DNA damage and mutagenesis induced by nitrogen mustards

Povirk, Lawrence F.; Shuker, David E. G.

doi:10.1016/0165-1110(94)90015-9

Cited by 266 publications

(213 citation statements)

References 81 publications

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“…In contrast, few DSBs were observed in quiescent cells, and recombination therefore seems dispensable for repair. The activity of the Rev3 protein (DNA polymerase ) is apparently more important for the processing of intermediates in stationary-phase cells, since rev3 disruptants were more sensitive in this phase than in the exponential growth phase.Many clinically important anticancer drugs such as those from the nitrogen mustard class, as well as many agents in development, exert their antitumor effects through the production of DNA interstrand cross-links (ICLs) (26,47). Agents such as cisplatin can also produce ICLs, but intrastrand adducts may also contribute to cytotoxicity (15).…”

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confidence: 99%

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Repair of Intermediate Structures Produced at DNA Interstrand Cross-Links in Saccharomyces cerevisiae

McHugh

Sones

Hartley

2000

Molecular and Cellular Biology

143

152

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Bifunctional alkylating agents and other drugs which produce DNA interstrand cross-links (ICLs) are among the most effective antitumor agents in clinical use. In contrast to agents which produce bulky adducts on only one strand of the DNA, the cellular mechanisms which act to eliminate DNA ICLs are still poorly understood, although nucleotide excision repair is known to play a crucial role in an early repair step. Using haploid Saccharomyces cerevisiae strains disrupted for genes central to the recombination, nonhomologous end-joining (NHEJ), and mutagenesis pathways, all these activities were found to be involved in the repair of nitrogen mustard (mechlorethamine)-and cisplatin-induced DNA ICLs, but the particular pathway employed is cell cycle dependent. Examination of whole chromosomes from treated cells using contour-clamped homogenous electric field electrophoresis revealed the intermediate in the repair of ICLs in dividing cells, which are mostly in S phase, to be double-strand breaks (DSBs). The origin of these breaks is not clear since they were still efficiently induced in nucleotide excision and base excision repair-deficient, mismatch repair-defective, rad27 and mre11 disruptant strains. In replicating cells, RAD52-dependent recombination and NHEJ both act to repair the DSBs. In contrast, few DSBs were observed in quiescent cells, and recombination therefore seems dispensable for repair. The activity of the Rev3 protein (DNA polymerase ) is apparently more important for the processing of intermediates in stationary-phase cells, since rev3 disruptants were more sensitive in this phase than in the exponential growth phase.Many clinically important anticancer drugs such as those from the nitrogen mustard class, as well as many agents in development, exert their antitumor effects through the production of DNA interstrand cross-links (ICLs) (26,47). Agents such as cisplatin can also produce ICLs, but intrastrand adducts may also contribute to cytotoxicity (15). It is well established that nucleotide excision repair (NER) plays a key early role in the repair of ICLs (3,8,27,37,39), but little is known about the nature of the incisions at these lesions, the resulting repair intermediates, and how they are resolved. The NER pathway acting on DNA intrastrand cross-links (e.g., UV-induced dipyrimidine photoproducts and the intrastrand crosslinks produced by cisplatin) in eukaryotes is well understood (22); excision of a 24-to 32-mer lesion-containing oligonucleotide is followed by repair synthesis and ligation. However, ICLs pose a unique problem because a one-step NER reaction releasing the DNA-drug adduct on one side of the cross-link leaves an oligonucleotide-drug moiety attached to the complementary strand. Since this will act as a block to DNA polymerases, the resynthesis-ligation portion of the NER reaction cannot proceed efficiently.It has been suggested that the information necessary to complete repair can be obtained by recombination with a sister chromatid or homolog (32) or by mutagenic DNA synthesis...

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mentioning

confidence: 99%

“…Many clinically important anticancer drugs such as those from the nitrogen mustard class, as well as many agents in development, exert their antitumor effects through the production of DNA interstrand cross-links (ICLs) (26,47). Agents such as cisplatin can also produce ICLs, but intrastrand adducts may also contribute to cytotoxicity (15).…”

mentioning

confidence: 99%

Repair of Intermediate Structures Produced at DNA Interstrand Cross-Links in Saccharomyces cerevisiae

McHugh

Sones

Hartley

2000

Molecular and Cellular Biology

143

152

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“…[16][17][18][19][20] Alkylating agents are known to induce interstrand crosslinking of DNA preventing transcription and replication, to form adducts with DNA bases resulting in gene mutations, and to induce various types of chromosome damage. 21,22 These effects are not restricted to specific genes or chromosome regions, and the predominance of cases of t-MDS and t-AML with loss of various parts of the long arms of chromosomes 5 and 7 possibly reflects a selection of cells with these abnormalities due to a proliferative advantage. Chromosome damage which may lead to deletions or total chromosomal loss is frequent following chemotherapy with alkylating agents, and because two different deletions of the long arm of a chromosome 5 or a chromosome 7 are sometimes observed in cytogenetically unrelated clones in the same patient, the chromosome defects most likely are secondary and potentiate or activate the effects of other more important preclinical genetic changes 23 (Figure 1a and c).…”

Section: The 'Alkylator Types' Of Mds and Amlmentioning

confidence: 99%

Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities

et al. 2002

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New insights into causative factors for the development of myelodysplasia (MDS) and acute myeloid leukemia (AML), with associations to specific cytogenetic and genetic abnormalities have been obtained primarily from studies of patients with the therapy-related subsets of the two diseases. Current knowledge now makes it possible to distinguish between at least seven major genetic subgroups of MDS and AML, and has directed research towards more specific causative factors also for de novo MDS and AML.

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“…Alkylating agents form a variety of DNA adducts in cancer cells, including mono-adducts on N 1 -alkylguanine, N 3 -alkyladenine, N 7 -alkylguanine or O 6 -alkylguanine, and di-adducts between or within DNA strands (1)(2)(3)(4). Bifunctional alkylating agents result in cytotoxicity due to the production of interstrand crosslinks, which are formed through the intermediate production of O 6 -alkylguanine (5,6).…”

Section: Monofunctional Agents Include Temozolomide [Tmz; Also Known mentioning

confidence: 99%

Leukemia cells are sensitized to temozolomide, carmustine and melphalan by the inhibition of O6-methylguanine-DNA methyltransferase

et al. 2015

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Abstract. The cytotoxicity of the monofunctional alkylator, temozolomide (TMZ), is known to be mediated by mismatch repair (MMR) triggered by O 6 -alkylguanine. By contrast, the cytotoxicity of bifunctional alkylators, including carmustine (BCNU) and melphalan (MEL), depends on interstrand crosslinks formed through O 6 -alkylguanine, which is repaired by nucleotide excision repair and recombination. O 6 -alkylguanine is removed by O 6 -methylguanine-DNA methyltransferase (MGMT). The aim of the present study was to evaluate the cytotoxicity of TMZ, BCNU and MEL in two different leukemic cell lines (HL-60 and MOLT-4) in the context of DNA repair. The transcript levels of MGMT, ERCC1, hMLH1 and hMSH2 were determined using reverse transcription-quantitative polymerase chain reaction. In addition, the proliferation was measured using the trypan blue exclusion assay. Drug sensitivity was found to vary between the two cell lines. Treatment of the cells with TMZ, BCNU or MEL in combination with O 6 -benzylguanine, an MGMT inhibitor, was demonstrated to sensitize the two cell lines to these agents. However, the extent of sensitization was not found to be correlated with the expression levels of MGMT transcripts. Furthermore, the drug sensitivity was also not associated with the transcript levels of ERCC1, hMLH1 and hMSH2. Thus, leukemic cells were sensitized to alkylating agents by the inhibition of MGMT.

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DNA damage and mutagenesis induced by nitrogen mustards

Cited by 266 publications

References 81 publications

Repair of Intermediate Structures Produced at DNA Interstrand Cross-Links in Saccharomyces cerevisiae

Repair of Intermediate Structures Produced at DNA Interstrand Cross-Links in Saccharomyces cerevisiae

Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities

Leukemia cells are sensitized to temozolomide, carmustine and melphalan by the inhibition of O6-methylguanine-DNA methyltransferase

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