A Phase I Study of Pivaloyloxymethyl Butyrate, a Prodrug of the Differentiating Agent Butyric Acid, in Patients with Advanced Solid Malignancies
Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological, pharmacological, and pharmaceutical properties tha...
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Veröffentlicht in: | Clinical cancer research 2002-07, Vol.8 (7), p.2142-2148 |
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creator | PATNAIK, Amita ROWINSKY, Eric K ECKHARDT, S. Gail VILLALONA, Miguel A HAMMOND, Lisa A BRITTEN, Carolyn D SIU, Lillian L GOETZ, Andrew FELTON, Sally A BURTON, Susan VALONE, Frank H |
description | Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than
BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological,
pharmacological, and pharmaceutical properties than BA in preclinical studies. The principal objective of this study was to
determine the feasibility of administering AN-9 as a 6-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced
solid malignancies. The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this
intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation.
None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m 2 /day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation,
hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation
of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely
on this schedule, resulting in a maximum deliverable dose of 3.3 g/m 2 /day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously
untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are
necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent. |
format | Article |
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BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological,
pharmacological, and pharmaceutical properties than BA in preclinical studies. The principal objective of this study was to
determine the feasibility of administering AN-9 as a 6-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced
solid malignancies. The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this
intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation.
None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m 2 /day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation,
hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation
of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely
on this schedule, resulting in a maximum deliverable dose of 3.3 g/m 2 /day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously
untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are
necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 12114414</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adult ; Aged ; Antineoplastic agents ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - therapeutic use ; Biological and medical sciences ; Butyrates - administration & dosage ; Butyrates - therapeutic use ; Cell Differentiation ; Chemotherapy ; Drug Administration Schedule ; Female ; Humans ; Male ; Maximum Tolerated Dose ; Medical sciences ; Middle Aged ; Neoplasms - drug therapy ; Neoplasms - metabolism ; Pharmacology. Drug treatments ; Prodrugs - adverse effects ; Prodrugs - therapeutic use ; Safety</subject><ispartof>Clinical cancer research, 2002-07, Vol.8 (7), p.2142-2148</ispartof><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13777549$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12114414$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>PATNAIK, Amita</creatorcontrib><creatorcontrib>ROWINSKY, Eric K</creatorcontrib><creatorcontrib>ECKHARDT, S. Gail</creatorcontrib><creatorcontrib>VILLALONA, Miguel A</creatorcontrib><creatorcontrib>HAMMOND, Lisa A</creatorcontrib><creatorcontrib>BRITTEN, Carolyn D</creatorcontrib><creatorcontrib>SIU, Lillian L</creatorcontrib><creatorcontrib>GOETZ, Andrew</creatorcontrib><creatorcontrib>FELTON, Sally A</creatorcontrib><creatorcontrib>BURTON, Susan</creatorcontrib><creatorcontrib>VALONE, Frank H</creatorcontrib><title>A Phase I Study of Pivaloyloxymethyl Butyrate, a Prodrug of the Differentiating Agent Butyric Acid, in Patients with Advanced Solid Malignancies</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than
BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological,
pharmacological, and pharmaceutical properties than BA in preclinical studies. The principal objective of this study was to
determine the feasibility of administering AN-9 as a 6-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced
solid malignancies. The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this
intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation.
None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m 2 /day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation,
hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation
of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely
on this schedule, resulting in a maximum deliverable dose of 3.3 g/m 2 /day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously
untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are
necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Butyrates - administration & dosage</subject><subject>Butyrates - therapeutic use</subject><subject>Cell Differentiation</subject><subject>Chemotherapy</subject><subject>Drug Administration Schedule</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrugs - adverse effects</subject><subject>Prodrugs - therapeutic use</subject><subject>Safety</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkF1LwzAUhosoTqd_Qc6NeLNCkiZLelm_BxMH0-uSJmkb6dqRZJv9F_5kOzbx6ryc9zmfJ9EFZozHCZmy00EjLmJEEzKKLr3_QghTjOh5NMIEY0oxvYh-MljU0huYwTJsdA9dCQu7lU3XN913vzKh7hu434TeyWAmIGHhOu021R4MtYFHW5bGmTZYGWxbQVYN-lBgFWTK6gnYFhaDOxgedjbUkOmtbJXRsOwaq-FNNrZqh4w1_io6K2XjzfUxjqPP56ePh9d4_v4ye8jmcU2maYipKIROGMMyLRGjqS4YU0ilRYmwYCkTU5PSpJgqlAouGDVpWRDOhUKUGCJZMo5uDn3Xm2JldL52diVdn_-9ZgBuj4D0Sjal2-_n_7mEcz4MHri7A1fbqt5ZZ3K1v8054410qs5FznOCKUl-AQd3fBA</recordid><startdate>20020701</startdate><enddate>20020701</enddate><creator>PATNAIK, Amita</creator><creator>ROWINSKY, Eric K</creator><creator>ECKHARDT, S. Gail</creator><creator>VILLALONA, Miguel A</creator><creator>HAMMOND, Lisa A</creator><creator>BRITTEN, Carolyn D</creator><creator>SIU, Lillian L</creator><creator>GOETZ, Andrew</creator><creator>FELTON, Sally A</creator><creator>BURTON, Susan</creator><creator>VALONE, Frank H</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>20020701</creationdate><title>A Phase I Study of Pivaloyloxymethyl Butyrate, a Prodrug of the Differentiating Agent Butyric Acid, in Patients with Advanced Solid Malignancies</title><author>PATNAIK, Amita ; ROWINSKY, Eric K ; ECKHARDT, S. Gail ; VILLALONA, Miguel A ; HAMMOND, Lisa A ; BRITTEN, Carolyn D ; SIU, Lillian L ; GOETZ, Andrew ; FELTON, Sally A ; BURTON, Susan ; VALONE, Frank H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h269t-48b8d3551a9f0549db55c0c9bf01859586e943b6c0987854e9fb2778c042e2a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Butyrates - administration & dosage</topic><topic>Butyrates - therapeutic use</topic><topic>Cell Differentiation</topic><topic>Chemotherapy</topic><topic>Drug Administration Schedule</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrugs - adverse effects</topic><topic>Prodrugs - therapeutic use</topic><topic>Safety</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PATNAIK, Amita</creatorcontrib><creatorcontrib>ROWINSKY, Eric K</creatorcontrib><creatorcontrib>ECKHARDT, S. Gail</creatorcontrib><creatorcontrib>VILLALONA, Miguel A</creatorcontrib><creatorcontrib>HAMMOND, Lisa A</creatorcontrib><creatorcontrib>BRITTEN, Carolyn D</creatorcontrib><creatorcontrib>SIU, Lillian L</creatorcontrib><creatorcontrib>GOETZ, Andrew</creatorcontrib><creatorcontrib>FELTON, Sally A</creatorcontrib><creatorcontrib>BURTON, Susan</creatorcontrib><creatorcontrib>VALONE, Frank H</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>PATNAIK, Amita</au><au>ROWINSKY, Eric K</au><au>ECKHARDT, S. Gail</au><au>VILLALONA, Miguel A</au><au>HAMMOND, Lisa A</au><au>BRITTEN, Carolyn D</au><au>SIU, Lillian L</au><au>GOETZ, Andrew</au><au>FELTON, Sally A</au><au>BURTON, Susan</au><au>VALONE, Frank H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Phase I Study of Pivaloyloxymethyl Butyrate, a Prodrug of the Differentiating Agent Butyric Acid, in Patients with Advanced Solid Malignancies</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2002-07-01</date><risdate>2002</risdate><volume>8</volume><issue>7</issue><spage>2142</spage><epage>2148</epage><pages>2142-2148</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than
BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological,
pharmacological, and pharmaceutical properties than BA in preclinical studies. The principal objective of this study was to
determine the feasibility of administering AN-9 as a 6-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced
solid malignancies. The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this
intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation.
None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m 2 /day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation,
hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation
of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely
on this schedule, resulting in a maximum deliverable dose of 3.3 g/m 2 /day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously
untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are
necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>12114414</pmid><tpages>7</tpages></addata></record> |
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source | MEDLINE; American Association for Cancer Research; Alma/SFX Local Collection; EZB Electronic Journals Library |
subjects | Adult Aged Antineoplastic agents Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Biological and medical sciences Butyrates - administration & dosage Butyrates - therapeutic use Cell Differentiation Chemotherapy Drug Administration Schedule Female Humans Male Maximum Tolerated Dose Medical sciences Middle Aged Neoplasms - drug therapy Neoplasms - metabolism Pharmacology. Drug treatments Prodrugs - adverse effects Prodrugs - therapeutic use Safety |
title | A Phase I Study of Pivaloyloxymethyl Butyrate, a Prodrug of the Differentiating Agent Butyric Acid, in Patients with Advanced Solid Malignancies |
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