COMPLICATIONS OF TREATMENTNew approaches to prevent intestinal toxicity of irinotecan-based regimens
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
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Cited by (90)
Irinotecan decreases intestinal UDP-glucuronosyltransferase (UGT) 1A1 via TLR4/MyD88 pathway prior to the onset of diarrhea
2022, Food and Chemical ToxicologyCitation 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 VitroCitation 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 TherapeuticsCitation 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).
Traditional Chinese medicine Gegen Qinlian decoction ameliorates irinotecan chemotherapy-induced gut toxicity in mice
2019, Biomedicine and PharmacotherapyHuman carboxylesterases: a comprehensive review
2018, Acta Pharmaceutica Sinica B
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These authors contributed equally to this work.