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WO1993012258A1 - Biomarqueurs du cancer et de lesions genotoxiques obtenus a partir de l'adn - Google Patents

Biomarqueurs du cancer et de lesions genotoxiques obtenus a partir de l'adn Download PDF

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Publication number
WO1993012258A1
WO1993012258A1 PCT/US1992/010669 US9210669W WO9312258A1 WO 1993012258 A1 WO1993012258 A1 WO 1993012258A1 US 9210669 W US9210669 W US 9210669W WO 9312258 A1 WO9312258 A1 WO 9312258A1
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Prior art keywords
dna
specimen
oxidatively modified
quantitating
modified nucleotides
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PCT/US1992/010669
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English (en)
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Donald C. Malins
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Pacific Northwest Research Foundation
Cytochem, Inc.
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Application filed by Pacific Northwest Research Foundation, Cytochem, Inc. filed Critical Pacific Northwest Research Foundation
Publication of WO1993012258A1 publication Critical patent/WO1993012258A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6804—Nucleic acid analysis using immunogens
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/142—Toxicological screening, e.g. expression profiles which identify toxicity

Definitions

  • This invention relates to the field of detection and assessment of oxidatively modified DNA nucleotide bases or their functional equivalents in eukaryotic systems and more particularly to the comparison of levels of such modified molecules to normal levels in eukaryotic systems as a means to determine genotoxic effects of environmental influences.
  • This reaction can be relatively slow; however, when catalyzed by metal ions [e.g., Fe +2 ], it is substantially accelerated and becomes especially relevant in the initiation of biological damage (Science 240, 640-642 (1988)). H 2 0 2 itself is converted to «0H through, the iron (Fe +2 )-catalyzed Fenton reaction (Science 240, 640-642 (1988)).
  • the proliferation of »OH may then result in an attack on most molecules in living cells with deleterious consequences (Science 227, 375-381 (1985)).
  • the primary defense against such radical-induced damage is provided by enzymes that catalytically scavenge the intermediates of oxygen reduction and by antioxidants, such as glutathione.
  • SOD superoxide dismutase
  • This type of damage may be an important factor in the etiology of cancer and other genetically-related diseases
  • DNA e.g. DNA
  • DNA is critical because of the pivotal role that it plays in information transfer between generations of somatic cells.
  • the inventor has been exploring the relationship between the generation of the »OH and the occurrence of disease conditions.
  • the inventor narrowed his research to determine the presence of a DNA modified nucleotide base — 2,6- diamino-4-hydroxy-5-formamidopyrimidine or FapyGua.
  • a DNA modified nucleotide base 2,6- diamino-4-hydroxy-5-formamidopyrimidine or FapyGua.
  • the inventor excised the hepatic tumors together with the surgical margin tissue.
  • the tumor tissues, but not the surgical margin showed substan ⁇ tially elevated levels of FapyGua, thus indicating that reaction of the •OH had resulted in this nucleotide base modification.
  • the present invention provides methods for determining oxidative modifications to DNA nucleotide bases or their functional equivalents in relation to their significance as biomarkers or sentinels for the diagnostic and prognostic monitoring of genotoxic changes in tissues, body fluids, and cell cultures of eukaryotic systems that are associated with pathologic or disease conditions.
  • the modifications of DNA bases may occur through disruptions in normal biochemical processes in vivo (e.g., alterations in enzyme activities), or through the influence of chemical exposures, such as those that occur through the acquisition of toxic substances from the environment.
  • one object of this invention is to provide a method for determining the presence and quantity of altered DNA nucleotide bases. By providing for this determination, a comparison can be made between these levels and those obtained from a baseline. By applying these findings with the disclosed knowledge that elevated levels of altered nucleotide bases are an indicator of genotoxic changes in tissue and body fluids, an -.t evaluation can be made relating to the presence or likelihood of pathologic or disease conditions of that tissue or body fluid. As a corollary, it is also an object of this invention is to provide a method whereby a subject is administered structurally equivalent "surrogate" compounds (biomarkers) for diagnosing or predicting the occurrence of genotoxic effects brought about by exposure of animal or plant systems to environmental chemicals.
  • surrogate biomarkers
  • a further object of this invention is to provide a method whereby the presence and quantity of such altered nucleotide bases or biomarkers can be used to assay the degree of exposure of a system to external chemicals and the rate and degree of decline in such alterations upon introduction of therapeutically-applied antioxidants or other radical trapping agents.
  • the method of determining such alteration is not limited to those employed by the inventor.
  • Other methods such as the use of monoclonal or polyclonal antibodies, or adducts utilizing uniquely identifiable labels are equally plausible, depending upon the needs of the analyst.
  • Fi ⁇ . 1 An explanation is given for the formation of the cleav ⁇ age product of adenine (FapyAde) resulting from the attack of the •OH at C-8 of the purine ring.
  • Fig. 2 Elevated concentrations in 8-hydroxyguanine in DNA are shown in neoplastic hepatic tissue of feral fish, compared to normal tissue.
  • Fig. 3A Elevated concentrations of 8-hydroxyadenine in DNA are shown in neoplastic hepatic tissue of feral fish, compared to normal tissue.
  • Fig. 3B Elevated concentrations of 4,6-diamino-5-formamido- pyrimidine (FapyAde) in DNA are shown in neoplastic tissue of feral fish, compared to normal tissue.
  • Fig. 4 Comparisons are made between English sole from “clean” reference areas and fish with normal livers from a mildly pollut ⁇ ed area having microscopically normal livers. These are also compared to the DNA lesions found in tumor tissue from fish living in a heavily polluted area.
  • Fig. 5 Comparisons of invasive ductal carcinoma tissue to normal DNA from calf thymus indicate that substantial changes in the nucleotide bases have taken place in the cancer tissue as a result of the attack of the »OH on the base structures.
  • the present invention provides for a method to quantitative ⁇ ly and structurally identifying oxidatively modified nucleotide bases or their functional equivalents, and the effect that such modified nucleotide bases have on the ability of the DNA to successfully act to self-replicate or the implications arising from alterations to functional equivalents.
  • DNA from neoplastic hepatic tissues of feral fish environmentally exposed to carcinogens was investigated by the inventor and it was found that an abnormally high concentra- s tion of an oxidatively modified DNA nucleotide base was present.
  • the results of this research confirmed for the first time that at 5 least one modified nucleotide base — FapyGua or 2,6-diamino-4- hydroxy-5-formamidopyrimidine — was present in the DNA of the carcinogenic hepatic tissue of feral fish.
  • hepatic tissue samples obtained from feral fish from non-contaminated sites.
  • the inventor analyzed tissue from female breast cancer patients using the same methods as described immediately above.
  • Biopsy specimens and blood samples are additional examples of materials that may be subjected to the DNA base determinations and used in conjunction with hi ⁇ tologic, pathologic and other information relating to disease or health status.
  • surrogate compounds that metabolically mimic the essential structure of the nucleotide bases, or otherwise serve as sentinels for the threat posed to the nucleotide bases from the attack of reactive oxygen compounds, may be administered under therapeutic or other conditions. Under these circumstances, the modifications in the surrogate compounds may be followed as undertaken with the normal DNA. Additionally, the use of the DNA biomarkers can be extended o "tracking" the effects of administered or dietary substances that have the ability to inhibit or essentially nullify the injurious effects of the oxidative injury to DNA by interacting with reactive oxygen species.
  • therapeutically-applied trapping agents include antioxidants (e.g., vitamin E, indoles,
  • mixtures of substances are vast and diverse, including soil, sediment, water, water surface microlayer, food chain organisms, air individual chemicals, chemical mixtures, extracts derived from biological material, drugs, pharmaceutical, carcinogenic materials, cosmetics, food products.
  • tissue to be tested is removed from the subject.
  • surgical margin tissue or other suitable "control” tissue is also analyzed to determine whether differences exist between "normal” and pathologic or diseased tissue.
  • the tissues are placed in liquid nitrogen and maintained at or below -70°C prior to extrac ⁇ tion of the DNA.
  • the DNA solution was then placed in an evacuated sealed tube at a temperature of 140 °C and allowed to react with concentrated * 5 formic acid (88%) for 30 minutes. This procedure did not alter the structure of the nucleotide bases being studied and achieved the goal of preparing trimethylsyl (TMS) derivatives for the GC- MS/SIM.
  • TMS trimethylsyl
  • the solution was then dried in a desiccator under vacuum and allowed to react with acetonitrile -bis(trimethylsilyl)tri-
  • FapyAde 8-hydroxymethyluracil
  • FapyGua 8-hydroxyadenine
  • the column of the GC/MS-SIM unit was a fused silica capillary column (15.0 m., 0.2 mm inner diameter) coated with cross-linked 5% phenylmethyl- silicone gum phase (film thickness, 0.33 um) .
  • the column temper ⁇ ature was increased from 120°C to 176°C at a rate of 3°C/min, and 25 from 176°C to 250°C at a rate of 6°C/min., after initially being held for 1.5 min. at 120°C.
  • a carrier gas of helium was used with a linear velocity of 23.5 cm/s through the column. Approxi ⁇ mately 0.7 ⁇ g of TMS hydrolysate was injected onto the column.
  • Quantification of DNA base derivatives was undertaken on the basis of the principal ions for the oxidized nucleotide bases, such as m/z 442, 440, 354 and 352 for FapyGua, 8-hydroxyguanine, FapyAde, and 8-hydroxyadenine, respectively. All spectra were compared to those from commercially obtained standards and authentic samples of TMS derivatives synthesized in the inven ⁇ tor's laboratory. The area counts for the principal ions were integrated and the data obtained included SIM plots and derived mass spectra.
  • the GC/MS-SIM equipment is sensitive enough to analyze the presence and quantity of trace concentrations of modified nucleo ⁇ tide bases in normal tissues and body fluids. By analyzing this baseline level against the level observed in the biological sample in question, one can accurately determine the percentage increase or decrease in the modified biomarker analyzed. The results from the analysis can then be used in conjunction with pathological and histological data that reflect the health status of the tissues, cells or body fluids examined. For example, in the case of exposed fish, ample documentation exists in the literature for the types of morphological changes that occur in relation to a variety of environmental contaminants (J. Natl. Cancer. Inst. 78, 333-363 (1987)). The success obtained from the use of this method is apparent from the results of the inventor's extended research efforts.
  • One such alternative method for assaying altered DNA nucleo ⁇ tide bases utilizes monoclonal or polyclonal antibodies with high specificity for the modified nucleotide bases.
  • Such antibodies can be prepared using described procedures and applied in a quantitative assay using the ELISA (Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988)) or radioimmunoassay (Monoclonal Antibody Technology, Elsevier Publishers (1984)) procedures. Examples of production of monoclonal and polyclonal antibodies follow this discussion.
  • DNA to be tested could be coupled to a solid support or coated onto plastic plates.
  • the samples would be blocked with a 5% BSA solution in PBS for 1 hour prior to incubation with appropriate mono- or polyclonal antibodies for 1 to 2 hours.
  • These primary antibodies could be used individually for a specific modified base or mixed together to broadly define the extent of base modification.
  • Monoclonal antibodies can be prepared in mice immunized as described for polyclonal antibody production prior to fusion. Cell fusion is conducted according to the method previously described (Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988)). X63-Ag8 cells grown in RPMI 1640 medium containing 10% FCS are used as the fusion partner. X63-Ag8 cells, 5xl0 7 , are mixed in a ratio of 1:4 with mouse spleen cells prior to fusion with PEG at room temperature.
  • the fusion from each spleen is mixed with thymocytes derived from a single thymus in HAT containing RPMI 1640, 10% FCS and plated into 4-96 well culture plates.
  • the outer wells of each 96 well plate contain serum free medium.
  • Screening of hybrid cells is conducted by binding assays with modified nucleotide bases. Positive clones are moved to 24 well plates and further tested by reactivity to unmodified bases. The clones showing proper specificity were then further cloned with a thymocyte feeder layer in a ratio of 50 cells per 96 well plate to achieve a uniform antibody producing cell population.
  • Polyclonal antibodies specific for oxidatively modified nucleotide bases can be prepared in New Zealand White rabbits by immunization with modified bases conjugated to a protein such as keyhole limpet hemocyanin using the procedures previously described (Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988)).
  • the modified base is either chemically prepared or extracted from preparative quantities of appropriate DNA.
  • the antigen is then mixed with 1 ml of Freund's incomplete adjuvant and emulsified.
  • the pooled serum can be purified by removing antibodies specific for the conjugation protein by chromatography on an affinity column containing the immobilized protein. The resulting serum is then assayed for reactivity with nucleotide bases and modified bases using binding assays as described (Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988)).
  • the embodiments of this patent are not restricted to the direct measurement of the biomarkers in excised tissues and body fluids, but incorporate usage in isolated cell systems maintained under suitable culture conditions.
  • the extraction procedure involved hydrolysis of the DNA with formic acid, followed by trimethylsilylation under a closed 10 system of pure nitrogen.
  • the DNA was quantified by measuring the UV absorbance to determine its purity.
  • the TMS derivatives were then analyzed by GC/MS-SIM.
  • the inlet pressure of helium was at 7 kpa and the column temperature was increased from 120 to 176°C at 3°C/min. and from 176 to 250°C at 6°/min., after initially 15 being held for 1.5 min at 120°C.
  • Mass spectra were obtained with 70 eV ionizing energy.
  • concentrations of oxidatively modified nucleotides in normal DNA are severely restricted metabolically, such as through the glycosylases and other enzymes that participate in the 20 excision repair process.
  • concentrations of oxidatively modified nucleotides in normal DNA are severely restricted metabolically, such as through the glycosylases and other enzymes that participate in the 20 excision repair process.
  • concentrations of oxidatively modified nucleotides in normal DNA are severely restricted metabolically, such as through the glycosylases and other enzymes that participate in the 20 excision repair process.
  • FapyGua from normal English sole liver (Carcinoqenesis 11, 1045- 1047 (1990)) was ⁇ 0.01 nmol/mg, which is the same as that obtained with calf thymus DNA (Journ. Biol. Chem. 264(22), 13025- 13028 (1989), Anal. Biochem. 156, 182-188 (1986)).
  • TMS derivatives of the nucleotide bases were analyzed by GC- MS/SIM, essentially as previously described herein. Briefly, as before, the nucleotide bases were allowed to react with acetoni-
  • a fused silica capillary column coated with 5% phenylmethylsilicone gum phase (15m; 0.2mm i.d., and 0.3 ⁇ m film thickness) was used for the separation of the DNA base derivatives.
  • the column temperature was maintained at 120°C for 1.5 min., increased to 176°C at 3°/min., and then to 250°C at 6°/min.
  • the injection port and ion source were kept at 250°C throughout the analysis.
  • Helium was the carrier gas and mass spectra were obtained with 70 eV ionizing energy.
  • the DNA lesions in hepatic tissues from the Port Madison fish were statistically compared to those from the tumor-bearing fish from Eagle Harbor and normal reference fish from the essen ⁇ tially uncontaminated sites of Newport OR and Elger Bay WA (Table II).
  • liver lesions **.** in the fish from Port Madison allowed samples to be obtained from a sub-population of English sole in one catching effort that showed no evidence of preneoplastic or neoplastic changes in the liver, as demonstrated on the basis of well-established histolog ⁇ ical criteria (J. Natl. Cancer. Inst. 78, 333-363 (1987))—that is, the livers were considered normal.
  • FapyGua concentrations were inteirmediate with respect to those of normal DNA from the reference fish from Newport and Elger Bay and the hepatic tumors of fish from Eagle Harbor. This is illustrated in Figure 4 where the present data from Port Madison are compared with previously obtained results from tumor-bearing fish from Eagle Harbor and the reference sites. Specifically, the relationships between the concentrations of the nucleotide base modifications in the hepatic DNA and the site of capture are shown. Statistical evaluation using single factor analysis of variance (ANOVA) revealed that, with the exception of FapyAde, significant differences existed between the concentrations of DNA lesions with respect to Eagle Harbor, Port Madison and the reference sites (Table 2).
  • ANOVA single factor analysis of variance
  • the present work is consistent with the inventor's hypothesis that the *OH-induced modification of the hepatic DNA in English sole is a progressive event initiated by exposure to environmental chemicals, the ultimate result being tumorigenesis.
  • Port Madison has a low incidence of tumor-bearing fish
  • the 8-OH-Gua, 8-OH-Ade, FapyGua and FapyAde may be close to threshold concentrations for the development of liver cancer in the population.
  • the DNA lesions have an important use in the future for predicting the occurrence of cancer in organisms exposed to carcinogens.
  • the DNA lesions represent readily evinced alterations at the molecular level that are highly relevant biomarkers for cytogenetic change in a variety of animal systems.
  • the TMS derivatives were analyzed by GC-MS/SIM as described previously, using a Hewlett-Packard Model 5890 microprocessor-controlled gas chromatograph interfaced to a HP Model 5970B mass selective detector. The injector port and interface were both maintained at 250°C.
  • the column was a fused silica capillary column (15.0 m., 0.2 mm inner diameter) coated with cross-linked 5% phenylmethylsilicone gum phase (film thickness, 0.33 ⁇ m) .
  • the column temperature was increased from 120 to 176°C at 3°C/min. and from 176 to 250°C at 6°/min., after initially being held for 1.5 min. at 120°C.
  • Helium was used as the carrier gas with a linear velocity of 23.5 cm./s through the column.
  • the amount of TMS hydrolysate injected onto the column was about 0.7 ⁇ g.
  • Quantitation of the modified nucleotide derivatives was undertaken on the basis of the principal ions, such as m/z 442 for the TMS derivative of FapyGua.
  • FapyAde is not a prominent indicator of altered DNA in breast cancer in contrast to the other base modifications.
  • the concentrations of each of the above base modifications were substantially higher in the carcinoma, with the exception of FBT- 5 which had relatively low concentrations of the base lesions (see legend to Figure 5).

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Abstract

Procédé de contrôle diagnostique et pronostique de changements génotoxiques se produisant dans des tissus, provenant de modifications oxydatives du genre constitué par les bases nucléotidiques de l'ADN contenant de la purine ou de la pyrimidine, ou des substituts structurellement et métaboliquement similaires, consistant à analyser les bases modifiées ou les substituts et à comparer les résultats obtenus avec des niveaux de base. [Voir dans re Harmisch, 206 USPQ 300 (1980)]. Le procédé consiste à diagnostiquer ou à prédire l'apparition de néoplasie (tumeur cancereuse), à déterminer l'impact des effets génotoxiques entraînés par une exposition aux agents chimiques de l'environnement, et à suivre les effets de telles modifications dans le temps en réponse à l'action d'agents oxydatifs répresseurs.
PCT/US1992/010669 1991-12-13 1992-12-10 Biomarqueurs du cancer et de lesions genotoxiques obtenus a partir de l'adn WO1993012258A1 (fr)

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US07/806,487 1991-12-13

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0706581A4 (fr) * 1993-04-30 1999-02-10 Pacific Northwest Research Fou Profiles d'adn indicateurs du potentiel cellulaire d'oxyreduction et du risque de cancer
EP0753146A4 (fr) * 1994-03-28 1999-05-26 Pacific Northwest Research Fou Techniques de determination de lesion de l'adn due a l'oxydation
US6187551B1 (en) 1995-09-19 2001-02-13 Cytochem, Inc. Detection and quantitation of 8-OH-Adenine using monoclonal antibodies
WO2002065889A1 (fr) * 2001-02-21 2002-08-29 Rubikon Ag Procede pour examiner des echantillons cellulaires et tissulaires
US9855233B2 (en) 2008-08-08 2018-01-02 City Of Hope Methods of quantifying N2-(1-carboxyethyl)-2′-deoxy-guanosine (CEdG) and synthesis of oligonucleotides containing CEdG
US11179361B2 (en) 2008-08-08 2021-11-23 City Of Hope Methods of quantifying N2-(1-carboxyethyl)-2′-deoxy-guanosine (CEdG) and synthesis of oligonucleotides containing CEdG
US11835499B2 (en) 2018-02-02 2023-12-05 City Of Hope Methods of quantifying methylglyoxal-induced nucleic acid adducts

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ANALYTICAL BIOCHEMISTRY, Vol. 156, issued 1986, DIZDAROGLU et al., "Characterization of Free Radical-Induced Base Damage in DNA at Biologically Relevant Levels", pages 182-188. *
CANCER RESEARCH, Vol. 51, issued 01 October 1991, MALINS et al., Major Alterations in the Nucleotide Structure of DNA in Cancer of the Female Breast", pages 5430-5432. *
CARCINOGENESIS, Vol. 11, issued June 1990, MALINS et al., "A Novel DNA Lesion in Neoplastic Livers of Feral Fish: 2,6-Diamino-4-Hydroxy-5-Formamidopyrimidine", pages 1045-1047. *
IARC SCIENCE PUBLICATION, Vol. 70, issued 1986, ADAMKIEWICZ et al., "Monoclonal Antibody-Based Immunoanalytical Methods for Detection of Carcinogen-Modified DNA Components", pages 403-411. *
INTERNATIONAL JOURNAL OF RADIATION BIOLOGY & RELATED STUDIES IN PHYSICS CHEMISTRY & MEDICINE, Vol. 42, issued 1982, WEST et al., "Radioimmunoassay of 7,8 Dihydro-8 Oxoadenine 8 Hydroxy Adenine". *
METHODS IN ENZYMOLOGY, Vol. 186, issued 1990, DIZAROGLU et al., "Selected-Ion Mass Spectrometry: Assays of Oxidative DNA Damage", pages 530-544. *
METHODS IN ENZYMOLOGY, Vol. 186, issued 1990, WAGNER et al., "Photodynamic Methods for Oxy Radical-Induced DNA Damage", pages 502-511. *
RADIATION RESEARCH, Vol. 90, Number 3, issued 1982, WEST et al., "Radioimmunoassay of a Thymine Glycol". *
THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 264, Number 22, issued 05 August 1989, AROUMA et al., "Iron Ion-Dependent Modification of Bases in DNA by the Superoxide Radical-Generating System Hypoxanthine/Xanthine Oxidase", pages 13024-13028. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0706581A4 (fr) * 1993-04-30 1999-02-10 Pacific Northwest Research Fou Profiles d'adn indicateurs du potentiel cellulaire d'oxyreduction et du risque de cancer
EP0753146A4 (fr) * 1994-03-28 1999-05-26 Pacific Northwest Research Fou Techniques de determination de lesion de l'adn due a l'oxydation
US6187551B1 (en) 1995-09-19 2001-02-13 Cytochem, Inc. Detection and quantitation of 8-OH-Adenine using monoclonal antibodies
US6900291B2 (en) 1995-09-19 2005-05-31 Cytochem, Inc. Detection and quantitation of 8-OH-adenine using monoclonal antibodies
WO2002065889A1 (fr) * 2001-02-21 2002-08-29 Rubikon Ag Procede pour examiner des echantillons cellulaires et tissulaires
US9855233B2 (en) 2008-08-08 2018-01-02 City Of Hope Methods of quantifying N2-(1-carboxyethyl)-2′-deoxy-guanosine (CEdG) and synthesis of oligonucleotides containing CEdG
US11179361B2 (en) 2008-08-08 2021-11-23 City Of Hope Methods of quantifying N2-(1-carboxyethyl)-2′-deoxy-guanosine (CEdG) and synthesis of oligonucleotides containing CEdG
US11266618B2 (en) 2008-08-08 2022-03-08 City Of Hope Methods of quantifying N2-(1-carboxyethyl)-2′-deoxy-guanosine (CEdG) and synthesis of oligonucleotides containing CEdG
US11835499B2 (en) 2018-02-02 2023-12-05 City Of Hope Methods of quantifying methylglyoxal-induced nucleic acid adducts

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CA2125778A1 (fr) 1993-06-24

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