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|Title:||Comet Assay Measures of DNA Damage as Biomarkers of Irinotecan Response in Colorectal Cancer In Vitro and In Vivo|
|Authors:||Wood, Joanna P.|
Smith, Andrew J. O.
Bowman, Karen J.
Thomas, Anne L.
Jones, George D. D.
|Publisher:||Wiley Open Access|
|Abstract:||The use of irinotecan to treat metastatic colorectal cancer (CRC) is limited by unpredictable response and variable toxicity, however, no reliable clinical biomarkers are available. Here we report a study to ascertain whether irinotecan-induced DNA damage measures are suitable/superior biomarkers of irinotecan effect. CRC-cell lines (HCT-116 & HT-29) were treated in vitro with irinotecan and peripheral blood lymphocytes (PBL) were isolated from patients before and after receiving irinotecan-based chemotherapy. Levels of in vitro, in vivo and ex vivo-induced DNA damage were measured using the Comet assay; correlations between damage levels with in vitro cell survival and follow-up clinical data were investigated. Irinotecan-induced DNA damage was detectable in both CRC cell-lines in vitro, with higher levels of immediate and residual damage noted for the more sensitive HT-29 cells. DNA damage was not detected in vivo but was measurable in PBLs upon mitogenic stimulation prior to ex vivo SN-38 treatment. Results showed that, following corrections for experimental error, those patients whose PBLs demonstrated higher levels of DNA damage following 10 hours of SN-38 exposure ex vivo had significantly longer times to progression than those with lower damage levels (median 291 versus 173 days, p = 0.014). To conclude, higher levels of irinotecan-induced initial and residual damage correlated with greater cell kill in vitro and a better clinical response. Consequently, DNA damage measures may represent superior biomarkers of irinotecan effect compared to the more often-studied genetic assays for differential drug metabolism.|
|Rights:||Creative Commons Attribution License|
|Appears in Collections:||Published Articles, Dept. of Cancer Studies and Molecular Medicine|
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