Isophosphoramide mustard analogues as prodrugs for anticancer gene-directed enzyme-prodrug therapy (GDEPT)
Two types of prodrugs, benzyl analogues of isophosphoramide mustard (iPAM), activated by cytochrome P450, and acylthioethyl analogues, activated by esterases, were designed. In contrast to iPAM that hydrolyse rapidly, the examined compounds are stable in phosphate-buffered saline and Tris buffer. Be...
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| Veröffentlicht in: | Acta biochimica polonica 2002, Vol.49 (1), p.169-176 |
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| container_title | Acta biochimica polonica |
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| creator | Misiura, Konrad Szymanowicz, Daria Kuśnierczyk, Halina Wietrzyk, Joanna Opolski, Adam |
| description | Two types of prodrugs, benzyl analogues of isophosphoramide mustard (iPAM), activated by cytochrome P450, and acylthioethyl analogues, activated by esterases, were designed. In contrast to iPAM that hydrolyse rapidly, the examined compounds are stable in phosphate-buffered saline and Tris buffer. Benzyl analogues of iPAM are poor substrates for cytochrome P450, are not cytotoxic and posses no antitumour activity. Acylthioethyl analogues of iPAM are good substrates for pig liver esterase, are cytotoxic and exert antitumour activity against L1210 leukaemia in mice. The observed correlation for iPAM analogues between their susceptibility to hydrolysis and cytotoxicity and antitumour activity suggests possible application of these compounds as the prodrugs in gene-directed enzyme-prodrug therapy. |
| doi_str_mv | 10.18388/abp.2002_3833 |
| format | Article |
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In contrast to iPAM that hydrolyse rapidly, the examined compounds are stable in phosphate-buffered saline and Tris buffer. Benzyl analogues of iPAM are poor substrates for cytochrome P450, are not cytotoxic and posses no antitumour activity. Acylthioethyl analogues of iPAM are good substrates for pig liver esterase, are cytotoxic and exert antitumour activity against L1210 leukaemia in mice. The observed correlation for iPAM analogues between their susceptibility to hydrolysis and cytotoxicity and antitumour activity suggests possible application of these compounds as the prodrugs in gene-directed enzyme-prodrug therapy.</description><identifier>ISSN: 0001-527X</identifier><identifier>EISSN: 1734-154X</identifier><identifier>DOI: 10.18388/abp.2002_3833</identifier><identifier>PMID: 12136937</identifier><language>eng</language><publisher>Poland</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Carcinoma - drug therapy ; Chromatography, High Pressure Liquid ; Cytochrome P-450 Enzyme System - metabolism ; Drug Stability ; Esterases ; Esters ; Humans ; Ifosfamide ; Leukemia - drug therapy ; Mice ; Mouth Neoplasms - drug therapy ; Nucleotides ; Phosphoramide Mustards - chemistry ; Prodrugs - pharmacology ; Tumor Cells, Cultured</subject><ispartof>Acta biochimica polonica, 2002, Vol.49 (1), p.169-176</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1387-4298206f52fcd82e61a0dba2c7b9502894711938d50d9b234a305d9ac6881b63</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4010,27900,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12136937$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Misiura, Konrad</creatorcontrib><creatorcontrib>Szymanowicz, Daria</creatorcontrib><creatorcontrib>Kuśnierczyk, Halina</creatorcontrib><creatorcontrib>Wietrzyk, Joanna</creatorcontrib><creatorcontrib>Opolski, Adam</creatorcontrib><title>Isophosphoramide mustard analogues as prodrugs for anticancer gene-directed enzyme-prodrug therapy (GDEPT)</title><title>Acta biochimica polonica</title><addtitle>Acta Biochim Pol</addtitle><description>Two types of prodrugs, benzyl analogues of isophosphoramide mustard (iPAM), activated by cytochrome P450, and acylthioethyl analogues, activated by esterases, were designed. 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The observed correlation for iPAM analogues between their susceptibility to hydrolysis and cytotoxicity and antitumour activity suggests possible application of these compounds as the prodrugs in gene-directed enzyme-prodrug therapy.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Carcinoma - drug therapy</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Drug Stability</subject><subject>Esterases</subject><subject>Esters</subject><subject>Humans</subject><subject>Ifosfamide</subject><subject>Leukemia - drug therapy</subject><subject>Mice</subject><subject>Mouth Neoplasms - drug therapy</subject><subject>Nucleotides</subject><subject>Phosphoramide Mustards - chemistry</subject><subject>Prodrugs - pharmacology</subject><subject>Tumor Cells, Cultured</subject><issn>0001-527X</issn><issn>1734-154X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkD1PwzAQhi0EoqWwMiJPCIYUfySxM6JSoFIlGDp0sxz70qbKF3YylF-PRSMYTjfcc69ePQjdUjKnkkv5pPNuzghhikvOz9CUCh5HNIm352hKCKFRwsR2gq68PwSK0yy-RBPKKE8zLqbosPJtt299GKfr0gKuB99rZ7FudNXuBvBYe9y51rph53HRunDpS6MbAw7voIHIlg5MDxZD832sIRph3O_B6e6IH95elp-bx2t0UejKw824Z2jzutws3qP1x9tq8byODOVSRDHLJCNpkbDCWMkgpZrYXDMj8iwhTGaxoDTj0ibEZjnjseYksZk2qZQ0T_kM3Z9iQ42vUL9XdekNVJVuoB28EkEBTwUP4PwEGtd676BQnStr7Y6KEvUrVwW56k9ueLgbk4e8BvuPjzb5D3ZQdjw</recordid><startdate>2002</startdate><enddate>2002</enddate><creator>Misiura, Konrad</creator><creator>Szymanowicz, Daria</creator><creator>Kuśnierczyk, Halina</creator><creator>Wietrzyk, Joanna</creator><creator>Opolski, Adam</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>2002</creationdate><title>Isophosphoramide mustard analogues as prodrugs for anticancer gene-directed enzyme-prodrug therapy (GDEPT)</title><author>Misiura, Konrad ; Szymanowicz, Daria ; Kuśnierczyk, Halina ; Wietrzyk, Joanna ; Opolski, Adam</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1387-4298206f52fcd82e61a0dba2c7b9502894711938d50d9b234a305d9ac6881b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Carcinoma - drug therapy</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Drug Stability</topic><topic>Esterases</topic><topic>Esters</topic><topic>Humans</topic><topic>Ifosfamide</topic><topic>Leukemia - drug therapy</topic><topic>Mice</topic><topic>Mouth Neoplasms - drug therapy</topic><topic>Nucleotides</topic><topic>Phosphoramide Mustards - chemistry</topic><topic>Prodrugs - pharmacology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Misiura, Konrad</creatorcontrib><creatorcontrib>Szymanowicz, Daria</creatorcontrib><creatorcontrib>Kuśnierczyk, Halina</creatorcontrib><creatorcontrib>Wietrzyk, Joanna</creatorcontrib><creatorcontrib>Opolski, Adam</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Acta biochimica polonica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Misiura, Konrad</au><au>Szymanowicz, Daria</au><au>Kuśnierczyk, Halina</au><au>Wietrzyk, Joanna</au><au>Opolski, Adam</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Isophosphoramide mustard analogues as prodrugs for anticancer gene-directed enzyme-prodrug therapy (GDEPT)</atitle><jtitle>Acta biochimica polonica</jtitle><addtitle>Acta Biochim Pol</addtitle><date>2002</date><risdate>2002</risdate><volume>49</volume><issue>1</issue><spage>169</spage><epage>176</epage><pages>169-176</pages><issn>0001-527X</issn><eissn>1734-154X</eissn><abstract>Two types of prodrugs, benzyl analogues of isophosphoramide mustard (iPAM), activated by cytochrome P450, and acylthioethyl analogues, activated by esterases, were designed. 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| subjects | Animals Antineoplastic Agents - pharmacology Carcinoma - drug therapy Chromatography, High Pressure Liquid Cytochrome P-450 Enzyme System - metabolism Drug Stability Esterases Esters Humans Ifosfamide Leukemia - drug therapy Mice Mouth Neoplasms - drug therapy Nucleotides Phosphoramide Mustards - chemistry Prodrugs - pharmacology Tumor Cells, Cultured |
| title | Isophosphoramide mustard analogues as prodrugs for anticancer gene-directed enzyme-prodrug therapy (GDEPT) |
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