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The effect of different chemotherapeutic agents on the enrichment of DNA mismatch repair-deficient tumour cells
- Source :
- British Journal of Cancer
- Publication Year :
- 1998
- Publisher :
- Nature Publishing Group, 1998.
-
Abstract
- Loss of DNA mismatch repair is a common finding in hereditary non-polyposis colon cancer as well as in many types of sporadic human tumours. We compared the effect of loss of DNA mismatch repair on drug sensitivity as measured by a clonogenic assay with its effect on the ability of the same drug to enrich for mismatch repair-deficient cells in a proliferating tumour cell population. Mixed populations containing 50% DNA mismatch repair-deficient cells constitutively expressing green fluorescent protein and 50% mismatch repair-proficient cells were exposed to different chemotherapeutic agents. 6-Thioguanine, to which DNA mismatch repair-deficient cells are known to be resistant, was included as a control. The results in the cytotoxicity assays and in the enrichment experiments were concordant. Treatment with either carboplatin, cisplatin, doxorubicin, etoposide or 6-thioguanine resulted in enrichment for mismatch repair-deficient cells, and clonogenic assays demonstrated resistance to these agents, which varied from 1.3- to 4.8-fold. Treatment with melphalan, paclitaxel, perfosfamide or tamoxifen failed to enrich for mismatch repair-deficient cells, and no change in sensitivity to these agents was detected in the clonogenic assays. These results identify the topoisomerase II inhibitors etoposide and doxorubicin as additional agents for which loss of DNA mismatch repair causes drug resistance. The concordance of the results from the two assay systems validates the enrichment assay as a rapid and reliable method for screening for the effect of loss of DNA mismatch repair on sensitivity to additional drugs.
- Subjects :
- Cancer Research
DNA Repair
Paclitaxel
DNA repair
Population
Antineoplastic Agents
Cell Separation
Biology
Adenocarcinoma
Carboplatin
chemistry.chemical_compound
medicine
Tumor Cells, Cultured
Humans
Enzyme Inhibitors
Clonogenic assay
education
Cytotoxicity
Thioguanine
Cyclophosphamide
Melphalan
Etoposide
Tumor Stem Cell Assay
Cisplatin
education.field_of_study
DNA, Neoplasm
Tamoxifen
Oncology
chemistry
Doxorubicin
Immunology
Cancer research
DNA mismatch repair
Colorectal Neoplasms
medicine.drug
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 15321827 and 00070920
- Volume :
- 77
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- British Journal of Cancer
- Accession number :
- edsair.doi.dedup.....7ffe6afd8e7d42e92fb38c239bc5b994