Analysis of microsatellite instability in acquired drug-resistance human tumor cell lines

Picard, Samy-Felix; Franco, Noreli; Sergent, C; Chauffert, Bruno; Lizard-Nacol, Sarab

doi:10.3892/or.9.5.971

Cited by 3 publications

(4 citation statements)

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“…In addition, it has been demonstrated that vinblastine (39) produces no major change in MSI frequency in either MMRproficient or -deficient cells, which is in contrast to 17 and 28 [113].…”

Section: Antimitotic Agentsmentioning

confidence: 95%

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DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents

Pors¹,

Patterson²

2005

CTMC

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DNA Mismatch Repair (MMR) deficiency results in resistance to platinating and alkylating agents, DNA minor groove binders, inhibitors of topoisomerases and antimetabolites. The cellular MMR pathway, involving hMLH1 and MSH2, detects and repairs DNA frame shifts replication errors and regulates recombination events. Tumour cells are able to cope with DNA damage caused by chemotherapy as long as the MMR-process is disabled and hence there is a need to develop agents that (i) restore MMR proficiency or (ii) are hypersensitive in cells that are irreversibly MMR deficient. Decitabine is suggested to restore MMR function by reversal of gene promoter hypermethylation of hMLH1. However, when MMR is deficient due to gene mutation it is not feasible to design agents, since the absence of functional proteins that constitute the MMR machinery are not available as targets. The evidence that resistance to chemotherapy is associated with hMSH2 and/or hMLH1 deficiency has revealed a new paradigm for drug discovery of agents that positively exploit this phenotype to therapeutic advantage. Even more attractive is the development of agents that are hypersensitive in the absence of functional MMR to enable even more effective treatment. In this regard, established agents such as mitomycin C, camptothecin or novel hydroxyethylaminoanthraquinones may represent opportunities for exploitation of MMR-deficiency in tumour cells.

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“…In addition, it has been demonstrated that vinblastine (39) produces no major change in MSI frequency in either MMRproficient or -deficient cells, which is in contrast to 17 and 28 [113].…”

Section: Antimitotic Agentsmentioning

confidence: 95%

“…Cisplatin (17) treatment is associated with hypermethylation of the hMLH1 gene promoter, whilst first-line chemotherapeutic agents including doxorubicin (28) cause a decrease in MMR [80,113]. In ovarian cancer, up to 50% of patients will achieve complete remission in response to taxane/platinum therapy.…”

Section: Future Directionmentioning

confidence: 99%

DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents

Pors¹,

Patterson²

2005

CTMC

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“…For example, it has been reported that the oxidized nucleoside triphosphate pool is a significant contributor to genomic instability in mismatched repair-deficient cells (25,26). However, this situation is unlikely for MCF-7 cells because there are reports of mismatch repair proficiency for these cells (27)(28)(29).…”

mentioning

confidence: 92%

Measurement of 7,8-dihydro-8-oxo-2′-deoxyguanosine metabolism in MCF-7 cells at low concentrations using accelerator mass spectrometry

Hah

Mundt

Kim

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Growing evidence suggests that oxidative damage to cells generates mutagenic 7,8-dihydro-8-oxo-2 -deoxyguanosine (8-oxodG), which may initiate diseases related to aging and carcinogenesis. Kinetic measurement of 8-oxodG metabolism and repair in cells has been hampered by poor assay sensitivity and by difficulty characterizing the flux of oxidized nucleotides through the relevant metabolic pathways. We report here the development of a sensitive and quantitative approach to characterizing the kinetics and metabolic sources of 8-oxodG in MCF-7 human breast cancer cells by accelerator mass spectrometry. We observed that [ 14 C]8-oxodG at medium concentrations of up to 2 pmol/ml was taken up by MCF-7 cells, phosphorylated to mono-, di-, and triphosphate derivatives, and incorporated into DNA. Oxidative stress caused by exposure of the cells to 17␤-estradiol resulted in a reduction in the rate of [ 14 C]8-oxodG incorporation into DNA and an increase in the ratio of 8-oxodG monophosphate (8-oxodGMP) to 8-oxodG triphosphate (8-oxodGTP) in the nucleotide pool. 17␤-Estradiolinduced oxidative stress up-regulated the nucleotide pool cleansing enzyme MTH1 and possibly other Nudix-related pyrophosphohydrolases. These data support the conclusion that 8-oxodGTP is formed in the nucleotide pool by both 8-oxodG metabolism and endogenous reactive oxygen species. The metabolism of 8-oxodG to 8-oxodGTP, followed by incorporation into DNA is a mechanism by which the cellular presence of this oxidized nucleoside can lead to mutations.DNA repair ͉ nucleoside metabolism ͉ oxidative stress ͉ breast cancer

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“…The study of hereditary non-polyposis colorectal carcinoma (HNPCC) revealed that loss of mismatch repair (MMR) gene products leads to MSI. In vitro studies have shown significant associations between MSI and drug resistance (1,2). In addition, MSI was reported to have predictive value for survival benefit from 5-fluorouracil/ levamisol adjuvant chemotherapy in colon carcinomas (3,4).…”

Section: Introductionmentioning

confidence: 99%

Patterns of loss of heterozygosity in breast carcinoma during neoadjuvant chemotherapy

Oudin

Bonnetain²,

Boidot³

et al. 2007

Int J Oncol

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Abstract. There is evidence indicating that resistance to some chemotherapy drugs is related to enhanced repair of DNA lesions. Microsatellite instability (MSI) and loss of heterozy-gosity (LOH) reflect genetic instability and are associated with specific DNA repair pathways. Despite the strong implication of genetic instability in breast cancer its association with chemotherapy is unknown. Thus, we analyzed microsatellite alterations with 12 markers in locally advanced breast carcinomas in relation to neoadjuvant epirubicin-cyclophosphamide-containing chemotherapy (FEC-100) and compared it to a docetaxol-based (Tax-Epi) regimen. Samples were obtained before, during and after treatments. In pre-treated samples, MSI was detected only in 2 cases (7%) whereas LOH was found in 23 of the 34 (68%) carcinomas including 10 belonging to the FEC-100 group and 13 to Tax-Epi one. LOH frequency decreased from the first course of both regimens, but differences between the patterns of LOH during treatment were found. Persistent LOH was more frequent in FEC-100 group (71% vs. 41%) that was detected only in biopsies belonging to nonresponder patients. Persistent LOH were clustered at particular loci located at regions containing common fragile sites (FHIT and FRA6E). Analysis of baseline LOH with 6 markers located at 3p indicates discontinuous patterns reflecting double-strand break (DSB) lesions. These results agree with a drug-dependent link between genetic instability and chemoresistance and show that FEC-100 treatment is associated with DSB accumulation manifested as LOH in tumor cells resistant to chemotherapy in breast carcinoma.

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Analysis of microsatellite instability in acquired drug-resistance human tumor cell lines

Cited by 3 publications

References 0 publications

DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents

DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents

Measurement of 7,8-dihydro-8-oxo-2′-deoxyguanosine metabolism in MCF-7 cells at low concentrations using accelerator mass spectrometry

Patterns of loss of heterozygosity in breast carcinoma during neoadjuvant chemotherapy

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