Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea
The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent rever...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2002, Vol.62 (1), p.179-187 |
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| creator | IKEGAMI, Tadashi LINAN HA ARIMORI, Kazuhiko LATHAM, Patricia KOBAYASHI, Kunihiko CERYAK, Susan MATSUZAKI, Yasushi BOUSCAREL, Bernard |
| description | The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time ( |
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This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time (<2 h) was sufficient to induce these events. Because the decreased initial uptake of SN-38 carboxylate resulted in a reduced cellular toxicity, we postulated that the CPT-11-induced diarrhea was preventable by influencing the equilibrium toward the carboxylate form and, thus, reducing its intestinal uptake. In the golden Syrian hamster model, p.o. sodium bicarbonate supplementation (5 mg/ml in drinking water) led to alkalization of the intestinal contents. In addition, this alkalization resulted in the reduction of the histopathological damage to the mucosa of the small and large intestine, as well as a 20% reduction of the intestinal SN-38 lactone concentration of animals receiving CPT-11 (20-50 mg/kg x 7 days). Taken together, these results from in vitro and in vivo studies support intestinal alkalization by sodium bicarbonate supplementation as a preventive mechanism against CPT-11-induced diarrhea. In addition, this provides a strong rationale for the usage of this measure as an adjunct to CPT-11 treatment.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 11782376</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic Agents, Phytogenic - adverse effects ; Antineoplastic Agents, Phytogenic - pharmacokinetics ; Apoptosis - drug effects ; Biological and medical sciences ; Camptothecin - adverse effects ; Camptothecin - analogs & derivatives ; Camptothecin - pharmacokinetics ; Carboxylic Acids - adverse effects ; Carboxylic Acids - pharmacokinetics ; Cell Cycle - drug effects ; Cell Division - drug effects ; Cricetinae ; Diarrhea - chemically induced ; Diarrhea - prevention & control ; Drug toxicity and drugs side effects treatment ; Glucuronides - adverse effects ; Glucuronides - pharmacokinetics ; HT29 Cells - drug effects ; HT29 Cells - metabolism ; Humans ; Hydrogen-Ion Concentration ; Intestines - cytology ; Intestines - drug effects ; Intestines - metabolism ; Lactones - adverse effects ; Lactones - pharmacokinetics ; Male ; Medical sciences ; Mesocricetus ; Pharmacology. Drug treatments ; Sodium Bicarbonate - pharmacology ; Toxicity: digestive system</subject><ispartof>Cancer research (Chicago, Ill.), 2002, Vol.62 (1), p.179-187</ispartof><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,4012</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13442623$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11782376$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>IKEGAMI, Tadashi</creatorcontrib><creatorcontrib>LINAN HA</creatorcontrib><creatorcontrib>ARIMORI, Kazuhiko</creatorcontrib><creatorcontrib>LATHAM, Patricia</creatorcontrib><creatorcontrib>KOBAYASHI, Kunihiko</creatorcontrib><creatorcontrib>CERYAK, Susan</creatorcontrib><creatorcontrib>MATSUZAKI, Yasushi</creatorcontrib><creatorcontrib>BOUSCAREL, Bernard</creatorcontrib><title>Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time (<2 h) was sufficient to induce these events. Because the decreased initial uptake of SN-38 carboxylate resulted in a reduced cellular toxicity, we postulated that the CPT-11-induced diarrhea was preventable by influencing the equilibrium toward the carboxylate form and, thus, reducing its intestinal uptake. In the golden Syrian hamster model, p.o. sodium bicarbonate supplementation (5 mg/ml in drinking water) led to alkalization of the intestinal contents. In addition, this alkalization resulted in the reduction of the histopathological damage to the mucosa of the small and large intestine, as well as a 20% reduction of the intestinal SN-38 lactone concentration of animals receiving CPT-11 (20-50 mg/kg x 7 days). Taken together, these results from in vitro and in vivo studies support intestinal alkalization by sodium bicarbonate supplementation as a preventive mechanism against CPT-11-induced diarrhea. In addition, this provides a strong rationale for the usage of this measure as an adjunct to CPT-11 treatment.</description><subject>Animals</subject><subject>Antineoplastic Agents, Phytogenic - adverse effects</subject><subject>Antineoplastic Agents, Phytogenic - pharmacokinetics</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Camptothecin - adverse effects</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - pharmacokinetics</subject><subject>Carboxylic Acids - adverse effects</subject><subject>Carboxylic Acids - pharmacokinetics</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Division - drug effects</subject><subject>Cricetinae</subject><subject>Diarrhea - chemically induced</subject><subject>Diarrhea - prevention & control</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>Glucuronides - adverse effects</subject><subject>Glucuronides - pharmacokinetics</subject><subject>HT29 Cells - drug effects</subject><subject>HT29 Cells - metabolism</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Intestines - cytology</subject><subject>Intestines - drug effects</subject><subject>Intestines - metabolism</subject><subject>Lactones - adverse effects</subject><subject>Lactones - pharmacokinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mesocricetus</subject><subject>Pharmacology. Drug treatments</subject><subject>Sodium Bicarbonate - pharmacology</subject><subject>Toxicity: digestive system</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFz0tLAzEUBeAgiq3VvyDZCLoI5D0zSylaCwVd1HW5eQy9OpMOybSgv96CFVeHAx8HzhmZCqNqVmltzsmUc14zoys5IVelfByrEdxckokQVS1VZafELdMYy4gJOgrdJ3T4DSPuEoVCgQ67UtB1kQ45HmIa8RBpH_0WEpaeYqKYMe3G6CHR-_nbmgnxwDCFvY-BBoSctxGuyUULXYk3p5yR9-en9fyFrV4Xy_njim2lbUamtPfagFPgfGO9bKSyYGVbB24VBKOVqnkTjLPatL7WjeHOgQAfXeuDBDUjt7-7w971MWyGjD3kr83f2SO4OwEoHro2Q_JY_p3SWlqp1A_ym196</recordid><startdate>2002</startdate><enddate>2002</enddate><creator>IKEGAMI, Tadashi</creator><creator>LINAN HA</creator><creator>ARIMORI, Kazuhiko</creator><creator>LATHAM, Patricia</creator><creator>KOBAYASHI, Kunihiko</creator><creator>CERYAK, Susan</creator><creator>MATSUZAKI, Yasushi</creator><creator>BOUSCAREL, Bernard</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>2002</creationdate><title>Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea</title><author>IKEGAMI, Tadashi ; LINAN HA ; ARIMORI, Kazuhiko ; LATHAM, Patricia ; KOBAYASHI, Kunihiko ; CERYAK, Susan ; MATSUZAKI, Yasushi ; BOUSCAREL, Bernard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h269t-34cc45ab3abc96c29236a62f8d063ad5433809d5b645fc84950bba1acebfcd2a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Antineoplastic Agents, Phytogenic - adverse effects</topic><topic>Antineoplastic Agents, Phytogenic - pharmacokinetics</topic><topic>Apoptosis - drug effects</topic><topic>Biological and medical sciences</topic><topic>Camptothecin - adverse effects</topic><topic>Camptothecin - analogs & derivatives</topic><topic>Camptothecin - pharmacokinetics</topic><topic>Carboxylic Acids - adverse effects</topic><topic>Carboxylic Acids - pharmacokinetics</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Division - drug effects</topic><topic>Cricetinae</topic><topic>Diarrhea - chemically induced</topic><topic>Diarrhea - prevention & control</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>Glucuronides - adverse effects</topic><topic>Glucuronides - pharmacokinetics</topic><topic>HT29 Cells - drug effects</topic><topic>HT29 Cells - metabolism</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Intestines - cytology</topic><topic>Intestines - drug effects</topic><topic>Intestines - metabolism</topic><topic>Lactones - adverse effects</topic><topic>Lactones - pharmacokinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mesocricetus</topic><topic>Pharmacology. Drug treatments</topic><topic>Sodium Bicarbonate - pharmacology</topic><topic>Toxicity: digestive system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>IKEGAMI, Tadashi</creatorcontrib><creatorcontrib>LINAN HA</creatorcontrib><creatorcontrib>ARIMORI, Kazuhiko</creatorcontrib><creatorcontrib>LATHAM, Patricia</creatorcontrib><creatorcontrib>KOBAYASHI, Kunihiko</creatorcontrib><creatorcontrib>CERYAK, Susan</creatorcontrib><creatorcontrib>MATSUZAKI, Yasushi</creatorcontrib><creatorcontrib>BOUSCAREL, Bernard</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>IKEGAMI, Tadashi</au><au>LINAN HA</au><au>ARIMORI, Kazuhiko</au><au>LATHAM, Patricia</au><au>KOBAYASHI, Kunihiko</au><au>CERYAK, Susan</au><au>MATSUZAKI, Yasushi</au><au>BOUSCAREL, Bernard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2002</date><risdate>2002</risdate><volume>62</volume><issue>1</issue><spage>179</spage><epage>187</epage><pages>179-187</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time (<2 h) was sufficient to induce these events. Because the decreased initial uptake of SN-38 carboxylate resulted in a reduced cellular toxicity, we postulated that the CPT-11-induced diarrhea was preventable by influencing the equilibrium toward the carboxylate form and, thus, reducing its intestinal uptake. In the golden Syrian hamster model, p.o. sodium bicarbonate supplementation (5 mg/ml in drinking water) led to alkalization of the intestinal contents. In addition, this alkalization resulted in the reduction of the histopathological damage to the mucosa of the small and large intestine, as well as a 20% reduction of the intestinal SN-38 lactone concentration of animals receiving CPT-11 (20-50 mg/kg x 7 days). Taken together, these results from in vitro and in vivo studies support intestinal alkalization by sodium bicarbonate supplementation as a preventive mechanism against CPT-11-induced diarrhea. In addition, this provides a strong rationale for the usage of this measure as an adjunct to CPT-11 treatment.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>11782376</pmid><tpages>9</tpages></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antineoplastic Agents, Phytogenic - adverse effects Antineoplastic Agents, Phytogenic - pharmacokinetics Apoptosis - drug effects Biological and medical sciences Camptothecin - adverse effects Camptothecin - analogs & derivatives Camptothecin - pharmacokinetics Carboxylic Acids - adverse effects Carboxylic Acids - pharmacokinetics Cell Cycle - drug effects Cell Division - drug effects Cricetinae Diarrhea - chemically induced Diarrhea - prevention & control Drug toxicity and drugs side effects treatment Glucuronides - adverse effects Glucuronides - pharmacokinetics HT29 Cells - drug effects HT29 Cells - metabolism Humans Hydrogen-Ion Concentration Intestines - cytology Intestines - drug effects Intestines - metabolism Lactones - adverse effects Lactones - pharmacokinetics Male Medical sciences Mesocricetus Pharmacology. Drug treatments Sodium Bicarbonate - pharmacology Toxicity: digestive system |
| title | Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea |
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