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At least 433 records · Page 24Linked to original sources
PubMed1993

Effects of temperature on the interaction of cisplatin and carboplatin with cellular DNA.

Increased levels of cisplatin (cDDP)- and carboplatin (CBDCA)-DNA adducts were detected in cDDP (10 microM)- and CBDCA (6 mM)-treated CC531 cells when the temperature was raised from 37 degrees to 43 degrees. In the case of cDDP, increased DNA adduct formation was already detectable at 38.5 degrees; additional temperature steps led to further increases in DNA modification. Increased CBDCA-DNA adduct formation was observed only at temperatures higher than 40 degrees. In vitro studies on the interaction of CDDP and CBDCA with isolated salmon sperm DNA, however, demonstrated no significant differences in the DNA binding rate between 37 degrees and 43 degrees for cDDP and a minor effect for CBDCA only at 43 degrees, almost totally excluding a direct temperature effect on DNA platination in this temperature range. Furthermore, neither the stability of the formed platinum-DNA adducts nor the rate of adduct loss in CC531 cells was changed at higher temperatures. The observed difference in cellular adduct formation, however, could be related to increased uptake of cDDP and CBDCA into CC531 cells at higher temperatures. In the case of cDDP, a temperature shift from 37 degrees to 38.5 degrees resulted in a significantly higher intracellular platinum concentration (0.03 +/- 0.01 vs 0.071 +/- 0.021 micrograms platinum/10(6) cells, respectively); for CBDCA, temperatures > or = 41.5 degrees were needed to increase the platinum concentration significantly above 37 degree values (0.3 +/- 0.1 vs 0.6 +/- 0.1 micrograms platinum/10(6) cells, respectively). In addition, the increase in DNA adduct formation of cDDP and CBDCA at elevated temperatures was comparable with the increase in cDDP-DNA adducts after a cDDP concentration escalation at 37 degrees, indicating a concentration-dependent increase in cDDP-DNA adducts. It seems that heat affects primarily the cellular uptake of cDDP and CBDCA and not their covalent binding to DNA.

Animals↗
PubMed1990

Suppression of nuclear ADP-ribosyltransferase activity in Ehrlich ascites tumor cells by 5-azacytidine. Modification of DNA as a cause of suppression.

Exposure of Ehrlich ascites tumor cells to 5-azacytidine for 5 h resulted in a partial loss of ability of DNA to stimulate ADP-ribosyltransferase activity, as assessed in a reconstituted in vitro enzyme system consisting of purified calf thymus enzyme, calf thymus whole histone and DNA isolated from the cells. The degree of suppression in vitro varied depending on the amount of histone and DNA added and it reached a maximum with a value of 83% and 62% of control for DNAs from cells exposed to 10 microM and 30 microM 5-azacytidine, respectively, at a histone/DNA mass ratio of 0.4. In the absence of histone (conditions of auto-ADP-ribosylation of the enzyme), no suppression was detectable.

Animals↗
PubMed1988

Modification of DNA by mitomycin C in cancer patients detected by 32P-postlabeling analysis.

DNA adducts of mitomycin C (MMC) were detected by 32P-postlabeling analysis in both surgical specimens and an autopsy sample of the liver of patients with hepatocellular carcinoma who had received chemotherapy with MMC. Four kinds of adducts were detected in all 6 patients treated with MMC. These adducts had identical chromatographic mobilities to those of adducts in the liver of rats treated with MMC, but 1 additional adduct was detected in rat liver. In patients treated with MMC, about 3 adducts/10(8) nucleotides were found 4 days after MMC treatment, and 1 adduct/10(8) nucleotides 14 days after treatment and the latter level was maintained for up to 56 days. MMC-DNA adducts were also detected in peripheral blood leukocytes from a patient 1 and 7 days after MMC treatment, at levels of 1 and 0.6 adduct/10(8) nucleotides, respectively. These results suggest the tumor-initiating activity of MMC in humans.

Animals↗
PubMed1996

Effect of methylglyoxal on human leukaemia 60 cell growth: modification of DNA G1 growth arrest and induction of apoptosis.

Methylglyoxal induced growth arrest in the G1 phase of the cell cycle and toxicity in human leukaemia 60 cells in vitro. Inhibition of DNA synthesis but not inhibition of RNA synthesis, protein synthesis or inhibition of glyceraldehyde-3-phosphate dehydrogenase activity correlated with cytotoxicity. Incubation of human leukaemia 60 cells with methylglyoxal led to the rapid accumulation of adducts of methylglyoxal with DNA, and a lower accumulation of methylglyoxal adducts with RNA and protein in the initial hour of culture; fragmentation of nuclear DNA characteristic of apoptosis developed in the second hour of culture. Methylglyoxal induced apoptosis in human leukaemia 60 cells but did not affect the growth and viability of concanavalin A-stimulated human peripheral lymphocytes in vitro. These effects confirm and further substantiate the anti-proliferative anti-tumour activity of methylglyoxal in vitro, which may mediate the anti-tumour activity of glyoxalase I inhibitors in vivo.

Apoptosis↗
PubMed1990

Modification of DNA by bile acids: a possible factor in the etiology of colon cancer.

Bile acids have been implicated as promoters and cocarcinogens in the etiology of colon cancer and as comutagens and mutagens in bacteria. These observations suggest the hypothesis that bile acids may interact directly with DNA. We treated the single stranded circular DNA of phage M13 with bile acids and found that the transfection efficiency of this DNA declined up to a 1000-fold. This result suggests that bile acids can damage DNA and thus may play an important role in the etiology of colon cancer.

Bile Acids and Salts↗
PubMed1992

HPLC separation of 32P-postlabelled benzo[b]fluoranthene-DNA adducts.

Analysis using 32P-postlabelling and a recently developed HPLC method resolved the adduct formed by reaction of the benzo[b]fluoranthene (BbF) anti-bay-region diol-epoxide with DNA from the more polar major adduct produced by the hydrocarbon in three different biological systems. In each case, the adduct formed from the anti-bay-region diol-epoxide constituted only a minor proportion of the total DNA modification. Comparisons of the DNA adducts formed from the hydrocarbon with those formed in microsomal incubations from the putative metabolites BbF-9,10-diol, anti-BbF-9,10-diol-11,12-oxide and the 5,9,10- and 6,9,10-BbF-triols indicate that the predominant pathway for BbF activation in skin probably involves a bay-region triol-epoxide possessing a phenolic OH-group on the peninsula ring.

Animals↗
PubMed1993

Diethylstilbestrol liver carcinogenicity and modification of DNA in rats.

Administration of diethylstilbestrol to female Sprague-Dawley rats at 10 mg/kg body weight daily by gavage for 1 year induced liver adenomas and carcinomas and pituitary adenomas. Using the 32P-postlabeling assay for DNA alterations, at 24 h after administration of a single dose of 100 mg/kg, modified bases were found.

Adenoma↗
PubMed1996

Modification of DNA topoisomerase I enzymatic activity with phosphotyrosyl protein phosphatase and alkaline phosphatase from the hepatopancreas of the shrimp Penaeus japonicus (Crustacea:Decapoda).

DNA topoisomerase I was partially purified from the hepatopancreas of the shrimp Penaeus japonicus. The specific activity of the final preparation was 7,000,000 units/mg of protein with SV40 viral DNA as substrate. SDD-polyacrylamide gel electrophoresis of the final preparation yielded two major bands of proteins with M(r) 70,000 and M(r) 67,000, as well as less intense bands of proteins with M, 64,000 and M(r) 56,000. Incubation of the partially purified enzyme fraction with rabbit antiserum against human DNA topoisomerase I, allowed all these proteins except that of M(r) 56,000, to be positively reacted. Treatment of the partially purified DNA topoisomerase I with tyrosine kinase p43v-abl resulted in phosphorylation of only the two major subunits. Phosphorylation by tyrosine kinase p43v-abl or dephosphorylation by phosphotyrosyl protein phosphatase resulted in a decrease of the enzymatic activity. The treatment with shrimp alkaline phosphatase abolished the enzymatic activity of the purified DNA topoisomerase I in a dose-dependent manner. Thus, the DNA topoisomerase I was apparently isolated from the hepatopancreas of the shrimp P. japonicus in a phosphorylated form, and this phosphorylation was essential for expression of enzymatic activity in vitro. The activity of DNA topoisomerase I is inhibited by ZnCl2, CuCl2 and Pb(NH3)3 at millimolar concentrations, but less inhibition was observed with CaCl2.

Alkaline Phosphatase↗
PubMed1986

Modification of DNA damage in transcriptionally active vs. bulk chromatin.

Our previous experiments have demonstrated that regions of nuclear chromatin, containing transcriptionally active DNA sequences and associated with the nuclear matrix, are hypersensitive to the production of both single-strand breaks and DNA-protein cross-links upon gamma-irradiation of exponentially growing mammalian cells. In this study, we have irradiated Chinese hamster V79 cells in buffered saline with or without DMSO to scavenge hydroxyl radicals and in buffered salines of various tonicities to expand or condense chromatin. The yield of DNA-protein cross-links was assayed by a nitrocellulose filter binding technique and the DNA recovered from the cross-links hybridized to 125I-poly(A+)RNA to determine the relative frequency of transcriptionally active sequences in the cross-links compared to the bulk DNA. In all cases, the data show that active DNA is affected to a greater extent than bulk, primarily inactive DNA. The more extensive alteration of the level of ionizing radiation-induced damage in active DNA by the diffusible agents tested suggests that other agents, such as chemical sensitizers and protectors, which need to diffuse to the nuclear DNA, may also be acting primarily on active, matrix-associated DNA.

Animals↗
PubMed1993

Co-chairman's remarks: reverse genetics: directed modification of DNA for functional analysis.

The classic paradigm for identifying the genetic basis of a particular organism's properties proceeds from the phenotype to the gene, and thence to the molecular structures of the corresponding DNA, RNA and protein. 'Positional cloning' of disease genes and the molecular characterization of the responsible mutations (inappropriately referred to as reverse genetics, initially) exemplifies this approach. Now, the ability to clone, modify and test the biological activities of DNA segments provides a new approach, referred to as 'reverse genetics'. This paradigm begins with a segment of DNA whose molecular structure is known, and proceeds to explore the gene's contribution to the organism's phenotype; thus, the experimental path is from the gene as a nucleotide sequence to the corresponding phenotypic characteristic. Such a strategy follows from the ability to modify these sequences in highly directed and nearly unlimited ways, and to assess the phenotypic relevance of such alterations either in vitro, in cultured cells, or even in whole organisms. This approach permits the full panoply of molecular techniques to be used for creating uniquely altered structures and obviates the reliance on chance events as the source of mutations. As a consequence, the range of questions that can be studied is greatly expanded, and the information that is obtained is all the richer.

Animals↗
PubMed2002

Supplementation with antioxidant vitamins prevents oxidative modification of DNA in lymphocytes of HIV-infected patients.

There is evidence suggesting that patients infected with human immunodeficiency virus (HIV) are under chronic oxidative stress. In the present study, the level of oxidatively modified bases in lymphocyte DNA and some other parameters of oxidative stress were measured in HIV-infected patients (n = 30), as well as in control groups (10 healthy volunteers and 15 HIV-seronegative injected drug users). Additional experiments were conducted using lymphocyte DNA samples from asymptomatic seropositive, HIV-infected patients who were supplemented with antioxidant vitamins A, C, and E or received placebo. Significant increases in the amount of the modified DNA bases were observed in HIV-infected patients when compared with the control group. The concentration of thiobarbituric acid reactive substances (TBARS) was higher and activities of antioxidant enzymes (superoxide dismutase and catalase) were lower in the group of HIV-infected patients in comparison to the control group. Vitamin supplementation resulted in the significant decrease in the levels of all modified DNA bases when compared to the patients who received placebo. The reduction of TBARS and the restoration of the activity of the enzymes were also observed. Our data suggest that people infected with HIV can benefit from treatment with antioxidant vitamins.

Adolescent↗