Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutional loss or inactivation of one copy of a tumor-suppressor gene, as exemplified by hereditary retinoblastoma, increases the propensity for malignancies by reducing the number of events necessary for the complete loss of the negative regulatory function. We developed a selectable mutation assay employing a human lymphoblastoid cell line (LCL) derived from a heterozygous carrier of 2,8-dihydroxyadenine urolithiasis, adenine phosphoribosyltransferase (APRT) deficiency, for dissecting the second step in loss-of-function mutations and for determining the potential of physical and chemical agents for producing such mutations. The mode of mutational events arising in the wild-type allele of the functionally heterozygous APRT gene resembled that reported for tumor-suppressor genes in malignancies in that mitotic non-disjunctions or recombinations as well as deletions prevailed. Ultraviolet light (UV) was much less efficient in inducing these types of mutations than ionizing radiation. A group of autosomal recessive cancer-prone diseases, including xeroderma pigmentosum (XP), has been characterized as being more susceptible to genomic insults, owing to some defects in DNA processing, such as replication, repair, or recombination. This increased genomic instability may accelerate the gain-of-function mutation at a proto-oncogene and/or the loss-of-function mutation at a tumor-suppressor gene. XP complementation group A (XP-A) LCLs were extremely sensitive to UV-mutagenesis at the hypoxanthine phosphoribosyltransferase (HPRT) locus even at equicytotoxic doses. Some unique mechanism may operate in UV-mutagenesis in XP-A. We have succeeded for the first time in rendering XP-A cells tumorigenic in athymic mice by applying multiple exposures to UV and subsequent treatment with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular bases for hereditary cancer-prone diseases. 129 55

Two aspects can be distinguished in multistage carcinogenesis: etiological one (every stage is induced by a specific for this stage agent) and morphobiological aspect (every stage is characterized by specific morphological, genetic and other properties). The schema of the multistage carcinogenesis is presented in which morphological stages (diffuse and focal hyperplasia, benign tumours, dysplasia, carcinoma in situ, various phases of malignant tumour progression) are placed against genetic alterations. L. Foulds concept of tumour progression is discussed with special emphasis on precancerous stages, possibilities of cancer development de novo, and independent progression of different tumour characters. The following types of carcinogenesis are listed on the basis of interrelationship between etiological and genetic factors: 1) carcinogenesis induced by genotoxic agents; a) one agent is acting at high dose and for a long time thus ensuring the activation of protooncogenes and all stages of tumour progression (initiation, promotion, various phases of malignant tumour); b) those acting during a very short time, however sufficient for developing the genetic program working automatically without further exposure to known carcinogens (irradiation in case of the atomic bomb explosion or effect of short-living alkylating agents): in this case there is no stage of promotion; 2) carcinogenesis by non-genotoxic carcinogens (their mode of action is still unclear, the only human example is carcinogenesis by hormones); 3) development of tumours in frane of the two (or three) stage carcinogenesis when every stage is provoked by its own etiological factor, no human examples are known as yet; 4) development of tumours due to the genetic mechanism making the organism highly susceptible to the minimal doses of carcinogens as is the case with skin cancer by ultraviolet light in patients with xeroderma pigmentosum, the genetic damage in itself has nothing to do with tumour formation; 5) genetic damage leading to the development of tumour without visible participation of any known carcinogens or promoters (gene Rb in retinoblastoma, gene Wt in Wilms tumour, etc.).
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PMID:[Progression of tumors: etiologic, morphologic and molecular-biological aspects]. 147 43

The frequencies of chromatid breaks and gaps in metaphase cells fixed 2 h after G2 phase X-irradiation (1 Gy) were in almost all cases at least two- to three-fold higher in skin fibroblasts from individuals with genetic conditions predisposing to cancer than in comparable cells from clinically normal controls. Previously, we reported this response in all cancer-prone genetic disorders tested including ataxia telangiectasia, Bloom's syndrome, Fanconi's anemia, xeroderma pigmentosum (XP), familial polyposis, Gardner's syndrome, hereditary malignant melanoma, dysplastic nevus syndrome and cancer family members. One exception was XP-A. In this report we add information on skin fibroblasts from retinoblastoma, Wilms' tumor and XP-C patients, 13 clinically normal controls and six cell lines from fetal or infant cells. Factors affecting the response are identified and include pH, temperature, cell density, culture medium or serum, microbial contamination and visible light exposure (effective wavelength 405 nm). Because of experimental variability, known normal controls should be used in each group of assays. With adequate control of the above factors this response could provide the basis of a test for detecting individuals carrying genes that predispose to a high risk of cancer.
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PMID:Factors affecting and significance of G2 chromatin radiosensitivity in predisposition to cancer. 256 34

We have developed a host cell reactivation assay of DNA repair utilizing UV-treated plasmid vectors. The assay primarily reflects cellular repair of transcriptional activity of damaged DNA measured indirectly as enzyme activity of the transfected genes. We studied three plasmids (pSV2cat, 5020 base pairs; pSV2catSVgpt, 7268 base pairs; and pRSVcat, 5027 base pairs) with different sizes and promoters carrying the bacterial cat gene (CAT, chloramphenicol acetyltransferase) in a construction that permits cat expression in human cells. All human simian virus 40-transformed cells studied expressed high levels of the transfected cat gene. UV treatment of the plasmids prior to transfection resulted in differential decrease in CAT activity in different cell lines. With pSV2catSVgpt, UV inactivation of CAT expression was greater in the xeroderma pigmentosum group A and D lines (D0 = 56 J X m-2) than in the other human cell lines tested (normal, ataxia-telangiectasia, Lesch-Nyhan, retinoblastoma)(D0 = 680 J X m-2)(D0 is the dose that reduces the percentage of CAT activity by 63% along the exponential portion of the dose-response curve). The D0 of the CAT inactivation curve was 50 J X m-2 for pSV2cat and for pRSVcat in the xeroderma pigmentosum group A cells. The similarity of the D0 data in the xeroderma pigmentosum group A cells for three plasmids of different size and promoters implies they all have similar UV-inactivation target size. UV-induced pyrimidine dimer formation in the plasmids was quantified by assay of the number of UV-induced T4 endonuclease V-sensitive sites. In the most sensitive xeroderma pigmentosum cells, with all three plasmids, one UV-induced pyrimidine dimer inactivates a target of about 2 kilobases, close to the size of the putative CAT mRNA.
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PMID:One pyrimidine dimer inactivates expression of a transfected gene in xeroderma pigmentosum cells. 299 75

Diseases associated with DNA and chromosomal instability, along with their underlying etiopathologic mechanisms, are among the most complex and poorly understood of any group of disorders known. Their pathogenesis is almost certainly intimately related to the most fundamental processes of life itself: the maintenance, replication, and expression of the genome. Include is a discussion of xeroderma pigmentosum, ataxia-telangiectasia. Cockayne's syndrome, Fanconi's anemia, retinoblastoma, and neurodegenerative diseases.
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PMID:Genetic diseases associated with DNA and chromosomal instability. 354 81

Retinoblastoma (RB) is a cancer of the retina which characteristically occurs in early childhood. Bilateral RB is an inherited form of this disease. Such patients are at greatly increased risk of subsequently developing second tumors in mesenchymal tissue, especially in areas exposed to ionizing radiation therapy. Fibroblasts from bilateral RB patients have been reported to be more sensitive than normal fibroblasts to the cytotoxic effects of ionizing radiation. Because xeroderma pigmentosum patients have a hereditary predisposition to UV-induced cancer and the cells of such patients are abnormally sensitive to the cytotoxic and mutagenic effects of UV radiation, we compared fibroblasts from 6 bilateral RB patients and 3 normal individuals for their sensitivity to the mutagenic effects of cobalt 60, using resistance to 6-thioguanine (TG) as the genetic marker. The results showed no statistically significant difference between the two types of cell lines. The slope of the weighted least squares line representing the frequency of TG-resistant cells induced in the RB populations as a function of dose was 17 +/- 6 (S.E.)/10(6) cells/Gy with an intercept of 0.09 Gy; that for the normal cells was 17 +/- 7/10(6) cells/Gy with an intercept of 0.14 Gy. We also compared 8 bilateral RB cell lines and 9 age-matched normal cell lines for their sensitivity to the cytotoxic effect of 60Co, using survival of colony-forming ability. The cloning efficiency of the unirradiated RB cell lines ranged from 22% to 76% with an average of 52%; that of the normal cell lines from 21% to 89% with an average of 64%. The results showed the RB cells were somewhat more sensitive than the normal cells. The mean D0 for the RB cell lines ranged from 0.99 +/- 0.01 (S.E.) to 1.69 +/- 0.04 Gy with a weighted average of 1.44 +/- 0.08 Gy; that of the normal cell lines ranged from 1.42 +/- 0.17 to 2.24 +/- 0.10 Gy, with a weighted average of 1.79 +/- 0.11 Gy. The difference in means was estimated to be 0.34 +/- 0.14. The mean for the RB cell lines is statistically significantly lower than the mean for the normal cell lines, at a significance level ca. 1%.
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PMID:Fibroblasts from patients with inherited predisposition to retinoblastoma exhibit normal sensitivity to the mutagenic effects of ionizing radiation. 376 76

Fibroblasts from patients with hereditary retinoblastoma reportedly exhibit increased sensitivity to killing by X-rays. Although some human syndromes with similar or greater hypersensitivity to DNA-damaging agents (e.g., X-rays, ultraviolet light, and chemical carcinogens), such as xeroderma pigmentosum, are deficient in DNA repair, most do not have such clearly demonstrable defects in repair. Retinoblastoma cells appear to be normal in repairing single-strand breaks and performing repair replication after X-irradiation and also in synthesizing poly(adenosine diphosphoribose). Semiconservative DNA replication in these cells, however, is slightly more resistant than normal after X-irradiation, suggesting that continued replication of damaged parental DNA could contribute to the pathogenesis of the disease. This effect is small, however, and may be a consequence rather than a cause of the fundamental enzymatic abnormality in retinoblastoma that causes the tumorigenesis.
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PMID:Repair and replication of DNA in hereditary (bilateral) retinoblastoma cells after X-irradiation. 706 11

gamma-Ray sensitivity for cell killing was assayed in 54 human cell strains, including some derived from individuals suffering from certain heritable diseases. The overall range of Do values in this study was 38 to 180 rads, indicating a considerable range of variability in humans. The normal sensitivity was described by a range of Do values of 97 to 180 rads. All ten ataxia telangiectasia cell strains tested proved radiosensitive and gave a mean Do value of 57 +/- 15 (S.E.) rads, and these represent the most radiosensitive human skin fibroblasts currently available. Representative cell strains from familial retinoblastoma, Fanconi's anemia, and Hutchinson-Gilford progeria occupied positions of intermediate sensitivity, as did one of two ataxia telangiectasia heterozygotes. Six xeroderma pigmentosum cell strains together with two Cockayne's syndrome cell strains (all known to be sensitive to ultraviolet light) fell into the normal range, indicating an absence of cross-sensitivity between ultraviolet light and gamma-irradiation.
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PMID:Survey of radiosensitivity in a variety of human cell strains. 747 Nov 6

The potential of enhanced chromatid damage, observed after X-irradiation of G2 phase, has been used to detect individuals genetically predisposed to cancer, utilising fibroblast/lymphocytes from these patients as well as fibroblasts derived from human tumours. Fibroblasts and/or lymphocyte samples of two autosomal recessive syndromes (xeroderma pigmentosum (XP), Fanconi's anaemia (FA)) and one congenital or acquired disorder, aplastic anaemia (AA), were employed for the G2 radiosensitivity assay. In addition, we have estimated the frequencies of spontaneously occurring chromosomal aberrations as well as G2 radiosensitivity of eight samples of fibroblasts/fibroblast-like cells (two normal, two colorectal carcinoma, two Wilms' tumour, one retinoblastoma and one polyposis coli), and three samples of lymphocytes (two normal and one from a lymphoma patient). The results obtained indicate that there were no differences between fibroblast cells derived from patients or tumours, except FA patients, in the frequency of spontaneously occurring chromosomal aberrations when compared to normal cells. Following X-irradiation we did not observe any significantly increased G2 radiosensitivity in FA and XP cells. Lymphocytes from AA and lymphoma patients, and all tumour cell lines except retinoblastoma, responded with increased frequencies of aberrations following G2 X-irradiation in comparison to cells derived from normal individuals. In our hands, the G2 sensitivity assay could not always discriminate cells from cancer-prone individuals from those of controls.
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PMID:G2 radiosensitivity of cells derived from cancer-prone individuals. 789 7

Hereditary cancers have been shown to develop through at least two mechanisms. Development of retinoblastoma and Wilms' tumor is usually not accompanied by other hereditary symptoms. Although they are inherited autosomal dominantly, gene mutations in recessive tumor suppressor genes were found to be responsible for these tumors. The other mechanism is the enhanced mutation in the cancer-prone hereditary diseases, such as xeroderma pigmentosum, Bloom's syndrome, etc. In xeroderma pigmentosum, for example, defects in DNA repair has been shown to enhance the frequency of mutation in the oncogenes and tumor suppressor genes. Recently, another repair-related mechanism, involving the mismatch repair, was found to be involved in the hereditary nonpolyposis colon cancer.
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PMID:[Mechanisms of hereditary tumorigenesis]. 853 18


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