Reactions of 4‐[Bis(2‐chloroethyl)amino]benzenebutanoic Acid (Chlorambucil) with DNA

Florea-Wang, Diana; Pawłowicz, Agnieszka J.; Sinkkonen, Jari; Krönberg, Leif; Vilpo, Juhani; Hovinen, Jari

doi:10.1002/cbdv.200800327

Cited by 10 publications

(19 citation statements)

References 32 publications

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“…All nitrogen mustards induce monofunctional guanine-N7 adducts, as well as interstrand N7-N7 CLs involving the two distal guanines within GNC sequences. In addition, melphalan and chlorambucil also induce substantial alkylation at adenine N 3 , including possible formation of guanine-adenine CLs [ 31 , 34 ]. On the other hand, the oxazaphosphorine cyclophosphamide undergoes metabolic activation into phosphoramide mustard and acrolein reactive species [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

DNA Damage and Repair in Human Cancer: Molecular Mechanisms and Contribution to Therapy-Related Leukemias

Casorelli

Bossa

Bignami

2012

IJERPH

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Most antitumour therapies damage tumour cell DNA either directly or indirectly. Without repair, damage can result in genetic instability and eventually cancer. The strong association between the lack of DNA damage repair, mutations and cancer is dramatically demonstrated by a number of cancer-prone human syndromes, such as xeroderma pigmentosum, ataxia-telangiectasia and Fanconi anemia. Notably, DNA damage responses, and particularly DNA repair, influence the outcome of therapy. Because DNA repair normally excises lethal DNA lesions, it is intuitive that efficient repair will contribute to intrinsic drug resistance. Unexpectedly, a paradoxical relationship between DNA mismatch repair and drug sensitivity has been revealed by model studies in cell lines. This suggests that connections between DNA repair mechanism efficiency and tumour therapy might be more complex. Here, we review the evidence for the contribution of carcinogenic properties of several drugs as well as of alterations in specific mechanisms involved in drug-induced DNA damage response and repair in the pathogenesis of therapy-related cancers.

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Section: Resultsmentioning

confidence: 99%

DNA Damage and Repair in Human Cancer: Molecular Mechanisms and Contribution to Therapy-Related Leukemias

Casorelli

Bossa

Bignami

2012

IJERPH

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“…The chemistry and reactivity of nitrogen 8-10, 18, 20, 24, 47-56 and sulfur 44, 57-64 mustards with nucleosides and DNA in vitro is well studied. There are also numerous studies that examine the mustard derived DNA adducts from treated cell culture and animals, 46,48,50,54,56,59,64,65 including white blood cells of patients on chemotherapeutic regimens that include a nitrogen mustard.…”

Section: Discussionmentioning

confidence: 99%

“…53, 57 A variety of methods have been used to identify these adducts including 32 P-postlabeling, 47, 58 co-chromatography by HPLC with authentic standards, 8, 9, 24, 48, 57 and mass spectrometry. 18, 20, 49-52, 56, 59, 64 Recently, tandem mass spectrometry with stable isotope dilution has been employed to identify and quantitate some of these DNA adducts. 53, 54, 61-63 Collectively, the studies indicate that these electrophiles react predominantly at the N7 atom of dG, although N3-dA modification can also be significant.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Nitrogen Mustard Formamidopyrimidine Adduct Formation of Bis(2-chloroethyl)ethylamine with Calf Thymus DNA and a Human Mammary Cancer Cell Line

Gruppi

Hejazi

Christov

et al. 2015

Chem. Res. Toxicol.

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A robust, quantitative ultraperformance liquid chromatography ion trap multistage scanning mass spectrometric (UPLC/MS3) method was established to characterize and measure five deoxyguanosine (dG) adducts formed by reaction of the chemotherapeutic nitrogen mustard (NM) bis-(2-chloroethyl)ethylamine with calf thymus (CT) DNA. In addition to the known N7-guanine (NM-G) adduct and its crosslink (G-NM-G), the ring-opened formamidopyrimidine (FapyG) mono-adduct (NM-FapyG) and cross-links in which one (FapyG-NM-G) or both (FapyG-NM-FapyG) guanines underwent ring-opening to FapyG units were identified. Authentic standards of all adducts were synthesized and characterized by NMR and mass spectrometry. These adducts were quantified in CT DNA treated with NM (1 μM) as their deglycosylated bases. A two-stage neutral thermal hydrolysis was developed to mitigate the artifactual formation of ring-opened FapyG adducts involving hydrolysis of the cationic adduct at 37 °C, followed by hydrolysis of the FapyG adducts at 95 °C. The limit of quantification values ranged between 0.3 and 1.6 adducts per 107 DNA bases, when the equivalent of 5 μg DNA hydrolysate was assayed on column. The principal adduct formed was the G-NM-G cross-link, followed by the NM-G mono-adduct; the FapyG-NM-FapyG adduct was at the limit of detection. The NM-FapyG adducts formed in CT DNA at a level of ~20% that of the NM-G adduct. NM-FapyG has not been previously quanitified and the FapyG-NM-G and FapyG-NM-FapyG adducts have not be previously characterized. Our validated analytical method was then applied to measure DNA adduct formation in the MDA-MB-231 mammary tumor cell line exposed to NM (100 μM) for 24 h. The major adduct formed was NM-G (970 adducts per 107 bases), followed by G-NM-G (240 adducts per 107 bases) and NM-FapyG (180 adducts per 107 bases), and lastly the FapyG-NM-G cross-link adduct (6.0 adducts per 107 bases). These lesions are expected to contribute to the NM-mediated toxicity and genotoxicity in vivo.

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“…1B). Other known sites of modification include N1and N3-dA (11,12,14,15), N3-dC (15,16), and O 6 -dG (17). Furthermore, the alkylated base can react with another DNA base (7, 10 -13, 15) or with a cysteine thiol within proteins (18,19) to form DNA-DNA or DNA-protein cross-links, respectively.…”

mentioning

confidence: 99%

Mutagenic potential of nitrogen mustard-induced formamidopyrimidine DNA adduct: Contribution of the non-canonical α-anomer

Minko¹,

Rizzo

Lloyd

2017

Journal of Biological Chemistry

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Nitrogen mustards (NMs) are DNA-alkylating compounds that represent the earliest anticancer drugs. However, clinical use of NMs is limited because of their own mutagenic properties. The mechanisms of NM-induced mutagenesis remain unclear. The major product of DNA alkylation by NMs is a cationic NM-N7-dG adduct that can yield the imidazole ring-fragmented lesion, -NM-substituted formamidopyrimidine (NM-Fapy-dG). Characterization of this adduct is complicated because it adopts different conformations, including both a canonical β- and an unnatural α-anomeric configuration. Although formation of NM-Fapy-dG in cellular DNA has been demonstrated, its potential role in NM-induced mutagenesis is unknown. Here, we created site-specifically modified single-stranded vectors for replication in primate (COS7) or cells. In COS7 cells, NM-Fapy-dG caused targeted mutations, predominantly G → T transversions, with overall frequencies of ∼11-12%. These frequencies were ∼2-fold higher than that induced by 8-oxo-dG adduct. Replication in was essentially error-free. To elucidate the mechanisms of bypass of NM-Fapy-dG, we performed replication assays with a high-fidelity DNA polymerase, polymerase (pol) δ. It was found that pol δ could catalyze high-fidelity synthesis past NM-Fapy-dG, but only on a template subpopulation, presumably containing the β-anomeric adduct. Consistent with the low mutagenic potential of the β-anomer, the mutation frequency was significantly reduced when conditions for vector preparation were modified to favor this configuration. Collectively, these data implicate the α-anomer as a major contributor to NM-Fapy-dG-induced mutagenesis in primate cells.

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Reactions of 4‐[Bis(2‐chloroethyl)amino]benzenebutanoic Acid (Chlorambucil) with DNA

Cited by 10 publications

References 32 publications

DNA Damage and Repair in Human Cancer: Molecular Mechanisms and Contribution to Therapy-Related Leukemias

DNA Damage and Repair in Human Cancer: Molecular Mechanisms and Contribution to Therapy-Related Leukemias

Characterization of Nitrogen Mustard Formamidopyrimidine Adduct Formation of Bis(2-chloroethyl)ethylamine with Calf Thymus DNA and a Human Mammary Cancer Cell Line

Mutagenic potential of nitrogen mustard-induced formamidopyrimidine DNA adduct: Contribution of the non-canonical α-anomer

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