Ribonucleotide reductase and thymidine phosphorylation: two potential targets of azodicarbonamide

Fagny, Christine; Vandevelde, Michel; Svoboda, Michal; Robberecht, Patrick

doi:10.1016/s0006-2952(02)01185-1

Cited by 10 publications

(5 citation statements)

References 19 publications

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“…Thus, the interaction of dRNs and nucleoside analog metabolites in cells can be directly examined. The use of this method will facilitate clinical studies of nucleoside analogs by overcoming the labor intensive nature and technical difficulties associated with current analytical methods for measuring intracellular dRNs[1-4]. …”

Section: Resultsmentioning

confidence: 99%

“…As a result, there is a clear need for a more sensitive and rapid assay to measure dRN pool sizes. The current analytical methods for measuring intracellular RNs and dRNs include an enzymatic assay using E. coli DNA polymerase and synthetic oligonucleotides, a radioimmunoassay (RIA), and high performance liquid chromatography (HPLC) methods with UV and mass spectrometry detector [1-4]. The DNA polymerase assay quantifies the amount of DNA synthesized in an in vitro polymerization system with the dRNs of interest as the limiting factor in the reaction mixture [5, 6].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of deoxyribonucleotide pools in human cancer cell lines using a liquid chromatography coupled with tandem mass spectrometry technique

Zhang

Tan

Paintsil

et al. 2011

Biochemical Pharmacology

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Endogenous ribonucleotides and deoxyribonucleotides play a critical role in cell function, and determination of their levels is of fundamental importance in understanding key cellular processes involved in energy metabolism and molecular and biochemical signaling pathways. In this study, we determined the respective ribonucleotide and deoxyribonucleotide pool sizes in different human cell lines using a simple sample preparation method and LC/MS/MS. This assay was used to determine alterations in deoxyribonucleotide pools in human pancreatic PANC-1 cells in response to hypoxia and to treatment with either hydroxyurea or aphidicolin. The levels of all deoxyribonucleotide metabolites decreased with hypoxia treatment, except for dUMP, which increased by two-fold. This LC/MS/MS assay is simple, fast, and sensitive, and it represents a significant advance over previously published methodologies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of deoxyribonucleotide pools in human cancer cell lines using a liquid chromatography coupled with tandem mass spectrometry technique

Zhang

Tan

Paintsil

et al. 2011

Biochemical Pharmacology

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“…Several recent studies provide renewed interest in targeting RNR in the development of anti-cancer and anti-HIV therapeutics (9)(10)(11)(12)(13). Antisense oligodeoxynucleotides (AS-ODN) are currently being studied for their potential use as therapeutic agents for a variety of diseases including cancer (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

GTI-2501, an antisense agent targeting R1, the large subunit of human ribonucleotide reductase, shows potent anti-tumor activity against a variety of tumors

Lee¹,

Vassilakos²,

Feng³

et al. 2006

Int J Oncol

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GTI-2501 is a 20-mer oligonucleotide that is complementary to a coding region in the mRNA of R1, the large subunit of ribonucleotide reductase (RNR). In vitro studies, have demonstrated that GTI-2501 decreases mRNA and protein levels of R1 in a sequence-specific and dosedependent manner. Furthermore, GTI-2501 inhibits the growth of human lung, liver, ovary, brain, melanoma, breast and pancreatic tumor cells in colony forming assays. In vivo studies have shown that GTI-2501 significantly inhibits growth of human colon, pancreas, lung, breast, renal, ovarian, melanoma, brain glioblastoma-astrocytoma, and prostatic tumors in CD-1 nude, Balb/c nude and/or SCID mice. GTI-2501 treatment caused total regression of human breast and renal tumor xenografts in mice. These effects are not observed with a scrambled control oligonucleotide containing the same base content but not complementary to R1. GTI-2501 specifically inhibits metastasis of human melanoma cells to the lungs in CD-1 athymic nude mice and prolongs the survival of mice bearing human lymphoma. Taken together these results suggest that an antisense mechanism of action is responsible for growth inhibition in vitro and in vivo and that GTI-2501 can act as a selective and specific anti-tumor agent.

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“…There was hardly any effect on the proliferation of the cells after 24 hours. In addition, azodicarbonamide concentrations in the range from 50 to 200 µmol/l induced the inhibition of thymidine phosphorylation (IC 50 = 70.5 µmol/l) (Fagny et al 2002).…”

Section: Other Effectsmentioning

confidence: 99%

Azodicarbonamide [MAK Value Documentation, 2017]

Hartwig

Arand²

2018

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated azodicarbonamide [123‐77‐3] to derive a maximum concentration at the workplace (MAK value), considering all toxicological endpoints. Available publications and unpublished study reports are described in detail. The critical effect is the occurrence of reactions in the airways in exposed workers. In the view of the Commission, the present inhalation studies in animals are not appropriate for the derivation of a MAK value as human airways are probably more sensitive than rodent airways. The workplace investigations show no clear correlation of exposure and frequency of respiratory symptoms. Nevertheless, from the NOAEC of 36 µg/m 3 for lung function measurements in a small group of injection‐molding workers in the plastics industry, a MAK value of 20 µg/m 3 I is established. Due to the incomplete information on the relevant exposure scenario and the uncertainty regarding first occurrence of workplace related symptoms, this value should be considered as preliminary. As local effects are critical, azodicarbonamide is assigned to Peak Limitation Category I and the default excursion factor of 1 is designated. Since developmental toxicity studies are not available, Pregnancy Risk Group D is assigned. There are no carcinogenicity studies and azodicarbonamide is not regarded as germ cell mutagen. Skin contact is not expected to contribute significantly to systemic toxicity. The metabolism of azodicarbonamide and its reactivity do not point to stable protein binding in vivo and therefore, skin or respiratory sensitization is unlikely. Clear‐cut clinical findings or positive results from animal studies on skin sensitization are not available, but the negative results in experimental animals are difficult to evaluate due to the low solubility of the compound. Although azodicarbonamide affects the respiratory tract in several case reports with positive bronchial provocation tests, sensitization by a known mechanism is not adequately verified. Additionally, it appears questionable whether a mono‐causal relationship of respiratory symptoms and azodicarbonamide exposure can really be assumed. In conclusion, a sensitizing effect of azodicarbonamide is not sufficiently proven. Completed: March 22, 2017

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Ribonucleotide reductase and thymidine phosphorylation: two potential targets of azodicarbonamide

Cited by 10 publications

References 19 publications

Analysis of deoxyribonucleotide pools in human cancer cell lines using a liquid chromatography coupled with tandem mass spectrometry technique

Analysis of deoxyribonucleotide pools in human cancer cell lines using a liquid chromatography coupled with tandem mass spectrometry technique

GTI-2501, an antisense agent targeting R1, the large subunit of human ribonucleotide reductase, shows potent anti-tumor activity against a variety of tumors

Azodicarbonamide [MAK Value Documentation, 2017]

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