In Vitro Evidence for Homologous Recombinational Repair in Resistance to Melphalan

Wang, Zhi Min; Chen, Zhong Ping; Xu, Zhi Yuan; Christodoulopoulos, G.; Bello, Vanessa; Mohr, Gérard; Aloyz, Raquel; Panasci, Lawrence C.

doi:10.1093/jnci/93.19.1473

Cited by 59 publications

(50 citation statements)

References 17 publications

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“…[76][77][78][79] Elevated levels of Rad51 detected in multiple tumor cell types may contribute to genomic instability by stimulating recombination between short repetitive elements and homologous sequences. 76,78,80 Expression of Rad51 is predictive of B-cell chronic lymphocytic leukemia patient response to nitrogen mustards, 81,82 as well as small-cell lung cancer cell sensitivity to VP-16. 83 Thus, the ability to modulate damage sensor and repair proteins will impact the ability of the CD34 ϩ subpopulation to protect against illegitimate repair of etoposide-induced DNA damage and potentially oncogenic rearrangements.…”

Section: Discussionmentioning

confidence: 99%

Therapy-related acute myeloid leukemia–like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion

Libura

Slater

Felix

et al. 2005

Blood

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Rearrangements involving the MLL gene on chromosome band 11q23 are a hallmark of therapy-related acute myeloid leukemias following treatment with topoisomerase II poisons including etoposide. Therapy-related and de novo genomic translocation breakpoints cluster within a well-characterized 8.3-kb fragment of MLL. Repair of etoposidestabilized DNA topoisomerase II covalent complexes may initiate MLL rearrangements observed in patients. We used a culture system of primary human hematopoietic CD34 ؉ cells and inverse polymerase chain reaction to characterize the spectrum of stable genomic rearrangements promoted by etoposide exposure originating within an MLL translocation hotspot in therapy-related leukemia. Alterations to the region were observed at a readily detectable frequency in etoposidetreated cells. Illegitimate repair events after minimal repair included MLL tandem duplications and translocations, with minor populations of deletions or insertions. In stably repaired cells that proliferated for 10 to 14 days, the significant majority of illegitimate events were MLL IntroductionGenome integrity is controlled by multiple damage surveillance pathways, cell-cycle checkpoints, and repair mechanisms. [1][2][3] Despite these safeguards, illegitimate repair of chromosomal doublestrand breaks (DSBs), such as those produced by chemotherapy agents that target topoisomerase II (topo II), can promote chromosomal rearrangements and, ultimately, tumorigenesis. Topo II is an essential cellular enzyme that catalyzes changes in DNA topology via its cleavage-religation equilibrium. Topo II-targeted drugs that are poisons of this enzyme stabilize topo II-DNA covalent complexes, most often by decreasing the rate of religation in a dose-dependent manner. Disruption of the cleavage-religation reaction results in accumulation of DSBs, p53 activation, and induction of apoptosis or repair. 4,5 Chromosomal DSBs are potent inducers of recombination, stimulating the exchange of homologous sequences between 2 DNA duplexes 1000-fold 6-8 not only between sister chromatids, but also between homologs, and sequence repeats on heterologous chromosomes. 9-12 DSBs may be repaired by homologous recombination or nonhomologous end joining (NHEJ), and both repair mechanisms have been associated with chromosomal translocations, a hallmark of leukemias, lymphomas, and soft-tissue sarcomas. [13][14][15] There is clear evidence that exposure to chemotherapy or irradiation can result in subsequent development of therapy-related leukemias, which occur in 1% to 15% of patients exposed to DNA-damaging agents in anticancer regimens. 16,17 Exposure to topo II poisons such as etoposide is predominantly associated with therapy-related leukemias characterized by rearrangements of the MLL gene on chromosome band 11q23. 16 MLL spans 100 kb, encodes a 430-kDa protein homologous to the Drosophila trithorax gene, and has important functions in embryogenesis and hematopoiesis. 18,19 Mixed-lineage leukemia (MLL) is a critical transcriptional regulator and numerous tr...

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Section: Discussionmentioning

confidence: 99%

Therapy-related acute myeloid leukemia–like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion

Libura

Slater

Felix

et al. 2005

Blood

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“…Thus many chemotherapeutic agents are highly recombinogenic. [24][25][26][27][28][29] Interestingly, elevated levels of HR proteins within tumor cells are associated with an increased resistance to many cancer chemotherapeutics [30][31][32][33][34][35] and a poor prognosis for cancer survival. 36 In contrast, cancer cells deficient in HR (e.g., breast tumors with BRCA2 mutations 37,38 ) are rendered sensitive to chemotherapeutic agents that induce replication fork breakdown.…”

Section: Homologous Recombination Modulates Cytotoxicity and Genomic mentioning

confidence: 99%

Applications of Fluorescence for Detecting Rare Sequence Rearrangements In Vivo

Wiktor-Brown

Hendricks²,

Olipitz³

et al. 2006

Cell Cycle

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“…It is unlikely that this mechanism would occur within 1 hour of exposure to ENU in our experiment. The hamster cell line irs1SF (XRCC3 mutant) has been shown to be modestly sensitive to DNA alkylating agents [50]. Therefore, the mechanism of XRCC3 in repair of alkylating DNA adduct should be explored further.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

Jiao

Chang

Firozi

et al. 2007

Mutation Research/Genetic Toxicology and Environmental Mutagene

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This study tested the hypothesis that genetic variants of phase II detoxification enzymes and DNA repair proteins affect individual response to DNA damage from alkylating agents. In 171 healthy individuals, an immunoslot blot assay was used to measure O 6 -ethylguanosine (O 6 -EtGua) adduct levels in peripheral blood lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in vitro. The genotypes of GSTM1, GSTT1, GSTP1 I 105 V and A 114 V, MGMT L 84 F and I 143 V, XPD D 312 N and K 751 Q, and XRCC3 T 241 M were determined. Demographic and exposure information was collected by in-person interview. Student's t test, analysis of (co)variance, and multiple linear regression models were used in statistical analyses. The mean and median (range) O 6 -EtGua levels were 94.6 and 84.8 (3.2-508.1) fmol/g DNA, respectively. The adduct level was significantly lower in people who smoked ≥ 25 years than that in never-smokers (square-root transformed mean values 8.20 versus 9.37, P = 0.03). Multiple linear regression models revealed that GSTT1 (β = −2.36, P = 0.009) polymorphism was a significant predictor of the level of adducts in 82 never-smokers, whereas the number of years smoked (β = −0.08, P = 0.005) and XRCC3 T 241 M (β = 2.22, P = 0.007) in 89 eversmokers. The association between GSTP1 I 105 V, MGMT I 143 V, and XPD D 312 N with the level of adducts was not conclusive. Each polymorphism could explain 2% to 10% of the variation of the adduct level. These observations suggest that GSTT1 null and XRCC3 T 241 M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent. Results from this exploratory study need to be confirmed in other experimental systems.

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In Vitro Evidence for Homologous Recombinational Repair in Resistance to Melphalan

Abstract: Correlations of melphalan resistance in epithelial tumor cell lines with Xrcc3 protein levels and melphalan-induced Rad51 foci density suggest that homologous recombinational repair is involved in resistance to this nitrogen mustard.

Cited by 59 publications

References 17 publications

Therapy-related acute myeloid leukemia–like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion

Therapy-related acute myeloid leukemia–like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion

Applications of Fluorescence for Detecting Rare Sequence Rearrangements In Vivo

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

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