Abstract:
:The efficacy of DNA-damaging anticancer drugs is highly influenced by cellular DNA repair capacity, and by inhibiting the relevant DNA repair pathway, efficacy of alkylating agents may be increased. Therefore, combining DNA repair inhibitors with anticancer agents that selectively target tumor tissue should improve cancer treatment. The objective of this study was to test the hypothesis that cotreatment of cancer cells with acylfulvene (AF, alkylating agent) and UCN-01 (DNA repair inhibitor) would improve drug efficacy and promote the persistence of DNA adducts. Previous data regarding the relative susceptibility of repair proficient versus deficient cells toward an AF analogue suggests that corresponding adducts are repaired by nuclear excision repair (NER), a cellular process that has been shown to be prevented with UCN-01. In this study, cells were cotreated with nontoxic levels of UCN-01 together with increasing doses of AF. The efficacy of AF was assessed by measuring cytotoxicity and DNA adducts. In addition, cells were cotreated with nontoxic levels of methoxyamine, a known base excision repair (BER) inhibitor, to determine if inhibiting BER also promotes cytotoxicity of AF. DNA-adducts were measured in a sensitive and precise manner by using stable isotope-labeled mass spectrometry analysis. The data obtained in this study demonstrate for the first time that pharmacological inhibition of the NER pathway of DNA repair leads to the persistence of AF-specific adducts and promotes AF cytotoxicity.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
van Midwoud PM,Sturla SJdoi
10.1021/tx400255fsubject
Has Abstractpub_date
2013-11-18 00:00:00pages
1674-82issue
11eissn
0893-228Xissn
1520-5010journal_volume
26pub_type
杂志文章abstract::Carbon disulfide (CS2) induces embryo implantation disorders. Macrophages participate in the process of pregnancy. Therefore, we want to explore the effects of CS2 exposure on polarization and immune function of macrophages in pregnant mice uteri. The exposure times were gestation days 3 (GD3), 4 (GD4), and 5 (GD5), a...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00119
更新日期:2019-10-21 00:00:00
abstract::Nitric oxide can be introduced slowly and steadily into aqueous solutions, including cell culture media, over extended periods of time via semipermeable Silastic (a registered trademark of the Dow Corning Corp.) polymer membranes. The rates of introduction are predictable and reproducible and can approach rates of nit...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00036a021
更新日期:1993-11-01 00:00:00
abstract::The reaction of the antitumor agent leinamycin with thiols converts this natural product into an episulfonium ion that alkylates the N7-position of guanine residues in double-stranded DNA. It is reported here that depurination of this adduct is unusually facile, occurring with a half-life of about 3.5 h at pH 7 and 37...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx049964k
更新日期:2004-07-01 00:00:00
abstract::Mouse models are powerful tools to study the developmental neurotoxicity of polychlorinated biphenyls (PCBs); however, studies of the oxidation of chiral PCB congeners to potentially neurotoxic hydroxylated metabolites (OH-PCBs) in mice have not been reported. Here, we investigate the atropselective oxidation of chira...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400229e
更新日期:2013-11-18 00:00:00
abstract::The present study describes a novel integrated approach for rapid analysis of reactive metabolites with a linear ion trap mass spectrometer (LTQ). In this approach, an isotope pattern-dependent scanning method was applied to the data acquisition of glutathione (GSH)-trapped reactive metabolites. Recorded full-scan MS ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx8001115
更新日期:2008-07-01 00:00:00
abstract::The chemical reactivity of styrene-7,8-oxide (SO), an alkylating agent with high affinity for the guanine–N7 position and a probable carcinogen for humans, with 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases, was investigated kinetically in...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx5002892
更新日期:2014-10-20 00:00:00
abstract::The synthesis of a series of 1,2,4-triazole-containing oligopeptide lexitropsins related to the natural antitumor antibiotic distamycin is described. The binding properties of these new agents to both native DNAs and synthetic polydeoxyribonucleotides were determined by UV absorption and circular dichroism studies. Th...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00020a019
更新日期:1991-03-01 00:00:00
abstract::Many organic sulfides (mono-, di-, and polysulfides) are present in our environment. Simple derivatives are produced by some plants and animals, while complex sulfides are secondary metabolites of several genera of bacteria and fungi. Sulfides play an important role in the smell and taste of food, and many such compou...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx200373u
更新日期:2012-01-13 00:00:00
abstract::2,3-dimethoxy-1,4-naphthoquinone (CAS-RN 6959-96-3) (DMNQ) and 2-methyl-1,4-naphthoquinone (CAS-RN 58-27-5) (MNQ:menadione) are effective one electron redox cycling chemicals in vitro. In addition, in vitro MNQ forms a thioether conjugate with glutathione by nucleophilic attack at the third carbon. In contrast, here w...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800472z
更新日期:2009-04-01 00:00:00
abstract::The worldwide outbreak of COVID-19 has drastically increased pressure on medical resources and highlighted the need for rapidly available, large-scale, and low-cost personal protective equipment (PPE). In this work, an alternative full-face mask is adapted from a modified snorkel mask to be used as PPE with two medica...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00371
更新日期:2021-01-18 00:00:00
abstract::Acrolein is a bifunctional electrophile, present as an ubiquitous environmental pollutant and an endogenous cellular product of lipid peroxidation. Reaction of acrolein with deoxyguanosine produces two regioisomeric DNA adducts, specifically gamma-hydroxypropanodeoxyguanosine (gamma-HOPdG) and alpha-hydroxypropanodeox...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx034066u
更新日期:2003-08-01 00:00:00
abstract::1,3-Butadiene (BD) is a high-volume industrial chemical and a common environmental pollutant. Although BD is classified as a "probable human carcinogen", only limited evidence is available for its tumorigenic effects in occupationally exposed populations. Animal studies show a surprisingly high sensitivity of mice to ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9700681
更新日期:1997-10-01 00:00:00
abstract::The need for large-scale direct synthesis of stereochemically defined and site-specific benzo[alpha]pyrenediol epoxide-oligodeoxyribonucleotide adducts for detailed NMR and other biochemical and physicochemical studies has necessitated a better understanding of variables that lead to an enhancement of the reaction yie...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx980006q
更新日期:1998-04-01 00:00:00
abstract::Nitrogen mustards (NM) are an important class of chemotherapeutic drugs used in the treatment of malignant tumors. The accepted mechanism of action of NM is through the alkylation of DNA bases. NM-adducts block DNA replication in cancer cells by forming cytotoxic DNA interstrand cross-links. We previously characterize...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00012
更新日期:2020-04-20 00:00:00
abstract::Cytochrome P-450 enzymes have been postulated to oxidize amines through a variety of mechanisms. One of the means of distinguishing among potential pathways involves the use of kinetic hydrogen isotope effects: low isotope effects are characteristic of aminium radical mechanisms while high values are consistent with h...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00013a004
更新日期:1990-01-01 00:00:00
abstract::The binding of arsenite, As(III), and arsenate, As(V), by molecules in the intracellular compartment of rabbit erythrocytes has been studied by 1H- and 31P-NMR spectroscopy, uptake of 73As, and ultrafiltration experiments. For intact erythrocytes to which 0.1-0.4 mM arsenite was added, direct evidence was obtained for...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00041a006
更新日期:1994-09-01 00:00:00
abstract::Copper is a physiologically important, redox-active metal that may be involved in endogenous DNA damage and mutagenesis. To understand the factors that affect the location and quantity of copper-induced oxidative DNA damage in cells, we used the 5S rDNA nucleosome as a model to assess the effect of chromatin structure...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0002278
更新日期:2001-04-01 00:00:00
abstract::Water samples from the Waka River, which runs through an area housing many chemical industry facilities in Wakayama, Japan, have been found to show significant mutagenicity, especially without a mammalian metabolic activation system (S9 mix) in the Salmonella typhimurium YG1024 strain. Mutagens in the river water were...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010163g
更新日期:2002-03-01 00:00:00
abstract::One possible mechanism linking inflammation with cancer involves the generation of reactive oxygen, nitrogen, and halogen species by activated macrophages and neutrophils infiltrating sites of infection or tissue damage, with these chemical mediators causing damage that ultimately leads to cell death and mutation. To ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300473n
更新日期:2013-04-15 00:00:00
abstract::A methodology called quantitative component analysis of mixtures (QCAM) was used to analyze an existing set of product formulation data to determine if the irritating ingredients in the mixtures could be identified. Eye irritation scores, based on a rat model, for 18 mixtures having a composite total of 37 components,...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx990098z
更新日期:1999-11-01 00:00:00
abstract::Methyleugenol (ME), an alkenylbenzene compound, is a natural ingredient of several herbs and is used as flavoring agent in foodstuffs and fragrance in cosmetics. The hepatotoxicity, cytotoxicity, and carcinogenesis of ME have been well documented, and metabolic activation has been suggested to involve in ME-induced to...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.6b00290
更新日期:2017-02-20 00:00:00
abstract::Cholyl adenylate is a putative intermediate for biosynthesis of cholic acid-coenzyme A (CoA) thioester conjugates by acyl-CoA synthetase. Early studies showed the conjugated acid anhydride moiety of cholyl adenylate to be reactive, attacking proteins to form protein-cholic acid adducts. In the present study, to clarif...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050159v
更新日期:2005-11-01 00:00:00
abstract::The conformation of the crotonaldehyde-derived N(2)-[3-oxo-1(S)-methyl-propyl]-dG adduct in the oligodeoxynucleotide 5'-d(G(1)C(2)T(3)A(4)G(5)C(6)X(7)A(8)G(9)T(10)C(11)C(12))-3'.5'-d(G(13)G(14)A(15)C(16)T(17)C(18)G(19)C(20)T(21)A(22)G(23)C(2)(4))-3', where X = N(2)-[3-oxo-1(S)-methyl-propyl]-dG, is reported. This addu...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0600604
更新日期:2006-08-01 00:00:00
abstract::Protein-xenobiotic adducts are byproducts of xenobiotic metabolism. While there is a correlation between protein adduction and target organ toxicity, a cause and effect relationship is not often clear. Naphthoquinone (NQ) and monocrotaline pyrrole (MCTP) are two pneumotoxic electrophiles that form covalent adducts wit...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx1002436
更新日期:2010-09-20 00:00:00
abstract::Hemoglobin adducts have been used to assess exposure to carcinogenic compounds in tobacco smoke. However, because of background levels in nonsmokers, most adducts that have been studied are not useful for monitoring low-level exposure. Bergmark [(1997) Chem. Res. Toxicol. 10, 78-84] showed that the level of adducts of...
journal_title:Chemical research in toxicology
pub_type: 临床试验,杂志文章
doi:10.1021/tx9900728
更新日期:1999-10-01 00:00:00
abstract::Glyoxal is generated endogenously from the degradation of glucose and the oxidation of carbohydrates, lipids, and the 2-deoxyribose moieties of DNA. Glyoxal is also widely used in industry and is present in cigarette smoke and food. Glyoxal can conjugate with nucleobases and proteins to give advanced glycation end pro...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx900286c
更新日期:2010-01-01 00:00:00
abstract::Basic research, exploring the hypothesis that 2-(ω-carboxyethyl)pyrrole (CEP) modifications of proteins are generated nonenzymatically in vivo is delivering a bonanza of molecular mechanistic insights into age-related macular degeneration, autism, cancer, and wound healing. CEPs are produced through covalent modificat...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx200206v
更新日期:2011-11-21 00:00:00
abstract::2-Nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-NO-MeIQx) is a nitrosation product of the food carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and is proposed to form in vivo under inflammatory conditions. This study evaluated the stability and reactivity of N-NO-MeIQx to assess its possible r...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050305x
更新日期:2006-02-01 00:00:00
abstract::Methylglyoxal is a mutagenic bis-electrophile that is produced endogenously from carbohydrate precursors. Methylglyoxal has been reported to induce DNA-protein cross-links (DPCs) in vitro and in cultured cells. Previous work suggests that these cross-links are formed between guanine and either lysine or cysteine side ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500068v
更新日期:2014-06-16 00:00:00
abstract::Dibenzo[a,l]pyrene (DB[a,l]P) is one of the most potent carcinogens ever tested in mouse skin and rat mammary gland. DB[a,l]P is present in cigarette smoke and, presumably, in other environmental pollutants. Metabolism and mutagenicity studies of this compound compared to the weak carcinogen dibenzo[a,e]pyrene (DB[a,e...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00018a014
更新日期:1990-11-01 00:00:00