Protective Effects of <i>Kampo</i> Medicines and Baicalin against Intestinal Toxicity of a New Anticancer Camptothecin Derivative, Irinotecan Hydrochloride (CPT‐11), in Rats

Takasuna, Kiyoshi; Kasai, Yoshio; Kitano, Yutaka; Mori, Kazuhiko; Kobayashi, Reiko; Hagiwara, Toshihiko; Kakihata, Kohji; Hirohashi, Masaaki; Nomura, Mamoru; Nagai, Eiichi; Kamataki, Tetsuya

doi:10.1111/j.1349-7006.1995.tb03010.x

Cited by 106 publications

(75 citation statements)

References 14 publications

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“…Furthermore, in a preliminary study, Fittkau et al (2004) did not confirm the anti-diarrhoeal activity of D-saccharic acid 1.4-lactone (a specific b-glucuronidase inhibitor), although Wallace et al (2010) showed an opposite result by oral administration of an inhibitor of the enzyme, which protected mice from irinotecan-induced toxicity. Takasuna et al (1996) also showed that inhibition of the b-glucuronidase activity of the intestinal microbiota could be the major protective mechanism of antibiotics. Thus, the relationship between b-glucuronidase activity and mucositis is still controversial.…”

Section: Discussionmentioning

confidence: 99%

“…After its action, SN-38 is inactivated by glucuronidation by the uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1) and eliminated in the bile as its glucuronidated form SN-38G (Sparreboom et al, 1998). However, this inactivated form might be re-activated in the intestine if bacteria producing b-glucuronidase are present in the local microbiota (Takasuna et al, 1996), although, in CV animals, most of the SN-38 produced from SN-38G by action of b-glucuronidase is rapidly adsorbed on the bacteria cell wall or intestinal dietary fibre, so that only 10 % remains in the unbound form that can be measured in the intestinal fluid (Takakura et al, 2012). This could explain, in part, the paradoxical higher levels of SN-38 observed in the intestinal luminal fluid of GF mice.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of mucositis induced by irinotecan after microbial colonization in germ-free mice

et al. 2015

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Mucositis is one of the most debilitating side effects of chemotherapy and some previous studies suggest a role for indigenous microbiota in the course of this pathology. Therefore, the aim of our study was to evaluate the differences in phenotype between germ-free (GF) and conventional (CV) mice, and the role of b-glucuronidase-producing bacteria in the development of irinotecan treatment in a murine model. After mucositis induction, CV mice showed a significant increase in all inflammatory parameters when compared to GF mice. CV animals also showed more lesions of the intestinal epithelium, coherent with their higher intestinal permeability. The conventionalization of GF animals reversed their phenotype to that found in CV mice. In addition, gnotobiotic mice monoassociated with an Escherichia coli strain producing b-glucuronidase showed an increased permeability when compared to gnotobiotic mice monoassociated with an E. coli strain deleted for the gene encoding b-glucuronidase, but these did not show any differences in the influx of neutrophils, eosinophils or histological characteristics. Our data confirmed that components of the gut microbiota are involved in the signs of mucositis. Nevertheless, other mechanisms than this enzyme are involved in the irinotecan treatment, since the monoassociation was not able to restore the entire phenotype observed in the CV animals with irinotecan treatment in our murine model.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation of mucositis induced by irinotecan after microbial colonization in germ-free mice

et al. 2015

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“…This contrasts with the tolerance in mice. Progresses in overcoming CPT-11 toxicity in humans should improve the clinical use of this compound (Takasuna et al, 1995(Takasuna et al, , 1996. Nevertheless, even at the moderate doses tolerable by human hosts, top1 inhibitors are active agents in patients with metastatic colorectal cancers (Conti et al, 1996;Pazdur et al, 1997) and reviewed in Rougier and Bugat (1996);Rothenberg (1997).…”

Section: Discussionmentioning

confidence: 99%

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Bras-Gonçalves

Rosty²,

Laurent‐Puig³

et al. 2000

Br J Cancer

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Summary Biological parameters influencing the response of human colorectal cancers (CRCs) to CPT-11, a topoisomerase 1 (top1) inhibitor, were investigated using a panel of nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status (wt or mut) and in their microsatellite instability phenotype (MSI + when altered). Five CRC xenografts were established from clinical samples. All five had a functional p53, two were MSI + and three were MSI -. Tumour-bearing nude mice were treated intraperitonealy (i.p.) with CPT-11. At 10 mg kg -1 of CPT-11, four injections at 4-day intervals, four of the five xenografts responded to CPT-11 (growth delay of up to 10 days); the non-responder tumour was MSI -. At 40 mg kg -1 of CPT-11, six injections at 4-day intervals, the five CRCs displayed variable but marked responses with complete regressions. In order to assess the role of p53 status in CPT-11 response, four CRC lines were used. HT29 cell line was MSI -/Ala273-mutp53, its subclone HT29A3 being transfected by wtp53. LoVo cell line was MSI + /wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 after transfection. LoVo tumours (MSI + /mutp53) were more sensitive than X17LoVo (MSI + /mutp53. HT 29 tumours (MSI -Imutp53), were refractory to CPT-11 while HT29A3 tumours (MSI -/wtp53) were sensitive, showing that wtp53 improves the drugresponse in these MSI -tumours. Levels of mRNA expression of top1, fasR, TP53 and mdr1 were semi-quantified by reverse transcription polymerase chain reaction. None of these parameters correlated with CPT-11 response. Taken together, these observations indicate that MSI and p53 alterations could be associated with different CPT-11 sensitivities; MSI phenotype moderately influences the CPT-11 sensitivity, MSI + being more sensitive than MSI -CRC freshly obtained from patients, mutp53 status being associated with a poor response to CPT-11. © 2000 Cancer Research Campaign Keywords: CPT-11; MSI; p53; top1; human colorectal cancer; nude mice (2000) 82(4), 913-923 © 2000 Cancer Research Campaign DOI: 10.1054/ bjoc.1999.1019, available online at http://www.idealibrary.com on et al, 1998). Cells with functional wtp53 are found to be dramatically more sensitive to many of the commonly used anticancer agents (Fujiwara et al, 1994;Lowe et al, 1993Lowe et al, , 1994McDonald and Brown 1998). In MSI + tumours, defects in mismatch repair genes could lead to the accumulation of unrepaired or misrepaired DNA during DNA replication, rendering them more sensitive for CPT-11 effect.Other resistance mechanisms to CPT-11 could also be implicated. Overexpression of the multidrug resistance gene product, P-glycoprotein, encoded by the mdr1 gene has been incriminated in tumour cell resistance to numerous compounds (Gottesman et al, 1996). Its role in the lack of sensitivity of tumour cells to CPT-11 has been described . Two groups have recently shown that colorectal cancers of the colonic mucosa express the fas receptor (fasR), a cell membrane determinant which triggers the apoptotic casc...

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“…Since SN-38G, once excreted in the intestinal lumen, is extensively hydrolyzed by bacterial ß-glucuronidase to free SN-38, it was thought that direct intestinal damage by the free intestinal luminal SN-38 was responsible for the delayed-onset diarrhea. Takasuna et al (10,18) reported on the good correlation between the fecal concentration of SN-38 and the anatomic damage of the intestinal mucosa in mice, as well as a greater degree of histological damage in the intestinal segments where the bacterial ß-glucuronidase activity was prominent (caecum and colon). However, our knowledge of the precise mechanism involved in the latter is far from complete.…”

Section: Discussionmentioning

confidence: 99%

“…SN-38G is the inactive metabolite and is secreted in the duodenum (5-7). Many authors consider that the intestinal bacterial microflora are responsible for the damage to the intestinal mucosa, because intestinal bacterial ß-glucuronidase can deconjugate SN-38G into active SN-38, which causes mucosal damage in the small intestine thus causing toxic diarrhea (8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Metabolism of irinotecan and its active metabolite SN-38 by intestinal microflora in rats

Yamamoto

Kurita²,

Asahara³

et al. 1994

Oncol Rep

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Abstract.One of the dose-limiting toxicities of irinotecan (CPT-11) is delayed-onset diarrhea, which is the greatest barrier to treatment with CPT-11-containing regimens. CPT-11 is converted to its active metabolite, SN-38, which is conjugated by hepatic uridine diphosphate glucuronosyl transferase to SN-38 glucuronide (SN-38G). SN-38G, once excreted in the intestinal lumen via bile, is extensively deconjugated by bacterial ß-glucuronidase with the regeneration of SN-38 in the intestinal lumen, which may cause diarrhea. However, the metabolism of CPT-11 and its metabolites by intestinal microflora are yet to be reported. This study was carried out to investigate the microbial transformation of CPT-11 and SN-38 using an anaerobic mixed culture of rat cecal microorganisms. No reaction in the mixed cultures was observed when CPT-11 or SN-38 lactone was added to the culture medium. When CPT-11 was added to the culture broth, a significant amount of water-soluble CPT-11 was detected in the spent culture medium. In contrast, only a slight amount of SN-38 was found in the supernatant when SN-38 lactone was added to the broth. A significant quantity of SN-38 was found in the sediment. In conclusion, these results strongly suggest that SN-38 produced from SN-38G by the action of bacterial ß-glucuronidase is rapidly adsorbed by the intestinal bacterial cell walls in the sediment because of the hydrophobic and lipophilic nature of SN-38, and a small amount of SN-38 remains in the intestinal luminal fluid. Thus, we need to reconsider the role of SN-38 in the intestinal lumen in CPT-11-induced late-onset diarrhea.

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Protective Effects of Kampo Medicines and Baicalin against Intestinal Toxicity of a New Anticancer Camptothecin Derivative, Irinotecan Hydrochloride (CPT‐11), in Rats

Cited by 106 publications

References 14 publications

Evaluation of mucositis induced by irinotecan after microbial colonization in germ-free mice

Evaluation of mucositis induced by irinotecan after microbial colonization in germ-free mice

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Metabolism of irinotecan and its active metabolite SN-38 by intestinal microflora in rats

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