Pilot study of biomarkers of chemotherapy-induced Gastrointestinal Toxicity

Abstract

Chemotherapy regimens containing 5-fl uorouracil, capecitabine or irinotecan are commonly associated with severe gastrointestinal toxicity. A predominant adverse event of these agents is complicated diarrhoea. There are currently no satisfactory ways to predict patients most at risk of developing diarrhoea during treatment, or adequate early markers to signal impending problems. As such, this pilot study investigated potential biomarkers of therapy-induced diarrhoea. Patients scheduled to receive anti-cancer regimens containing 5-fl uorouracil, capecitabine or irinotecan were recruited from a single institution. Patient blood and stool samples were collected before starting, and on day 2, 5, and 10 of one chemotherapy cycle. Serum extracellular matrix proteins, MMP-2, -3 and -9, and pro-infl ammatory cytokines, TNF-alpha, Il-1B and NFkB were assayed by ELISA. Fecal DNA was extracted and examined for Bifi dobacterium and Ecoli microfl ora gene expression. Time course data was grouped to assess overall changes in biomarkers levels. Patient data was also paired, where possible, to observe inter-individual variability. All data presented as mean ± SEM. Sixteen patients participated in the study between April 2009 and July 2009. All patients provided at least one blood and stool sample. MMP3 increased 5.74-fold from baseline on day 2 (0.303 ± 0.98 vs 1.740 ± 0.71 ng/ml). NFkB levels showed a peak increase of 4.51-fold from baseline on day 2 (0.190 ± 0.16 vs 0.856 ± 0.63) and TNFa rose 6.38-fold on day 10 (0.929 ± 0.89 vs 5.932 ± 4.90 pg/ml). Potentially pathogenic microfl ora, Ecoli, was increased 5.16-fold from baseline on day 10 (0.028 ± 0.008 vs 0.146 ± 0.07). All other biomarkers remained relatively unchanged. Our preliminary fi ndings suggest that MMP3, NFkB, TNFa and Ecoli are potential biomarkers of gastrointestinal toxicity induced by specific chemotherapy agents. Further analysis is required to determine if biomarker levels correlate with patient symptoms. Confi rmation of these fi ndings in a larger cohort would enable improved detection of pre-toxic patients allowing early interventions for chemotherapy-induced diarrhoea.