Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer

Fujita, Ken‐ichi; Kubota, Yutaro; Ishida, Hiroo; Sasaki, Yasutsuna

doi:10.3748/wjg.v21.i43.12234

Cited by 248 publications

(173 citation statements)

References 103 publications

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“…Interestingly, cimetidine is a well-characterized inhibitor of OCT2 (36). Irinotecan usually co-administration with morphine in advanced colorectal cancer (12,44). Our present study demonstrated that irinotecan had the most potent inhibitory effect among these tested drugs on the uptake of morphine mediated by the hepatic OCT1 and by the renal OCT2.…”

Section: Discussionmentioning

confidence: 99%

Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

et al. 2018

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Purpose The organic cation transporters (OCTs) and multi-drug and toxin extrusions (MATEs) together are regarded as an organic cation transport system critical to the disposition and response of many organic cationic drugs. Patient response to the analgesic morphine, a characterized substrate for human OCT1, is highly variable. This study was aimed to examine whether there is any organic cation transporter-mediated drug and drug interaction (DDI) between morphine and commonly co-administrated drugs. Methods The uptake of morphine and its inhibition by six drugs which are commonly co-administered with morphine in the clinic were assessed in human embryonic kidney 293 (HEK293) cells stably expressing OCT1, OCT2 and MATE1. The in vivo interaction between morphine and the select irinotecan was determined by comparing the disposition of morphine in the absence versus presence of irinotecan treatment in mice. Results The uptake of morphine in the stable HEK293 cells expressing human OCT1 and OCT2 was significantly increased by 3.56 and 3.04 fold, respectively, than that in the control cells, with no significant uptake increase in the cells expressing human MATE1. All of the six drugs examined, including amitriptyline, fluoxetine, imipramine, irinotecan, ondansetron, and verapamil, were inhibitors of OCT1/2-mediated morphine uptake. The select irinotecan significantly increased the plasma concentrations and decreased hepatic and renal accumulation of morphine in mice. Conclusions Morphine is a substrate of OCT1 and OCT2. Clinician should be aware that the disposition of and thus the response to morphine may be altered by co-administration of an OCT1/2 inhibitor, such as irinotecan.

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Section: Discussionmentioning

confidence: 99%

Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

et al. 2018

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“…For instance, irinotecan is key chemotherapeutic drug for metastatic colorectal cancer and other types of tumors. 33 Topotecan is used to treat cancer of the ovaries when other treatments have failed and may also be used in certain types of lung cancer (small cell lung cancer). Since Tdp1 is involved in the removal of DNA damage caused by CPT, it is believed that Tdp1 is responsible for drug resistance of some cancers.…”

Section: Synergistic Activity With Camptothecin Against Tumor Cellsmentioning

confidence: 99%

New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

Khomenko

Zakharenko

Odarchenko

et al. 2016

Bioorganic & Medicinal Chemistry

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“…Future research on the protective activities of the metabolic products of resveratrol are necessary to elucidate their interaction with DNA-damaging drugs used in the treatment of cancer. Of note, camptothecins are used in the combinatorial treatment of colorectal cancers (46)(47)(48). The increased DNA damage and apoptosis of cells treated with camptothecin and topotecan following pretreatment with resveratrol aglycone in the present study suggests that dietary resveratrol may be a useful addition for treating gastrointestinal cancers that have direct contact with unmetabolized resveratrol.…”

Section: Discussionmentioning

confidence: 63%

Resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin

Zunino

Storms

2017

Oncology Letters

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Abstract.Resveratrol has been reported to inhibit or induce DNA damage, depending upon the type of cell and the experimental conditions. Dietary resveratrol is present in the body predominantly as metabolites and limited data is available concerning the activities of these metabolic products. In the present study, physiologically obtainable levels of the resveratrol metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide and resveratrol-3-O-sulfate were evaluated for their ability to protect Jurkat T cells against DNA damage induced by the topoisomerase I inhibitors camptothecin and topotecan. The cells were pretreated for 24 h with 10 µM resveratrol aglycone or each resveratrol metabolite prior to the induction of DNA damage with camptothecin or topotecan. In separate experiments, the cells were co-treated with resveratrol or its metabolites, and a topoisomerase I inhibitor. The detection of histone 2AX phosphorylation and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) were used to determine DNA damage, and apoptosis was measured using an antibody against cleaved poly ADP-ribose polymerase. It was identified that pretreatment of the cells with resveratrol-3-O-glucuronide and resveratrol-4'-O-glucuronide reduced the mean fluorescence intensity of staining for DNA strand breaks following treatment with camptothecin, while the percentage of cells undergoing apoptosis was unchanged. However, pretreatment of the cells with resveratrol aglycone increased the DNA damage and apoptosis induced by the drugs. These results suggest that the glucuronide metabolites of resveratrol partially protected the cells from DNA damage, but did not influence the induction of cell death by camptothecin and topotecan. These data suggest that resveratrol aglycone treatment may be beneficial for treating types of cancer that have direct contact with resveratrol prior to its metabolism, including gastrointestinal cancers, which are routinely treated with topoisomerase I inhibitors.

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Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer

Cited by 248 publications

References 103 publications

Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

Resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin

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