The subtlety of alkylating agents in reactions with biological macromolecules

Vogel, E.; Nivard, Madeleine J.M.

doi:10.1016/0027-5107(94)90123-6

Cited by 63 publications

(32 citation statements)

References 76 publications

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“…Particularly susceptible to mutation were guanine bases in exon 3 where six guanines are found in a row (cDNA bases 207-212). EMS follows a mixed S N 1/S N 2 type reaction and is believed to be mutagenic by reaction with the O 6 position, and, to a lesser extent, to the N 1 position of guanine [34,35]. The N-alkylation products yield apurinic sites that are processed further by base excision repair and may cause mutations by mis-incorporation or error-prone repair processes [35][36][37][38].…”

Section: Resultsmentioning

confidence: 99%

“…EMS follows a mixed S N 1/S N 2 type reaction and is believed to be mutagenic by reaction with the O 6 position, and, to a lesser extent, to the N 1 position of guanine [34,35]. The N-alkylation products yield apurinic sites that are processed further by base excision repair and may cause mutations by mis-incorporation or error-prone repair processes [35][36][37][38]. The 0 6 -ethylguanine is mutagenic through direct miscoding by pairing with thymine during replication [35,39].…”

Section: Resultsmentioning

confidence: 99%

“…The N-alkylation products yield apurinic sites that are processed further by base excision repair and may cause mutations by mis-incorporation or error-prone repair processes [35][36][37][38]. The 0 6 -ethylguanine is mutagenic through direct miscoding by pairing with thymine during replication [35,39]. The spectrum of EMS is dominated by G > A transitions, and EMS has a relatively low efficiency for deletions in exponentially growing cells [35].…”

Section: Resultsmentioning

confidence: 99%

“…The 0 6 -ethylguanine is mutagenic through direct miscoding by pairing with thymine during replication [35,39]. The spectrum of EMS is dominated by G > A transitions, and EMS has a relatively low efficiency for deletions in exponentially growing cells [35].…”

Section: Resultsmentioning

confidence: 99%

“…This results in a higher number of intragenic deletions and G > A mutations due to impaired ligation of singlestrand breaks generated during base excision repair and a reduced capacity to remove 0 6 -ethylguanine. ENU reacts by an S N 1 mechanism and produces significant levels of alkylation of oxygens, such as the Opposition of guanine and the O 2 and O 4 positions of thymine, resulting in miscoding or misrepair [34,35]. The mutational spectrum in ENUtreated mammalian cells is predominantly G > A and to a lesser extent A > G transitions and T > A transversions [35,49,50].…”

Section: Resultsmentioning

confidence: 99%

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Effect of Folate on the Efficacy and Toxicity of Cancer Chemotherapy

Branda¹

2000

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and PERFORMING ORGANIZATION NAME{S) AND ADDRESS(ES)The University of Vermont Burlington, Vermont 05405-0160 E-MAIL:rbranda@zoo .uvm.edu The purpose of this research project is to understand better the effect of dietary folate levels on the cellular pharmacology and toxicology of chemotherapeutic agents. The scope of the research involves in vitro studies with cell lines and in vivo assessments in rats of folate-chemotherapeutic drug interactions. Studies at a molecular level led to a new model to explain the synergy between nutritional folate deficiency and alkylating agents. Our studies at a cellular level suggest that folate metabolism can modulate glutathione levels. This observation may explain at least in part why dietary folate levels influence the efficacy and toxicity of alkylating agents. Studies in rats confirm that dietary folate levels affect the toxicity of cyclophosphamide, but there may be an optimal amount of dietary folate to reduce that toxicity. These in vivo studies also indicate that other aspects of diet are important in determining sensitivity to chemotherapy. Rats maintained on a cereal-based diet were much more resistant to the toxic effects of cyclophosphamide than rats eating a Purified Diet. Taken together, our studies suggest that dietary changes can have a profound and largely unappreciated effect on the outcome of cancer chemotherapy. Where copyrighted material is quoted, permission has been obtained to use such material. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U SUBJECT TERMS Breast CancerWhere material from documents designated for limited distribution is quoted, permission has been obtained to use the material.1 Citations of commercial organizations and trade names in this report do not constitute an official Department of Army endorsement or approval of the products or services of these organizations.«PR. In conducting research using animals, the investigator(s) adhered to the "Guide for the Care and Use of Laboratory Animals," prepared by the Committee on Care and use of Laboratory Animals of the Institute of Laboratory Resources, national Research Council (NIH Publication No. 86-23, Revised 1985).For the protection of human subjects, the investigator(s) adhered to policies of applicable Federal Law 45 CFR 46. N/A In conducting research utilizing recombinant DNA technology, the investigator(s) adhered to current guidelines promulgated by the National Institutes of Health. N/A In t...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Effect of Folate on the Efficacy and Toxicity of Cancer Chemotherapy

Branda¹

2000

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Detection of DNA-crosslinking agents with the alkaline comet assay

Pfuhler¹,

Wolf²

1996

Environ. Mol. Mutagen.

175

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Nutritional folate deficiency augments the in vivo mutagenic and lymphocytotoxic activities of alkylating agents

Branda

Hacker

Lafayette

et al. 1998

Environ. Mol. Mutagen.

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To investigate the interaction of folate deficiency and alkylating agents in vivo, weanling Fischer 344 rats were maintained for 5 weeks on a folate replete, moderately folate deficient, or a severely folate deficient diet. Mutant frequencies at the HPRT locus in splenic lymphocytes were 1.2 ± 0.6, 1.9 ±1.1, and 6.4 ± 4.0 × 10−6, respectively (P < 0.01). N‐nitroso‐N‐ethylurea (ENU), 100 mg/kg body weight, was much more mutagenic with progressive folate deficiency (5.0 ± 2.4 vs. 16.2 ± 7.3 vs. 39.2 ± 21.0 × 10−6), suggesting a synergistic interaction (P ≪ 0.01). Neither moderate nor severe folate deficiency significantly enhanced the mutagenic effects of cyclophosphamide, 50 mg/kgbody weight (18.0 ± 7.9 vs. 6.0 ± 2.8 vs. 28.5 ± 28.2 × 10−6). The number of cloning cells/spleen were reduced 68% in moderately folate deficient rats and by 87% in severely deficient animals (P < 0.05). The combination of folate deficiency and cyclophosphamide reduced the total number of cloning cells further, but ENU alone, or in combination with folate deficiency, did not. These findings indicate that folate deficiency increases the risk of somatic mutations and is lymphocytotoxic in rats. Folate deficiency enhances the mutagenic but not the lymphotoxic effects of ENU, while it increases the lymphotoxic but not the mutagenic activity of cyclophosphamide. Correction of folate deficiency may decrease the immunologic and genetic damage caused by some alkylating agents. Environ. Mol. Mutagen. 32:33–38, 1998 © 1998 Wiley‐Liss, Inc.

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The subtlety of alkylating agents in reactions with biological macromolecules

Cited by 63 publications

References 76 publications

Effect of Folate on the Efficacy and Toxicity of Cancer Chemotherapy

Effect of Folate on the Efficacy and Toxicity of Cancer Chemotherapy

Detection of DNA-crosslinking agents with the alkaline comet assay

Nutritional folate deficiency augments the in vivo mutagenic and lymphocytotoxic activities of alkylating agents

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