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Stephen B. Howell - One of the best experts on this subject based on the ideXlab platform.
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Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells
Clinical Cancer Research, 1997Co-Authors: Stefan Aebi, Daniel Fink, Hua Zheng, Robert Gordon, Heung Ki Kim, J. L. Fink, Stephen B. HowellAbstract:Loss of DNA mismatch repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in mismatch repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-Nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA mismatch repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-Nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.
Eugenia Dogliotti - One of the best experts on this subject based on the ideXlab platform.
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mutagenic processing of ethylation damage in mammalian cells the use of methoxyamine to study apurinic apyrimidinic site induced mutagenesis
Cancer Research, 1993Co-Authors: Paola Fortini, A. Calcagnile, Harry Vrieling, A.a. Van Zeeland, M. Bignami, Eugenia DogliottiAbstract:The aldehyde reagent methoxyamine is able to interact with apurinic/apyrimidinic sites formed in vivo within cells and displays both an anti-cytotoxic and an antimutagenic activity on N-ethyl-N'-nitro-N-Nitrosoguanidine-induced DNA damage in Chinese hamster ovary cells. To clarify the underlying mechanism we have examined the mutational spectra induced by N-ethyl-N'-nitro-N-Nitrosoguanidine alone and in the presence of methoxyamine in the hypoxanthine-guanine phosphoribosyltransferase gene of Chinese hamster ovary cells. In both cases all mutations were base pair substitutions, and their distribution among various classes did not differ significantly. Almost 60% were transitions, predominantly GC to AT, and the remaining 40% were transversions, mainly at AT base pairs. The analysis of the proportion of the different types of mutations showed that in the presence of methoxyamine, GC to AT transitions decreased by a factor of 1.8, and AT to CG transversions were reduced by a factor of 13. These data indicate that in mammalian cells the fixation of ethylation damage into mutations occurs by both (a) direct mutagenesis likely driven by O6-ethylguanine adducts and to a minor extent by O4-ethylthymine and (b) apurinic/apyrimidinic site-mediated mutagenesis. These apurinic/apyrimidinic sites are formed during the processing of ethylation at critical sites and are likely to involve O6-ethylguanine and O2-ethylthymine adducts.
Halfdan Sorbye - One of the best experts on this subject based on the ideXlab platform.
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gastric mucosa lesions induced by duodenogastric reflux increase penetration of n 3h methyl n nitro n Nitrosoguanidine into corpus mucosa of rats
Digestive Diseases and Sciences, 2002Co-Authors: Kjell Ovrebo, Knut Svanes, S Aase, Ketil Grong, Steinar Kvinnsland, Halfdan SorbyeAbstract:The mucosal changes by which duodenogastric reflux may predispose to gastric cancer have not been fully clarified. In this study in rats, duodenal fluid was directed into the stomach through a gastroenterostomy (jejunal reflux, N = 29) or through the pylorus (pyloric reflux, N = 30) and compared with 30 controls. Twenty-four weeks later the stomach was exposed to N-[3H]methyl-N-nitro-N-Nitrosoguanidine ([3H]MNNG). The corpus mucosa was examined for proliferating cells (bromodeoxyuridine labeled) and cells at risk of methyl-N-nitro-N-Nitrosoguanidine-induced carcinogenesis (cells labeled with bromodeoxyuridine and [3H]MNNG). The number of double-labeled cells increased from 0.8 ± 0.1/mm mucosa in the control group to 5.2 ± 0.9 in the jejunal reflux group (P < 0.05) and 2.7 ± 0.5 in the pyloric reflux group (P < 0.05). An erosion or ulcer appeared at the gastroenterostomy in 52% of animals with jejunal reflux and 17% of those with pyloric reflux (P < 0.006). Within erosions the mean number of double-labeled cells was 9.6 ± 2.2 in the jejunal reflux group and 7.7 ± 4.8 in the pyloric reflux group, and significantly higher than in the nonlesion area of the mucosa (0.6 ± 0.2 and 0.8 ± 0.3). In erosions the distance between the gastric lumen and the proliferating cells was significantly shorter and the cell proliferation significantly higher than in the nonlesion area of the mucosa. We conclude that duodenogastric reflux increases the penetration of [3H]MNNG into the corpus mucosa of rats and also induces mucosa lesions, which further increase the penetration of [3H]MNNG into the corpus mucosa.
Nohee Park - One of the best experts on this subject based on the ideXlab platform.
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introduction of human telomerase reverse transcriptase to normal human fibroblasts enhances dna repair capacity
Clinical Cancer Research, 2004Co-Authors: Kihyuk Shin, Mo K Kang, Erica Dicterow, Ayako Kameta, Marcel A Baluda, Nohee ParkAbstract:Purpose: From numerous reports on proteins involved in DNA repair and telomere maintenance that physically associate with human telomerase reverse transcriptase (hTERT), we inferred that hTERT/telomerase might play a role in DNA repair. We investigated this possibility in normal human oral fibroblasts (NHOF) with and without ectopic expression of hTERT/telomerase. Experimental Design: To study the effect of hTERT/telomerase on DNA repair, we examined the mutation frequency rate, host cell reactivation rate, nucleotide excision repair capacity, and DNA end-joining activity of NHOF and NHOF capable of expressing hTERT/telomerase (NHOF-T). NHOF-T was obtained by transfecting NHOF with hTERT plasmid. Results: Compared with parental NHOF and NHOF transfected with empty vector (NHOF-EV), we found that (a) the N -methyl- N′ -nitro- N -Nitrosoguanidine-induced mutation frequency of an exogenous shuttle vector was reduced in NHOF-T, ( b ) the host cell reactivation rate of N -methyl- N′ -nitro- N -Nitrosoguanidine-damaged plasmids was significantly faster in NHOF-T; ( c ) the nucleotide excision repair of UV-damaged DNA in NHOF-T was faster, and ( d ) the DNA end-joining capacity in NHOF-T was enhanced. We also found that the above enhanced DNA repair activities in NHOF-T disappeared when the cells lost the capacity to express hTERT/telomerase. Conclusions: These results indicated that hTERT/telomerase enhances DNA repair activities in NHOF. We hypothesize that hTERT/telomerase accelerates DNA repair by recruiting DNA repair proteins to the damaged DNA sites.
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12 o tetradecanoylphorbol 13 acetate tpa induced c jun n terminal kinase jnk phosphatase renders immortalized or transformed epithelial cells refractory to tpa inducible jnk activity
Journal of Biological Chemistry, 2000Co-Authors: Heng Zhou, Anning Lin, Sam Chen, Nohee Park, Robert ChiuAbstract:c-Jun N-terminal kinase (JNK) regulates gene expression in response to various extracellular stimuli. JNK can be activated by the tumor promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA) in normal human oral keratinocytes but not in human keratinocytes that have been immortalized (HOK-16B and HaCaT) or transformed (HOK-16B-Bap-T) nor in a cervical carcinoma cell line (HeLa). The refractory JNK activation response to TPA is not due a defect in the JNK pathway, because JNK can be activated by other stimuli, e.g. UV irradiation and an alkylating agent N-methyl-N′-Nitrosoguanidine in these immortalized or transformed cells. More importantly, the refractory JNK and JNKK activation response to TPA can be restored by treatment of the cells with a combination of TPA and a protein-tyrosine phosphatase inhibitor, sodium orthovanadate. Furthermore, pretreatment of cells with TPA partially inhibited UV- orN-methyl-N′-Nitrosoguanidine-induced JNK activity. These results suggest that a TPA-inducible, orthovanadate-sensitive protein-tyrosine phosphatase may specifically down-regulate JNK signaling pathway in these immortalized/transformed epithelial cells. In contrast, ERK and p38/Mpk2 are not regulated by this TPA-induced phosphatase. This putative protein-tyrosine phosphatase appears to be JNK pathway-specific.
Thomas A Kunkel - One of the best experts on this subject based on the ideXlab platform.
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correction of hypermutability n methyl n nitro n Nitrosoguanidine resistance and defective dna mismatch repair by introducing chromosome 2 into human tumor cells with mutations in msh2 and msh6
Cancer Research, 1997Co-Authors: Asad Umar, Carl J Barrett, Minoru Koi, John I Risinger, Warren E Glaab, Kenneth R Tindall, Richard D Kolodner, Richard C Boland, Thomas A KunkelAbstract:The human DNA mismatch repair genes hMSH2 and hMSH6 encode the proteins that, together, bind to mismatches to initiate repair of replication errors. Human tumor cells containing mutations in these genes have strongly elevated mutation rates in selectable genes and at microsatellite loci, although mutations in these genes cause somewhat different mutator phenotypes. These cells are also resistant to killing by certain drugs and are defective in mismatch repair. Because the elevated mutation rates in these cells may lead to mutations in additional genes that are causally related to the other defects, here we attempt to establish a cause-effect relationship between the hMSH2 and hMSH6 gene mutations and the observed phenotypes. The endometrial tumor cell line HEC59 contains mutations in both alleles of hMSH2 . The colon tumor cell line HCT15 contains mutations in hMSH6 and also has a sequence change in a conserved region of the coding sequence for DNA polymerase δ, a replicative DNA polymerase. We introduced human chromosome 2 containing the wild-type hMSH2 and hMSH6 genes into HEC59 and HCT15 cells. Introduction of chromosome 2 to HEC59 cells restored microsatellite stability, sensitivity to N -methyl- N ′-nitro- N -Nitrosoguanidine treatment, and mismatch repair activity. Transfer of chromosome 2 to HCT15 cells also reduced the mutation rate at the HPRT locus and restored sensitivity to N -methyl- N ′-nitro- N -Nitrosoguanidine treatment and mismatch repair activity. The results demonstrate that the observed defects are causally related to mutations in genes on chromosome 2, probably hMSH2 or hMSH6 , but are not related to sequence changes in other genes, including the gene encoding DNA polymerase δ.