title: Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: the role of inflammation.
abstract: Chemotherapy-induced diarrhea (CID) is a common and often severe side effect experienced by colorectal cancer (CRC) patients during their treatment. As chemotherapy regimens evolve to include more efficacious agents, CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation. Inflammation is a key factor behind gastrointestinal (GI) toxicity of chemotherapy. Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa. Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC. Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed. The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity, thus conferring added benefit against tumor recurrence and improving patient survival. We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer. Finally, the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed.
authors.affiliation: Chun Seng Lee, Elizabeth J Ryan, Glen A Doherty, Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland.
authors.forename: Chun Seng
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Chun Seng Lee, Elizabeth J Ryan, Glen A Doherty, Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Ryan
authors.affiliation: Chun Seng Lee, Elizabeth J Ryan, Glen A Doherty, Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland.
authors.forename: Glen A
authors.initials: GA
authors.lastname: Doherty
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D016923:Cell Death; D015179:Colorectal Neoplasms / Q000150:complications / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000009:adverse effects / Q000494:pharmacology; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007413:Intestinal Mucosa / Q000187:drug effects; D000077146:Irinotecan; D052016:Mucositis / Q000188:drug therapy / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000494:pharmacology; D000077150:Oxaliplatin
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin
keywords: Chemotherapy; Diarrhea; Immunogenic cell death; Pro-inflammatory cytokines; Side-effects
references.citation: J Neurophysiol. 2011 Aug;106(2):704-9
references.pmid: 21593386
references.citation: J Natl Cancer Inst. 1995 Dec 20;87(24):1876-83
references.pmid: 7494232
references.citation: J Clin Oncol. 2009 Jul 1;27(19):3109-16
references.pmid: 19451431
references.citation: Cell Prolif. 2004 Dec;37(6):385-400
references.pmid: 15548172
references.citation: Cancer Chemother Pharmacol. 2012 Jul;70(1):39-48
references.pmid: 22729158
references.citation: Anticancer Res. 2012 Jul;32(7):2807-12
references.pmid: 22753741
references.citation: Gut. 2000 Jul;47(1):112-9
references.pmid: 10861272
references.citation: Support Care Cancer. 2000 Jan;8(1):65-7
references.pmid: 10650901
references.citation: Cancer Chemother Pharmacol. 2012 Apr;69(4):931-42
references.pmid: 22101361
references.citation: Cancer Manag Res. 2013 Apr 12;5:49-55
references.pmid: 23610528
references.citation: Oncology. 2013;84(1):6-13
references.pmid: 23075905
references.citation: PLoS One. 2012;7(3):e31808
references.pmid: 22412841
references.citation: Cancer Chemother Pharmacol. 2011 Jul;68(1):87-96
references.pmid: 20844880
references.citation: Eur J Pharmacol. 2004 Mar 19;488(1-3):213-8
references.pmid: 15044053
references.citation: Cancer Res. 2002 Oct 15;62(20):5778-84
references.pmid: 12384538
references.citation: Pain. 2011 Jul;152(7):1621-1631
references.pmid: 21481532
references.citation: J Natl Cancer Inst. 1994 Mar 16;86(6):446-9
references.pmid: 8120919
references.citation: Jpn J Cancer Res. 1993 Jun;84(6):697-702
references.pmid: 8340259
references.citation: N Engl J Med. 2004 Jun 3;350(23):2335-42
references.pmid: 15175435
references.citation: N Engl J Med. 2005 Jun 30;352(26):2696-704
references.pmid: 15987918
references.citation: Oncogene. 2011 Mar 10;30(10):1147-58
references.pmid: 21151176
references.citation: Cancer Chemother Pharmacol. 2005 Dec;56(6):623-8
references.pmid: 15999272
references.citation: Ann Oncol. 1999 Oct;10(10):1251-3
references.pmid: 10586346
references.citation: Int J Cancer. 2004 Jan 20;108(3):433-42
references.pmid: 14648711
references.citation: Cell Death Differ. 2014 Jan;21(1):39-49
references.pmid: 23832118
references.citation: Cancer Chemother Pharmacol. 2007 Feb;59(3):337-48
references.pmid: 16799812
references.citation: Oncology. 2005;68(4-6):326-32
references.pmid: 16020959
references.citation: Drugs. 1978 Jan;15(1):33-52
references.pmid: 342229
references.citation: Cancer Invest. 2008 Nov;26(9):956-63
references.pmid: 18798075
references.citation: Am J Physiol Gastrointest Liver Physiol. 2012 May 15;302(10):G1133-42
references.pmid: 22403796
references.citation: Gut. 1994;35(3 Suppl):S5-10
references.pmid: 8206397
references.citation: Clin Cancer Res. 2010 Jun 15;16(12):3100-4
references.pmid: 20421432
references.citation: J Clin Oncol. 2004 Jul 15;22(14):2918-26
references.pmid: 15254061
references.citation: Therap Adv Gastroenterol. 2013 Mar;6(2):137-56
references.pmid: 23503968
references.citation: Histopathology. 2007 Jan;50(1):113-30
references.pmid: 17204026
references.citation: Cancer. 1993 Sep 1;72(5):1543-6
references.pmid: 8348489
references.citation: Support Care Cancer. 2006 Sep;14(9):890-900
references.pmid: 16604351
references.citation: Gastroenterology. 2000 Mar;118(3):515-24
references.pmid: 10702202
references.citation: Immunol Rev. 2007 Dec;220:47-59
references.pmid: 17979839
references.citation: J Clin Oncol. 1999 Nov;17(11):3553-9
references.pmid: 10550154
references.citation: Cytokine. 2013 Jan;61(1):46-9
references.pmid: 23107827
references.citation: Biomed Pharmacother. 2011 Aug;65(5):339-44
references.pmid: 21723691
references.citation: CA Cancer J Clin. 2009 Nov-Dec;59(6):366-78
references.pmid: 19897840
references.citation: Clin Colorectal Cancer. 2011 Dec;10(4):238-44
references.pmid: 21820973
references.citation: Gut. 2000 Nov;47(5):632-7
references.pmid: 11034578
references.citation: Support Care Cancer. 2013 Jan;21(1):313-26
references.pmid: 23142924
references.citation: N Engl J Med. 2001 Jul 12;345(2):144-5; author reply 146
references.pmid: 11450666
references.citation: Oncogene. 2010 Jan 28;29(4):482-91
references.pmid: 19881547
references.citation: Cancer Chemother Pharmacol. 2007 Jan;59(1):23-33
references.pmid: 16685529
references.citation: Nat Rev Cancer. 2012 Dec;12(12):860-75
references.pmid: 23151605
references.citation: J Clin Oncol. 2006 Oct 20;24(30):4914-21
references.pmid: 17050875
references.citation: Ann Intern Med. 1995 Mar 1;122(5):321-6
references.pmid: 7847642
references.citation: J Clin Oncol. 2003 Aug 1;21(15):2896-903
references.pmid: 12885807
references.citation: N Engl J Med. 2004 Jun 3;350(23):2343-51
references.pmid: 15175436
references.citation: J Clin Oncol. 1993 Jan;11(1):148-51
references.pmid: 8418225
references.citation: J Clin Oncol. 2007 Jan 1;25(1):102-9
references.pmid: 17194911
references.citation: Aliment Pharmacol Ther. 2001 Dec;15(12):1889-97
references.pmid: 11736719
references.citation: Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7911-6
references.pmid: 8755576
references.citation: Ann Oncol. 2001 Feb;12(2):227-9
references.pmid: 11300329
references.citation: Cancer Treat Rev. 2007 Aug;33(5):448-60
references.pmid: 17507164
references.citation: J Clin Oncol. 2005 Aug 1;23(22):4866-75
references.pmid: 15939922
references.citation: Br J Cancer. 2012 Nov 6;107(10):1678-83
references.pmid: 23033005
references.citation: J Clin Oncol. 2007 Sep 20;25(27):4224-30
references.pmid: 17548839
references.citation: Nat Med. 2007 Sep;13(9):1050-9
references.pmid: 17704786
references.citation: Br J Cancer. 2011 Jul 12;105(2):206-11
references.pmid: 21750558
references.citation: J Surg Res. 2000 Jun 1;91(1):77-82
references.pmid: 10816354
references.citation: Drugs. 2011 Dec 3;71(17):2257-75
references.pmid: 22085384
references.citation: Cancer Chemother Pharmacol. 2008 Jun;62(1):33-41
references.pmid: 17703303
references.citation: Anticancer Drugs. 1993 Aug;4(4):443-5
references.pmid: 8400346
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G211-21
references.pmid: 17395898
references.citation: Cancer Treat Rep. 1978 Apr;62(4):533-45
references.pmid: 657150
references.citation: J Exp Med. 2005 Dec 19;202(12):1691-701
references.pmid: 16365148
references.citation: J Gastroenterol Hepatol. 2003 Sep;18(9):1095-100
references.pmid: 12911669
references.citation: Eur J Cancer. 1992;28(2-3):482-3
references.pmid: 1591068
references.citation: J Clin Oncol. 2001 Sep 15;19(18):3801-7
references.pmid: 11559717
references.citation: Support Care Cancer. 2006 Jun;14(6):505-15
references.pmid: 16601950
references.citation: Cancer Res. 1998 Dec 1;58(23):5453-65
references.pmid: 9850079
references.citation: J Clin Oncol. 2004 Aug 15;22(16):3238-47
references.pmid: 15310767
references.citation: J Pediatr Surg. 2000 Feb;35(2):357-9
references.pmid: 10693696
references.citation: N Engl J Med. 2004 Jul 22;351(4):337-45
references.pmid: 15269313
references.citation: Cancer Chemother Pharmacol. 2008 Apr;61(5):775-84
references.pmid: 17624531
references.citation: Gastroenterology. 1994 Apr;106(4):899-906
references.pmid: 8143995
references.citation: Nature. 2007 Sep 27;449(7161):419-26
references.pmid: 17898760
references.citation: Oral Oncol. 2004 Feb;40(2):170-6
references.pmid: 14693241
references.citation: Cancer Chemother Pharmacol. 2009 Jan;63(2):239-51
references.pmid: 18351341
references.citation: Gut. 2014 Mar;63(3):433-41
references.pmid: 23436336
references.citation: Cancer Biol Ther. 2012 Nov;13(13):1269-75
references.pmid: 22895076
references.citation: Cancer Res. 1998 Mar 1;58(5):933-9
references.pmid: 9500453
references.citation: J Clin Oncol. 2011 Apr 10;29(11):1465-71
references.pmid: 21383294
references.citation: CA Cancer J Clin. 2013 Jan;63(1):11-30
references.pmid: 23335087
references.citation: Cancer Res. 2001 Jan 15;61(2):687-93
references.pmid: 11212269
references.citation: Ann Oncol. 2012 May;23(5):1190-1197
references.pmid: 21896539
references.citation: Cancer. 2004 May 1;100(9 Suppl):1995-2025
references.pmid: 15108222
references.citation: Gut. 2013 Dec;62(12):1724-33
references.pmid: 23086829