Elsevier

Cancer Treatment Reviews

Volume 30, Issue 6, October 2004, Pages 555-562
Cancer Treatment Reviews

COMPLICATIONS OF TREATMENT
New approaches to prevent intestinal toxicity of irinotecan-based regimens

https://doi.org/10.1016/j.ctrv.2004.05.002Get rights and content

Abstract

Background. Irinotecan is a selective inhibitor of topoisomerase I, an enzyme part of the replication and transcription system of DNA. Irinotecan is employed, with different modalities, in the treatment of metastatic colorectal cancer, and recently it has been officially approved in association with fluorouracil (FU) and leucovorin (LV) as a first-line option in metastatic colorectal cancer.

Results. One of the problems linked to the administration of this drug is the high intestinal toxicity, which constitutes its dose limiting toxicity (DLT). In routine practice, loperamide is employed as symptomatic drug for the treatment of CPT-11-induced diarrhoea, but is not completely adequate to control the problem. The role of the intestinal bacterial microflora in the pathogenesis of CPT-11-induced intestinal toxicity has been recently discovered. The active metabolite of CPT-11, SN38, is generated from CPT-11 by sieric carboxylesterase, and subsequently conjugated to SN38-G by hepatic UDP–glucuronyltransferase. SN38-G is the inactive metabolite of CPT-11 and is excreted into the small intestine, from which it is eliminated in the faeces. Some studies have shown the ability of intestinal bacterial β-glucoronidases to transform SN38-G into SN38, causing direct damage to the intestinal mucosa. Thus, alternative strategies such as intestinal alkalinization and anti-cyclooxygenase 2 (COX-2) therapy have been explored.

Conclusions. In this review, we will illustrate the mechanisms which cause the CPT-11-induced diarrhoea and the potential measures available to prevent it.

Introduction

Irinotecan (CPT-11) is a semisynthetic analogue of camptothecin, the active agent isolated in the United States in 1966 from Camptotheca Acuminata, a plant native only to China and Tibet. Although camptothecin demonstrated significant anticancer activity in experimental studies, its clinical development was halted due to unacceptable toxicity. In 1985, with the discovery that topoisomerase I was the molecular target of camptothecin, a new wave of research on analogues with a more favorable profile began, leading to the discovery, in the 1990s, of a new and less toxic molecule, CPT-11.

CPT-11 is a selective inhibitor of topoisomerase I, an enzyme involved in DNA replication and transcription. In 1998, it received full FDA approval for treatment of metastatic colorectal carcinoma that has recurred or progressed after standard chemotherapy.[1], [2] Recently, CPT-11 has been approved in association with fluorouracil (FU) and leucovorin (LV) as first line treatment of metastatic colorectal cancer.[3], [4]

The role of CPT-11 as single agent or in combined modality regimens has been investigated in a number of other cancers, including small and non-small cell lung cancer, gastric cancer, cervical cancer, malignant brain tumours, ovarian cancer and pancreatic cancer.[5], [6], [7], [8], [9], [10] Results are promising, especially in small and non-small cell lung cancer.

Severe intestinal toxicity remains one of the still unresolved problems linked to irinotecan administration and constitutes its dose limiting toxicity (DLT). Recent clinical trials have shown that CPT-11 causes G3–G4 diarrhoea in at least 40% of patients,11 leading to a premature interruption of chemotherapy.12 Leucopenia is another frequent side effect but is more easily managed by administration of granulocyte colony stimulated factor (GCSF).13

In this review, we will illustrate the mechanisms that underlie CPT-11-induced diarrhoea and relevant prevention strategies.

Section snippets

Mechanism of action

In 1985, Liu and colleagues[14], [15] demonstrated that camptothecin creates an unusual type of DNA damage in cancer cells by trapping the enzyme topoisomerase I during its normal action in regulating DNA structure. During DNA replication topoisomerase I produces reversible single-strand breaks in DNA by cutting and reattaching the double chain of DNA. These single-strand breaks relieve the torsional strain generated by advancing replication forks and allow DNA replication to proceed.

Irinotecan

Pharmacokinetics and pharmacodynamics

Irinotecan is a pro-drug converted to its active metabolite, SN-38, by the enzyme carboxylesterase (CE). CE is present abundantly in the liver but can also be found in the duodenum, jejunum, ileum, colon, and rectum. Carboxylesterases cleave the piperidine side chain present at the C-10 position of the irinotecan molecule yielding the 100- to 1000-fold more biologically active metabolite, 7-ethyl-10-hydroxycamptothecin or SN-38.17 After administration, irinotecan has a terminal half life (t1/2)

Inhibitors of bacterial β-glucuronidase

CPT-11/SN-38-induced diarrhoea may occur in one or both of two different time settings. The first occurs early within 24 h of infusion. Early onset diarrhoea is thought to be part of a cholinergic syndrome mediated by increased anticholinesterase activity of the irinotecan parent compound. It may be accompanied by other cholinergic symptoms such as rhinitis, hypersalivation, miosis, lacrimation, diaphoresis, flushing, and abdominal cramping. It is usually prevented or rapidly suppressed by

Conclusions

During last years CPT-11 has shown huge activity in several cancers and future perspectives could be open for other indications. In the era of dose intensification, many drugs have shown better results when used at higher dose levels or with more dose dense schedules.[63], [64] Thus, increasing CPT-11 dose could be a useful strategy to improve patient outcome. However, irinotecan-induced intestinal toxicity seems to be the greatest barrier to such an approach. Nowadays, loperamide is employed

References (64)

  • P. Rougier et al.

    Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy

    J. Clin. Oncol

    (1997)
  • S. Kudoh et al.

    Phase II study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer. West Japan Lung Cancer Group

    J. Clin. Oncol

    (1998)
  • W.P. Irvin et al.

    A Phase II study of irinotecan in patients with advanced squamous-cell carcinoma of the cervix

    Cancer

    (1998)
  • K. Noda et al.

    Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer

    N. Engl. J. Med

    (2002)
  • M.H. Jagasia et al.

    Weekly irinotecan and cisplatin in advanced non-small cell lung cancer: a multicenter phase II study

    Clin. Cancer. Res

    (2001)
  • C. Rocha Lima et al.

    Multicenter phase II trial of first-line irinotecan and gemcitabine (irimogem) in patients with locally advanced or metastatic pancreatic cancer (PC)

    Proc. Am. Soc. Clin. Oncol

    (2000)
  • J.R. Hecht

    Gastrointestinal toxicity of irinotecan

    Oncology

    (1998)
  • D.J. Sargent et al.

    Reccomendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer

    N. Engl. J. Med

    (2001)
  • D. Cunningham et al.

    Optimizing the use of irinotecan in colorectal cancer

    Oncologist

    (2001)
  • L.F. Liu et al.

    Mechanism of action of camptothecin

    Ann. N. Y. Acad. Sci

    (2000)
  • R.G. Shao et al.

    Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA: DNA-PK complexes

    EMBO J

    (1999)
  • A. Sparreboom et al.

    Irinotecan Metabolism and Disposition in cancer patients

    Clinical Cancer Research

    (1998)
  • N. Kaneda et al.

    Nonlinear pharmacokinetics of CPT-11 in rats

    Cancer Res

    (1990)
  • E. Gupta et al.

    Metabolic fate of irinotecan in humans correlation of glucuronidation with diarrhoea

    Cancer Res

    (1994)
  • L.P. Rivory et al.

    Pharmacokinetic interrelationship of Irinotecan and its three major plasma metabolites in patients enrolled in phase I/II trial

    Clinical Cancer Research

    (1997)
  • L.P. Rivory et al.

    Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients

    Cancer Res

    (1996)
  • R. Xie et al.

    Clinical Pharmacokinetics of Irinotecan and Its Metabolites: A Population Analysis

    J. Clin. Oncol

    (2002)
  • R.H.J. Mathijssen et al.

    Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11)

    Clin. Cancer Res

    (2001)
  • L. Iyer et al.

    Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism

    Clin. Pharmacol. Ther

    (1999)
  • L. Iyer et al.

    Genetic predisposition to the metabolism of irinotecan (CPT-11) Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes

    J. Clin. Invest

    (1998)
  • N. Kaneda et al.

    Intravenous administration of Irinotecan elevates the blood Beta-Glucuronidase activity in rats

    Cancer Research

    (1997)
  • K. Takasuna et al.

    Involvement of β-Glucuronidase in Intestinal Microflora in the Intestinal Toxicity of the Antitumour Camptothecin Derivative Irinotecan Hydrochloride

    Cancer Res

    (1996)
  • Cited by (90)

    • Irinotecan decreases intestinal UDP-glucuronosyltransferase (UGT) 1A1 via TLR4/MyD88 pathway prior to the onset of diarrhea

      2022, Food and Chemical Toxicology
      Citation Excerpt :

      Current anti-diarrhea agents, loperamide and budesonide are not adequately effective (Abigerges et al., 1994; Lenfers et al., 1999). Around 30% cancer patients have to withdraw irinotecan therapy even after taking highest dose of loperamide (Abigerges et al., 1994; Alimonti et al., 2004). Most preclinical studies investigated irinotecan-induced gut injury after mice showing diarrhea, but very few explored the period before diarrhea onset.

    • P53 activation suppresses irinotecan metabolite SN-38-induced cell damage in non-malignant but not malignant epithelial colonic cells

      2020, Toxicology in Vitro
      Citation Excerpt :

      Concentration-response curves demonstrated the comparative sensitivity of the CRC cell lines to SN-38 in comparison with the non-malignant FHs 74 cells, reflective of the high rate of proliferation rendering them susceptible to the cytotoxic irinotecan metabolite. SN-38 is recognised as S-phase active (Alimonti et al., 2004) and can elicit cell death independent of p53 status (Levesque et al., 2008). This was further demonstrated by the results showing that HCT116 cells did not display altered sensitivity or potency to SN-38 between their wild-type and deleted p53 status, a result similar to that observed in a previous study (Boyer et al., 2004).

    • Intestinal bacterial β-glucuronidase as a possible predictive biomarker of irinotecan-induced diarrhea severity

      2019, Pharmacology and Therapeutics
      Citation Excerpt :

      This meta-analysis will use a similar methodology to that used in previous GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) studies (GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group et al., 2013). Several prophylactic or curative measures have been considered and assessed in preclinical and clinical studies to avoid the serious, debilitating and life-threatening side effects of irinotecan-induced diarrhea (Alimonti et al., 2004; Swami et al., 2013). Such strategies showed encouraging results in animal studies, but they were not tested in solid RCTs (Swami et al., 2013).

    • Human carboxylesterases: a comprehensive review

      2018, Acta Pharmaceutica Sinica B
    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text