Are we turning to more than a first line treatment of metastatic colorectal cancer with high dose irinotecan ?: A monocentric institution safety analysis of 46 patients

Mineur, Laurent; Sabatier, Renaud; Kirscher, Sylvie; Plat, F.; Goubely, Y.; Molinari, Nicolas

doi:10.1016/j.gcb.2009.11.005

Cited by 5 publications

(4 citation statements)

References 16 publications

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“…Mucositis is a major adverse effect associated with chemotherapy and radiotherapy during antineoplastic treatment. 8,9 We report that treatment with the chemotherapeutic agent irinotecan induces mucositis, which is in agreement with previous studies reporting this association in both humans and mice. 13,14,36 More importantly, we define the crucial role played by ASC/caspase-1 activation and consequent IL-1b and IL-18 production for establishment of the inflammatory response in irinotecan-induced mucositis.…”

Section: Discussionsupporting

confidence: 92%

“…7 Therefore, treatment with irinotecan is associated with several adverse effects, such as leukopenia, diarrhea, and mucositis. 8,9 It is thought that mucositis arises from lesions of the basal cells in the gastrointestinal tract due to chemotherapy or radiotherapy, resulting in mucosal damage, an intense inflammatory reaction, and consequent ulceration. 7,10e12 Irinotecan may induce mucosal damage directly; DNA damage due to topoisomerase I inhibition activates several pathways involved in apoptosis and inflammation.…”

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confidence: 99%

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Inflammasome Activation Is Reactive Oxygen Species Dependent and Mediates Irinotecan-Induced Mucositis through IL-1β and IL-18 in Mice

Arifa

Madeira

Paula

et al. 2014

The American Journal of Pathology

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Irinotecan is a useful chemotherapeutic for the treatment of various cancers. Irinotecan treatment is associated with mucositis, which clearly limits the use of the drug. Mechanisms that account for mucositis are only partially known. This study assessed mechanisms and the role of inflammasome activation in irinotecan-induced mucositis. Mucositis in mice was induced by irinotecan injection in C57BL/6 wild-type, gp91phox(-/-), il-18(-/-), casp-1(-/-), and asc(-/-) mice once a day for 4 consecutive days. In some experiments, mice received apocynin to inhibit NADPH oxidase (NOX), IL-1 receptor antagonist, or IL-18 binding protein to prevent activation of IL-1 and IL-18 receptors, respectively. Mice were euthanized 7 days after the beginning of irinotecan treatment, and small intestines were collected for analysis. Irinotecan treatment resulted in increased IL-1β and IL-18 production in ileum and NOX-2-dependent oxidative stress. gp91phox(-/-) and apocynin-treated mice had diminished oxidative stress and less severe mucositis. Furthermore, treatment with apocynin decreased caspase-1 activation and IL-1β and IL-18 production in the ileum. asc(-/-) and casp-1(-/-) mice also had less intestinal injury and decreased IL-1β and IL-18 production. Finally, both the absence of IL-18 and IL-1β resulted in reduced inflammatory response and attenuated intestinal injury. NOX-2-derived oxidative stress mediates inflammasome activation and inflammasome-dependent production of IL-1β and IL-18, which mediate tissue injury during irinotecan-induced mucositis in mice.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Inflammasome Activation Is Reactive Oxygen Species Dependent and Mediates Irinotecan-Induced Mucositis through IL-1β and IL-18 in Mice

Arifa

Madeira

Paula

et al. 2014

The American Journal of Pathology

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“…Various studies have shown that dose escalation of standard regimens and high dose CPT-11 administration is feasible and may leads to greater benefit [61, 62]. However, delayed onset diarrhea still remains a predicament and it needs to be supplemented with an effective preventive or therapeutic approach.…”

Section: Strategies To Block Delayed Diarrheamentioning

confidence: 99%

Therapeutic Targeting of CPT-11 Induced Diarrhea: A Case for Prophylaxis

Swami

Goel

Mani

2013

CDT

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CPT-11 (irinotecan), a DNA topoisomerase I inhibitor is one of the main treatments for colorectal cancer. The main dose limiting toxicities are neutropenia and late onset diarrhea. Though neutropenia is manageable, CPT-11 induced diarrhea is frequently severe, resulting in hospitalizations, dose reductions or omissions leading to ineffective treatment administration. Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT-11 induced late onset diarrhea. It is predicted that prophylaxis of CPT-11 induced diarrhea will reduce sub-therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates. This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity. Covered topics include schedule/dose modification, intestinal alkalization, structural/chemical modification, genetic testing, anti-diarrheal therapies, transporter (ABCB1, ABCC2, BCRP2) inhibitors, enzyme (β-glucuronidase, UGT1A1, CYP3A4, carboxylesterase, COX-2) inducers and inhibitors, probiotics, antibiotics, adsorbing agents, cytokine and growth factor activators and inhibitors and other miscellaneous agents.

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“…Irinotecan (CPT-11) is a topoisomerase I inhibitor useful for the treatment of several solid tumours [8][9][10]. Its use, however, is frequently associated with side effects, including leukopenia, diarrhoea and mucositis [11,12]. These side effects are generated because healthy cells that display high mitotic rates, such as crypt stem cells of the gut, are susceptible to the drug [13].…”

Section: Introductionmentioning

confidence: 99%

Eosinophil plays a crucial role in intestinal mucositis induced by antineoplastic chemotherapy

et al. 2022

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Mucositis is a major clinical complication associated with cancer treatment and may limit the benefit of chemotherapy. Leukocytes and inflammatory mediators have been extensively associated with mucositis severity. However, the role of eosinophils in the pathophysiology of chemotherapy-induced mucositis remains to be elucidated. Here, using GATA-1-deficient mice, we investigated the role of eosinophils in intestinal mucositis. There was marked accumulation of eosinophils in mice given irinotecan and eosinophil ablation inhibited intestinal mucositis. Treatment with Evasin-4, a chemokine receptor antagonist, reduced the recruitment of eosinophils and decreased irinotecan-induced mucositis. Importantly, Evasin-4 did not interfere negatively with the antitumour effects of irinotecan. Evasin-4 was of benefit for mice given high doses of irinotecan once Evasin-4-treated mice presented delayed mortality. Altogether, our findings suggest that Evasin-4 may have significant mucosalprotective effects in the context of antineoplastic chemotherapy and may, therefore, be useful in combination with anticancer treatment in cancer patients.

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Are we turning to more than a first line treatment of metastatic colorectal cancer with high dose irinotecan ?: A monocentric institution safety analysis of 46 patients

Cited by 5 publications

References 16 publications

Inflammasome Activation Is Reactive Oxygen Species Dependent and Mediates Irinotecan-Induced Mucositis through IL-1β and IL-18 in Mice

Inflammasome Activation Is Reactive Oxygen Species Dependent and Mediates Irinotecan-Induced Mucositis through IL-1β and IL-18 in Mice

Therapeutic Targeting of CPT-11 Induced Diarrhea: A Case for Prophylaxis

Eosinophil plays a crucial role in intestinal mucositis induced by antineoplastic chemotherapy

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