Drug-Related Carcinogenesis: Risk Factors and Approaches for Its Prevention

Belitskiy, G A; Кирсанов, Кирилл И.; Lesovaya, Ekaterina A.; Yakubovskaya, Marianna G.

doi:10.1134/s0006297920140059

Cited by 5 publications

(1 citation statement)

References 155 publications

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“…The risk for secondary malignancies after NM chemotherapies is well established and is largely dependent on dose intensity and the length of treatment. 58,59,81 One study examined over 19,000 patients with nonuroepithelial cancers and estimated that CPA increased the risk of bladder cancer 9-fold compared to those not treated with the drug. 82 Our study shows that the secondary NM-induced DNA lesions G-NM-G and NM-Fapy-G are more resistant to DNA removal than NM-G, and they persist for more than 7 days in mouse organs.…”

Section: ■ Conclusionmentioning

confidence: 99%

Kinetics of DNA Adducts and Abasic Site Formation in Tissues of Mice Treated with a Nitrogen Mustard

Chen

Cui

Hejazi

et al. 2020

Chem. Res. Toxicol.

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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 characterized several adducts formed by reaction of bis(2-chloroethyl)ethylamine (NM) with calf thymus (CT) DNA and the MDA-MB-231 mammary tumor cell line. The monoalkylated N7-guanine (NM-G) adduct and its cross-link (G-NM-G) were major lesions. The cationic NM-G undergoes a secondary reaction through depurination to form an apurinic (AP) site or reacts with hydroxide to yield the stable ring-opened N 5-substituted formamidopyrimidine (NM-Fapy-G) adduct. Both of these lesions are mutagenic and may contribute to secondary tumor development, a major clinical limitation of NM chemotherapy. We established a kinetic model with NM-treated female mice and measured the rates of formation and removal of NM-DNA adducts and AP sites. We employed liquid chromatography–mass spectrometry (LC–MS) to measure NM-G, G-NM-G, and NM-Fapy-G adducts in liver, lung, and spleen over 168 h. NM-G reached a maximum level within 6 h in all organs and then rapidly declined. The G-NM-G cross-link and NM-FapyG were more persistent with half-lives over three-times longer than NM-G. We quantified AP site lesions in the liver and showed that NM treatment increased AP site levels by 3.7-fold over the basal levels at 6 h. The kinetics of AP site repair closely followed the rate of removal of NM-G; however, AP sites remained 1.3-fold above basal levels 168 h post-treatment with NM. Our data provide new insights into NM-induced DNA damage and biological processing in vivo. The quantitative measurement of the spectrum of NM adducts and AP sites can serve as biomarkers in the design and assessment of the efficacy of novel chemotherapeutic regimens.

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