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)

Cytogenetic investigation was carried out on fibroblasts stored in liquid nitrogen during a period of 7-99 months. Cell strains were from 9 individuals, 2 of whom were affected by xeroderma pigmentosum group C (XPC), and 2 XPC heterozygotes. In cell samples from 3 normal subjects and from 1 patient, high frequencies of abnormal mitoses were observed at the first passage after thawing, which returned to normal values after a few subcultures. The most frequent lesions were chromosome gaps and breaks. The cells damaged the most were those from one XP patient. These findings indicate that cells from some individuals are hypersensitive to clastogenic factors acting during freezing and thawing procedures. This sensitivity could be related to the genetic constitution, although the XP homozygous condition is not an essential or sufficient factor.
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PMID:Different rate of chromosome breakage in human fibroblast strains after storage in liquid nitrogen. 137 88

The aromatic N-heterocyclic 7H-dibenzo(c,g)carbazole (DBC), like polynuclear aromatic hydrocarbons, is a potent inducer of local sarcomas, papillomas, and respiratory tumors, but unlike such compounds it also induces hepatomas. The N-methyl derivative of DBC, N-methyl-dibenzo(c,g)carbazole (MeDBC), also induces sarcomas, papillomas, and respiratory tumors but at a lower frequency than DBC. However, MeDBC lacks hepatocarcinogenic potential, suggesting that DBC undergoes metabolic activation at its carbon atoms and also at the nitrogen position and that the N-7 position plays a role in liver carcinogenesis by DBC. We compared the cytotoxic and mutagenic potential of DBC and MeDBC using a human epithelial cell-mediated activation assay. Repair-deficient, diploid human fibroblasts derived from a xeroderma pigmentosum (XP) patient were used as target cells, and a human hepatoma cell line, Hs703T, was used as a source of exogenous metabolism. Resistance to 6-thioguanine served as the genetic marker for mutations. The Hs703T cells, but not the target XP cells, activated DBC and MeDBC into forms capable of interacting with DNA. In the cell-mediated assay, both DBC and MeDBC induced cytotoxicity and mutations in the target XP cells in a dose-dependent manner. However, DBC was effective at 2-fold lower concentrations than MeDBC. DNA adduct analysis using a 32P-postlabeling assay showed that at biologically significant low doses DBC was 2.5 times more effective than MeDBC in covalent binding to DNA. At higher doses, the difference in ability to bind to DNA was 1.3-fold. In both XP and Hs703T cells, DBC produced three major adducts, while MeDBC produced two major adducts, one of which was the same as one detected in the DBC adduct pattern. The number of DBC- and MeDBC-induced DNA adducts corresponding to a particular level of cytotoxicity and mutagenicity in the XP cells was 10 times lower than that for (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene.
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PMID:Human cell-mediated cytotoxicity, mutagenicity, and DNA adduct formation of 7H-dibenzo(c,g)carbazole and its N-methyl derivative in diploid human fibroblasts. 373 Nov 21

Cytogenetic damage was investigated in long term lymphoid cell lines derived from normal individuals, patients with Fanconi's anemia (FA), ataxia telangiectasia (AT), xeroderma pigmentosum (XP), and FA heterozygotes. The cell lines were exposed to various concentrations of four chemical clastogens, including the alkylating agents diepoxybutane, mitomycin C, and nitrogen mustard, as well as the antitumor glycopeptide bleomycin. The FA cells exhibited chromosomal hypersensitivity to all four clastogens and could be distinguished from the other genotypes. AT cells were identified by bleomycin, while FA heterozygotes could not be reliably detected. Discriminant function analysis was used to describe the cytogenetic response to the various clastogens. This method might prove useful for evaluation and classification of multivariate chromosome breakage studies.
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PMID:The cytogenetic response of Fanconi's anemia lymphoblastoid cell lines to various clastogens. 618 57

Nonmelanoma skin cancers, like most malignancies, increase in incidence with increasing age. However, in general they are not due to the aging process but are primarily due to solar radiation. Clinically, squamous cell carcinomas and basal cell epitheliomas are the most common cancers that occur in the Caucasian population in the United States. The role of radiation from the sun was suggested by a number of astute clinical observations reported around 1900 and subsequently has been established by epidemiologic and experimental studies. Action spectrum evaluations indicate that the ultraviolet B (UVB) rays are the most carcinogenic. However, recent studies indicate that the UVA rays can augment the cancer-producing effects of UVB rays. Other physical stimuli, including heat and wind, can also accelerate UVB carcinogenesis. Chemicals such as the polycyclic hydrocarbons, the nitrosoureas, and nitrogen mustard have an additive carcinogenic effect with UVB radiation. Also, some chemicals such as croton oil, the phorbol ester--TPA, and all-trans-retinoic (RA) acid can promote UVB-initiated carcinogenesis. RA can also inhibit UVB-induced cancer formation. The role of the immune status has received a great deal of attention. Both in experimental and clinical situations, nonspecific immune suppression results in increased cancer formation. Also, recent studies indicate that a specific T cell suppressor population can be induced in experimental animals with UVB which will inhibit rejection of tumors produced by UVB radiation. Finally, damage to DNA by UVB radiation is well established. Studies with the genetic disease xeroderma pigmentosum support the concept that such damage, if not repaired, will lead to cancer formation. It also has been suggested that unrepaired damage to deoxyribonucleic (DNA) and other macromolecules is at least in part responsible for the aging process in general.
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PMID:Photocarcinogenesis, skin cancer, and aging. 635 13

In order to develop the usefulness of Fanconi's anemia (FA) lymphoblast lines for biochemical and genetic studies, we have determined their sensitivity to a variety of DNA-damaging chemicals. We have adapted a growth inhibiton protocol in which the sensitivity of a cell line is characterized by the drug concentration yielding a 50% inhibiton of growth (EC50). The DNA-cross-linking agents, mitomycin C, nitrogen mustard, melphalan, 1,3-butadiene diepoxide, cis-diaminedichloroplatinum(II), and cyclophosphamide, were all more toxic to four FA cell lines than to five normal lines. Three lines, HSC 72 (FA), 99 (FA) and 230 (FA), had EC50s that were 10 to 20 times lower than that of controls while the fourth line, HSC 62 (FA), had an intermediate EC50. Three nitrosourea compounds were also more toxic to FA cells than to controls. However, 2 normal cell lines (HSC 92 and 93) had nitrosourea EC50s 4 to 7 times lower than the other nine controls and overlapped the sensitivity of the intermediate [HSC 62 (FA)] cell line. The same 2 normal cell lines were also more sensitive than 12 other controls, including FA heterozygotes, xeroderma pigmentosum, and ataxia telangiectasis, to the monofunctional alkylating agents, ethyl methane sulfonate, methyl methane sulfonate, and N-methyl-N'-nitro-N-nitrosoguanidine. Heterogeneity was also found with FA lines. Two FA cell lines (HSC 72 and 230) had EC50s lower than all control lines while one FA line (HSC 99) had an EC50 similar to that of the resistant normal lines. FA and normal cells had nearly the same sensitivity to 4-nitroquinoline-1-oxide and bleomycin. These results demonstrate that FA lymphoblast lines are more sensitive than normal cell lines to all DNA-cross-linking agents examined. These cell lines should therefore be useful for the analysis of DNA cross-link repair and the biochemical defect in FA. We have also found an unexpected sensitivity of some FA and normal lines to monofunctional alkylating agents.
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PMID:Susceptibility of Fanconi's anemia lymphoblasts to DNA-cross-linking and alkylating agents. 680 8

A 37-year-old, white woman with xeroderma pigmentosum had reduced vision for many years because of primary and secondary corneal epithelial edema and stromal haze. Corneal grafting was required, but was not successful. Numerous primary dermal tumors of various types involving the lids of both eyes had been excised surgically or treated by freezing with liquid nitrogen. Squamous cell carcinomas involving the limbal area of the globe and adjacent tissues were excised from the left eye at age 12, the right eye at age 32, and the left eye (again) at age 36. The right limbal tumor soon recurred and invaded the orbit despite radiation treatment; this required right orbital exenteration. The second left limbal tumor recurred one year later, soon after the recurrence of a left lower lid basal cell carcinoma. Left orbital exenteration was required. Corneal graft failures and recurrent ocular squamous cell carcinoma involving the eye in xeroderma pigmentosum can be difficult management problems.
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PMID:Ocular involvement in xeroderma pigmentosum. 713 43

Xeroderma pigmentosum complementation group E binding factor (XPE-BF) is a damaged DNA binding protein that is deficient in a subset of patients from complementation group E of xeroderma pigmentosum. The protein recognizes various forms of DNA damage including some cyclobutane pyrimidine dimers, 6-4 photoproducts, cis-diamminedichloroplatinum(II) adducts, and single-stranded DNA. We now show that it also recognizes damage induced by nitrogen mustard; N-methyl-N'-nitro-N-nitrosoguanidine, and depurination, but has no detectable affinity for DNA adducts generated by trans-diamminedichloroplatinum(II), 4-nitroquinoline-N-oxide, 8-methoxypsoralen, or enzymatically methylated cytosine and adenine. The failure to recognize 4-nitroquinoline-N-oxide and 8-methoxypsoralen adducts is consistent with previous reports that XPE cells carry out wild-type levels of repair synthesis after DNA damage by those drugs. These results demonstrate that XPE-BF is a versatile damage recognition protein, but suggest that other proteins must contribute to the recognition of DNA lesions for the human excision repair pathway.
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PMID:Xeroderma pigmentosum group E binding factor recognizes a broad spectrum of DNA damage. 752 88

Sun exposure is clearly implicated in premature skin ageing and neoplastic development. These features are exacerbated in patients with Xeroderma pigmentosum (XP), a hereditary disease associated at the cellular level with DNA repair defects and a low catalase activity. The implications of oxidative stress in the defects and cancer proneness of XP skin cells (keratinocytes, fibroblasts) are multiple and remain unclear. They were investigated here at the level of a single fibroblast by an electrochemical method based on microelectrodes we have developed previously. These microelectrodes permit a real-time quantification and identification of superoxide and nitric oxide derivatives (H2O2, ONOO-, NO*, NO2-) released by a living cell following its stimulation. Then, the oxidative bursts produced by fibroblasts from normal strains were compared with those of fibroblasts from several XP group A (XPA) and XP group D (XPD) strains. All XPA and XPD strains provided responses of higher amplitude and duration than controls. The XP specific oxidative response could not be correlated with DNA repair ability since the transduction of XPD strains with the wild-type XPD gene did not modify their production of reactive oxygen and nitrogen species. The nature of these species was investigated and revealed that cancer prone XPD fibroblasts produced higher amounts of O2*- and H2O2 and lower amounts of NO* and ONOO than normal fibroblasts.
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PMID:Oxidative stress in cancer prone xeroderma pigmentosum fibroblasts. Real-time and single cell monitoring of superoxide and nitric oxide production with microelectrodes. 1468 28

Xeroderma pigmentosum (XP) is characterised by defects in nucleotide excision repair, ultraviolet (UV) radiation sensitivity and increased skin carcinoma. Compared to other complementation groups, XP-F patients show relatively mild cutaneous symptoms. DNA interstrand cross-linking agents are a highly cytotoxic class of DNA damage induced by common cancer chemotherapeutics such as cisplatin and nitrogen mustards. Although the XPF-ERCC1 structure-specific endonuclease is required for the repair of ICLs cellular sensitivity of primary human XP-F cells has not been established. In clonogenic survival assays, primary fibroblasts from XP-F patients were moderately sensitive to both UVC and HN2 compared to normal cells (2- to 3-fold and 3- to 5-fold, respectively). XP-A fibroblasts were considerably more sensitive to UVC (10- to 12-fold) but not sensitive to HN2. The sensitivity of XP-F fibroblasts to HN2 correlated with the defective incision or 'unhooking' step of ICL repair. Using the comet assay, XP-F cells exhibited only 20% residual unhooking activity over 24 h. Over the same time, normal and XP-A cells unhooked greater than 95% and 62% of ICLs, respectively. After HN2 treatment, ICL-associated DNA double-strand breaks (DSBs) are detected by pulse field gel electrophoresis in dividing cells. Induction and repair of DNA DSBs was normal in XP-F fibroblasts. These findings demonstrate that in primary human fibroblasts, XPF is required for the unhooking of ICLs and not for the induction or repair of ICL-associated DNA DSBs induced by HN2. In terms of cancer chemotherapy, people with mild DNA repair defects affecting ICL repair may be more prevalent in the general population than expected. Since cellular sensitivity of primary human fibroblasts usually reflects clinical sensitivity such patients with cancer would be at risk of increased toxicity.
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PMID:Chemosensitivity of primary human fibroblasts with defective unhooking of DNA interstrand cross-links. 1718 78

Nonmelanoma skin cancer (NMSC) is the most common type of human cancer. Solar ultraviolet radiation (UVR) is the main causative factor in the development of NMSC. UVR plays a variety of roles in the induction of skin cancers. It can serve as a complete carcinogen or as a promoter of carcinogenesis. The typical UV-induced DNA damage is the generation of dimeric photoproducts between adjacent pyrimidine bases. Tumor suppressor gene p53 is a common target of UVR-induced mutations. There is a proliferative advantage of p53 mutant keratinocytes over normal keratinocytes that eventuates in neoplastic transformation. While UVB causes considerable DNA damage in the skin, UVA has only recently been shown to induce pyrimidine dimers and oxygen and nitrogen reactive species which damage DNA, proteins and lipids. The immunosuppressive effect of UVR contributes to its carcinogenic activity. Finally, any one of these effects of UVR may contribute to the induction of skin cancers by other agents such as X-rays, viruses, or chemical carcinogens. The mechanism by which UVR leads to cutaneous malignant melanoma is less clear and it may be a cofactor rather than an initiator of this tumor. Primary prevention of UVR exposure is the most effective means of reducing UVR carcinogenesis. Systemic retinoids may influence the appearance of new tumors in patient populations at increased risk of developing NMSC such as xeroderma pigmentosum and organ transplant recipients, but their efficacy is hindered by their side effects.
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PMID:Ultraviolet radiation and cutaneous carcinogenesis. 1764 87


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