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)

The phage T4 denV gene, coding for the pyrimidine-dimer specific T4 endonuclease V, was transfected into human repair-proficient fibroblasts, repair-deficient xeroderma pigmentosum fibroblasts, and into wild type CHO hamster cells. Transfectants maintained denV DNA and expressed denV mRNA. Purified T4 endonuclease V encapsulated in liposomes was also used to treat repair-proficient and -deficient human cells. The denV transfected clones and liposome-treated cells showed increased unscheduled DNA synthesis and enhanced removal of pyrimidine dimers compared to controls. Both denV gene transfection and endonuclease V liposome treatment enhanced post-UV survival in xeroderma pigmentosum cells but had no effect on survival in repair-proficient human or hamster cells. The results demonstrate that an exogenous DNA repair enzyme can correct the DNA repair defect in xeroderma pigmentosum cells and enhance DNA repair in normal cells.
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PMID:Enhancement of ultraviolet-DNA repair in denV gene transfectants and T4 endonuclease V-liposome recipients. 166 12

Epidermal keratinocytes cultured from explants of skin cancer patients, including biopsies from xeroderma pigmentosum patients, were ultraviolet light-irradiated and DNA repair synthesis was measured. Repair capacity was much lower in xeroderma pigmentosum patients than in normal patients. The extent of DNA repair replication did not decline with the age of the normal patient. Treatment with T4N5 liposomes containing a DNA repair enzyme enhanced repair synthesis in both normal and xeroderma pigmentosum keratinocytes in an irradiation- and liposome-dose dependent manner. These results provide no evidence that aging people or skin cancer patients are predisposed to cutaneous malignancy by a DNA repair deficiency, but do demonstrate that T4N5 liposomes enhance DNA repair in the keratinocytes of the susceptible xeroderma pigmentosum and skin cancer population.
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PMID:Enhanced unscheduled DNA synthesis in UV-irradiated human skin explants treated with T4N5 liposomes. 205 85

Xeroderma pigmentosum (XP) is a rare genetic disease in which patients are defective in DNA repair and are extremely sensitive to solar UV radiation exposure. A new treatment approach was tested in these patients, in which a prokaryotic DNA repair enzyme specific for UV-induced DNA damage was delivered into the skin by means of topically applied liposomes to supplement the deficient activity. Acute and chronic safety testing in both mice and humans showed neither adverse reactions nor significant changes in serum chemistry or in skin histology. The skin of XP patients treated with the DNA repair liposomes had fewer cyclobutylpyrimidine dimers in DNA and showed less erythema than did control sites. The results encourage further clinical testing of this new enzyme therapy approach.
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PMID:Enzyme therapy of xeroderma pigmentosum: safety and efficacy testing of T4N5 liposome lotion containing a prokaryotic DNA repair enzyme. 895 62

A new approach to photoprotection is to repair DNA damage after UV exposure. This can be accomplished by delivery of a DNA repair enzyme with specificity to UV-induced cyclobutane pyrimidine dimers into skin by means of specially engineered liposomes. Treatment of DNA-repair-deficient xeroderma pigmentosum patients or skin cancer patients with T4N5 liposome lotion containing such DNA repair liposomes increases the removal of DNA damage in the first few hours after treatment. In these studies, a DNA repair effect was observed in some patients treated with heat-inactivated enzyme. Unexpectedly, it was discovered that the heat-inactivated T4 endonuclease V enzyme refolds and recovers enzymatic activity. These studies demonstrate that measurements of molecular changes induced by biological drugs are useful adjuvants to clinical studies.
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PMID:Photoprotection by topical DNA repair enzymes: molecular correlates of clinical studies. 1004 8

Carboxymethylating agents are potential sources of endogenous DNA damage that have been proposed as possible contributors to gastrointestinal carcinogenesis. The cytotoxicity of the model DNA carboxymethylating agent azaserine was investigated in human cells. Expression of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) did not affect sensitivity to the drug in two related Raji Burkitt's lymphoma cell lines. DNA mismatch repair-defective variants of Raji cells which display increased tolerance to DNA methylation damage were not selectively resistant to azaserine. Complementary results were obtained with a second carboxymethylating agent, potassium diazoacetate. In contrast, lymphoblastoid cell lines representative of each of the xeroderma pigmentosum complementation groups, including the variant, were all significantly more sensitive to azaserine than nucleotide excision repair-proficient cells. The hypersensitivity of XP cells was not due to systematic differences in the concentrations of intracellular thiol compounds or related thiol metabolizing enzymes. The data indicate that of the two types of potentially lethal DNA damage which azaserine introduces, carboxymethylated bases and O(6)-methylguanine, the former are repaired by nucleotide excision repair and are a more significant contributor to azaserine lethality in human cells.
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PMID:The cytotoxicity of DNA carboxymethylation and methylation by the model carboxymethylating agent azaserine in human cells. 1046 34

Interaction of DNA repair proteins with damaged DNA in eukaryotic cells is influenced by the packaging of DNA into chromatin. The basic repeating unit of chromatin, the nucleosome, plays an important role in regulating accessibility of repair proteins to sites of damage in DNA. There are a number of different pathways fundamental to the DNA repair process. Elucidation of the proteins involved in these pathways and the mechanisms they utilize for interacting with damaged nucleosomal and nonnucleosomal DNA has been aided by studies of genetic diseases where there are defects in the DNA repair process. Two of these diseases are xeroderma pigmentosum (XP) and Fanconi anemia (FA). Cells from patients with these disorders are similar in that they have defects in the initial steps of the repair process. However, there are a number of important differences in the nature of these defects. One of these is in the ability of repair proteins from XP and FA cells to interact with damaged nucleosomal DNA. In XP complementation group A (XPA) cells, for example, endonucleases present in a chromatin-associated protein complex involved in the initial steps in the repair process are defective in their ability to incise damaged nucleosomal DNA, but, like the normal complexes, can incise damaged naked DNA. In contrast, in FA complementation group A (FA-A) cells, these complexes are equally deficient in their ability to incise damaged naked and similarly damaged nucleosomal DNA. This ability to interact with damaged nucleosomal DNA correlates with the mechanism of action these endonucleases use for locating sites of damage. Whereas the FA-A and normal endonucleases act by a processive mechanism of action, the XPA endonucleases locate sites of damage distributively. Thus the mechanism of action utilized by a DNA repair enzyme may be of critical importance in its ability to interact with damaged nucleosomal DNA.
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PMID:DNA repair and chromatin structure in genetic diseases. 1050 34

Xeroderma pigmentosum (XP) is an autosomal recessive photosensitive disorder with an extremely high incidence of UV-related skin cancers associated with impaired ability to repair UV-induced DNA damage. There are seven nucleotide excision repair (NER) complementation groups (A through G) and an NER proficient form (XP variant). XPA, B, D and G patients may also develop XP neurological disease. The laboratory diagnosis of XP can be performed by autoradiography. Recently, the isolation and characterization of the genes responsible for XP have made it possible to use molecular biological techniques to diagnose XP patients, for carrier detection and for prenatal diagnosis, especially in Japanese XPA patients. These techniques include polymerase chain reaction (PCR) and plasmid host cell reactivation assays with cloned XP genes. DNA damage is not repaired by the NER system equally throughout the genome. There are two DNA repair pathways: 1) transcription-coupled repair, and 2) global genome repair. Many factors involved in these pathways are related to the pathogenesis of XP and a related photosensitive disease, Cockayne syndrome. Clinical management consists of early diagnosis followed by a rigorous program of sun protection including avoidance of unnecessary UV exposure, wearing UV blocking clothing, and use of sunblocks on the skin. Although there is no cure for XP, the efficacy of oral retinoids for the prevention of new skin cancers, local injection of interferon, and the external use of a prokaryotic DNA repair enzyme have been reported.
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PMID:Xeroderma pigmentosum--bridging a gap between clinic and laboratory. 1133 1

The goal of DNA repair enzyme therapy is the same as that for gene therapy: to rescue a defective proteome/genome by introducing a substitute protein/DNA. The danger of inadequate DNA repair is highlighted in the genetic disease xeroderma pigmentosum. These patients are hypersensitive to sunlight and develop multiple cutaneous neoplasms very early in life. The bacterial DNA repair enzyme T4 endonuclease V was shown over 25 years ago to be capable of reversing the defective repair in xeroderma pigmentosum cells. This enzyme, packaged in an engineered delivery vehicle, has been shown to traverse the stratum corneum, reach the nuclei of living cells of the skin, and enhance the repair of UV-induced cyclobutane pyrimidine dimers (CPD). In such a system, changes in DNA repair, mutagenesis, and cell signaling can be studied without manipulation of the genome.
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PMID:Enhanced DNA repair of cyclobutane pyrimidine dimers changes the biological response to UV-B radiation. 1242 41

Xeroderma pigmentosum is based on a genetic defect in the DNA repair system, which is diagnosed in early childhood. Xeroderma pigmentosum is a rare disorder, which is transmitted in an autosomal recessive manner. Children with xeroderma pigmentosum display hypersensitivity to ultraviolet (UV) radiation. These patients experience serious sunburns with minimal exposure and then develop poikiloderma in the sun-exposed areas. Squamous cell carcinomas, basal cell carcinomas and malignant melanomas all appear during childhood. The majority of patients do not reach adult, but die from metastatic cutaneous malignancies. Genetically, xeroderma pigmentosum is differentiated into 7 complementation groups (XP-A to XP-G) and the xeroderma pigmentosum variants (XP-V). The assignment to the specific complementation group is made by fusing of xeroderma pigmentosum fibroblasts. Xeroderma pigmentosum must be distinguished from other so-called DNA repair deficiency syndromes, including Cockayne syndrome and trichothiodystrophy. A topical DNA repair enzyme appears to be helpful. A recombinant liposomal encapsulated T4 endonuclease V repairs UV-induced cyclobutane-pyrimidine dimers. Direct curative treatment of xeroderma pigmentosum could be achieved with gene therapy in future. Transfection of an intact repair gene which specifically codes for the missing repair protein could open new possibilities in the therapy of xeroderma pigmentosum.
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PMID:[Xeroderma pigmentosum: children of the moon]. 1628 94

The association between oxidative or ultraviolet (UV) light induced DNA damage in the lens epithelium and the development of lens opacities, and the existence of DNA repair in lens epithelial cells have been reported. Polymorphisms of DNA repair enzymes may affect repair efficiency. In this study, we aimed to determine the frequency of polymorphisms in two DNA repair enzyme genes, xeroderma pigmentosum complementation group D (XPD) codon 751 and X-ray cross-complementing group 1 (XRCC1) codon 399, in a sample of Turkish patients with maturity onset cataract. By using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), we analysed XRCC1-Arg399Gln and XPD-Lys751Gln polymorphisms in 195 patients with cataract (75 patients with cortical, 53 with nuclear, 37 with posterior subcapsular, and 30 with mixed type) and in 194 otherwise healthy control group of similar age. There was a significant difference between frequencies for XPD-751 Gln/Gln genotype in cataract patients (12%) and healthy controls (20%) (P=0.008, OR=0.40, 95% CI=0.20-0.81). After stratification by the cataract subtypes, XPD-751 Gln/Gln genotype was found to be significantly different in patients with cortical (4%) type cataract in respect to control subjects (20%) (P=0.038, OR=0.16, 95% CI=0.04-0.64). In addition, the allele frequency of the C (Gln)-allele of XPD-Lys751Gln was found to be significantly different in mixed type cataract group (P=0.008, OR=0.48, 95% CI: 0.26-0.90). No statistically significant difference was found for the genotypic and allelic distributions of the polymorphisms in XRCC1 gene between the groups. These findings suggest that polymorphism in XPD codon 751 may be associated with the development of maturity onset cataract.
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PMID:Polymorphisms of DNA repair genes XPD and XRCC1 and risk of cataract development. 1763 62


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