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  • 1
    ISSN: 1432-069X
    Keywords: Dermatologic, ophthalmologic, neurologic findings in XP patients ; Skin tumors ; DNA repair ; Colony-forming ability ; Unscheduled DNA synthesis ; Complementation groups
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Dermatologic, ophthalmologic, and neurologic examinations were carried out on 33 patients with clinical symptoms of xeroderma pigmentosum (XP). Complementation groups were determined for 23 patients. Types of tumors and complementation group were found to be related in the following way: In the XP variant groups basaliomas were the most frequently occurring malignant tumors, whereas in the D group pigmentary tumors, such as melanotic precanceroses and melanomas prevailed; in the A and the C group, spinaliomas seem to be the most frequent malignomas. The DNA repair activity was measured using colony-forming ability and unscheduled DNA synthesis. Colony-forming ability was quantitated as a function of 12 different UV doses and expressed in terms of D0. Unscheduled DNA synthesis was determined autoradiographically by establishing dose-response curves, which analyzed by the characteristic value of linear regression. G0, defined as the linear increase in the mean number of silver grains per nucleus when the UV dose is multiplied by the factor of e (i. e., 2.72), was derived from the slopes of the regression lines. The repair capability of XP fibroblast lines was classified on the basis of D0 and G0.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1335
    Keywords: DNA repair capacity ; Normal and xeroderma pigmentosum fibroblasts ; Alkaline elution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary DNA repair capacity was investigated in 25 normal and XP fibroblast lines after UV damage was induced, using the following methods: colonyforming ability, unscheduled DNA synthesis, and alkaline elution (which can serve as a measure of repair-specific DNA incision). The majority of the XP fibroblast lines was derived from biopsies of patients who are at present under clinical observation by Dr. E.G. Jung (Dept. of Dermatology, Mannheim Medical School). Colony-forming ability was determined at 12 different UV dose levels and expressed in terms of D 0. Unscheduled DNA synthesis was measured autoradio-graphically. Dose-response curves (grains per nucleus versus UV dose) were established and analyzed by linear regression. The characteristic value of G 0, defined as the linear increase in the mean number of grains per nucleus when the UV dose is multiplied by the factor e (i.e., 2.72), was derived from the slope of the regression lines. For quantitating DNA-incising activity of a cell line, DNA elution curves were determined at several UV dose levels. Plotting of the initial velocities of the elution curves versus the UV doses yielded a regression line, the slope of which was used to obtain the characteristic elution value, E 0. A descriptive correlation of all three characteristic values, D 0, G 0 and E 0, showed that in all cell lines in which colony-forming ability and unscheduled DNA synthesis were diminished, a reduction of DNA-incising activity occurred. We conclude that this reduction accounts for both the decreased colony-forming ability and unscheduled DNA synthesis.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1335
    Keywords: DNA repair ; Colony-forming ability ; 6-Methylguanine-DNA methyltransferase ; 6-Methylguanine ; 6-Methylguanosine ; HECNU
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The XP cell strain XP29MA, its malignant counterpart XP29MAmal and a normal human fibroblast strain were tested for colony-forming ability after treatment with HECNU in the presence of m6G, m6Gua, and he7G. In XP29MAmal, inhibition of post-HECNU colony-forming ability was 35% when 0.25 mM of either m6G or m6Gua were present, whereas in XP29MA and the normal fibroblast strain no inhibition was detected. The he7G caused a similar but smaller inhibitory effect in XP29MAmal, but failed to do so in XP29MA. HECNU predominantly exerts its killing effect by alkylating O-6 of DNA-bound guanine and causing DNA interstrand crosslinks. Alkylation of O-6 of guanine can be repaired by 6-methylguanine-DNA methyltransferase. From our experiments we conclude that in XP29MAmal this methyltransferase was inhibited in the presence of the 6-alkylguanines, thus leaving more 2-chloroethylated sites in DNA unrepaired. This results in sensitization in terms of decreased colony-forming ability observed only in the malignant cell line.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1335
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The DNA-incising capacity was determined in 8 normal and 23 XP fibroblast strains of the Mannheim XP collection using the alkaline elution technique after treatment with both UV light and the “UV-like” carcinogen (Ac)2ONFln. Experimental conditions were chosen to allow for selective monitoring of repair-specific enzyme-catalyzed breaks. In order to compare DNA-incising capacities of the various cell strains after UV irradiation with those after treatment with (Ac)2ONFln, dose-response experiments including up to 8 dose levels were performed. The elution curves were analyzed by linear regression analysis. Elution velocities (in terms of DNA singlestrand breaks per 106 nucleotides) were plotted against the square root of the doses. The slope of the resulting regression line yielded a characteristic term, designated E 0, for the DNA-incising capacity of each cell strain. In contrast to normal fibroblasts, E 0 was found to be reduced in all XP cell strains belonging to the complementation groups A, C, D, E, F (or G) and I investigated, after treatment with both UV light or (Ac)2ONFln. Surprisingly, XP variant strains also exhibited lower E 0 values. A comparison of post-UV with post-(Ac)2ONFln DNA-incising capacities revealed that reduction in the E 0 values was very similar in all XP cell strains tested. These data suggest that the sensitivity of XP cells towards UV light or (Ac)2ONFln is due to the same enzymatic defect, namely impaired incision of DNA containing pyrimidine dimers or (Ac)2ONFln-DNA adducts.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Journal of cancer research and clinical oncology 120 (1994), S. 454-464 
    ISSN: 1432-1335
    Keywords: Xeroderma pigmentosum fibroblasts ; DNA repair ; Recombinant DNA ; cDNA libraries ; Phage λgt10 ; pBluescript vector ; In vitro transcripts ; Differential hybridization ; Mitochondrial neuromyopathies ; Genetic defects ; Uracil-DNA glycosylase ; Glyceraldehyde-3-phosphate dehydrogenase ; Lactate dehydrogenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Differential hybridization was used to detect repair defects in xeroderma pigmentosum (XP) that are not amenable to current analyses. cDNA libraries were constructed from cytoplasmic RNA of normal and XP fibroblast strains (complementation groups A and D) and analyzed for differential gene expression. More than 40000 λgt10 cDNA clones were differentially screened with in vitro transcripts made from cDNA in the pBluescript vector. Six differential clones were detected in the libraries of the XP group A and D strains which caused stronger or weaker signals when probed with transcripts from XP strains than with those from the normal strains. Two clones coded for mitochondrial genes: mitochondrial 16 S rRNA and ATPase 6L. Overexpression of mitochondrial genes in XP may indicate that functions of the ATP-generating system are impaired since such functions are intensified whenever they become insufficient, for example as a consequence of DNA damage. It is tempting to assume that abnormal mitochondria are one of the causes for the neurological malfunctions in XP. Furthermore, densitometric analysis of Northern blots revealed that mRNA of lactate dehydrogenase, chain M, was less abundant in four XP group A strains (extent of reduction: 70%) and in two XP group D strains (extent of reduction: 58%). Enzyme activity was also diminished. In addition, mRNA of the gene for glyceraldehyde-3-phosphate dehydrogenase was less expressed in the same XP group A and D fibroblast strains investigated (reduction in both complementation groups: 50%). Both glycolytic enzymes have nuclear functions apart from their role in sugar metabolism. Lactate dehydrogenase, chain M, is identical to a helix-destabilizing protein; it is closely associated with chromatin and unfolded DNA, suggesting a role in DNA synthesis and transcription. The 37-kDa subunit of glyceraldehyde-3-phosphate dehydrogenase is involved in transcription and was shown to be identical to uracil-DNA glycosylase, a base-excision repair enzyme. We presume that the nuclear functions of these glycolytic enzymes may be thwarted in the XP strains investigated and may account for malfunctions in XP, particularly for neurological disturbances.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Journal of cancer research and clinical oncology 124 (1998), S. 355-366 
    ISSN: 1432-1335
    Keywords: Key words Immunohistochemistry ; DNA repair ; Radiation-inducible response ; Apoptosis ; p16 ; Bax protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract DNA topoisomerase IIα was monitored with the monoclonal antibody Ki-S1 in human fibroblasts after irradiation of cells with γ rays from a 137Cs source or treatment with the DNA topoisomerase II inhibitor doxorubicin. DNA topoisomerase IIα was localized immunohistochemically as bright fluorescent dots in the karyoplasm. The fibroblasts investigated originated from normal human donors and a xeroderma pigmentosum (XP) patient (XP12BE). All cell lines examined showed a time- and dose-dependent increase in DNA topoisomerase IIα abundance after irradiation or treatment with doxorubicin. No principal difference in response was seen between normal and XP fibroblasts towards either treatment alone. After irradiation with 9 Gy, the effect was detectable after as little as 30 min and lasted for at least 6 h. After doxorubicin treatment, topoisomerase II overexpression occurred within less than 2 h. It passed through a maximum and began to decrease after approximately 6 h. In principle, the increase in DNA topoisomerase IIα may result from (i) architectural changes of interphase chromatin leading to enhanced accessibility of preformed enzyme to the antibody, (ii) enhanced gene expression, or (iii) enhanced stabilization of mRNA or protein molecules. The increase in enzyme levels may be part of the well-known DNA damage responses that operate in cell-protective or DNA-reparative pathways. Thus, the action of DNA topoisomerase II would serve to catalyze preparatory steps in DNA repair. We also found overexpression of the Bax protein and p16 predominantly in treated XP cells, suggesting that the DNA-damaging protocols elicited signals for apoptosis and cell-cycle arrest. From the simultaneous increase in DNA topoisomerase IIα and Bax, one may conclude that DNA topoisomerase IIα also plays role in apoptosis.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1246
    Keywords: Key words Chemical carcinogens ; List of MAK and BAT Values ; Cancer risk
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Carcinogenic chemicals in the work area are currently classified into three categories in section III of the German List of MAK and BAT Values (list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these categories – IIIA1, IIIA2, IIIB – be retained as Categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics, and for which risk at low doses can be assessed are classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented.
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  • 8
    ISSN: 1432-1335
    Keywords: DNA repair synthesis ; Human fibroblast strains ; Actinic keratosis ; Malignant melanoma ; Squamous cell carcinoma ; Basal cell carcinoma ; Ultraviolet light ; N-Acetoxy-2-acetylaminofluorene ; Methylating carcinogens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Fibroblast strains derived from skin biopsies of patients with actinic keratosis (6), malignant melanoma (18), squamous cell carcinoma (11), and basal cell carcinoma (12) were investigated for DNA repair synthesis, with 16 fibroblast strains for normal donors as controls. Cells were exposed to UV light, the “UV-like” carcinogen (Ac)2ONFln, and the methylating carcinogenes MeSO2OMe and MeNOUr. Dose-response experiments, which included 10 dose levels, were performed, the data analyzed by linear regression, and the slope of the regression line (term: G 0) used as a measure of DNA repair synthesis. The mean experimental variability of G 0 of individual fibroblast strains was 9.5%–15.4%, depending upon exposure. For comparison of all cell strains belonging to the same skin malignancy group with those of the control group, G 0 values of the individual strains were combined to yield group-specific weighted mean G 0 values. In addition, the capacity to incise UV-damaged DNA was measured in 24 cell strains from patients with skin tumors using the alkaline elution technique. For quantitating DNA-incising capacity, the initial velocities of the elution curves were plotted versus the UV dose, and the slope of the resulting regression line was used to obtain the characteristic value E 0. The mean experimental variability of E 0 of individual strains was ±22%. These E 0 values were combined to yield weighted mean values of groups. The fibroblast strains in the groups of patients with actinic keratosis and malignant melanoma were found to have normal mean G 0 values when DNA repair synthesis was challenged with UV light or one of the three carcinogens. However, the squamous cell carcinoma group exhibited significantly lower mean G 0 values after treatment with UV light (82% that of normal donors), (Ac)2ONFln (70%), MeSO2OMe (70%), and MeNOUr (69%). The basal cell carcinoma group showed significantly diminished repair synthesis upon treatment with UV light (81% that of normal donors) and MeSO2OMe (67%). In contrast to these findings, in no skin malignancy group was post UV DNA-incising capacity (E 0) significantly diminished, although it should be noted that group sizes were only half as large as for G 0 determinations. These data may be interpreted as indicating that DNA excision repair is impaired in fibroblast strains from patients with squamous cell carcinoma and — to a lesser extent — basal cell carcinoma. This deficiency seems to pertain to several DNA repair mechanisms, as excision of both alkylation and UV-induced damage is involved. Although the repair impairments are statistically significant, the relative risks at which the investigated patients are do not seem to be high enough as to be of immediate practical value. Our results indicate further studies would be useful.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1335
    Keywords: Mutant DNA polymerases ; Mutator properties ; Catalytic domains of DNA polymerases ; Physico-chemical constants of DNA polymerases ; Rat liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract DNA polymerases α, δ and ε from normal regenerating rat liver and Novikoff hepatoma cells were purified about 300-fold, characterized, and checked for sensitivity towards drugs known to inhibit cell proliferation. Characterization included (a) identification of associated proteins, (b) measurement of physicochemical constants (including sedimentation coefficients, diffusion coefficients, calculation of relative molecular masses), (c) quantification of catalytic activities using specific DNA primer templates (K m values) and specific inhibitors (K i values), and (d) discrimination between DNA polymerases from normal cells and those from malignant cells using inhibitors of cell proliferation. (a) DNA primase associated with DNA polymerase α, and 3′–5′ exonuclease accompanying DNA polymerases δ and ε had similar activities. (b) Comparison of physicochemical and catalytic properties of DNA polymerases from both sources revealed similarities but also some important differences. Sedimentation and diffusion coefficients of DNA polymerases α and ε from malignant cells differed significantly. (c) The DNA-binding domain of DNA polymerases α and ε from hepatoma cells was altered sinceK m values, determined with several specific DNA primer-templates, were higher. Furthermore, dNTP-binding sites of DNA polymerases from malignant cells; when probed with specific inhibitors (aphidicolin, butylphenyl-dGTP, carbonyldiphosphonate, and dideoxy-TTP) showed significantly lowerK i values, indicating lower affinity to deoxyribonucleoside 5′-triphosphates. (d) Sixteen drugs representative of various modes of interaction with DNA and protein were chosen. Dose/response experiments were performed and the concentration at which the polymerizing activity was reduced to 50% was calculated (K 50 values). Preferential inhibition of DNA polymerases α,δ, and ε from Novikoff hepatoma cells was found for: the intercalating drugs doxorubicin, daunorubicin, amsacrine, mitoxantrone, quinacrine and ethidium bromide, the minor-groove binders distamycin and netropsin, the ATPase-blocking agents novobiocin and coumamycin, and the topoisomerase I inhibitors camptothecin and topotecan. When the sensitivity of polymerases δ and ε was measured using poly(dA·dT) as a primer-template, the preferential inhibition of the enzymes from malignant cells was even more pronounced. Drugs known to trap the DNA-topoisomerase-II complex, etoposide, nalidixic acid, teniposide, and merbarone did not affect DNA polymerases irrespective of the source. Since the majority of the inhibitors used, particularly intercalators and minor-groove binders, act by modification of the primer-template, inhibition of DNA synthesis must have occurred through weakening of non-covalent bonds between DNA and catalytic polypeptides. Consequently, preferential inhibition of DNA polymerases from malignant cells seems to be indicative of abnormally diminished binding of the enzymes to their primer-templates. This effect may be caused by conformational alterations in polymerases from malignant cells which affect the DNA binding domains. Similarly, changes in physicochemical and kinetic constants are indicative of alterations of dNTP-binding domains.
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  • 10
    ISSN: 1432-1335
    Keywords: Transformation ; Xeroderma pigmentosum ; Induction of SOS-type repair functions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Human fibroblasts irradiated with UV light were infected with simian virus 40 and tested either for transformation or T-antigen production. At UV doses that allowed approximately 5–10% of the irradiated cells to survive, the number of surviving transformed colonies increased. This result was confirmed by testing for T-antigen 96 h post infection by means of indirect immunofluorescence. Since these results were obtained for a normal cell line as well as for two UV excision repair-deficient ones (XP groups A and D), it was concluded that excision repair functions cannot play a decisive role in the events leading to increased transformation and T-antigen production. It is proposed that the relative increase of transformation and T-antigen production is the expression of host functions which are induced by DNA damage threatening cell survival.
    Type of Medium: Electronic Resource
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