Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A Phase I and pharmacokinetic study of its prodrug, CB1954
CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] is converted by the bacterial enzyme nitroimidazole reductase (NTR) into a potent cytotoxic bifunctional alkylating agent, which can be delivered to tumors in adenoviral vectors as virus-directed, enzyme prodrug therapy. This report summarizes a Phase...
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| Veröffentlicht in: | Clinical cancer research 2001-09, Vol.7 (9), p.2662-2668 |
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| creator | CHUNG-FAYE, Guy PALMER, Daniel HARRIS, Peter A FERRY, David KERR, David J ANDERSON, David CLARK, Joanna DOWNES, Mandy BADDELEY, Joanna HUSSAIN, Syed MURRAY, Philip I SEARLE, Peter SEYMOUR, Leonard |
| description | CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] is converted by the bacterial enzyme nitroimidazole reductase (NTR) into a potent cytotoxic bifunctional alkylating agent, which can be delivered to tumors in adenoviral vectors as virus-directed, enzyme prodrug therapy. This report summarizes a Phase I and pharmacokinetic study of the prodrug, CB1954. Thirty patients, ages 23-78 years (median 62 years), with predominantly gastrointestinal malignancies were treated. CB1954 was administered by i.v. injection every 3 weeks or i.p. followed by 3-weekly i.v. injections, toward a maximum of six cycles. The dose was escalated from 3 to 37.5 mg/m2. No significant toxicity was seen until 24 mg/m2 (recommended i.v. dose). Dose-limiting toxicities (DLT) were diarrhea and hepatic toxicity, seen at 37.5 mg/m2. DLT has not been observed at the current i.p. dose of 24 mg/m2. There was no alopecia, marrow suppression, or nephrotoxicity. Clearance data suggest hepatic metabolism, and |
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This report summarizes a Phase I and pharmacokinetic study of the prodrug, CB1954. Thirty patients, ages 23-78 years (median 62 years), with predominantly gastrointestinal malignancies were treated. CB1954 was administered by i.v. injection every 3 weeks or i.p. followed by 3-weekly i.v. injections, toward a maximum of six cycles. The dose was escalated from 3 to 37.5 mg/m2. No significant toxicity was seen until 24 mg/m2 (recommended i.v. dose). Dose-limiting toxicities (DLT) were diarrhea and hepatic toxicity, seen at 37.5 mg/m2. DLT has not been observed at the current i.p. dose of 24 mg/m2. There was no alopecia, marrow suppression, or nephrotoxicity. Clearance data suggest hepatic metabolism, and <5% of CB1954 was renally excreted. There was a nonlinear relationship between i.v. dose and area under the curve (AUC). At the recommended i.v. dose of 24 mg/m2, the AUC was 5.8 microM/h. Intraperitoneal administration (24 mg/m2) achieved an AUC of 387 microM/h, giving a considerable regional advantage. In vitro, the AUC required to achieve the IC50 for CB1954, in NTR-expressing cancer cells, ranges from 10-50 microM/h. Thus, CB1954 is well tolerated at a dose of 24 mg/m2, and sufficient serum/peritoneal levels are achieved for an enzyme-prodrug approach to be feasible. We are now conducting a Phase I trial combining adenovirus-mediated NTR and i.v. CB1954 (24 mg/m2) in patients with primary and secondary liver tumors.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 11555577</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Abdominal Pain - chemically induced ; Adenoviridae - genetics ; Adult ; Aged ; Anorexia - chemically induced ; Antineoplastic agents ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Aziridines - adverse effects ; Aziridines - pharmacokinetics ; Aziridines - therapeutic use ; Biological and medical sciences ; Chemotherapy ; Diarrhea - chemically induced ; Dose-Response Relationship, Drug ; Fatigue - chemically induced ; Female ; Gastrointestinal Neoplasms - genetics ; Gastrointestinal Neoplasms - metabolism ; Gastrointestinal Neoplasms - therapy ; Genetic Vectors - administration & dosage ; Humans ; Injections, Intraperitoneal ; Injections, Intravenous ; Male ; Medical sciences ; Middle Aged ; Nausea - chemically induced ; Nitroreductases - genetics ; Pharmacology. Drug treatments ; Prodrugs - adverse effects ; Prodrugs - pharmacokinetics ; Prodrugs - therapeutic use ; Treatment Outcome ; Vomiting - chemically induced</subject><ispartof>Clinical cancer research, 2001-09, Vol.7 (9), p.2662-2668</ispartof><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1138214$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11555577$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CHUNG-FAYE, Guy</creatorcontrib><creatorcontrib>PALMER, Daniel</creatorcontrib><creatorcontrib>HARRIS, Peter A</creatorcontrib><creatorcontrib>FERRY, David</creatorcontrib><creatorcontrib>KERR, David J</creatorcontrib><creatorcontrib>ANDERSON, David</creatorcontrib><creatorcontrib>CLARK, Joanna</creatorcontrib><creatorcontrib>DOWNES, Mandy</creatorcontrib><creatorcontrib>BADDELEY, Joanna</creatorcontrib><creatorcontrib>HUSSAIN, Syed</creatorcontrib><creatorcontrib>MURRAY, Philip I</creatorcontrib><creatorcontrib>SEARLE, Peter</creatorcontrib><creatorcontrib>SEYMOUR, Leonard</creatorcontrib><title>Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A Phase I and pharmacokinetic study of its prodrug, CB1954</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] is converted by the bacterial enzyme nitroimidazole reductase (NTR) into a potent cytotoxic bifunctional alkylating agent, which can be delivered to tumors in adenoviral vectors as virus-directed, enzyme prodrug therapy. This report summarizes a Phase I and pharmacokinetic study of the prodrug, CB1954. Thirty patients, ages 23-78 years (median 62 years), with predominantly gastrointestinal malignancies were treated. CB1954 was administered by i.v. injection every 3 weeks or i.p. followed by 3-weekly i.v. injections, toward a maximum of six cycles. The dose was escalated from 3 to 37.5 mg/m2. No significant toxicity was seen until 24 mg/m2 (recommended i.v. dose). Dose-limiting toxicities (DLT) were diarrhea and hepatic toxicity, seen at 37.5 mg/m2. DLT has not been observed at the current i.p. dose of 24 mg/m2. There was no alopecia, marrow suppression, or nephrotoxicity. Clearance data suggest hepatic metabolism, and <5% of CB1954 was renally excreted. There was a nonlinear relationship between i.v. dose and area under the curve (AUC). At the recommended i.v. dose of 24 mg/m2, the AUC was 5.8 microM/h. Intraperitoneal administration (24 mg/m2) achieved an AUC of 387 microM/h, giving a considerable regional advantage. In vitro, the AUC required to achieve the IC50 for CB1954, in NTR-expressing cancer cells, ranges from 10-50 microM/h. Thus, CB1954 is well tolerated at a dose of 24 mg/m2, and sufficient serum/peritoneal levels are achieved for an enzyme-prodrug approach to be feasible. We are now conducting a Phase I trial combining adenovirus-mediated NTR and i.v. CB1954 (24 mg/m2) in patients with primary and secondary liver tumors.</description><subject>Abdominal Pain - chemically induced</subject><subject>Adenoviridae - genetics</subject><subject>Adult</subject><subject>Aged</subject><subject>Anorexia - chemically induced</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Aziridines - adverse effects</subject><subject>Aziridines - pharmacokinetics</subject><subject>Aziridines - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Chemotherapy</subject><subject>Diarrhea - chemically induced</subject><subject>Dose-Response Relationship, Drug</subject><subject>Fatigue - chemically induced</subject><subject>Female</subject><subject>Gastrointestinal Neoplasms - genetics</subject><subject>Gastrointestinal Neoplasms - metabolism</subject><subject>Gastrointestinal Neoplasms - therapy</subject><subject>Genetic Vectors - administration & dosage</subject><subject>Humans</subject><subject>Injections, Intraperitoneal</subject><subject>Injections, Intravenous</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Nausea - chemically induced</subject><subject>Nitroreductases - genetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrugs - adverse effects</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Prodrugs - therapeutic use</subject><subject>Treatment Outcome</subject><subject>Vomiting - chemically induced</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpN0MtKw0AYBeAgiq3VV5B_4bKBuSUzcVeLl0JBF-q2zC1mNDdmJki68tEN2IKrcxYfZ3FOkjnOMp5SkmenU0dcpIhRMksuQvhECDOM2Hkyw5OaHJ8nP-_ODyE1zlsdrVmCbfdjY6H3nfHDB8TKetmP8O1iBa2LvnONM3Lf1Ra8NYOOMthbWMFLNRXYgGwN9JX0jdTdl2ttdBpCHMwIXQkuhuPyEtZ3uMjYZXJWyjrYq0MukreH-9f1U7p9ftysV9u0JzSPKZdE56JQAhGKGBZYC2YoowqXhuSFIoYww1WGS6ELrASnBVIcYZ4ZzaxidJFc_-32g2qs2fXeNdKPu-MVE7g5ABm0rEsvW-3CP0cFwYz-Ant0aKA</recordid><startdate>20010901</startdate><enddate>20010901</enddate><creator>CHUNG-FAYE, Guy</creator><creator>PALMER, Daniel</creator><creator>HARRIS, Peter A</creator><creator>FERRY, David</creator><creator>KERR, David J</creator><creator>ANDERSON, David</creator><creator>CLARK, Joanna</creator><creator>DOWNES, Mandy</creator><creator>BADDELEY, Joanna</creator><creator>HUSSAIN, Syed</creator><creator>MURRAY, Philip I</creator><creator>SEARLE, Peter</creator><creator>SEYMOUR, Leonard</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>20010901</creationdate><title>Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A Phase I and pharmacokinetic study of its prodrug, CB1954</title><author>CHUNG-FAYE, Guy ; PALMER, Daniel ; HARRIS, Peter A ; FERRY, David ; KERR, David J ; ANDERSON, David ; CLARK, Joanna ; DOWNES, Mandy ; BADDELEY, Joanna ; HUSSAIN, Syed ; MURRAY, Philip I ; SEARLE, Peter ; SEYMOUR, Leonard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p236t-7a2c689b802304181c84d343b1fd269b2d24d7b51f8c91b87390b70175dc4eb43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Abdominal Pain - chemically induced</topic><topic>Adenoviridae - genetics</topic><topic>Adult</topic><topic>Aged</topic><topic>Anorexia - chemically induced</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Aziridines - adverse effects</topic><topic>Aziridines - pharmacokinetics</topic><topic>Aziridines - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Chemotherapy</topic><topic>Diarrhea - chemically induced</topic><topic>Dose-Response Relationship, Drug</topic><topic>Fatigue - chemically induced</topic><topic>Female</topic><topic>Gastrointestinal Neoplasms - genetics</topic><topic>Gastrointestinal Neoplasms - metabolism</topic><topic>Gastrointestinal Neoplasms - therapy</topic><topic>Genetic Vectors - administration & dosage</topic><topic>Humans</topic><topic>Injections, Intraperitoneal</topic><topic>Injections, Intravenous</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Nausea - chemically induced</topic><topic>Nitroreductases - genetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrugs - adverse effects</topic><topic>Prodrugs - pharmacokinetics</topic><topic>Prodrugs - therapeutic use</topic><topic>Treatment Outcome</topic><topic>Vomiting - chemically induced</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CHUNG-FAYE, Guy</creatorcontrib><creatorcontrib>PALMER, Daniel</creatorcontrib><creatorcontrib>HARRIS, Peter A</creatorcontrib><creatorcontrib>FERRY, David</creatorcontrib><creatorcontrib>KERR, David J</creatorcontrib><creatorcontrib>ANDERSON, David</creatorcontrib><creatorcontrib>CLARK, Joanna</creatorcontrib><creatorcontrib>DOWNES, Mandy</creatorcontrib><creatorcontrib>BADDELEY, Joanna</creatorcontrib><creatorcontrib>HUSSAIN, Syed</creatorcontrib><creatorcontrib>MURRAY, Philip I</creatorcontrib><creatorcontrib>SEARLE, Peter</creatorcontrib><creatorcontrib>SEYMOUR, Leonard</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>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CHUNG-FAYE, Guy</au><au>PALMER, Daniel</au><au>HARRIS, Peter A</au><au>FERRY, David</au><au>KERR, David J</au><au>ANDERSON, David</au><au>CLARK, Joanna</au><au>DOWNES, Mandy</au><au>BADDELEY, Joanna</au><au>HUSSAIN, Syed</au><au>MURRAY, Philip I</au><au>SEARLE, Peter</au><au>SEYMOUR, Leonard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A Phase I and pharmacokinetic study of its prodrug, CB1954</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2001-09-01</date><risdate>2001</risdate><volume>7</volume><issue>9</issue><spage>2662</spage><epage>2668</epage><pages>2662-2668</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] is converted by the bacterial enzyme nitroimidazole reductase (NTR) into a potent cytotoxic bifunctional alkylating agent, which can be delivered to tumors in adenoviral vectors as virus-directed, enzyme prodrug therapy. This report summarizes a Phase I and pharmacokinetic study of the prodrug, CB1954. Thirty patients, ages 23-78 years (median 62 years), with predominantly gastrointestinal malignancies were treated. CB1954 was administered by i.v. injection every 3 weeks or i.p. followed by 3-weekly i.v. injections, toward a maximum of six cycles. The dose was escalated from 3 to 37.5 mg/m2. No significant toxicity was seen until 24 mg/m2 (recommended i.v. dose). Dose-limiting toxicities (DLT) were diarrhea and hepatic toxicity, seen at 37.5 mg/m2. DLT has not been observed at the current i.p. dose of 24 mg/m2. There was no alopecia, marrow suppression, or nephrotoxicity. Clearance data suggest hepatic metabolism, and <5% of CB1954 was renally excreted. There was a nonlinear relationship between i.v. dose and area under the curve (AUC). At the recommended i.v. dose of 24 mg/m2, the AUC was 5.8 microM/h. Intraperitoneal administration (24 mg/m2) achieved an AUC of 387 microM/h, giving a considerable regional advantage. In vitro, the AUC required to achieve the IC50 for CB1954, in NTR-expressing cancer cells, ranges from 10-50 microM/h. Thus, CB1954 is well tolerated at a dose of 24 mg/m2, and sufficient serum/peritoneal levels are achieved for an enzyme-prodrug approach to be feasible. We are now conducting a Phase I trial combining adenovirus-mediated NTR and i.v. CB1954 (24 mg/m2) in patients with primary and secondary liver tumors.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>11555577</pmid><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2001-09, Vol.7 (9), p.2662-2668 |
| issn | 1078-0432 1557-3265 |
| language | eng |
| recordid | cdi_pubmed_primary_11555577 |
| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Abdominal Pain - chemically induced Adenoviridae - genetics Adult Aged Anorexia - chemically induced Antineoplastic agents Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Aziridines - adverse effects Aziridines - pharmacokinetics Aziridines - therapeutic use Biological and medical sciences Chemotherapy Diarrhea - chemically induced Dose-Response Relationship, Drug Fatigue - chemically induced Female Gastrointestinal Neoplasms - genetics Gastrointestinal Neoplasms - metabolism Gastrointestinal Neoplasms - therapy Genetic Vectors - administration & dosage Humans Injections, Intraperitoneal Injections, Intravenous Male Medical sciences Middle Aged Nausea - chemically induced Nitroreductases - genetics Pharmacology. Drug treatments Prodrugs - adverse effects Prodrugs - pharmacokinetics Prodrugs - therapeutic use Treatment Outcome Vomiting - chemically induced |
| title | Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A Phase I and pharmacokinetic study of its prodrug, CB1954 |
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