Cytochrome P450s in the development of target-based anticancer drugs
Abstract Enzymes of the cytochrome P450 (CYP) superfamily are the major determinants of half-life and execute pharmacological effects of many therapeutic drugs. In new drug discovery research, recombinant (human) CYPs are also used for identifying active or inactive metabolites that could lead to in...
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Veröffentlicht in: | Cancer letters 2008-01, Vol.259 (1), p.1-15 |
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description | Abstract Enzymes of the cytochrome P450 (CYP) superfamily are the major determinants of half-life and execute pharmacological effects of many therapeutic drugs. In new drug discovery research, recombinant (human) CYPs are also used for identifying active or inactive metabolites that could lead to increased potency or toxicity of a molecule. In addition, CYP inhibition by anticancer drugs might lead to adverse drug reactions, multiple-drug resistance, and drug–drug interactions. During the discovery and pre-clinical evaluation of a New Chemical Entity (NCE), large amounts of purified recombinant CYPs are required for studying metabolism and pharmacokinetic parameters. Therefore, present research efforts are focused to over-express these human CYPs in bacteria, yeast, insect and mammalian cells, followed by their purification on an industrial scale to facilitate identification of novel anticancer drugs. This review summarizes the merits and limitations of these expression systems for an optimized production of individual CYP isoforms, and their usefulness in the discovery and development of target-based, safe and efficacious NCEs for the treatment of cancer. |
doi_str_mv | 10.1016/j.canlet.2007.10.024 |
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In new drug discovery research, recombinant (human) CYPs are also used for identifying active or inactive metabolites that could lead to increased potency or toxicity of a molecule. In addition, CYP inhibition by anticancer drugs might lead to adverse drug reactions, multiple-drug resistance, and drug–drug interactions. During the discovery and pre-clinical evaluation of a New Chemical Entity (NCE), large amounts of purified recombinant CYPs are required for studying metabolism and pharmacokinetic parameters. Therefore, present research efforts are focused to over-express these human CYPs in bacteria, yeast, insect and mammalian cells, followed by their purification on an industrial scale to facilitate identification of novel anticancer drugs. This review summarizes the merits and limitations of these expression systems for an optimized production of individual CYP isoforms, and their usefulness in the discovery and development of target-based, safe and efficacious NCEs for the treatment of cancer.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2007.10.024</identifier><identifier>PMID: 18053638</identifier><language>eng</language><publisher>Ireland: Elsevier Ireland Ltd</publisher><subject>Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Biotransformation ; Cancer ; Cloning, Molecular ; CYP ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P-450 Enzyme System - metabolism ; Drug Design ; Drug discovery ; Drug Evaluation, Preclinical ; Drug Interactions ; Drug Resistance, Neoplasm ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Expression ; Genes ; Hematology, Oncology and Palliative Medicine ; Humans ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - metabolism ; Pharmaceutical industry ; Pharmacogenetics ; Pharmacokinetics ; Recombinant P450 ; Recombinant Proteins - antagonists & inhibitors ; Recombinant Proteins - metabolism ; Reproducibility of Results ; Rodents</subject><ispartof>Cancer letters, 2008-01, Vol.259 (1), p.1-15</ispartof><rights>Elsevier Ireland Ltd</rights><rights>2007 Elsevier Ireland Ltd</rights><rights>Copyright Elsevier Limited Jan 18, 2008</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-b58c23174070ed5e88fe0847c82a6502d6ba7a05b931d8e1c33fc13113a27be13</citedby><cites>FETCH-LOGICAL-c474t-b58c23174070ed5e88fe0847c82a6502d6ba7a05b931d8e1c33fc13113a27be13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0304383507005095$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18053638$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Purnapatre, Kedar</creatorcontrib><creatorcontrib>Khattar, Sunil K</creatorcontrib><creatorcontrib>Saini, Kulvinder Singh</creatorcontrib><title>Cytochrome P450s in the development of target-based anticancer drugs</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>Abstract Enzymes of the cytochrome P450 (CYP) superfamily are the major determinants of half-life and execute pharmacological effects of many therapeutic drugs. In new drug discovery research, recombinant (human) CYPs are also used for identifying active or inactive metabolites that could lead to increased potency or toxicity of a molecule. In addition, CYP inhibition by anticancer drugs might lead to adverse drug reactions, multiple-drug resistance, and drug–drug interactions. During the discovery and pre-clinical evaluation of a New Chemical Entity (NCE), large amounts of purified recombinant CYPs are required for studying metabolism and pharmacokinetic parameters. Therefore, present research efforts are focused to over-express these human CYPs in bacteria, yeast, insect and mammalian cells, followed by their purification on an industrial scale to facilitate identification of novel anticancer drugs. This review summarizes the merits and limitations of these expression systems for an optimized production of individual CYP isoforms, and their usefulness in the discovery and development of target-based, safe and efficacious NCEs for the treatment of cancer.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biotransformation</subject><subject>Cancer</subject><subject>Cloning, Molecular</subject><subject>CYP</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Drug Design</subject><subject>Drug discovery</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug Interactions</subject><subject>Drug Resistance, Neoplasm</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Expression</subject><subject>Genes</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - metabolism</subject><subject>Pharmaceutical industry</subject><subject>Pharmacogenetics</subject><subject>Pharmacokinetics</subject><subject>Recombinant P450</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Recombinant Proteins - metabolism</subject><subject>Reproducibility of Results</subject><subject>Rodents</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkVtrGzEQhUVpaNy0_6CUhULe1hndVvJLoThpUgi00PZZaKXZRO5eXEkb8L-vFhsCeenTwHDOmZlvCPlAYU2BNle7tbNjj3nNAFRprYGJV2RFtWK12mh4TVbAQdRcc3lO3qa0AwAplHxDzqkGyRuuV-R6e8iTe4zTgNUPISFVYazyI1Yen7Cf9gOOuZq6Ktv4gLlubUJf2TGHMtxhrHycH9I7ctbZPuH7U70gv7_e_Nre1fffb79tv9zXTihRzFI7xqkSoAC9RK07BC2U08w2EphvWqssyHbDqddIHeedo5xSbplqkfILcnnM3cfp74wpmyEkh31vR5zmZBiFhm00L8JPL4S7aY5j2c1QuUAQHJY4cVS5OKUUsTP7GAYbD4aCWRibnTkyNgvjpVsYF9vHU_jcDuifTSeoRfD5KMDC4ilgNMkFLLh8iOiy8VP434SXAa4PY0He_8EDpudbTGIGzM_lz8ubC1eQsJH8HzpkoXY</recordid><startdate>20080118</startdate><enddate>20080118</enddate><creator>Purnapatre, Kedar</creator><creator>Khattar, Sunil K</creator><creator>Saini, Kulvinder Singh</creator><general>Elsevier Ireland Ltd</general><general>Elsevier Limited</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>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20080118</creationdate><title>Cytochrome P450s in the development of target-based anticancer drugs</title><author>Purnapatre, Kedar ; Khattar, Sunil K ; Saini, Kulvinder Singh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-b58c23174070ed5e88fe0847c82a6502d6ba7a05b931d8e1c33fc13113a27be13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biotransformation</topic><topic>Cancer</topic><topic>Cloning, Molecular</topic><topic>CYP</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Drug Design</topic><topic>Drug discovery</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug Interactions</topic><topic>Drug Resistance, Neoplasm</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Expression</topic><topic>Genes</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - metabolism</topic><topic>Pharmaceutical industry</topic><topic>Pharmacogenetics</topic><topic>Pharmacokinetics</topic><topic>Recombinant P450</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Recombinant Proteins - metabolism</topic><topic>Reproducibility of Results</topic><topic>Rodents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Purnapatre, Kedar</creatorcontrib><creatorcontrib>Khattar, Sunil K</creatorcontrib><creatorcontrib>Saini, Kulvinder Singh</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Purnapatre, Kedar</au><au>Khattar, Sunil K</au><au>Saini, Kulvinder Singh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytochrome P450s in the development of target-based anticancer drugs</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2008-01-18</date><risdate>2008</risdate><volume>259</volume><issue>1</issue><spage>1</spage><epage>15</epage><pages>1-15</pages><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>Abstract Enzymes of the cytochrome P450 (CYP) superfamily are the major determinants of half-life and execute pharmacological effects of many therapeutic drugs. In new drug discovery research, recombinant (human) CYPs are also used for identifying active or inactive metabolites that could lead to increased potency or toxicity of a molecule. In addition, CYP inhibition by anticancer drugs might lead to adverse drug reactions, multiple-drug resistance, and drug–drug interactions. During the discovery and pre-clinical evaluation of a New Chemical Entity (NCE), large amounts of purified recombinant CYPs are required for studying metabolism and pharmacokinetic parameters. Therefore, present research efforts are focused to over-express these human CYPs in bacteria, yeast, insect and mammalian cells, followed by their purification on an industrial scale to facilitate identification of novel anticancer drugs. This review summarizes the merits and limitations of these expression systems for an optimized production of individual CYP isoforms, and their usefulness in the discovery and development of target-based, safe and efficacious NCEs for the treatment of cancer.</abstract><cop>Ireland</cop><pub>Elsevier Ireland Ltd</pub><pmid>18053638</pmid><doi>10.1016/j.canlet.2007.10.024</doi><tpages>15</tpages></addata></record> |
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subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Biotransformation Cancer Cloning, Molecular CYP Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - genetics Cytochrome P-450 Enzyme System - metabolism Drug Design Drug discovery Drug Evaluation, Preclinical Drug Interactions Drug Resistance, Neoplasm Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Expression Genes Hematology, Oncology and Palliative Medicine Humans Isoenzymes - antagonists & inhibitors Isoenzymes - metabolism Pharmaceutical industry Pharmacogenetics Pharmacokinetics Recombinant P450 Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - metabolism Reproducibility of Results Rodents |
title | Cytochrome P450s in the development of target-based anticancer drugs |
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