DNA repair mechanisms and acute myeloblastic leukemia

Das‐Gupta, Emma; Seedhouse, Claire; Russell, Nigel H.

doi:10.1002/1099-1069(200009)18:3<99::aid-hon662>3.0.co;2-z

Cited by 10 publications

(6 citation statements)

References 57 publications

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“…Defects in these genes result in the so-called 'mutator phenotype', which leads to the accumulation of mutations which may contribute to the development of t-leuk/ MDS upon exposure to genotoxic stress. 4 A number of studies, including our own, 5 have demonstrated that defects in DNA repair play a role in the predisposition to develop t-leuk/MDS. In recent years, technical improvements have enabled studying MMR with greater precision.…”

Section: Introductionmentioning

confidence: 96%

Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients

Rund¹,

Krichevsky²,

Bar-Cohen³

et al. 2005

Leukemia

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Therapy-related leukemia or myelodysplasia (t-leuk/MDS) is a serious problem that is increasing in frequency. We studied the clinical characteristics of 96 patients (pts) with a mean age of 48 years, and analyzed the molecular parameters that could predispose to t-leuk/MDS. Hematological malignancies were the most common primary (53%), followed by breast and ovarian cancer (30% combined). The mean latency until the development of t-AML was 45.5 months. Median survival was 10 months. Cytogenetics was abnormal in 89% of pts. FLT3 internal tandem duplications were found in six of 41 (14.6%) pts, of whom four had an abnormal karyotype. Analysis of drug metabolism and disposition genes showed a protective effect of the CYP3A4 1 n B genotype against the development of t-leuk/ MDS, whereas the CC genotype of MDR1 C3435T and the NAD(P)H:quinone oxidoreductase1 codon 187 polymorphism were both noncontributory. Microsatellite instability (MSI) analysis using fluoresceinated PCR with ABI sequence analyzer demonstrated that 41% of pts had high levels of MSI in four or more of 10 microsatellite loci. Immunohistochemistry demonstrated reduced expression of MSH2 and MLH1 in 6/10 pts with MSI as compared to 0/5 of pts without MSI. In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS.

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Section: Introductionmentioning

confidence: 96%

Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients

Rund¹,

Krichevsky²,

Bar-Cohen³

et al. 2005

Leukemia

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“…Drug resistance can emerge from altered metabolism or cellular accumulation of antileukemic agents, from altered drug targets, or from changes in cellular responses downstream of drug-target interactions (Johnstone et al, 2002). For example, abnormalities of DNA repair proteins have been linked to both the pathogenesis of several human malignancies and the therapeutic effects of medications (Das-Gupta et al, 2000;FloresRozas and Kolodner, 2000;Olipitz et al, 2002). The postreplicative mismatch repair (MMR) system has been shown to modulate in vitro cytotoxicity of several anticancer chemotherapeutic agents, including busulfan, cisplatin, temozolomide, doxorubicin, etoposide, thiopurines, and N-methyl-NЈ-nitro-N-nitrosoguanidine (Fink et al, 1998), each targeting DNA.…”

mentioning

confidence: 99%

“…It has been shown in vitro that G S -inserts in DNA change DNA-protein interactions with restriction endonucleases, RNaseH and topoisomerase II (Iwaniec et al, 1991;Krynetskaia et al, 1999;Krynetskaia et al, 2000). The mechanisms of cellular response to DNA damaged by thiopurine incorporation are not well defined but presumably involve cellular systems such as DNA repair, transcription control, cell cycle arrest, and/or apoptosis (Karran and Bignami, 1996;Das-Gupta et al, 2000). The putative mechanism by which the MMR system promotes thiopurine cytotoxicity involves the initiation of apoptosis after futile efforts to repair DNA containing thioguanine mismatch pairs (Karran and Bignami, 1996;Durant et al, 1999).…”

mentioning

confidence: 99%

Msh2 Deficiency Attenuates But Does Not Abolish Thiopurine Hematopoietic Toxicity inMsh2^-/-Mice

Krynetskaia¹,

Brenner²,

Krynetski³

et al. 2003

Mol Pharmacol

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The amount of MSH2 protein, a major component of the mismatch repair system, was found to differ Ͼ10-fold in leukemia cells from children with newly diagnosed acute lymphoblastic leukemia, with a subgroup of patients (17%) having undetectable MSH2 protein. We therefore used a murine Msh2 knockout model to elucidate the in vivo importance of MSH2 protein expression in determining thiopurine hematopoietic cytotoxicity. After mercaptopurine (MP) treatment (30 mg/kg/day for 14 days), there was a significantly greater decrease in circulating leukocytes in Msh2

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“…Another way in which cells can become resistant is through the action of DNA repair proteins [26]. The cells to survive must repair the damages caused to the DNA by the genotoxic drugs, but if the damage is very serious and the cell cannot be reversed it would go into apoptosis.…”

Section: Pharmacological Resistance Mediated By Dna Repair Mechanismmentioning

confidence: 99%

General Mechanisms of Resistance to Pharmacological Therapy Applied to Tumor Cells

Diego¹

2018

CRJ

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The management of cancer involves procedures, which include surgery, radiotherapy and chemotherapy, whose are aimed at destroying tumor cells and preserving healthy tissues. Development of drug resistance is one of problems during the treatment of local and/or disseminated disease, also is one of the biggest problems in relapses of cancer. A plethora of cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA alkylating agents, antimetabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of response to druginduced tumor growth inhibition. This article discusses the various mechanisms of acquired drug resistance that have been reported in the context of cancer drug therapies. The drug resistance may be inherent in a subpopulation of heterogeneous cancer cells or be acquired as a cellular response to drug exposure. Also, different mechanisms have been proposed that could explain tumor refractoriness due to resistance to anti-tumor drugs, some of them are: intrinsic resistance due to their genetic characteristics, acquisition of resistance mechanisms after exposure to a drug, mechanisms that alter transport of the drug. drug through the plasma membrane, DNA repair, alterations in target molecules, difficulty of the drug to access the target cells and growth factors. The knowledge of these mechanisms of resistance, could serve as a therapeutic strategy to control or delay the progression of the disease and therefore improve the quality of life of the patient.

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DNA repair mechanisms and acute myeloblastic leukemia

Cited by 10 publications

References 57 publications

Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients

Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients

Msh2 Deficiency Attenuates But Does Not Abolish Thiopurine Hematopoietic Toxicity inMsh2^-/-Mice

General Mechanisms of Resistance to Pharmacological Therapy Applied to Tumor Cells

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DNA repair mechanisms and acute myeloblastic leukemia

Cited by 10 publications

References 57 publications

Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients

Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients

Msh2 Deficiency Attenuates But Does Not Abolish Thiopurine Hematopoietic Toxicity inMsh2-/-Mice

General Mechanisms of Resistance to Pharmacological Therapy Applied to Tumor Cells

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Msh2 Deficiency Attenuates But Does Not Abolish Thiopurine Hematopoietic Toxicity inMsh2^-/-Mice