Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N
The bioreductive drug, AQ4N, is metabolized under hypoxic conditions and has been shown to enhance the antitumor effects of radiation and chemotherapy drugs. We have investigated the role of cytochrome P 450 3A4 (CYP3A4) in increasing the metabolism of AQ4N using a gene-directed enzyme prodrug thera...
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| Veröffentlicht in: | Cancer gene therapy 2003-01, Vol.10 (1), p.40-48 |
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| creator | McCarthy, Helen O Yakkundi, Anita McErlane, Verna Hughes, Ciara M Keilty, Gillian Murray, Margaret Patterson, Laurence H Hirst, David G McKeown, Stephanie R Robson, Tracy |
| description | The bioreductive drug, AQ4N, is metabolized under hypoxic conditions and has been shown to enhance the antitumor effects of radiation and chemotherapy drugs. We have investigated the role of cytochrome
P
450 3A4 (CYP3A4) in increasing the metabolism of AQ4N using a gene-directed enzyme prodrug therapy (GDEPT) strategy. RIF-1 murine tumor cells were transfected with a mammalian expression vector containing
CYP3A4
cDNA.
In vitro
AQ4N metabolism, DNA damage, and clonogenic cell kill were assessed following exposure of transfected and parental control cells to AQ4N. The presence of exogenous CYP3A4 increased the metabolism of AQ4N and significantly enhanced the ability of the drug to cause DNA strand breaks and clonogenic cell death. Cotransfection of
CYP reductase
with
CYP3A4
showed a small enhancement of the effect in the DNA damage assay only. A single injection of
CYP3A4
into established RIF-1 murine tumors increased the metabolism of AQ4N, and when used in combination with radiation, three of nine tumors were locally controlled for >60 days. This is the first demonstration that CYPs alone can be used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N. AQ4N is the only CYP-activated bioreductive agent in clinical trials. Combination with a GDEPT strategy may offer a further opportunity for targeting radiation-resistant and chemo-resistant hypoxic tumor cells. |
| doi_str_mv | 10.1038/sj.cgt.7700522 |
| format | Article |
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P
450 3A4 (CYP3A4) in increasing the metabolism of AQ4N using a gene-directed enzyme prodrug therapy (GDEPT) strategy. RIF-1 murine tumor cells were transfected with a mammalian expression vector containing
CYP3A4
cDNA.
In vitro
AQ4N metabolism, DNA damage, and clonogenic cell kill were assessed following exposure of transfected and parental control cells to AQ4N. The presence of exogenous CYP3A4 increased the metabolism of AQ4N and significantly enhanced the ability of the drug to cause DNA strand breaks and clonogenic cell death. Cotransfection of
CYP reductase
with
CYP3A4
showed a small enhancement of the effect in the DNA damage assay only. A single injection of
CYP3A4
into established RIF-1 murine tumors increased the metabolism of AQ4N, and when used in combination with radiation, three of nine tumors were locally controlled for >60 days. This is the first demonstration that CYPs alone can be used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N. AQ4N is the only CYP-activated bioreductive agent in clinical trials. Combination with a GDEPT strategy may offer a further opportunity for targeting radiation-resistant and chemo-resistant hypoxic tumor cells.</description><identifier>ISSN: 0929-1903</identifier><identifier>EISSN: 1476-5500</identifier><identifier>DOI: 10.1038/sj.cgt.7700522</identifier><identifier>PMID: 12489027</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Animals ; Anthraquinones - metabolism ; Anthraquinones - pharmacology ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Biomedical and Life Sciences ; Biomedicine ; Biotransformation ; Blotting, Western ; Cancer ; Care and treatment ; Cell Hypoxia ; Combined Modality Therapy ; Comet Assay ; Cytochrome P-450 ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System - genetics ; DNA Damage - drug effects ; DNA Damage - radiation effects ; DNA, Neoplasm - drug effects ; Dosage and administration ; Drug therapy, Combination ; Fibrosarcoma - enzymology ; Fibrosarcoma - therapy ; Gene Expression ; Gene Therapy ; Genetic Therapy - methods ; Health aspects ; Humans ; Methods ; Mice ; Mice, Inbred C3H ; NADPH-Ferrihemoprotein Reductase - genetics ; original-article ; Prodrugs ; Prodrugs - metabolism ; Prodrugs - pharmacology ; Radiation Dosage ; Transfection ; Tumor Stem Cell Assay</subject><ispartof>Cancer gene therapy, 2003-01, Vol.10 (1), p.40-48</ispartof><rights>Springer Nature America, Inc. 2003</rights><rights>COPYRIGHT 2003 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 2003</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-3e1d6e1d20e02fdb34baa856fbce23d085a9cada19611149f7215f6c583bc7fd3</citedby><cites>FETCH-LOGICAL-c487t-3e1d6e1d20e02fdb34baa856fbce23d085a9cada19611149f7215f6c583bc7fd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.cgt.7700522$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.cgt.7700522$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12489027$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McCarthy, Helen O</creatorcontrib><creatorcontrib>Yakkundi, Anita</creatorcontrib><creatorcontrib>McErlane, Verna</creatorcontrib><creatorcontrib>Hughes, Ciara M</creatorcontrib><creatorcontrib>Keilty, Gillian</creatorcontrib><creatorcontrib>Murray, Margaret</creatorcontrib><creatorcontrib>Patterson, Laurence H</creatorcontrib><creatorcontrib>Hirst, David G</creatorcontrib><creatorcontrib>McKeown, Stephanie R</creatorcontrib><creatorcontrib>Robson, Tracy</creatorcontrib><title>Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N</title><title>Cancer gene therapy</title><addtitle>Cancer Gene Ther</addtitle><addtitle>Cancer Gene Ther</addtitle><description>The bioreductive drug, AQ4N, is metabolized under hypoxic conditions and has been shown to enhance the antitumor effects of radiation and chemotherapy drugs. We have investigated the role of cytochrome
P
450 3A4 (CYP3A4) in increasing the metabolism of AQ4N using a gene-directed enzyme prodrug therapy (GDEPT) strategy. RIF-1 murine tumor cells were transfected with a mammalian expression vector containing
CYP3A4
cDNA.
In vitro
AQ4N metabolism, DNA damage, and clonogenic cell kill were assessed following exposure of transfected and parental control cells to AQ4N. The presence of exogenous CYP3A4 increased the metabolism of AQ4N and significantly enhanced the ability of the drug to cause DNA strand breaks and clonogenic cell death. Cotransfection of
CYP reductase
with
CYP3A4
showed a small enhancement of the effect in the DNA damage assay only. A single injection of
CYP3A4
into established RIF-1 murine tumors increased the metabolism of AQ4N, and when used in combination with radiation, three of nine tumors were locally controlled for >60 days. This is the first demonstration that CYPs alone can be used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N. AQ4N is the only CYP-activated bioreductive agent in clinical trials. Combination with a GDEPT strategy may offer a further opportunity for targeting radiation-resistant and chemo-resistant hypoxic tumor cells.</description><subject>Animals</subject><subject>Anthraquinones - metabolism</subject><subject>Anthraquinones - pharmacology</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Biotransformation</subject><subject>Blotting, Western</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Cell Hypoxia</subject><subject>Combined Modality Therapy</subject><subject>Comet Assay</subject><subject>Cytochrome P-450</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>DNA Damage - drug effects</subject><subject>DNA Damage - radiation effects</subject><subject>DNA, Neoplasm - drug effects</subject><subject>Dosage and administration</subject><subject>Drug therapy, Combination</subject><subject>Fibrosarcoma - enzymology</subject><subject>Fibrosarcoma - therapy</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Genetic Therapy - methods</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Methods</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>NADPH-Ferrihemoprotein Reductase - genetics</subject><subject>original-article</subject><subject>Prodrugs</subject><subject>Prodrugs - metabolism</subject><subject>Prodrugs - pharmacology</subject><subject>Radiation Dosage</subject><subject>Transfection</subject><subject>Tumor Stem Cell Assay</subject><issn>0929-1903</issn><issn>1476-5500</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kd1rFDEUxYModlt99VGCQt9mm89J8rjWbRWKVqjPIZNJdrPMTGqSUfrfm2UXqlIJl0Du7xxy7wHgDUZLjKi8yLul3ZSlEAhxQp6BBWaibThH6DlYIEVUgxWiJ-A05x1CtSnoS3CCCZMKEbEA6w8hJtfPtoSfDl5_XN_ewTmHaQPtQ4l2m-Lo4C3jCNIVg2GCNo5dmEwJcYK_QtnC1Tf25RV44c2Q3evjfQa-X63vLj81N1-vP1-ubhrLpCgNdbhvaxHkEPF9R1lnjOSt76wjtEeSG2VNb7BqMcZMeUEw963lknZW-J6egfOD732KP2aXix5Dtm4YzOTinDWWLeetlBV89w-4i3Oa6t80wYJJhjCu0PsDtDGD02HysSRj9456hSURrVBYVWr5BFVP78Zg4-R8qO9_Cc7_EGydGco2x2Heryw_6WxTzDk5r-9TGE160Bjpfbo673RNVx_TrYK3x6nmbnT9I36MswIXByDX1rRx6XHs_1j-BuAyq-s</recordid><startdate>20030101</startdate><enddate>20030101</enddate><creator>McCarthy, Helen O</creator><creator>Yakkundi, Anita</creator><creator>McErlane, Verna</creator><creator>Hughes, Ciara M</creator><creator>Keilty, Gillian</creator><creator>Murray, Margaret</creator><creator>Patterson, Laurence H</creator><creator>Hirst, David G</creator><creator>McKeown, Stephanie R</creator><creator>Robson, Tracy</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><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>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7QO</scope></search><sort><creationdate>20030101</creationdate><title>Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N</title><author>McCarthy, Helen O ; Yakkundi, Anita ; McErlane, Verna ; Hughes, Ciara M ; Keilty, Gillian ; Murray, Margaret ; Patterson, Laurence H ; Hirst, David G ; McKeown, Stephanie R ; Robson, Tracy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c487t-3e1d6e1d20e02fdb34baa856fbce23d085a9cada19611149f7215f6c583bc7fd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Anthraquinones - metabolism</topic><topic>Anthraquinones - pharmacology</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Biotransformation</topic><topic>Blotting, Western</topic><topic>Cancer</topic><topic>Care and treatment</topic><topic>Cell Hypoxia</topic><topic>Combined Modality Therapy</topic><topic>Comet Assay</topic><topic>Cytochrome P-450</topic><topic>Cytochrome P-450 CYP3A</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>DNA Damage - drug effects</topic><topic>DNA Damage - radiation effects</topic><topic>DNA, Neoplasm - drug effects</topic><topic>Dosage and administration</topic><topic>Drug therapy, Combination</topic><topic>Fibrosarcoma - enzymology</topic><topic>Fibrosarcoma - therapy</topic><topic>Gene Expression</topic><topic>Gene Therapy</topic><topic>Genetic Therapy - methods</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Methods</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>NADPH-Ferrihemoprotein Reductase - genetics</topic><topic>original-article</topic><topic>Prodrugs</topic><topic>Prodrugs - metabolism</topic><topic>Prodrugs - pharmacology</topic><topic>Radiation Dosage</topic><topic>Transfection</topic><topic>Tumor Stem Cell Assay</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McCarthy, Helen O</creatorcontrib><creatorcontrib>Yakkundi, Anita</creatorcontrib><creatorcontrib>McErlane, Verna</creatorcontrib><creatorcontrib>Hughes, Ciara M</creatorcontrib><creatorcontrib>Keilty, Gillian</creatorcontrib><creatorcontrib>Murray, Margaret</creatorcontrib><creatorcontrib>Patterson, Laurence H</creatorcontrib><creatorcontrib>Hirst, David G</creatorcontrib><creatorcontrib>McKeown, Stephanie R</creatorcontrib><creatorcontrib>Robson, Tracy</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>Biotechnology Research Abstracts</collection><jtitle>Cancer gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McCarthy, Helen O</au><au>Yakkundi, Anita</au><au>McErlane, Verna</au><au>Hughes, Ciara M</au><au>Keilty, Gillian</au><au>Murray, Margaret</au><au>Patterson, Laurence H</au><au>Hirst, David G</au><au>McKeown, Stephanie R</au><au>Robson, Tracy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N</atitle><jtitle>Cancer gene therapy</jtitle><stitle>Cancer Gene Ther</stitle><addtitle>Cancer Gene Ther</addtitle><date>2003-01-01</date><risdate>2003</risdate><volume>10</volume><issue>1</issue><spage>40</spage><epage>48</epage><pages>40-48</pages><issn>0929-1903</issn><eissn>1476-5500</eissn><abstract>The bioreductive drug, AQ4N, is metabolized under hypoxic conditions and has been shown to enhance the antitumor effects of radiation and chemotherapy drugs. We have investigated the role of cytochrome
P
450 3A4 (CYP3A4) in increasing the metabolism of AQ4N using a gene-directed enzyme prodrug therapy (GDEPT) strategy. RIF-1 murine tumor cells were transfected with a mammalian expression vector containing
CYP3A4
cDNA.
In vitro
AQ4N metabolism, DNA damage, and clonogenic cell kill were assessed following exposure of transfected and parental control cells to AQ4N. The presence of exogenous CYP3A4 increased the metabolism of AQ4N and significantly enhanced the ability of the drug to cause DNA strand breaks and clonogenic cell death. Cotransfection of
CYP reductase
with
CYP3A4
showed a small enhancement of the effect in the DNA damage assay only. A single injection of
CYP3A4
into established RIF-1 murine tumors increased the metabolism of AQ4N, and when used in combination with radiation, three of nine tumors were locally controlled for >60 days. This is the first demonstration that CYPs alone can be used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N. AQ4N is the only CYP-activated bioreductive agent in clinical trials. Combination with a GDEPT strategy may offer a further opportunity for targeting radiation-resistant and chemo-resistant hypoxic tumor cells.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>12489027</pmid><doi>10.1038/sj.cgt.7700522</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0929-1903 |
| ispartof | Cancer gene therapy, 2003-01, Vol.10 (1), p.40-48 |
| issn | 0929-1903 1476-5500 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_18655688 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SpringerLink Journals - AutoHoldings |
| subjects | Animals Anthraquinones - metabolism Anthraquinones - pharmacology Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Biomedical and Life Sciences Biomedicine Biotransformation Blotting, Western Cancer Care and treatment Cell Hypoxia Combined Modality Therapy Comet Assay Cytochrome P-450 Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System - genetics DNA Damage - drug effects DNA Damage - radiation effects DNA, Neoplasm - drug effects Dosage and administration Drug therapy, Combination Fibrosarcoma - enzymology Fibrosarcoma - therapy Gene Expression Gene Therapy Genetic Therapy - methods Health aspects Humans Methods Mice Mice, Inbred C3H NADPH-Ferrihemoprotein Reductase - genetics original-article Prodrugs Prodrugs - metabolism Prodrugs - pharmacology Radiation Dosage Transfection Tumor Stem Cell Assay |
| title | Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N |
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