UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
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Recently, it has been demonstrated that N-alkylpurines produced by nitrogen mustard are excised more rapidly from actively transcribing genes compared to non-coding regions of the overall genome. Such studies have suggested that transcriptional activity is a determinant of the rate of removal of these DNA lesions. We have examined the removal of nitrogen mustard-induced N-alkylpurines in the actively transcribed/translocated and transcriptionally repressed native alleles of the c-myc gene in Burkitt's lymphoma, CA46 cells. Burkitt's lymphoma cells, exhibiting a c-myc translocation that can be distinguished from the native allele by Southern blotting, provide a useful model system in which to explore regulatory elements that govern DNA repair in transcriptionally active genes. Northern analysis verified the selective allelic expression of the translocated c-myc gene in CA46 cells. At the drug exposure examined, nitrogen mustard produced a similar level of N-alkylpurines in the two alleles of c-myc. Also, the kinetics of lesion repair from both c-myc alleles over a 24 h repair incubation period was of the same order of magnitude: approximately 34% and approximately 25% of nitrogen mustard-induced N-alkylpurines were removed by 8 h; approximately 72% and approximately 66% of nitrogen mustard lesions were removed by 24 h from the untranslocated and translocated alleles respectively. The untranslocated allele did not become transcriptionally activated upon drug treatment and nitrogen mustard produced a suppression of c-myc message levels from the translocated allele. Therefore, our results suggest that the rate of repair of nitrogen mustard-induced N-alkylpurines is independent of transcriptional activity of the c-myc gene in Burkitt's lymphoma. These findings are discussed in terms of the current views about the mechanisms of gene-specific repair.
Carcinogenesis 1994 Sep
PMID:Transcription-independent repair of nitrogen mustard-induced N-alkylpurines in the c-myc gene in Burkitt's lymphoma CA46 cells. 792 69

The oligonucleotide 5'-d(CCTATAGATATCC) has been reacted with the (+)- or (-)-enantiomers of trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)- and (-)-anti-BPDE respectively]. Consistent with previous studies employing single-stranded oligonucleotides, adduct formation of both anti-BPDE enantiomers preferentially involved trans-addition of the C10 position of the diol-epoxide to the exocyclic nitrogen of deoxyguanosine [in the following abbreviated as (+)-BPDEt-N2-G and (-)-BPDEt-N2-G adducts respectively]. The unmodified or (+)-BPDEt-N2-G-modified oligonucleotide was allowed to form duplexes with the complementary sequence 5'-d(GGATATCTATAGG) or sequences in which C has been replaced with T, G or A and analysed with regard to thermal stability. The presence of a (+)-BPDEt-N2-G adduct in oligonucleotide duplexes substantially decreased the value of the melting point relative to the corresponding unmodified duplex. In mismatched complexes containing the (+)-BPDEt-N2-G adduct, a further decrease in thermal stability was observed. The presence of a (+)-BPDEt-N2-G adduct did not seem to change the extent of hyperchromicity (approximately 20%) upon melting. 5'-d(GGATATCTATAGG) or strands in which C was replaced with T, G or A were gradually added to (+)- or (-)-BPDEt-N2-G-modified oligonucleotides and the fluorescence emission intensity was determined. In all cases with (+)-BPDEt-N2-G, except when C was replaced with A in the complement, the fluorescence intensity steadily decreased and became constant at equal strand concentrations. When a strand containing A in place of C was gradually added to the (+)-BPDEt-N2-G oligonucleotide, a marked increase in the fluorescence intensity was observed (> 3-fold). In contrast, addition of strands containing A, T or G to the (-)-BPDEt-N2-G-modified oligonucleotide increased the fluorescence intensity from 1.5- to > 5-fold. Addition of the fully complementary sequence to the (-)-BPDEt-N2-G-containing oligonucleotide resulted in reduced fluorescence, however less pronounced than with the (+)-BPDEt-N2-G-modified analogue. Significant changes in spectral properties of the adducts were observed in the duplexes. The absorption and fluorescence excitation maxima of the single-stranded (+)-BPDEt-N2-G-modified oligonucleotide were at 353 nm. Insertion of C or A opposite the adduct caused a significant shift of these maxima to shorter wavelengths (347-348 nm). Addition of acrylamide, a fluorescence quencher, reduced the fluorescence intensity in all cases, but to variable extents.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1994 Oct
PMID:Spectroscopic studies of the trans adducts derived from (+)- and (-)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide and the oligonucleotide 5'-d(CCTATAGATATCC). 795 55

Nitric oxide (NO) has been shown to be involved in a number of physiological processes. In the presence of oxygen, this reactive diatomic molecule is capable of generating reactive nitrogen oxide species (NOx) which possess both nitrosating and oxidizing ability for various substrates, including certain biological macromolecules. This report shows the inhibition of the DNA repair protein, O6-methylguanine-DNA-methyltransferase, by Et2N[N(O)NO]Na (DEA/NO), a compound which decomposes with concurrent release of NO. The inhibition of the purified transferase activity by NO was dose- and time-dependent and the extent of inhibition by DEA/NO corresponded to the total quantity of NO released. This inhibitory effect by NO was also demonstrated to be reversible over time. The reaction of the NO released from DEA/NO with cysteine under aerobic conditions resulted in the formation of an S-nitrosothiol adduct, suggesting that a similar adduct could be responsible for the inactivation.
Carcinogenesis 1994 Mar
PMID:Inhibition by nitric oxide of the repair protein, O6-methylguanine-DNA-methyltransferase. 811 26

Ascorbic acid (ASC) consumption is negatively correlated with the incidence of certain cancers. This is a review and update of the theory, which has recently been neglected, that this negative correlation is due to ASC inhibition of in vivo nitrosation. The review covers the older literature on ASC inhibition of carcinogenesis by nitrite administered with amines or amides and more recent studies on ASC inhibition of nitrosation by bacteria, nitrogen oxides, and activated macrophages; the role of oxygen in ASC inhibition of gastric nitrosation; ASC inhibition of N-nitrosoproline formation in subjects from areas with high incidences of certain cancers; dose and temporal relationships between ASC and in vivo nitrosation in humans; the role of substances other than ASC in the inhibition of nitrosation by vegetables and fruits; and the active secretion of ASC into the human stomach.
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PMID:Experimental evidence for inhibition of N-nitroso compound formation as a factor in the negative correlation between vitamin C consumption and the incidence of certain cancers. 813 17

Chemical carcinogenesis is a multistage process that includes initiation, promotion, and progression. Some carcinogenic PACs have been shown to activate proto-oncogenes and deactivate tumor-suppression genes in the carcinogenic process. The function of DNA repair processes appears to be changed in some cases by PACs. Many PACs are well known for their carcinogenic activity, but for this activity to be exerted, metabolic activation by microsomal enzymes must occur. The enzyme system responsible for PAC activation is the mixed-function oxidase system and, in particular, cytochrome P-450. In the case of PAHs, oxidation predominantly produces reactive diol-epoxides that can then be converted to carbonium ions as the reactive electrophiles that can then covalently bind to DNA. Regions of high activity exist in PAHs, namely, the "bay," "K," and "L" regions which are associated with pi electron distribution. The diol-epoxides can exist in either syn or anti forms, each of which has two enantiomers producing four stereoisomers in all. Energy considerations favor the formation of the anti form. Nitrogen-containing PACs can be metabolically activated in a manner similar to that for PAHs, or the nitrogen atom can be oxidized to form hydroxylamines. These reactive electrophiles can then form covalently bound DNA adducts. The monitoring of DNA adducts has been used in risk assessment for human exposure to PACs. This form of biomonitoring has advantages over the monitoring of external exposure or body levels of the chemicals in question. In the case of PACs, binding to DNA is an important step in the multistage carcinogenic process. The estimation of DNA adducts has been used in the monitoring of humans exposed to PAHs in a wide range of industrial situations. Recent research has shown a dose-response relationship between PAH adduct levels and human cancer, thus developing molecular epidemiology as a relevant science for the field of risk assessment. Techniques have been developed for the determination of DNA adducts and these include immunochemical, fluorescence spectroscopic, GC-MS, and 32P-postlabeling methods. The 32P-postlabeling assay is by far the most sensitive, with limits of detection being of the order of one adduct in 10(10) normal nucleotides. The use of HPLC for separation of adducted nucleotides in this postlabeling assay is becoming more common and gives better resolution of adducts than does the TLC technique used in the traditional assay. The detection of adducts on hemoglobin and other proteins has been used as a surrogate for DNA adduct estimation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prediction and monitoring of the carcinogenicity of polycyclic aromatic compounds (PACs). 817 Dec 14

A 276 bp region from the tetracycline resistance gene of the plasmid pBR322 was modified with 2-acetylaminofluorene (AAF), 2-aminofluorene (AF), 4-aminobiphenyl (ABP), N'-acetylbenzidine or 1-aminopyrene (AP) in order to determine the effect of adduct structure upon mutation induction. Each modification reaction gave one major adduct and these adducts had chromatographic properties, as determined by 32P-postlabeling, identical to those in which substitution had occurred at C8 of deoxyguanosine through the amine or amide nitrogen. The types and distribution of mutations were then characterized following introduction of the modified plasmids into SOS-induced Escherichia coli using Hanahan et al.'s procedure (Methods Enzymol., 204, 63-113, 1991). With AAF-modified plasmid, 60% of the mutations were deletions or additions, and these were detected primarily at NarI sites or in repetitive G sequences. Modification with AF gave -G deletions, primarily in runs of Gs, and base substitution mutations, which were mainly G to T transversions. Substitution with ABP or N'-acetylbenzidine resulted in G to T and G to C transversions, the latter being a mutation not detected with AF; in addition, -G deletions were detected at only very low frequency. AP modification gave both -G frameshift and base substitution mutations, of which G to T transversions predominated. A comparison of the mutation frequencies per adduct indicated that the mutagenic efficiencies of the adducts decreased in the order AP > AF > AAF approximately ABP approximately N'-acetylbenzidine. AAF- and ABP-modified pBR322 were also introduced with a CaCl2 method. The mutation frequency per adduct increased with this transformation procedure, and this appeared to be a reflection of a greater percentage of frameshift mutations. These data indicate that a series of structurally related aromatic amines will induce both base substitution and frameshift mutations when incorporated into pBR322, but that frameshift mutations occur almost exclusively with the planar derivatives. Furthermore, the ability to induce frameshift mutations increases the mutagenic efficiency of an adduct.
Carcinogenesis 1994 May
PMID:Mutations induced by aromatic amine DNA adducts in pBR322. 820 92

Recent studies have demonstrated that nitric oxide (NO) rapidly and spontaneously decomposes in oxygenated solutions to generate potent N-nitrosating agents. These electrophilic substances have been shown to mediate mutagenesis and carcinogenesis via the formation of aliphatic and aromatic nitrosamines. We have also demonstrated that extravasated neutrophils and macrophages produce significant amounts of N-nitrosating agents derived exclusively from NO. During the course of these studies, we found that certain antioxidants, including 5-aminosalicylic acid (5-ASA), inhibited the leukocyte-mediated N-nitrosation reaction. Because 5-ASA and other anti-inflammatory and immunosuppressive drugs are used to treat inflammatory bowel disease, we wondered if any of these other compounds might also modulate N-nitrosation reactions in vitro. Therefore, the objectives of this study were to assess the ability of aminosalicylates and certain immunosuppressive agents to inhibit NO-dependent N-nitrosation of a model aromatic amine (2,3-diaminonaphthalene) and to determine whether this inhibitory activity correlated with their oxidation potential. We found that the concentrations necessary to inhibit the N-nitrosation reaction by 50% (IC50) were 25, 50 and 100 microM for 5-ASA, olsalazine (dimeric 5-ASA) and sulfasalazine, respectively. In contrast, sulfapyridine, 4-ASA, N-acetyl-5-ASA, 6-mercaptopurine, azathioprine, and methotrexate were either much less effective or inactive at inhibiting the N-nitrosation reaction. Although 5-ASA was able to fully scavenge the stable free radical 1,1-diphenyl-2-picrylhydrazyl, neither olsalazine nor sulfasalazine was found to be effective at scavenging this weak oxidant. We did find that olsalazine possessed an oxidation potential substantially less than that of sulfasalazine, suggesting that it may, in fact, scavenge more potent oxidizing agents such as the N-nitrosating agent. We conclude that 5-ASA and olsalazine inhibit NO-dependent N-nitrosation reactions by scavenging or decomposing the nitrosating agent(s). We propose that the secondary nitrogen unique to sulfasalazine interacts with the nitrosating agent to yield a secondary nitrosamine, thereby competing for N-nitrosation of our detector.
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PMID:Effects of aminosalicylates and immunosuppressive agents on nitric oxide-dependent N-nitrosation reactions. 820 7

Concurrent administration of para-aminobenzoic acid (PABA) reduced the toxicity of cis-diamminedichloroplatinum(II) (DDP) in a dose-related manner in rats. When administered i.p. simultaneously with 7.5 mg/kg DDP, PABA (100 mg/kg) significantly reduced plasma urea nitrogen (PUN) and plasma creatinine levels as well as DDP-induced weight loss. Increasing doses of PABA (25, 50 and 100 mg/kg) correlated with progressively better parameters of renal activity and body wt and with lower levels of platinum in plasma and tissues in rats killed 5 days after drug administration. The formation of cisplatin-DNA adducts, the total platinum levels in kidney and testes and the DDP-induced tumor response were investigated in the presence and absence of PABA exposure in mice bearing P388 leukemic cells. Renal and testicular DNA-adducts in mice treated i.p. with 16 mg/kg DDP in normal saline were higher than those observed in mice receiving the same protocol and added PABA. Analysis of tissue platinum content demonstrated significantly lower platinum levels both in kidneys (P < 0.05) and testes (P < 0.01) of mice receiving DDP and PABA in normal saline compared to those receiving only DDP in normal saline. PABA did not affect the in vivo and in vitro antitumor activity of DDP against P388 leukemia, and there was no significant PABA-induced modification in the concentration of platinum both in the tumor cells and in DNA samples isolated from P388 leukemic cells of DDP-treated mice. We conclude that PABA may be a promising compound for reducing DDP-toxic side effects, including nephrotoxicity, without compromising its antitumor activity.
Carcinogenesis 1993 Dec
PMID:Para-aminobenzoic acid suppression of cis-diamminedichloroplatinum(II) nephrotoxicity. 826 32

The relationship between the structures of different alkylating agents and the relative extents to which they modify the oxygen and nitrogen centers of nucleic acid bases has been discussed in the literature from several points of view, although each effectively attributes the increasing preference for oxygen alkylation to the increasing importance of electrostatic interactions between the reacting moieties. This is in direct contradiction to the published electrostatic potential data for cytosine which indicate the most attractive potential to lie in the vicinity of the 3-nitrogen. However, we have discovered the latter to be an artefact of the use of inadequate levels of theory. When the electrostatic potentials of cytosine are computed using more sophisticated ab initio Hartree-Fock/6-31G* calculations the global minimum does indeed lie in the vicinity of the O2-position as required by the various rationalizations of the alkylation data.
Carcinogenesis 1993 Jul
PMID:The updated electrostatic potential for cytosine completes the qualitative explanations of base alkylation regiochemistry. 833 Mar 65

We have measured the DNA damage formation and repair in the ribosomal and the dihydrofolate reductase (DHFR) genes after treatment of hamster cells with different types of DNA damaging agents. In mammalian cells, the ribosomal DNA (rDNA) is transcribed by RNA polymerase I, whereas the DHFR is transcribed by RNA polymerase II, whereas the DHFR is transcribed by RNA polymerase II. Cells were treated with agents that induce different types of lesions, and that are known to be repaired via different pathways. We used UV (254 nm) irradiation, treatment with cisplatin and treatment with the alkylating agents nitrogen mustard (HN2) and methyl methanesulphonate (MMS). UV induced pyrimidine dimers were detected with the enzyme T4 endonuclease V, which creates nicks at the dimer sites; the breaks are then resolved and identified by denaturing electrophoresis and Southern blot. Intrastrand adducts formed by the alkylating agents HN2 and MMS were quantitated by generating strand breaks at abasic sites after neutral depurination. Interstrand crosslinks (ICL) formed by HN2 and cisplatin were detected by a denaturation-reannealing reaction before neutral agarose gel-electrophoresis. We find that the repair of the pyrimidine dimers is significantly less efficient in the RNA polymerase I transcribed rDNA genes than in RNA polymerase II transcribed DHFR gene at 8 and 24 h after irradiation. ICL and intrastrand adducts induced by HN2 are also removed more slowly from the rDNA than from the DHFR gene. In contrast, MMS induced intrastrand adducts and cisplatin induced ICL are repaired equally efficiently in the RNA polymerase I and RNA polymerase II transcribed genes. We conclude that for some types of DNA damage, there is less repair in the ribosomal genes than in the DHFR; but for other DNA lesions there is no difference. The difference in repair efficiency between the rDNA and the DHFR genes may reflect the different RNA polymerase involved in their transcription. It may, however, alternatively, reflect the different nuclear localization of these genes.
Carcinogenesis 1993 Aug
PMID:Repair of ribosomal RNA genes in hamster cells after UV irradiation, or treatment with cisplatin or alkylating agents. 835 43

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