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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently showed that the DNA repair processes occurring after u.v. light induce double strand breaks (DSBs) in the DNA of normal human fibroblast (IMR-90) but not of xeroderma pigmentosum group A cells. We call these lesions 'repair-induced double strand breaks' (RDSBs), since they only occur in excision repair competent cells. In this work, we asked whether these RDSBs occur in IMR-90 cells at low u.v. doses and whether the RDSBs are themselves repairable. We reasoned that holding open the excision-repair induced gaps by inhibiting nucleotide polymerization after u.v. light with hydroxyurea/ara C or aphidocolin should allow us to answer these questions. The results show that as little as 2.5 J.m-2 of u.v. light induces RDSBs during repair incubation when repair inhibitors are present. This suggests that 'hot spots' of high lesion frequency occur and the overlapping excision in these areas will produce RDSBs. Without repair inhibitors, the frequency of such RDSBs will be much lower; but even one unrepaired RDSB is likely to have profound biological effects. By removing aphidocolin from the medium after incubation of RDSBs, we were able to test the repairability of these lesions. The results show that RDSBs are only partially repairable with between 15 and 40% of the breaks unrepaired at 24 h. Because the lesions are partially repairable they should not always cause toxicity and may be involved in processes such as mutation, transformation, and chromosome or chromatid type aberrations of the sort associated with human tumors.
Carcinogenesis 1983 Dec
PMID:Repair-induced DNA double strand breaks after ultraviolet-light and either aphidocolin or 1-beta-D-arabinofuranosylcytosine/hydroxyurea. 641 2

Cells from Gardner's syndrome (GS) and familial polyposis coli (FP) patients, persons with a hereditary predisposition to colon cancer, were compared to those of normal persons for sensitivity to the cytotoxic and mutagenic action of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a model compound chosen because methylating agents have been implicated in colon carcinogenesis. FP cell line GM2355 and GS cell lines 2938 and GM3948 exhibited normal sensitivity to the cytotoxic and mutagenic effects of MNNG. In contrast, GS cell line GM3314 and cells from an apparently normal fetus GM0011 showed extreme sensitivity to the killing and mutagenic effect of this alkylating agent. To determine if the resistance of the various cell lines to MNNG correlated with their ability to remove methyl groups from the O6-position of guanine, we measured their O6-methylguanine-DNA methyltransferase (MT) activity. The resistant cell lines exhibited normal levels of MT; the sensitive strains showed virtually non-detectable levels of this activity. We also compared fibroblasts from a xeroderma pigmentosum (XP) patient (XP12BE, complementation group A), an SV40 virus-transformed XP cell line (XP12ROSV) and a normal cell line transformed by this virus (GM637) for their response to the cytotoxic and mutagenic effect of MNNG and for MT activity. XP12BE cells showed normal sensitivity and a normal level of MT; GM637 cells showed an intermediate level of sensitivity and a reduced level of MT activity; XP12ROSV cells were extremely sensitive to the cytotoxic and mutagenic effect of MNNG and showed virtually non-detectable levels of MT activity. The MT did not remove methyl group from O4-methyl-thymine. These results suggest that O6-methylguanine and/or any other adduct repaired by the methyltransferase, is a potentially cytotoxic and mutagenic lesion. They also indicate that the predisposition to colon cancer of FP and GS patients is not necessarily correlated with an increased sensitivity of their fibroblasts to mutations induced by methylating carcinogens.
Carcinogenesis 1984 Dec
PMID:Correlation between O6-methylguanine-DNA-methyltransferase activity and resistance of human cells to the cytotoxic and mutagenic effect of N-methyl-N'-nitro-N-nitrosoguanidine. 649 16

Recent research support the idea that DNA damage is the initial event in the process of carcinogenesis. Involvement of DNA repair in the fixation of DNA damage leading to cancer has been suggested by the presence of several cancer-prone hereditary diseases associated with DNA repair deficiency. Among them, xeroderma pigmentosum has been most extensively investigated and the "SOS response" hypothesis, originally implied to the mechanism of mutagenesis in bacteria, appears to be an attractive hypothesis for the understanding of the cancer-proneness in xeroderma pigmentosum. The DNA repair of ionizing radiation damage, however, has not been clearly demonstrated in association with the process of radiation carcinogenesis, and further studies will be needed to understand the mechanisms of radiation carcinogenesis and the involvement of DNA repair in it.
 ...
PMID:[DNA repair and carcinogenesis]. 651 96

The mutagenic and lethal effects of u.v. light exposure in the DNA synthetic phase of the cell cycle were determined in xeroderma pigmentosum complementation group A (XP-A), hereditary adenomatosis of the colon and rectum (ACR), and a normal, foreskin derived cell strain (AG1522). For AG1522, an increased sensitivity to the cytotoxic effects of u.v. light (survival curve D0 = 3.2 J/m2) was observed as compared to previous findings for confluent, non-proliferating cultures (D0 = 4.2 J/m2). XP-A fibroblasts were markedly hypersensitive (D0 = 0.5 J/m2) and ACR fibroblasts exhibited an intermediate response (D0 = 2.0 J/m2). The mutagenic response of ACR fibroblasts, however, was similar to normal fibroblasts. A threshold of 1.5-2 J/m2 was observed for u.v. induced mutagenesis in normal and ACR fibroblasts. XP fibroblasts, on the other hand, were strikingly hypermutable and demonstrated little or no threshold. When S phase mutagenesis was considered as a function of survival level rather than u.v. light dose, XP fibroblasts remained significantly hypermutable as compared with normal fibroblasts at all survival levels. Previous mutagenesis results with confluent, nonproliferating cultures of XP and normal fibroblasts were reanalyzed as a function of cytotoxicity; XP hypermutability at all survival levels was also observed.
Carcinogenesis 1983 Nov
PMID:Mutagenesis and lethality following S phase irradiation of xeroderma pigmentosum and normal human diploid fibroblasts with ultraviolet light. 664 Aug 42

Specific excision of thymine dimers from isolated normal human and xeroderma pigmentosum (XP complementation groups A, C, D and G) chromatin was investigated under cell-free conditions. Crude extracts derived from unirradiated XP groups A, C and G cells were unable to excise dimers from their own nuclear sonicates, native chromatin and whole-cell sonicates prepared after exposure to 100 J/m2 of u.v. radiation at 254 nm, while normal-cell extracts were able to do so from all substrates including purified DNA. However, the extracts of XP groups A, C and G cells became capable of excising thymine dimers from chromatin preparations depleted of loosely bound nonhistone proteins with 0.35 M NaCl and from purified DNA. Extracts of XP group D cells catalyzed normal levels of excision from nuclear sonicates, native chromatin and 0.35 M NaCl-treated chromatin. These results suggest that none of the XP groups examined is deficient in a dimer-specific u.v. endonuclease. XP groups A, C and G cells are apparently defective in 'XP factors' present in the non-histone protein fraction, which are required for the excision of thymine dimers from chromatin. The XP group D factor appears to be different from the others. Extracts from XP groups A, C and G cells were able to complement each other with respect to dimer excision from chromatin. Novobiocin (200 micrograms/ml) completely inhibited dimer excision effected by extracts of normal cells or by complementing extracts of XP cells.
Carcinogenesis 1983 Nov
PMID:Defective thymine dimer excision from xeroderma pigmentosum chromatin and its characteristic catalysis by cell-free extracts. 664 Aug 43

Xeroderma pigmentosum (XP), is a rare, autosomal recessive disease with sun sensitivity and multiple neoplasms in association with reduced DNA repair. As a reflection of the clinical consequences of deficient DNA repair, XP serves as a model for determining the effects of proficient DNA repair. To estimate the risk of developing neoplasms in XP, we abstracted reports of 726 XP patients (from 41 countries) published from 1874 to 1982. Despite limitations of a literature survey, the XP patients under age 20 years had an estimated 2000-fold increase in frequency of basal cell and squamous cell carcinoma of the skin, of cutaneous melanoma, of cancer of the anterior eye, and of cancer of the anterior tongue, in comparison to the general population. These sites are all potentially exposed to u.v. radiation, a strong carcinogen which produces DNA damage that is poorly repaired by XP cells. XP patients under age 20 years also had an estimated 12-fold increase in occurrence of neoplasms in sites not exposed to u.v. radiation. Among the XP patients under age 40 years with internal cancer, there was a disproportionate representation of malignant neoplasms of the brain (especially sarcomas), and oral cavity (excluding tongue) compared to US whites under age 40 years. These internal neoplasms may be related to exposure to chemical environmental carcinogens that cause DNA damage which, like u.v.-induced damage, is poorly repaired by XP cells. These reports provide no evidence of an increase in XP of common lethal neoplasms such as lymphomas, or female genital tract or endocrine system cancers. These findings suggest that DNA repair plays a role in protection against u.v.-induced neoplasia and in protection against some internal neoplasms in the general population.
Carcinogenesis 1984 Apr
PMID:DNA repair protects against cutaneous and internal neoplasia: evidence from xeroderma pigmentosum. 670 49

4-Nitroquinoline-1-oxide (4NQO) damage to DNA and its repair in normal and xeroderma pigmentosum (XP) fibroblast stains were followed by sedimentation in an alkaline sucrose gradient. Two forms of analysis were employed. In the brief lysis technique, the cells were exposed to alkali for 30 min before centrifuging. In the long lysis technique, the cells were exposed to alkali overnight before centrifuging. The fibroblast cultures were derived from 6 normal individuals, 2 XP variants, 2 from complementation group C and 1 each from complementation groups A, B and E. by means of the brief lysis technique all of the fibroblasts were found to repair the 4NQO induced damage. By means of the long lysis technique the fibroblasts from normal individuals, from XP variants and from XP group E were found to repair the 4NQO induced damage. The fibroblasts from groups A, B and C showed no repair of the lesion. This latter result, on the repair capability of 4NQO damaged XP cells, correlates with the repair capability of XP cells shown by other methods. It suggest that if sedimentation analysis in alkaline sucrose is to be used to demonstrate the induction of chemically induced damage to DNA and its repair, both brief and long lysis periods should be employed.
Carcinogenesis 1981
PMID:Alkaline sucrose sedimentation analysis as an indicator of repair capability of xeroderma pigmentosum fibroblasts for 4-nitroquinoline-1-oxide damage. 679 57

Aphidicolin is a specific inhibitor of DNA polymerase alpha. Its influence of DNA repair has been studied in both normal and excision deficient xeroderma pigmentosum cells exposed to u.v. irradiation at 254 nm. Single strand DNA breaks accumulated in u.v. irradiated normal cells when the inhibitor was present. Such breaks were absent in both unirradiated normal cells and in u.v. irradiated excision efficient cells incubated with the compound. The data therefore indicate that aphidicolin prevents the rejoining of single strand breaks formed during the excision repair process and imply that DNA polymerase alpha is involved in the repair of DNA in human cells.
Carcinogenesis 1981
PMID:Aphidicolin: an inhibitor of DNA repair in human fibroblasts. 679 60

Normal human or excision deficient xeroderma pigmentosum (XP) fibroblasts were exposed to either the potent carcinogen 4-nitroquinoline 1-oxide (4NQO) or the weaker acting 3 methyl derivative of this compound. The inhibition of cell growth, DNA damage and DNA repair were then monitored in these cells. The data indicate that the modification of 4NQO by methylation actually changes the type and amount of DNA damage induced by this carcinogen. More specifically, the methylation of 4NQO at the three position prevented the formation of 4NQO induced DNA adducts manifesting themselves as alkaline stable lesions whose repair was cytosine arabinoside inhibitable in normal cells, but defective in excision deficient XP cells. Alkaline labile lesions induced by 4NQO which are repairable in the above XP cells were still induced by the 3 methyl derivative but a lower frequency on an equimolar basis.
Carcinogenesis 1981
PMID:DNA damage and its repair in human normal or xeroderma pigmentosum fibroblasts treated with 4-nitroquinoline 1-oxide or its 3-methyl derivative. 679 19

Using xeroderma pigmentosum fibroblasts, deficient in excision repair, as controls to measure the initial rate of (+/-)7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]PDE)--DNA adducts removal in normal human fibroblasts, it was found that the maximum amount of carcinogen DNA adducts occurred 1 h after the addition of B[a]PDE, and that during the first hour approximately 12% of the DNA--carcinogen adducts had already been removed. Thus the formation and removal of DNA--carcinogen adducts occurred simultaneously within the first hour after B[a]PDE addition to confluent fibroblasts. Examination of excision repair over an extended period showed that during a further 6 h, DNA adducts were removed at a rate four times slower than that observed during the first hour. Since the maximum level of B[a]PDE--DNA adducts was observed 1 h after the addition of B[a]PDE to the cells in culture, this suggested that the rate of breakdown of B[a]PDE was much slower than that observed in vitro. Further experiments indeed indicated that the rate of hydrolysis of B[a]PDE within the cell was significantly decreased. Thus, the stability of B[a]PDE inside the cell is governed by very different parameters than those observed in vitro.
Carcinogenesis 1982
PMID:Formation and removal of B[a]P diol epoxide--DNA adducts in human fibroblasts. 681 77


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