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)

Xeroderma pigmentosum is an autosomal recessive, precancerous dermatosis caused by defective repair of ultraviolet-damaged DNA. Characterized clinically by progressive cutaneous pigmentary alterations and tumorigenesis, it serves as a model for ultraviolet carcinogenesis. We describe the clinical and histopathologic findings in a 31-year-old woman with xeroderma pigmentosum and a massive iris melanoma of the left eye. Histologic examination following enucleation revealed diffuse iris replacement by spindle and epithelioid cells with extension into the trabecular meshwork. Evidence of direct extraocular extension was absent, and a metastatic evaluation showed no abnormalities. To our knowledge, this is the first reported case of xeroderma pigmentosum complicated by melanoma of the iris. It provides further evidence suggesting a role for sunlight exposure in the pathogenesis of uveal melanoma.
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PMID:Malignant melanoma of the iris in xeroderma pigmentosum. 292 65

Cells derived from patients with xeroderma pigmentosum (XP) are known to be compromised in excision repair after u.v. irradiation, but the exact site of the molecular defect in the repair pathway is not known. The purpose of this study was to examine the ability of XP cells to alter their chromatin in preparation for excision repair. Treatment of quiescent normal human fibroblasts with u.v. light results in two types of chromatin changes that can be visualized in G1 phase prematurely condensed chromosomes (PCC): a generalized elongation of the G1 PCC, and regions of localized elongation or gaps. Quiescent XP cells (complementation groups A, C, D and G) were treated with u.v. light, and their G1 PCC were examined for chromatin changes in response to damage. All cell lines tested showed a normal generalized chromatin elongation response to u.v. treatment. However, the XP cell lines were found to be deficient in the generation of localized regions of decondensation, even when incubated after u.v. treatment in the presence of cytosine arabinoside and hydroxyurea. Since the regions of localized decondensation in the G1 PCC have been previously shown to be the sites of unscheduled DNA synthesis, these results suggest that while XP cells do exhibit a generalized chromatin response to u.v. irradiation, they are defective in their ability to alter the chromatin in a localized fashion in preparation for excision repair after u.v. irradiation.
Carcinogenesis 1986 Dec
PMID:Visualization of chromatin events during DNA excision repair in XP cells: deficiency in localized but not generalized chromatin events. 302 61

Recent studies by others have shown that the endonuclease complex coded for by the uvrA, uvrB and uvrC genes of Escherichia coli (UVR ABC excision nuclease) can incise DNA containing a variety of 'bulk-type' lesions, such as those resulting from u.v. light, (+/-)-7 alpha,8 beta-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE), and N-acetoxy-2-acetylaminofluorene. Using partially purified UVR ABC excision nuclease, we have quantitated the number of endonuclease sensitive sites (ESS) in purified DNA isolated from human fibroblasts treated with u.v. light or BPDE. The number of ESS/10(8) daltons of DNA were calculated from the number average mol. wt. of the DNA as determined by sedimentation in alkaline sucrose gradients. The number of endonuclease sites increased linearly with increasing doses of either u.v. light or BPDE. The UVR ABC excision nuclease was able to incise a majority of the BPDE-DNA adducts. Xeroderma pigmentosum fibroblasts, complementation group A (XP12BE) had 20-25% more ESS at each dose than the BPDE-treated normal (HSBP) cells. Cells treated with 4 microM BPDE and allowed 12 h of incubation to perform excision repair showed removal of 60% of the initial number of ESS from HSBP DNA and 40% of the ESS from XP-A DNA. Beyond 12 h XP12BE cells lost no additional ESS while HSBP cells continued to lose ESS, although at a slower rate, until at 48 h only 22% of the initial ESS remained. In cells treated with 10 J/m2 of u.v. light, the UVR ABC excision nuclease detected 60% of the sites recognized by the pyridimine dimer specific Micrococcus luteus glycosylase/apyrimidinic endonuclease. These results demonstrate the potential use of the UVR ABC excision nuclease in a quantitative assay for determining the number of carcinogen-induced lesions in human DNA.
Carcinogenesis 1986 Jan
PMID:Quantitation of carcinogen-induced DNA damage and repair in human cells with the UVR ABC excision nuclease from Escherichia coli. 308 Feb 55

Xeroderma pigmentosum (XP) variant cells are characterized by an abnormal pattern of replication of DNA damaged by 254 nm radiation (u.v.). To see whether benzo[a]pyrene-diol-epoxide-I (BPDE-I) elicits the same response, we have compared the effects of u.v. and BPDE-I on DNA replication in XP variant and normal skin fibroblasts. Doses of u.v. that only affected replicon initiation in normal cells, inhibited DNA strand growth in the XP variant. These results were confirmed by measurements of the rate of growth of single-stranded nascent DNA in cells synchronized at the beginning of the S phase. Identical analyses using BPDE-I, however, indicated that the two cell types were equally sensitive to the inhibitions of both replicon initiation and DNA strand growth. These results indicate that the XP variant phenotype cannot be recognized in vitro by the pattern of response of fibroblasts to the inhibition of DNA replication by BPDE-I.
Carcinogenesis 1986 Oct
PMID:Xeroderma pigmentosum variant and normal fibroblasts show the same response to the inhibition of DNA replication by benzo[a]pyrene-diol-epoxide-I. 309 15

The data in this paper show that when the inhibition of growth is measured, xeroderma pigmentosum (XP) complementation groups A, G and D are very sensitive to 4-nitroquinoline-1-oxide (4NQO), whereas only XP groups G and D are very sensitive to 3-methyl-4NQO (3me4NQO). Cells belonging to XP-C group are not particularly sensitive to either agent. Thus there are different epistasis groups for the excision repair of DNA adducts induced by these agents as opposed to the repair of u.v. damage. DNA polymerase alpha is involved in the repair of 4NQO-induced lesions because aphidicolin blocks their repair. XP cells from all the above groups are defective to some extent in this repair. The degree of repair defectiveness follows that seen after u.v., with even the XP-C cell line used having reduced repair (despite the fact that the inhibition of growth by 4NQO in this cell line was not markedly different from normal). Aphidicolin did not induce breaks in the normal or XP cell lines exposed to 3me4NQO, thus the repair of lesions induced by 3me4NQO does not involve DNA polymerase alpha in any of the cell lines. Finally, catalase reduces the alkaline labile lesions induced by 4NQO, but not 3me4NQO, suggesting the latter agent does not induce substantial amounts of DNA damage by the generation of radicals.
Carcinogenesis 1987 Aug
PMID:The response to DNA damage induced by 4-nitroquinoline-1-oxide or its 3-methyl derivative in xeroderma pigmentosum fibroblasts belonging to different complementation groups: evidence for different epistasis groups involved in the repair of large adducts in human DNA. 311 41

When dermal fibroblast strains derived from ataxia telangiectasia (AT) and clinically normal donors were exposed to 4-nitroquinoline 1-oxide (4NQO) and their DNA subjected to velocity sedimentation analysis in alkaline sucrose gradients, the incidence of single-strand interruptions detected in the AT strains (AT2BE, AT3BI and AT4BI) was 1.4-1.8 times higher than that seen in the seven normal controls. Cellular uptake of exogenous radiolabelled 4NQO occurred at similar rates in AT and control cultures, arguing against increased influx of the chemical as the root cause of the elevated yield of strand breakage in the former cultures. However, sonicates of each AT strain contained an enhanced capacity to catalyze the reduction of 4NQO to the proximate carcinogen 4-hydroxyaminoquinoline 1-oxide; the differences in bioreductase activity between AT and normal cell sonicates correlated closely with those for the incidence of DNA strand openings in 4NQO-treated cultures. Our data further indicated that these single-strand scissions, seen under alkaline conditions, are not manifestations of intermediate reactions in the multistep excision repair process operative on 4NQO lesions because: (i) the interruptions were observed at comparable levels in AT2BE and AT3BI cells, the former purportedly deficient and the latter proficient in 4NQO adduct removal; and (ii) cells known to be defective in repairing all types of 4NQO lesions, namely, xeroderma pigmentosum complementation group A fibroblasts, accumulated breaks at normal rates during 4NQO treatment. Consequently, these breaks appear to represent a class of 4NQO lesions which are themselves alkali-labile and therefore become converted to single-strand interruptions in vitro during exposure of DNA to alkali before velocity sedimentation. We conclude that AT strains tend to sustain abnormally high amounts of DNA damage upon 4NQO exposure due to an elevated capacity to bioactivate the inert parent compound into a proximate carcinogen.
Carcinogenesis 1988 Sep
PMID:Enhanced bioreduction of 4-nitroquinoline 1-oxide by cultured ataxia telangiectasia cells. 313 48

Using conventional alkaline sucrose sedimentation analysis, we have compared the initial yield and subsequent enzymatic repair of DNA damage induced in cultured human [normal (GM38 and GM43) and xeroderma pigmentosum (XP12BE)] fibroblasts by the monofunctional alkylating agent methylmethanesulfonate (MMS). Exposure of both cell types to MMS (0-20 mM) resulted in a linear dose-response relationship for the formation of DNA alkali-labile sites (i.e. structurally altered sites that appeared as single-strand interruptions at alkaline pH). The majority (approximately 90%) of the sites detected in the normal cells immediately after chemical treatment (less than or equal to 8 mM) disappeared rapidly, with a half-life of less than or equal to 3 h; the remainder, however, persisted in genomic DNA for at least 72 h. Approximately 40% of the alkali-labile sites induced by 5 mM MMS could be stabilized by methoxyamine, a chemical which is known to react with apurinic/apyrimidinic (AP) sites in DNA so as to prevent alkali-catalyzed beta-elimination; thus this fraction of the alkali-labile sites, which is estimated to constitute approximately 4% of the total genomic injury inflicted by the chemical, may be ascribable to AP sites. XP12BE cells responded normally to MMS exposure as judged by: (i) the rate of initial induction of alkali-labile sites, including those (AP sites) subject to methoxyamine stabilization; (ii) the incidence of alkali-labile sites in cellular DNA at various times (0-72 h) after administration of the alkylating agent; and (iii) the capacity to execute the long-patch mode of excision repair as measured by accumulation of 1-beta-D-arabinofuranosylcytosine-induced strand breaks during post-treatment cell incubation. In addition, we have found that a significant portion of the genetic material in human fibroblasts undergoes degradation upon sustaining MMS damage, as indicated by the appearance of small DNA fragments (sedimenting near the top of alkaline sucrose gradients) in chemically treated cultures incubated for 24 h. Interestingly, the extent of this type of DNA injury proved to be markedly greater in XP12BE than in GM38 cells, and in exponentially growing than in G2-arrested normal cultures.
Carcinogenesis 1988 Dec
PMID:Methylmethanesulfonate-induced DNA damage and its repair in cultured human fibroblasts: normal rates of induction and removal of alkali-labile sites in xeroderma pigmentosum (group A) cells. 319 70

A monoclonal antibody specific for u.v.-induced thymine-thymine dimers in single-stranded DNA has been used in an enzyme immunoassay to investigate the loss of antigenicity associated with repair of this lesion in the first 2 h following 10 J/m2 254 nm radiation. Variances of +/- 10% for the method and +/- 6.5% for individuals were established using primary cultures of biopsies from healthy individuals. No differences in the rate of loss of antigenicity was observed between 20 normal lymphocyte samples and 10 normal skin biopsies. Of three xeroderma pigmentosum (XP) variant cell lines tested, GM3617 could not be distinguished from normal cells but GM1227 and GM3053 showed lower rates of loss than any of the healthy samples. When the group mean values were compared there was no significant difference between normals and biopsies from sun-shielded skin areas from 16 basal cell carcinomas but similar material from 10 melanoma patients showed a significantly reduced (P = 0.001) rate of loss of antigenicity. Since the rate of loss of antigenicity in normal and XP variant cells reflected their relative abilities to perform unscheduled DNA synthesis, our results suggest that some melanoma patients may also have a minor deficiency in an early stage of excision repair.
Carcinogenesis 1987 Sep
PMID:Immunochemical determination of an initial step in thymine dimer excision repair in xeroderma pigmentosum variant fibroblasts and biopsy material from the normal population and patients with basal cell carcinoma and melanoma. 330 92

In light of recent studies implicating low catalase activities in the pathogenesis of the cancer-prone disease xeroderma pigmentosum (XP) we have measured catalase activity, protein levels, and mRNA concentrations in six XP fibroblast strains and three normal controls. Only one XP strain of complementation group A (XP1223) possessed significantly lower catalase by all three criteria. The other five XP strains (two XP variants, two strains of complementation group D, and one strain of complementation group C) possessed catalase levels which fell into the range of the interindividual variations of normal controls. We further assessed the total enzymatic antioxidant defense status by measuring the levels of copper, zinc, and manganese superoxide dismutase and glutathione peroxidase. None of these enzymes showed significant deviations from controls in XP cells. Our results do not support the notion that a deficient enzymatic antioxidant defense facilitates the establishment of a prooxidant state in XP upon exposure to near-UV. However, they do not argue against the participation of active oxygen in near-UV-induced carcinogenesis in XP.
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PMID:Antioxidant enzymes in xeroderma pigmentosum fibroblasts. 334 84

We utilized a plasmid vector host cell reactivation assay to probe the biological functioning of DNA expression vectors and their encoded genes. We studied the effect of ultraviolet radiation or acid-heat treatment on the transient expression of genes transfected into normal human cells and into DNA repair deficient (xeroderma pigmentosum) cells and modification of gene expression by sodium butyrate. U.v. inactivation of transient expression of the bacterial gpt gene contained in a non-replicating expression vector plasmid, pSV2catSVgpt, was much greater in three xeroderma pigmentosum lines than in the four other human cell lines tested. In contrast, treatment of pSV2catSVgpt with acid and heat to produce apurinic sites resulted in a similar slope of the inactivation curve of the bacterial cat gene in the repair deficient and repair proficient cells. Thus, u.v. damage of DNA expression vectors was subject to repair by the normal host cells, but acid-heat treatment resulted in damage (apurinic sites) that was handled in a similar manner by excision repair deficient and excision repair proficient human cells. In both normal and xeroderma pigmentosum cells sodium butyrate treatment of cells resulted in a greater stimulation of chloramphenicol acetyltransferase expression with u.v. damaged than with undamaged plasmid. This assay thus permits examination of the effects of defined types of DNA damage on plasmid expression and study of its modulation by cellular repair activities.
Carcinogenesis 1986 Oct
PMID:Host cell reactivation by human cells of DNA expression vectors damaged by ultraviolet radiation or by acid-heat treatment. 346 38


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