Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The time course of induction of SOS-like stress responses such as enhanced reactivation (ER) and enhanced mutagenesis (EM) has been investigated in UV-C-irradiated skin fibroblasts from a xeroderma pigmentosum (XP) family, using herpes simplex virus type 1 as a probe. Similar ER studies were performed in a Li-Fraumeni syndrome (LFS) family and in a family with a high incidence of breast, ovarian, and colon cancer. In two XP (complementation group B) patients, with a striking absence of skin tumors even at an age of >40 years, only induction of EM was observed, whereas ER was absent (XPER-). The ER- phenotype was inherited from the father, whereas cells from the mother exhibited normal expression of ER and EM. This suggests that the absence of ER is a hereditary trait that is not correlated with a repair-deficient phenotype. Abnormally high levels of ER were observed in UV-C-exposed skin fibroblasts from rive LFS patients. The inheritance of the ER response was studied in one LFS family. High levels of ER were observed only in cells derived from affected individuals carrying one mutated p53 allele, whereas cells from unaffected family members, carrying two wild-type p53 alleles, exhibited normal ER levels. This result shows that abnormally high levels of ER positively correlate with the occurrence of cancer in affected individuals from a LFS family. Interestingly, abnormally high levels of ER were observed in cells from afflicted as well as from unafflicted members of a family with a high incidence of breast, ovarian, colon, and stomach cancer. This suggests that these latter individuals have inherited a mutated, putative predisposing gene, resulting in abnormal expression of ER, but that cancer had not yet developed. The results indicate that the ER response can possibly be used as a prognostic marker to identify carriers in various hereditary cancer-prone syndromes at an early age.
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PMID:Inheritance of abnormal expression of SOS-like response in xeroderma pigmentosum and hereditary cancer-prone syndromes. 865 7

Protooncogenes are cell cycle-related genes that are involved in cell growth of proliferation. Alterations in the level of expression of these genes, or expression of aberrant gene productions, have been observed in tumors and precancerous conditions. To determine if expression of these genes is altered in patients with inflammatory bowel disease (IBD) --who are at risk for development of colon cancer--we assayed transcripts of 15 protooncogenes in colonic epithelial cells of IBD patients and controls. Nine of these genes (H-ras, c-myc, c-fos, c-jun, junB, N-myc, c-abl, c-yes, and p53) were expressed in epithelial cells, whereas two (RB1 and N-ras) were not. expression of four other genes (c-src, K-ras, c-raf, and c-myb) was observed, but the intensity of these bands was too low for densitometric analysis. The steady-state levels of transcripts of H-ras and five nuclear protooncogenes (c-myc, c-fos, c-jun, junB, and N-myc) were lower in epithelial cells from involved or uninvolved IBD samples than in normal epithelial cells from either sporadic colon cancer or diverticulitis patients. The level of c-fos mRNA was two- to threefold higher in involved than in uninvolved areas of the colons of two ulcerative colitis (UC) patients, but not in one Crohn's disease (CD) patient. Message abundance of c-abl transcripts was two- to threefold lower in UC epithelial cells than in either the CD or control samples. The steady-state level of c-yes-encoded mRNA was considerably higher in IBD patients resected for colon cancer than in patients resected for active chronic IBD or in controls. The level of p53 message was constant in these samples. Increased levels of c-fos mRNA in involved UC relative to uninvolved UC may be related to the disease process. Decreased expression of c-abl transcript in UC may be a diagnostic marker for UC and may be related to the rate of cell turnover in these diseases. Enhanced expression of c-yes in IBD patients with tumors compared to active chronic IBD and controls suggests that expression of this gene may be a marker for development of colon cancer in IBD.
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PMID:Expression of protooncogene-encoded mRNA by colonic epithelial cells in inflammatory bowel disease. 867 85

We showed the possibility of significant decreasing of the frequency of chemically induced colon cancer in rats by vaccination with polyclonal rabbit IgG generated against purified tumor-associated antigens (TAA). TAA were isolated from benign rat colon tumors by the method developed in our laboratory (Zusman et al 1994) using affinity chromatography columns with gel fiberglass membranes (R. Zusman, 1992) containing anti-tumor IgG. The IgG was isolated from rabbits following their vaccination with TAA. Sprague Dawley rats were vaccinated with anti-TAA IgG (100 micrograms/rat) suspended in Freunds adjuvant by weekly subcutaneous injections for 5 weeks. The induction of colon cancer was caused by weekly injections with 1,2-dimethylhydrazine (DMH) (20 mg/kg) for 7 weeks and was started one week after the end of the vaccination. The results of experiments were evaluated 6 months after the start of cancer induction. IgG protected against the carcinogenic effects of DMH. The number of tumor-bearing rats decreased to 64% as compared with 90% in the control group. In vaccinated rats, the incidence of tumors was almost 3 times less than of control, i.e. 3.6 and 9.3, respectively. The number of malignant tumors was also significantly smaller in vaccinated rats than in controls, being 24% and 58%, respectively. Metastases were found only in controls, 4 of 30 rats. The results of our experiments have shown that anti-TAA IgG not only has anti-tumor effects but also prevents the malignization of benign tumors. As one of the main components of TAA which was isolated from colon cancer rats was soluble p53 antigen (Zusman et al 1994), we suggest that the vaccine which has been generated in our experiments may be regarded as acting mainly against p53 antigen, and its antitumor effects should also be considered as effects of p53 antibodies. The further studies will be performed to clarify this.
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PMID:IgG generated against benign tumor-associated antigens prevented the effects of 1,2-dimethylhydrazine in rats. 870 33

Mutation of the APC gene may be a common denominator of all human colon cancer--polypoid and non-polypoid familial cancer as well as sporadic occurrences. Fearon and Vogelstein (1990) have described a series of molecular changes during the progression of human colon cancer, beginning with mutations in APC. Min is a strain of the laboratory mouse carrying a nonsense mutation in Apc, the mouse homologue of APC. The Min strain has been used to test the effect of germline alterations in certain genes identified in the progression pathway of Fearon and Vogelstein. A deficiency in DNA cytosine methylase leads to a reduction in the tumour multiplicity of Min mice contrary to the a priori expectation based on the global hypomethylation of the DNA of early colonic neoplasms. Alterations in Kras had no perceptible effect on the tumour multiplicity of Min mice but may not have been successfully directed to the proliferative cell population. Constitutional mutation of p53 did not influence the multiplicity or histopathology of early Min induced intestinal tumours. The cause and effect analysis of the genetics of colon cancer is clearly in an early phase. An unlinked genetic factor interacting with Min in controlling intestinal tumour multiplicity is Mom1. A central goal for the near future is to identify the Mom1 gene product and to identify other loci that can interact with the Min mutation and affect tumour multiplicity or progression. Mouse chimaeras will permit an analysis of the clonality and cell autonomy of Min induced neoplasms and also of the action of Mom1. The results of these analyses will inform investigators as to what modes of prevention and therapy might be designed for particular tumour types. The Min strain thereby presents an opportunity to discover protective factors against human colon cancer.
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PMID:Emergent issues in the genetics of intestinal neoplasia. 871 26

Fluoropyrimidines radiosensitize human colon cancer cells that progress into S phase in the presence of drug (M.A. Davis, H-Y. Tang, J. Maybaum, and T.S. Lawrence. Int. J. Radiat. Biol. 67. 509-512, 1995). We hypothesized that progression occurs in cells that generate elevated levels of cyclin E-dependent kinase activity despite the presence of the fluoropyrimidine. To test this hypothesis, we treated HT29 and SW620 human colon cancer cells with fluorodeoxyuridine under conditions that produced nearly complete inhibition of thymidylate synthase but which sensitized only the HT29 cells. We found that, whereas HT29 cells progressed into S phase and demonstrated increased cyclin E-dependent kinase activity, SW620 cells arrested just past the G1-S boundary and showed no change in kinase activity. Because these cell lines have the same p53 mutation, these findings suggest that there is a p53-independent G1-S checkpoint that mediates radiosensitization produced by fluorodeoxyuridine.
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PMID:Fluoropyrimidine-mediated radiosensitization depends on cyclin E-dependent kinase activation. 876 7

PTH-related peptide (PTHrP) is the major factor responsible for humoral hypercalcemia of malignancy. This paraneoplastic syndrome has been described in association with a number of malignancies, but rarely with carcinoma of the colon. Moreover, little is known about the molecular mechanisms that underlie PTHrP overexpression in tumors. Here we report a patient who presented with hypercalcemia 6 months after resection of a neuroendocrine colonic carcinoma (tumor I). At the time of admission, intact PTH was decreased, circulating PTHrP levels were elevated, and there was tumor recurrence (tumor II). Immunohistochemical staining of paraffin-embedded sections from tumor I did not stain for PTHrP, whereas cells from tumor II stained intensely positive. Southern blot analysis and differential PCR of genomic DNAs from tumor specimens and the patient's leukocytes demonstrated amplification of the PTHrP gene in tumor II. Moreover, staining for p53 protein was evident in tumor II, but not in tumor I, consistent with the presence of a mutant form of p53 and associated loss of tumor suppressor function in the recurrent tumor. PTHrP gene amplification was also detected in one of five other tumors associated with humoral hypercalcemia of malignancy. These findings suggest that a potential mechanism contributing to PTHrP overexpression in malignancies is gene amplification, which could arise from increased genomic instability associated with the progressive stages of neoplasia.
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PMID:Amplification of the parathyroid hormone-related peptide gene in a colonic carcinoma. 876 40

Aberrant crypt foci (ACF) are putative precursor lesions of colon cancer, recently identified on the methylene blue-stained mucosal surface of human colon. No mutations in K-ras or p53 genes were found by non-radioactive single-strand conformation polymorphism analysis in 14 ACF collected from five patients. Using the more sensitive method of allele-specific polymerase chain reaction (PCR) for K-ras, 8 of 14 ACF were found to contain K-ras mutations, suggesting that mutated cells are present in minute clones in ACF. No dysplasia was observed in any of the ACF containing a mutated clone. The presence of K-ras mutations in ACF suggests that these lesions occur at a very early stage in human colorectal carcinogenesis.
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PMID:K-ras and p53 mutations in human colorectal aberrant crypt foci. 877 29

There have been many new developments in our understanding of esophageal carcinoma biology over the past several years. Information regarding both of the major forms of this disease, adenocarcinoma and squamous cell carcinoma, has accumulated in conjunction with data on precursor conditions such as Barrett's esophagus. Some of the most interesting and promising findings have included aneuploidy (abnormal DNA content), amplification and overexpression of proto-oncogenes, loss of heterozygosity at multiple chromosomal loci, and tumor suppressor gene inactivation. Of particular importance is mutation and deletion involving the tumor suppressor gene p53, but abnormalities in the retinoblastoma, deleted in colon cancer, and adenomatous polyposis coli genes have been described as well. Recently, two important cancer pathways implicated in the genesis of multiple tumor types have also been inculpated in esophageal carcinogenesis: the cyclin kinase inhibitor cascade and the DNA mismatch repair process. Alterations in the p16 and p15 cyclin kinase inhibitors, including point mutation and homozygous deletion, have been reported in primary esophageal tumors and/or tumor-derived cell lines. Microsatellite instability, the hallmark of DNA mismatch repair defects, has been detected in esophageal cancers, particularly those associated with Barrett's metaplasia (where it may represent an early event). Further developments in the field of molecular carcinogenesis of esophageal malignancies promise to yield improvements in the early detection, prognostic categorization, and perhaps eventual gene-based therapy of this deadly disease.
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PMID:The molecular biology of esophageal carcinoma. 889 31

Camptothecin (CPT) traps covalent DNA topoisomerase I-linked DNA single-strand breaks (cleavable complexes). To determine the differences in DNA damage signalling leading to differential sensitivity to CPT, two human colon cancer cell lines, SW620 and KM12, with nonfunctional p53 and the same level of topoisomerase I cleavable complex formation but differential sensitivity to CPT (Cancer Res. 56:4430-7; 1996) were studied. The levels of mRNA expression of DNA damage-inducible or death-related genes were measured at different times after CPT treatment. KM12 cells exhibited 3-fold higher basal levels of BCL-2 mRNA. Consistently, secondary DNA fragmentation, quantitated using a filter elution assay, was detected 24 h later and was 2-4-fold lower in KM12 cells than in SW620 cells. No induction of BAX was detected in either cell line. Consistent with the absence of functional p53, p21CIP1/WAF1 and GADD45 genes were not induced within the first 24 h. However, in SW620 cells, both mRNA levels were increased more than 10-fold at 48 h. The BCL-2-related gene MCL-1 and topoisomerase II mRNA were induced at 24 h, and topoisomerase I mRNA levels increased 3-fold at 48 h, only in SW620 cells. We conclude that cellular response to CPT-induced DNA damage can involve p53-independent pathways leading to the induction of p53-effector genes. Induction of these genes at the onset of apoptosis is associated with CPT sensitivity.
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PMID:Differential GADD45, p21CIP1/WAF1, MCL-1 and topoisomerase II gene induction and secondary DNA fragmentation after camptothecin-induced DNA damage in two mutant p53 human colon cancer cell lines. 893 95

Cytoplasmic sequestration of wild-type p53 protein occurs in a subset of primary human tumors including breast cancer, colon cancer, and neuroblastoma (NB). The sequestered p53 localizes to punctate cytoplasmic structures that represent large protein aggregates. One functional consequence of this blocked nuclear access is impairment of the p53-mediated G1 checkpoint after DNA damage. Here we show that cytoplasmic p53 from NB cells is incompetent for specific DNA binding, probably due to its sequestration. Importantly, the C-terminal domain of sequestered p53 is masked, as indicated by the failure of a C-terminally directed antibody to detect p53 in these structures. To determine (i) which domain of p53 is involved in the aggregation and (ii) whether this phenotype is potentially reversible, we generated stable NB sublines that coexpress the soluble C-terminal mouse p53 peptide DD1 (amino acids 302-390). A dramatic phenotypic reversion occurred in five of five lines. The presence of DD1 blocked the sequestration of wild-type p53 and relocated it to the nucleus, where it accumulated. The nuclear translocation is due to shuttling of wild-type p53 by heteroligomerization to DD1, as shown by coimmunoprecipitation. As expected, the nuclear heterocomplexes were functionally inactive, since DD1 is a dominant negative inhibitor of wild-type p53. In summary, we show that nuclear access of p53 can be restored in NB cells.
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PMID:Cytoplasmically sequestered wild-type p53 protein in neuroblastoma is relocated to the nucleus by a C-terminal peptide. 898 86


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