Mutagenic damage to mammalian cells by therapeutic alkylating agents

Sanderson, Barbara J.S.; Shield, Alison

doi:10.1016/0027-5107(96)00021-8

Cited by 134 publications

(76 citation statements)

References 76 publications

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“…It is known that fludarabine and cyclophosphamide, 2 of the most common drugs used in the clinical treatment of CLL, interact with DNA (incorporation or alkylating) and are able to cause mutations. 59,60 Because mtDNA is particularly vulnerable to damage (compared with nuclear DNA) because of the lack of histone protection and a weak DNA repair capacity in the mitochondria, it is possible that prior treatments of CLL patients with such antileukemia drugs may cause mutations in the mtDNA. As discussed earlier, certain mutations of mtDNA are likely to cause an increase of superoxide generation because of inefficient respiration coupling and leakage of electrons.…”

Section: Discussionmentioning

confidence: 99%

Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents

Zhou

Hileman

Plunkett

et al. 2003

Blood

295

199

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2-Methoxyestradiol (2-ME), a new anticancer agent currently in clinical trials, has been demonstrated to inhibit superoxide dismutase (SOD) and to induce apoptosis in leukemia cells through a free radicalmediated mechanism. Because the accumulation of superoxide (O 2 ؊ ) by inhibition of SOD depends on the cellular generation of O 2 ؊ , we hypothesized that the endogenous production of superoxide may be a critical factor that affects the antileukemia activity of 2-ME. In the present study, we investigated the relationship between cellular O 2 ؊ contents and the cytotoxic activity of 2-ME in primary leukemia cells from 50 patients with chronic lymphocytic leukemia (CLL). Quantitation of O 2؊ revealed that the basal cellular O 2 ؊ contents are heterogeneous among patients with CLL. The O 2 ؊ levels were significantly higher in CLL cells from patients with prior chemotherapy. CLL cells with higher basal O 2 ؊ contents were more sensitive to 2-ME in vitro than those with lower O 2 ؊ contents. There was a significant correlation between the 2-ME-induced O 2 ؊ increase and the loss of cell viability. Importantly, addition of arsenic trioxide, a compound capable of causing reactive oxygen species (ROS) generation, significantly enhanced the activity of 2-ME, even in the CLL cells that were resistant to 2-ME alone. These results suggest that the cellular generation of O 2 ؊ plays an important role in the cytotoxic action of 2-ME and that it is possible to use exogenous ROS-producing agents such as arsenic trioxide in combination with 2-ME to enhance the antileukemia activity and to overcome drug resistance. Introduction 2-Methoxyestradiol (2-ME) is an endogenous metabolite of 17␤-estradiol that is present in human urine and blood. 2-ME is produced by sequential 2-hydroxylation and O-methylation. 1 This metabolic modification causes a loss of its ability to bind the estrogen receptor. 2-ME has been shown to have potent tumorinhibiting effects in a number of cancer cell lines in vitro and in tumor xenograft models in vivo. [2][3][4][5][6][7][8][9] This compound is currently in clinical trials, as a single agent or in combination with other anticancer agents, for treatment of several types of human cancer, including breast cancer, prostate cancer, and multiple myeloma. 2-ME also shows antileukemia activity in vitro with therapeutic selectivity. 10

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Section: Discussionmentioning

confidence: 99%

Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents

Zhou

Hileman

Plunkett

et al. 2003

Blood

295

199

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“…[16][17][18] The full mutagenic potential is realised in Salmonella typhimurium after metabolic activation, principally by cytochromes P-450. 19 The induction of micronuclei, sister chromatid exchanges, chromosome aberrations, 20 specific-locus mutations, 21 dominant lethal mutations and inheritable translocations in post-meiotic germ cells in mice 22 observed. In vivo data on melphalan toxicity modification by WR-2721 [23][24][25] prompted us to evaluate the modulating effect of amifostine with different genetic endpoints, in various cellular systems.…”

Section: Introductionmentioning

confidence: 99%

Amifostine (WR-2721) selective protection against melphalan genotoxicity

et al. 2000

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“…The altered cells then either engage their apoptotic programme or accumulate genetic alterations (Morris et al, 1995). Alkylating agents transfer alkyl groups to cellular constituents, inducing DNA adducts as well as DNA crosslinking that may lead to point mutations (Sanderson and Shield, 1996;Hunter et al, 2006). A recent study using microarray-based CGH on 21 breast tumours before and after epirubicin/cyclophosphamide chemotherapy showed a significant acquired copy number gain on 11p15.2 -11p15.5 after treatment (Pierga et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Changes in allelic imbalances in locally advanced breast cancers after chemotherapy

et al. 2007

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In advanced breast cancers, TP53 mutation is highly predictive of complete response to high-dose epirubicin/cyclophosphamide chemotherapy. In these tumours with an altered control of genomic stability, accumulation of chemotherapy-induced genetic alterations may contribute to cell death and account for complete response. To explore the effects of chemotherapy on stability of the tumour genome, allelic profiles were obtained from microdissected tumour samples before and after chemotherapy in 29 unresponsive breast cancers (9 with TP53 mutation). Ninety-four per cent allelic profiles remained unchanged after treatment. Interestingly, 11 profiles (6%) showed important changes after treatment; allelic imbalances significantly increased (four cases) or decreased (seven cases) after chemotherapy in three distinct experiments, two of which using laser microdissected tumour cells. These genetic changes were not linked to the TP53 status, but one tumour showed complete disappearance of TP53-mutated cells in the residual tumour after treatment. Altogether, these observations carry important implications for the clonal evolution of breast cancers treated with DNA-damaging agents, as they point both to the importance of tumour heterogeneity and chemotherapydriven selection of subclones.

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Mutagenic damage to mammalian cells by therapeutic alkylating agents

Cited by 134 publications

References 76 publications

Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents

Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents

Amifostine (WR-2721) selective protection against melphalan genotoxicity

Changes in allelic imbalances in locally advanced breast cancers after chemotherapy

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