DNA Repair and Its Influence on Points of Departure for Alkylating Agent Genotoxicity

Thomas, Alex; Johnson, George E.

doi:10.1016/b978-0-12-801663-3.00005-4

Cited by 3 publications

(2 citation statements)

References 85 publications

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“…Dose-response relationships for genotoxic carcinogens have been a topic of intense scientific and public debate. It is gradually shifting away from a linear non-threshold approach towards quantitative approaches using PoD metrics for defining acceptable exposure limits and assessing the human risk of genotoxic carcinogens (8,(19)(20)(21)(22)(23). The findings of the present study argue for the presence of no effect levels of IQ for mutagenicity and hepatocarcinogenicity: 1) only in the group administered 100 ppm were statistically significant increases in mutations and also altered mutation spectrum and also GST-P positive foci observed; 2) none of the measured parameters of mutagenicity and carcinogenicity was statistically altered by administration of IQ at a dose of 0.1 ppm.…”

Section: Discussionmentioning

confidence: 99%

“…However, as experimental evidence continues to accumulate showing that the carcinogenic effects of genotoxic carcinogens can be negligible at low doses (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), the non-threshold approach has been challenged by quantitative approaches using point-ofdeparture (PoD) metrics (8,(19)(20)(21)(22)(23)(24)(25). Using PoD metrics, with an acceptable daily intake and margin of exposure, is superior to non-threshold approaches for defining acceptable human exposure limits and assessing human risk (19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

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Quantitative analysis of mutagenicity and carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in F344 gpt delta transgenic rats

Fujioka

Totsuka

et al. 2019

Mutagenesis

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Quantitative analysis of the mutagenicity and carcinogenicity of the low doses of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the mutagenicity and carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Male F344 gpt delta transgenic rats were fed diets supplemented with 0, 0.1, 1, 10 or 100 ppm IQ for 4 weeks. The frequencies of gpt transgene mutations in the liver were significantly increased in the 10 and 100 ppm groups. In addition, the mutation spectra was altered in the 1, 10 and 100 ppm groups: frequencies of G:C to T:A transversion were significantly increased in groups administered 1, 10 and 100 ppm IQ in a dose-dependent manner, and the frequencies of G:C to A:T transitions, A:T to T:A transversions and A:T to C:G transversions were significantly increased in the 100 ppm group. Increased frequencies of single base pair deletions and Spi− mutants in the liver, and an increase in glutathione S-transferase placental form (GST-P)-positive foci, a preneoplastic lesion of the liver in rats, was also observed in the 100 ppm group. In contrast, neither mutations nor mutation spectra or GST-P-positive foci were statistically altered by administration of IQ at 0.1 ppm. We estimated the point of departure for the mutagenicity and carcinogenicity of IQ using the no-observed-effect level approach and the Benchmark dose approach to characterise the dose–response relationship of low doses of IQ. Our findings demonstrate the existence of no effect levels of IQ for both in vivo mutagenicity and hepatocarcinogenicity. The findings of the present study will facilitate an understanding of the carcinogenic effects of low doses of IQ and help to determine a margin of exposure that may be useful for practical human risk assessment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative analysis of mutagenicity and carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in F344 gpt delta transgenic rats

Fujioka

Totsuka

et al. 2019

Mutagenesis

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Mechanisms of Action of Carcinogenic Chemicals Including Occupational Carcinogens

Kobets

Williams

2023

Patty's Toxicology

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This chapter provides an overview of the diverse mechanisms, which are involved in the induction of neoplasia produced by chemical carcinogens, including occupational carcinogens. The key events involved in the process of carcinogenesis are discussed, and the broad classification of carcinogens based on their primary mechanism of action is delineated. Two major classes of carcinogens are discussed: ( 1 ) DNA‐reactive (genotoxic) carcinogens, which react with nuclear DNA directly producing DNA damage in the target tissue and ( 2 ) epigenetic (nongenotoxic) carcinogens, which either indirectly interact with DNA or affect other regulatory macromolecules altering cellular processes involved in growth control and/or cell death in the target tissue. Examples of human carcinogens are provided. In addition, methods of human risk assessment are discussed.

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Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production

et al. 2023

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During therapy, adaptations driven by cellular plasticity are partly responsible for driving the inevitable recurrence of glioblastoma (GBM). To investigate plasticity-induced adaptation during standard-of-care chemotherapy temozolomide (TMZ), we performed in vivo single-cell RNA sequencing in patient-derived xenograft (PDX) tumors of GBM before, during, and after therapy. Comparing single-cell transcriptomic patterns identified distinct cellular populations present during TMZ therapy. Of interest was the increased expression of ribonucleotide reductase regulatory subunit M2 ( RRM2 ), which we found to regulate dGTP and dCTP production vital for DNA damage response during TMZ therapy. Furthermore, multidimensional modeling of spatially resolved transcriptomic and metabolomic analysis in patients’ tissues revealed strong correlations between RRM2 and dGTP. This supports our data that RRM2 regulates the demand for specific dNTPs during therapy. In addition, treatment with the RRM2 inhibitor 3-AP (Triapine) enhances the efficacy of TMZ therapy in PDX models. We present a previously unidentified understanding of chemoresistance through critical RRM2-mediated nucleotide production.

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DNA Repair and Its Influence on Points of Departure for Alkylating Agent Genotoxicity

Cited by 3 publications

References 85 publications

Quantitative analysis of mutagenicity and carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in F344 gpt delta transgenic rats

Quantitative analysis of mutagenicity and carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in F344 gpt delta transgenic rats

Mechanisms of Action of Carcinogenic Chemicals Including Occupational Carcinogens

Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production

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