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 and 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 h of SN-38 exposure ex vivo had significantly longer times to progression than those with lower damage levels (median 291 vs. 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.
Highlights
Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in the developed world [1, 2]
Cancer Medicine published by John Wiley & Sons Ltd
We report the combined findings of an investigation to ascertain whether DNA damage, as assessed by alkaline Comet assay (ACA), induced following irinotecan exposure is predictive of cancer cell response in vitro, plus the design and conduct of the first prospective clinical study to assess whether DNA damage induced in peripheral blood lymphocytes (PBL) following irinotecan or SN-38 exposure are potential predicitve biomarkers of drug effect
Summary
Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in the developed world [1, 2]. Often curable at a sufficiently early stage, around 20–25% of CRC patients present with metastasis and an additional 25–35% develop metastasis during their illness [3, 4]. These patients receive systemic treatment with palliative intent, with several licensed cytotoxic and biological agents proven to increase overall survival. Triplet chemotherapy (FOLFIRINOX) alone or combined with targeted therapies is a viable option to improve the response rate, due to toxicity this regimen is only appropriate in select patient groups [13,14,15]
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