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2015 ; 4
(9
): 1309-21
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Comet assay measures of DNA damage as biomarkers of irinotecan response in
colorectal cancer in vitro and in vivo
#MMPMID26108357
Wood JP
; Smith AJ
; Bowman KJ
; Thomas AL
; Jones GD
Cancer Med
2015[Sep]; 4
(9
): 1309-21
PMID26108357
show ga
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.
|*Comet Assay
[MESH]
|Adult
[MESH]
|Aged
[MESH]
|Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use
[MESH]
|Antineoplastic Combined Chemotherapy Protocols/therapeutic use
[MESH]
|Biomarkers
[MESH]
|Camptothecin/*analogs & derivatives/pharmacology/therapeutic use
[MESH]