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Comet assay measures of DNA damage as biomarkers of irinotecan response in colorectal cancer in vitro and in vivo.

Wood JP, Smith AJ, Bowman KJ, Thomas AL, Jones GD - Cancer Med (2015)

Bottom Line: 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.To conclude, higher levels of irinotecan-induced initial and residual damage correlated with greater cell kill in vitro and a better clinical response.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Studies & Molecular Medicine, University of Leicester, Leicester, United Kingdom.

No MeSH data available.


Related in: MedlinePlus

Ex vivo study results. Correlating corrected ACA data with clinical outcome. (A) is a box and whisker plot demonstrating the association of response to irinotecan chemotherapy with corrected DNA damage induced in PBLs treated with 0.5 μmol/L SN-38 for 1 h. (B) is a Kaplan–Meier plot demonstrating the TTP for patients grouped according to the level of corrected DNA damage, induced in PBLs treated with 5 μmol/L SN-38 for 10 h. (C) is a Kaplan-Meier plot demonstrating the TTP for patients selected according to irradiated control being within 1 standard deviation of the mean grouped according to level of DNA damage adjusted using the selected irradiated control correction factor, measured using the ACA, induced in PBLs treated ex vivo with: 5 μM SN-38 for 4 hours. P values were calculated using the log rank test.
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fig05: Ex vivo study results. Correlating corrected ACA data with clinical outcome. (A) is a box and whisker plot demonstrating the association of response to irinotecan chemotherapy with corrected DNA damage induced in PBLs treated with 0.5 μmol/L SN-38 for 1 h. (B) is a Kaplan–Meier plot demonstrating the TTP for patients grouped according to the level of corrected DNA damage, induced in PBLs treated with 5 μmol/L SN-38 for 10 h. (C) is a Kaplan-Meier plot demonstrating the TTP for patients selected according to irradiated control being within 1 standard deviation of the mean grouped according to level of DNA damage adjusted using the selected irradiated control correction factor, measured using the ACA, induced in PBLs treated ex vivo with: 5 μM SN-38 for 4 hours. P values were calculated using the log rank test.

Mentions: To assess whether experimental error was masking any clinical associations, control data were also analyzed. The presence of interexperimental variation was confirmed; DNA damage in the irradiated control cells was more consistent than in those control cells treated with SN-38 (coefficient of variation 0.25 vs. 0.54). The more consistent irradiated controls (results available in 37 patients) were therefore used to correct the raw ex vivo data. There was no association of this corrected data with toxicities to treatment or UGT1A1 genotype. In 32 assessable patients, it was observed that SN-38 induced DNA damage following 1 h treatment was generally lower in those with PD but this did not reach statistical significance (Fig.5A). However, it was noted that TTP was significantly increased in those patients with higher corrected DNA damage at 10 h of drug exposure (median 291 vs. 173 days, P = 0.014) (Fig.5B). This was further supported by the observation that TTP was also significantly increased in selected patients with higher corrected DNA damage following 4 h of drug exposure; these subjects being selected according to their irradiated control being within 1 standard deviation of the mean and grouped according to level of DNA damage adjusted using the selected irradiated control correction factor. This latter analysis was undertaken in an attempt to assess whether trends could be strengthened if the assay variability was less and, on this basis, 22 patients were selected to have similar assay efficacy. Clearly this analysis was limited due to smaller patient numbers but, within this selected group, six had severe toxicities, four had PD, and two were UGT1A1*28 homozygotes.


Comet assay measures of DNA damage as biomarkers of irinotecan response in colorectal cancer in vitro and in vivo.

Wood JP, Smith AJ, Bowman KJ, Thomas AL, Jones GD - Cancer Med (2015)

Ex vivo study results. Correlating corrected ACA data with clinical outcome. (A) is a box and whisker plot demonstrating the association of response to irinotecan chemotherapy with corrected DNA damage induced in PBLs treated with 0.5 μmol/L SN-38 for 1 h. (B) is a Kaplan–Meier plot demonstrating the TTP for patients grouped according to the level of corrected DNA damage, induced in PBLs treated with 5 μmol/L SN-38 for 10 h. (C) is a Kaplan-Meier plot demonstrating the TTP for patients selected according to irradiated control being within 1 standard deviation of the mean grouped according to level of DNA damage adjusted using the selected irradiated control correction factor, measured using the ACA, induced in PBLs treated ex vivo with: 5 μM SN-38 for 4 hours. P values were calculated using the log rank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4567016&req=5

fig05: Ex vivo study results. Correlating corrected ACA data with clinical outcome. (A) is a box and whisker plot demonstrating the association of response to irinotecan chemotherapy with corrected DNA damage induced in PBLs treated with 0.5 μmol/L SN-38 for 1 h. (B) is a Kaplan–Meier plot demonstrating the TTP for patients grouped according to the level of corrected DNA damage, induced in PBLs treated with 5 μmol/L SN-38 for 10 h. (C) is a Kaplan-Meier plot demonstrating the TTP for patients selected according to irradiated control being within 1 standard deviation of the mean grouped according to level of DNA damage adjusted using the selected irradiated control correction factor, measured using the ACA, induced in PBLs treated ex vivo with: 5 μM SN-38 for 4 hours. P values were calculated using the log rank test.
Mentions: To assess whether experimental error was masking any clinical associations, control data were also analyzed. The presence of interexperimental variation was confirmed; DNA damage in the irradiated control cells was more consistent than in those control cells treated with SN-38 (coefficient of variation 0.25 vs. 0.54). The more consistent irradiated controls (results available in 37 patients) were therefore used to correct the raw ex vivo data. There was no association of this corrected data with toxicities to treatment or UGT1A1 genotype. In 32 assessable patients, it was observed that SN-38 induced DNA damage following 1 h treatment was generally lower in those with PD but this did not reach statistical significance (Fig.5A). However, it was noted that TTP was significantly increased in those patients with higher corrected DNA damage at 10 h of drug exposure (median 291 vs. 173 days, P = 0.014) (Fig.5B). This was further supported by the observation that TTP was also significantly increased in selected patients with higher corrected DNA damage following 4 h of drug exposure; these subjects being selected according to their irradiated control being within 1 standard deviation of the mean and grouped according to level of DNA damage adjusted using the selected irradiated control correction factor. This latter analysis was undertaken in an attempt to assess whether trends could be strengthened if the assay variability was less and, on this basis, 22 patients were selected to have similar assay efficacy. Clearly this analysis was limited due to smaller patient numbers but, within this selected group, six had severe toxicities, four had PD, and two were UGT1A1*28 homozygotes.

Bottom Line: 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.To conclude, higher levels of irinotecan-induced initial and residual damage correlated with greater cell kill in vitro and a better clinical response.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Studies & Molecular Medicine, University of Leicester, Leicester, United Kingdom.

No MeSH data available.


Related in: MedlinePlus