analysis of cellular and molecular aberrations during malignant transformation and tumor progression. The rat has served as an important experimental model to investigate various steps in oncogenesis. An attempt was made to compile data on rat tumor cytogenetics from previously published data in order to provide a basis for further research, especially when combining classic and molecular cytogenetics, a yet underdeveloped area of research in rat tumorigenesis. The wealth of data presented here provides a contrast to its impact on biological specificity. Because of the different experimental procedures involved with tumor induction and the application of carcinogens at relatively high dosages, as well as occasional less than careful histological documentation, a delineation of unambiguous chromosome alterations, critical in the process of carcinogenesis, is rare in the rat. Future studies should be performed with spontaneously arising rat tumors and/or tumors after low, single-dose carcinogen exposure in order to reduce unspecific karyotype alterations not intrinsically related to tumor initiation and progression. Short-term culture or early passages in vitro should be methods of choice, especially for solid tumors, to avoid erroneous karyotype analyses because of contaminating normal cells. The combined karyological and molecular genetic approach to an analysis of tumor-specific changes, still hindered by an almost complete lack of cell type-, chromosome-, or gene-specific molecular probes for the rat, should become a focus of research in order to continue having the advantages this species offers for stage-specific analysis of tumorigenesis.
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PMID:Rat tumor cytogenetics: a critical evaluation of the literature. 784 88

N- and K-ras oncogene mutations represent the most frequent molecular lesions in plasma cell dyscrasias. They are not randomly distributed since they are detectable in multiple myeloma (MM) (9-31%) and plasma cell leukemia (PCL) (30%), and not in monoclonal gammopathy of undetermined significance (MGUS) and solitary plasmacytoma (SP). Codons 12, 13 and 61 of N- and K-ras genes have been found mutated. Mutations affecting codon 61 of N-ras gene are the most frequent finding. A heterogeneous pattern of mutations is described with a prevalence of purine-pyrimidine transversions. Ras gene mutations have been predominantly detected in myelomas characterized by an advanced stage disease, and adverse prognostic parameters. These findings suggest that ras mutations represent a late molecular lesion and may be implicated in tumor progression rather than tumor initiation.
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PMID:N- and K-ras oncogenes in plasma cell dyscrasias. 785 96


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