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)

Thymidylate synthetase (TS) and thymidine kinase (TK) are known to catalyse the methylation of dUMP for the de novo synthesis of dTMP and the phosphorylation of thymidine for the salvage synthesis of dTMP in the pyrimidine pathway, respectively. High TS and TK activities and the existence of TK isozymes have been observed in rapidly proliferating tissues. TS and TK activities in 1,2-dimethylhydrazine (DMH)-induced colon carcinomas in rats increased significantly to 331 and 207% of the activities in normal colon, respectively, and were well correlated inversely (y = -0.93x + 5.24), with a correlation coefficient of -0.787. The colonic TK isozymes were separated into two types by DEAE-cellulose column chromatography. The TK isozyme eluted from the column by the elution buffer alone without NaCl was markedly higher (23.6-fold) in activity in DMH-induced colon carcinoma than in normal control colon and was not affected by deoxycytidine triphosphate. This isozyme, whose mol. wt is 100,000 by h.p.l.c., is thought to be closely involved in rapid DNA replication. These results indicate that early biochemical changes in DMH-induced colon carcinoma in rats may serve as a useful model and provide valuable insight into the mechanisms involved in colonic carcinogenesis.
Carcinogenesis 1987 Mar
PMID:Relative activities of thymidylate synthetase and thymidine kinase in 1,2-dimethylhydrazine-induced colon carcinomas in rats. 381 35

Since the results of an earlier study indicating no effect of dietary fat on dimethylhydrazine (DMH)-induced colon cancer in rats differed from those of other investigators, the present study was initiated to determine if the modulating effect of fat intake on colon tumorigenesis was dependent on the route of DMH administration. Male weanling Sprague-Dawley rats (160) were fed one of two nutritionally balanced diets containing 5% or 24% corn oil (CO). Following 3 weeks adaptation to their respective diets, 40 rats from each diet group were treated with five doses of DMH (30 mg/kg) by intragastric (i.g.) gavage or subcutaneous (s.c.) injection, over a 3 week period. Rats were sacrificed when they showed clinical signs of colon tumor and surviving animals were killed 51 weeks after the initial DMH treatment. The cumulative probability of death with colon carcinoma did not differ between the dietary or treatment groups. There was no effect of route of administration or dietary fat on total intestinal tumor incidence. The number of rats with colon carcinoma was: 5% CO.IG = 25; 24% CO.IG = 27; 5% CO.SC = 23; 24% CO.SC = 19. Polypoid tumor incidence was significantly higher in the 24% CO.SC group (12/40) compared to the 5% CO.SC group (3/40) (Chi-squared = 5.25; p less than 0.03) while sessile tumor incidence was the inverse. Marginally significant differences in tumor morphology were noted between the IG groups.
Carcinogenesis 1985 Mar
PMID:Interaction of dietary fat and route of carcinogen administration on 1,2-dimethylhydrazine-induced colon tumorigenesis in rats. 397 50

Thymidine kinase (TK), the enzyme in the pyrimidine salvage pathway, and its isozymes were examined in 15 specimens of normal mucosa, 14 polyps and 14 carcinomas in human colon. The average TK activities in colon polyps and carcinomas were about 1.6 and 2.9 times that in normal colon mucosa, respectively. The colon TK isozymes were separated into 2 types by DEAE-cellulose column chromatography. The activity of the TK isozyme eluted with 0.1 M NaCl in buffer was 1.6-fold higher in colon polyp and 1.5-fold higher in colon carcinoma than that in normal colon mucosa. In colon carcinoma, but not colon polyp, the activity of the other isozyme eluted with buffer alone was increased to 5.1-fold that in normal tissues. As the activity of the latter isozyme was not affected by deoxycytidine triphosphate, it may be involved in DNA replication. The results suggest that increases in the activities in the former and latter TK isozymes may indicate tumorigenesis and carcinogenesis, respectively, in the human colon.
Carcinogenesis 1985 Jun
PMID:Increased activities of thymidine kinase isozymes in human colon polyp and carcinoma. 400 80

Development of 1,2-dimethylhydrazine (DMH) induced colonic neoplasia were studied using male Wistar rats given 120 mg DMH per kg s.c. weekly for 5 weeks. During the course of colon carcinogenesis, changes in cellular proteins of colonic mucosa were analysed by two-dimensional gel electrophoresis. Rats were sacrificed just before and at 10, 15 and 20 weeks after the initial DMH treatment together with controls. Incidence and number of colorectal tumors gradually increased. At the 20th week, colon carcinoma was found in every rat. Most tumors (92%) were found in the major flexure and the distal colon and rectum, while only 1% and 7% were found in the cecum and proximal colon, respectively. Histologically, most (92%) were classified as well differentiated or moderately differentiated adenocarcinoma. Eighty-five percent of the tumors were semipedunculated or sessile without depression, and the remainder were sessile with depression. All of the latter were carcinomas with invasion to the submucosa or further. Two-dimensional gel electrophoresis revealed 180 spots in cellular proteins before and after the initial treatment. Three new spots appeared and four spots greatly increased during the course of carcinogenesis, while one spot disappeared. The above results suggest that the appearing and increasing spots may be associated with cancer and that the disappearing spot may be associated with the normal colon.
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PMID:[Development of 1,2-dimethylhydrazine-induced colonic neoplasia in rats and changes in cellular proteins of colonic mucosa]. 408 89

DNAS of some human tumours can transform NIH 3T3 fibroblast cells, thus demonstrating the transforming potential of human ras genes (Hu-rasHa, Hu-rasKi, and Hu-rasN, respectively Harvey, Kirsten and neuroblastoma ras genes). Only a small percentage of a given type of human carcinoma, however, scores positive in this assay system. Activation of ras and subsequent transformation of NIH 3T3 cells are either by a point mutation in the ras gene or enhanced expression of the normal, or proto-onc, ras gene. If the transformation of a given human tumour involves the enhanced expression of the normal or cellular ras gene and the resulting gene product, the tumour DNA would probably score negative in the NIH 3T3 transfection assay. In human colon carcinoma, for example, lesions at position 12 of Hu-rasKi have been found. None of nine colon carcinomas obtained at biopsy, however, contain the ras lesion at this position, using a Hu-rasHa probe; one other colon carcinoma does appear to contain amplified proto-onc ras, and other colon carcinomas do have increased levels of ras RNA. There are at least three explanations for these observations. Either very few colon carcinomas contain point-mutated ras, the lesion in the majority of colon carcinomas is at a position other than 12 or ras activation in many colon carcinomas involves the enhanced expression of either the point-mutated or proto-onc form of a ras gene. We have now used monoclonal antibodies directed against a synthetic peptide reflecting sequences of the human T24 ras gene product to define ras p21 protein expression in a spectrum of colonic disease states. Immunohistochemical analyses of individual cells within tissue sections reveal differences in ras p21 expression in colon carcinomas compared with normal colonic epithelium, benign colon tumours and inflammatory or dysplastic colon lesions. Our data suggest that ras p21 expression is correlated with depth of carcinoma within the bowel wall, and is probably a relatively late event in colon carcinogenesis.
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PMID:Monoclonal antibodies define differential ras gene expression in malignant and benign colonic diseases. 648 68

The influence of 12-O-tetradecanoylphorbol 13-acetate (TPA) and vincristine (VCR) on the development of colon carcinoma induced by 1,2-dimethylhydrazine (DMH) has been studied by light and electron microscopy. The ability of TPA to induce the appearance of cells with a heterogeneous genotype has been investigated by cytophotometric evaluation of DNA content. The TPA-induced phenotypic alterations have been studied by quantitative histochemistry. The influence of promoters on the outcome of DMH-induced carcinogenesis has been investigated in DMH-resistant C57 Black mice. Aneuploid DNA populations were detected in hyperplasias induced by DMH or TPA; in carcinomas, the percentage of hyperdiploid cell populations was further increased. DNA aneuploidy is defined as the genetic instability of cells that can be induced by TPA treatment alone. TPA can induce dedifferentiation of hyperplastic cells, as demonstrated by quantitative histochemistry of the intestinal mucins. TPA increased the colon tumour incidence in DMH-resistant C57 Black mice. A promoter-like action of VCR could also be observed.
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PMID:The effect of promoters on 1,2-dimethylhydrazine-induced colon carcinogenesis. 653 94

We have recently shown that a variety of human tumor cell lines are capable of preventing chloroethylnitrosourea (CNU)-induced DNA crosslinks, presumably by removing guanine O6-chloroethyl DNA monoadducts before crosslinks can form. Those cells capable of preventing crosslinking were of the Mer+ (Methylation repair) phenotype, and have been shown to be proficient at repair of O6-methyl-guanine adducts by the repair enzyme guanine-O6-methyl-transferase. Mer- tumor cell lines are: deficient at O6-methyl-guanine repair, incapable of preventing CNU interstrand crosslinking, and have recently been shown to lack the repair enzyme O6-methyl-transferase. We wish to report that pretreatment of Mer+ cells (HT-29 human colon carcinoma cells and IMR-90 normal human fibroblasts) with the DNA methylating agent MNNG, under conditions which should inactivate O6-methyl-transferase, apparently saturates the monoadduct repair system, and allows CNU to form interstrand crosslinks in these cells. This effect was also seen when MNU pretreatment was used, but not with MMS or streptozotocin. The formation of CNU-induced interstrand crosslinks following MNNG or MNU pretreatment was coincident with a dramatic increase in cytotoxicity as measured by colony formation assays. In contrast, cytotoxicity was only slightly increased when MMS or streptozotocin pretreatment was used.
Carcinogenesis 1984 Jan
PMID:Pretreatment of human colon tumor cells with DNA methylating agents inhibits their ability to repair chloroethyl monoadducts. 669 90

The effect of alterations in the quality and quantity of dietary fat on N-nitrosomethyl urea (NMU)-induced colon cancer in rats was studied. Weanling Sprague-Dawley rats were fed semipurified diets containing 24% beef fat, 24% corn oil, 24% Crisco or the three fats in equal parts to make a total of 5% fat. Macronutrients and micronutrients were adjusted to balance the nutrient to calorie ratios. After 4 weeks of dietary treatment, all rats, except vehicle-treated animals received NMU (1.5 mg) via intrarectal instillation, twice a week for 2 weeks. The animals continued receiving the experimental diets until intestinal tumors developed and surviving animals were sacrificed at 43 weeks. There was no effect of any of the high fat diets tested on intestinal tumor incidence, latency, distribution or size. Cumulative probability of death with colon carcinoma did not differ significantly among the dietary groups.
Carcinogenesis 1984 Feb
PMID:Lack of effect of dietary fat on N-nitrosomethyl urea (NMU)-induced colon tumorigenesis in rats. 669 42

The ability of extracts of human tumor cells to demethylate O6-methylguanine (O6-MeG) in DNA was assayed using the synthetic DNA polymer poly(dC,dG,m6dG). Cell strains proficient in repair of O6-MeG in vivo (Mer+ phenotype) contained a methyltransferase activity while repair deficient cells (Mer- phenotype) had little or no activity. Mixing extracts of different Mer- strains did not result in the appearance of the activity. Extracts of Mer- cells did not inhibit the activity in extracts of Mer+ cells. Both Mer+ and Mer- strains contained methylnitrosourea-damage-specific endonuclease activity. The data suggest that the Mer- strains are deficient in methyltransferase and that this is the fundamental reason for their hypersensitivity to the cytotoxic effects of DNA alkylation. The activity was partially purified from a Mer+ colon carcinoma cell strain. Its kinetics parallel the repair of O6-MeG in DNA in vivo and suggest that the activity is inactivated during repair of DNA.
Carcinogenesis 1983
PMID:Repair of O6-methylguanine in DNA by demethylation is lacking in Mer- human tumor cell strains. 682 8

Several groups have shown that the malignant phenotype can be transferred to NIH/3T3 fibroblasts by incorporation of DNA isolated from tumour cell lines. These studies have demonstrated that the transforming activity of DNA isolated from human bladder, lung and colon carcinoma cell lines is related to an alteration of the cellular homologues of the ras genes of Harvey or Kirsten murine sarcoma viruses. It is, however, unclear what relevance these observations have to the multi-stage nature of tumorigenesis in vivo, in which several independent events are required in both humans and experimental animals. The activation of a cellular oncogene in a defined experimental system for the progressive induction of solid tumours has not yet been demonstrated. We report here that high molecular weight DNA from transplanted squamous cell carcinomas induced by sequential treatment of mouse skin with initiators and promoters of carcinogenesis causes morphological transformation of NIH/3T3 fibroblasts at high frequency. The transforming properties are due to the transfer of an activated cellular homologue of the Harvey-ras (rasH) oncogene.
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PMID:Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. 684 61


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