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    Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer.

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    Authors
    Ledermann, J A
    Gabra, H
    Jayson, Gordon C
    Spanswick, V J
    Rustin, G J S
    Jitlal, Mark
    James, L E
    Hartley, J A
    Affiliation
    UCL Hospitals, UCL Cancer Institute, London, United Kingdom. j.ledermann@ctc.ucl.ac.uk
    Issue Date
    2010-10-01
    
    Metadata
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    Abstract
    BACKGROUND: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in platinum-resistant ovarian cancer. Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair. PATIENTS AND METHODS: Forty patients received carboplatin target area under concentration-time curve (AUC 4) followed by gemcitabine 1,000 mg/m(2) with a second dose of gemcitabine on day 8. Peripheral blood lymphocytes were obtained in 12 patients before and at intervals during the first cycle of chemotherapy. DNA cross-link formation and repair (unhooking) were measured by the single-cell gel electrophoresis (comet) assay following ex vivo incubation. RESULTS: The global response rate was 47% (Response Evaluation Criteria in Solid Tumors rate, 29%; CA125 rate, 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA cross-linking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA cross-links following administration of gemcitabine. CONCLUSION: An enhanced activity of carboplatin in platinum-resistant ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA cross-links. Future studies should explore coadministration of these drugs, as this may be a more effective schedule.
    Citation
    Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer. 2010, 16 (19):4899-905 Clin Cancer Res
    Journal
    Clinical Cancer Research
    URI
    http://hdl.handle.net/10541/115827
    DOI
    10.1158/1078-0432.CCR-10-0832
    PubMed ID
    20719935
    Type
    Article
    Language
    en
    ISSN
    1078-0432
    ae974a485f413a2113503eed53cd6c53
    10.1158/1078-0432.CCR-10-0832
    Scopus Count
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    All Christie Publications
    Medical Oncology

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