Genetic determinants of methotrexate responsiveness and resistance in colon cancer cells

Morales, Cristina; Ribas, M.; Aiza, Gemma; Peinado, Miguel A.

doi:10.1038/sj.onc.1208834

Cited by 33 publications

(29 citation statements)

References 45 publications

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“…We have confirmed the karyotypic features of this cell line by using conventional comparative genomic hybridization (CGH) and FISH (22) and CGH array (data not shown). A high-level gain affecting a 25-Mb region at 8q23qter was observed (Supplementary Fig.…”

Section: Characterization Of a Preexisting Ampliconsupporting

confidence: 52%

“…As reported in a previous study, SW480 and SK-CO-1 colon cancer cell lines that show amplification capability are unable to survive MTX treatment even at low doses of the cytotoxic drug (22). It is of note that they only contained a single intact chromosome 5, whereas the untreated HT29 cells had three intact copies.…”

Section: Discussionmentioning

confidence: 77%

“…It is of note that they only contained a single intact chromosome 5, whereas the untreated HT29 cells had three intact copies. It has been hypothesized that at least two homologue chromosomes are needed in the amplification event (4,7,22,35). One chromosome 5 would be reorganized, whereas the other will remain stable (39).…”

Section: Discussionmentioning

confidence: 99%

“…mol/L MTX-resistant clones (clones 2, 3, and 6) were generated in a previous study (22). Cells were propagated and maintained in T25 flasks (25 cm 2 ) with DMEM-F12 (parental cells) and DMEM (clones) culture medium (Life Technologies Ltd.) supplemented with 10% fetal bovine serum (Life Technologies) at 37jC in an atmosphere of 5% (24).…”

Section: à6mentioning

confidence: 99%

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Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells

Morales

García

Ribas

et al. 2009

Molecular Cancer Therapeutics

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Gene amplification is one of the most frequent manifestations of genomic instability in human tumors and plays an important role in tumor progression and acquisition of drug resistance. To better understand the factors involved in acquired resistance to cytotoxic drugs via gene amplification, we have analyzed the structure and dynamics of dihydrofolate reductase (DHFR) gene amplification in HT29 cells treated with methotrexate (MTX). Analysis of the DHFR gene amplification process shows that the amplicon exhibits a complex structure that is consistently reproduced in independent treatments. The cytogenetic manifestation of the amplification in advanced stages of the treatment may be in the form of double minutes or as a homogeneously stained region. To get insights into the mechanisms of resistance, we have also investigated the sensitization to MTX of MTX-resistant cells after drug withdrawal and reexposure to MTX. Passive loss of the DHFR amplicon by withdrawal of the drug results in MTXsensitive cells exhibiting a substantial reduction of their capacity or even an incapacity to generate resistance when submitted to a second cycle of MTX treatment. On a second round of drug administration, the resistant cells generate a different amplicon structure, suggesting that the formation of the amplicon as in the first cycle of treatment is not feasible. These results indicate that DHFR gene amplification is a ''wear and tear'' process in HT29 cells and that MTX-resistant cells may become responsive to a second round of treatment if left untreated during a sufficient period of time. [Mol Cancer Ther 2009; 8(2):424 -32]

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Section: Characterization Of a Preexisting Ampliconsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: à6mentioning

confidence: 99%

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Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells

Morales

García

Ribas

et al. 2009

Molecular Cancer Therapeutics

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“…Multiple mechanisms operate in MTX resistance in colon cancer cells, and both the capacity to develop resistance and the mechanism(s) involved are associated with the genetic features of the tumour, namely the karyotype and the presence of a microsatellite mutator phenotype. This implies that an appropriate genetic profiling of tumours before treatment may allow the design of personalised therapeutic strategies with improved response rates [14].…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

Antimetabolites and cancer: emerging data with a focus on antifolates

Scagliotti

Selvaggi

2006

Expert Opinion on Therapeutic Patents

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Antimetabolites, especially antifolates, play an important role in the treatment of a variety of both malignant, and non-malignant diseases, such as rheumatoid arthritis, and bacterial and parasitic infections. Recently, new antimetabolites have become an area for anticancer drug expansion. Gemcitabine has emerged as an important new agent in several tumour types, including non-small cell lung cancer, pancreatic, bladder, breast and ovarian cancers. Capecitabine is an intriguing new prodrug, offering tumour selectivity and prolonged tumour exposure to 5-FU. More potent thymidylate synthase inhibitors have also been developed; raltitrexed and pemetrexed are now commercially available for the treatment of mesothelioma, non-small cell lung cancer and other solid cancer types. This review will describe the most recent findings and their potential clinical applications.

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Search for Master Regulators in Walking Cancer Pathways

Kel

2017

Methods in Molecular Biology

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In this chapter, we present an approach that allows a causal analysis of multiple "-omics" data with the help of an "upstream analysis" strategy. The goal of this approach is to identify master regulators in gene regulatory networks as potential drug targets for a pathological process. The data analysis strategy includes a state-of-the-art promoter analysis for potential transcription factor (TF)-binding sites using the TRANSFAC database combined with an analysis of the upstream signal transduction pathways that control the activity of these TFs. When applied to genes that are associated with a switch to a pathological process, the approach identifies potential key molecules (master regulators) that may exert major control over and maintenance of transient stability of the pathological state. We demonstrate this approach on examples of analysis of multi-omics data sets that contain transcriptomics and epigenomics data in cancer. The results of this analysis helped us to better understand the molecular mechanisms of cancer development and cancer drug resistance. Such an approach promises to be very effective for rapid and accurate identification of cancer drug targets with true potential. The upstream analysis approach is implemented as an automatic workflow in the geneXplain platform ( www.genexplain.com ) using the open-source BioUML framework ( www.biouml.org ).

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Genetic determinants of methotrexate responsiveness and resistance in colon cancer cells

Cited by 33 publications

References 45 publications

Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells

Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells

Antimetabolites and cancer: emerging data with a focus on antifolates

Search for Master Regulators in Walking Cancer Pathways

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