Bioreductive prodrugs as cancer therapeutics： targeting tumor hypoxia
Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct class...
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| Veröffentlicht in: | Ai zheng 2014-02, Vol.33 (2), p.80-86 |
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| creator | Guise, Christopher P Mowday, Alexandra M Ashoorzadeh, Amir Yuan, Ran Lin, Wan-Hua Wu, Dong-Hai Smaill, Jeff B Patterson, Adam V Ding, Ke |
| description | Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen- sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and E09 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples. |
| doi_str_mv | 10.5732/cjc.012.10285 |
| format | Article |
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Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen- sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and E09 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. 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We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.</description><subject>Anthraquinones - chemistry</subject><subject>Anthraquinones - pharmacology</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Aziridines - chemistry</subject><subject>Aziridines - pharmacology</subject><subject>Cell Hypoxia - drug effects</subject><subject>Humans</subject><subject>Indolequinones - chemistry</subject><subject>Indolequinones - pharmacology</subject><subject>Molecular Structure</subject><subject>NAD(P)H Dehydrogenase (Quinone) - chemistry</subject><subject>NAD(P)H Dehydrogenase (Quinone) - pharmacology</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>Nitrogen Mustard Compounds - chemistry</subject><subject>Nitrogen Mustard Compounds - pharmacology</subject><subject>Nitroimidazoles - chemistry</subject><subject>Nitroimidazoles - pharmacology</subject><subject>Phosphoramide Mustards - chemistry</subject><subject>Phosphoramide Mustards - pharmacology</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacology</subject><subject>Review</subject><subject>Tirapazamine</subject><subject>Triazines - chemistry</subject><subject>Triazines - pharmacology</subject><subject>前体药物</subject><subject>生物还原</subject><subject>癌症治疗</subject><subject>硝基化合物</subject><subject>细胞毒素</subject><subject>缺氧</subject><subject>肿瘤</subject><subject>药物前体</subject><issn>1000-467X</issn><issn>1944-446X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkN1KwzAUgIMo_kwvvZWK150nycna3gg6dAqCNwq7CzFNug7X1LSdzkfxWXwnX8Ho5tCrhJyPL4ePkEMKfZFwdqqnug-U9SmwVGyQXZohxoiD8Wa4A0CMg2S8Q_aaZgqANEvSbbLDeIqCIt8lo4vSeZN3ui3nJqq9y31XNJFqIq0qbXzUToxXtenaUjefH-9Rq3xh2rIqorabOR9NFrV7LdU-2bLqqTEHq7NHHq4u74fX8e3d6GZ4fhtrRNrGmU6ACpFahmKAoEWS5yo3IPSj0iZDxbVOBiKx3CpEZo21Jryw1FrIcq54j5wtvXX3ODO5NlXr1ZOsfTlTfiGdKuX_SVVOZOHmkmdcAGRBcLIUvKjKqqqQU9f5KqwszRsDisAARKDiJaW9axpv7PoHCvK7uwzdZeguf7oH_ujvWmv6N3QAjlfCiauK59BvzWCGPCgS_gVB9o2o</recordid><startdate>20140201</startdate><enddate>20140201</enddate><creator>Guise, Christopher P</creator><creator>Mowday, Alexandra M</creator><creator>Ashoorzadeh, Amir</creator><creator>Yuan, Ran</creator><creator>Lin, Wan-Hua</creator><creator>Wu, Dong-Hai</creator><creator>Smaill, Jeff B</creator><creator>Patterson, Adam V</creator><creator>Ding, Ke</creator><general>Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand%The Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, P. 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Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen- sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and E09 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.</abstract><cop>England</cop><pub>Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand%The Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, P. R. China</pub><pmid>23845143</pmid><doi>10.5732/cjc.012.10285</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Anthraquinones - chemistry Anthraquinones - pharmacology Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Aziridines - chemistry Aziridines - pharmacology Cell Hypoxia - drug effects Humans Indolequinones - chemistry Indolequinones - pharmacology Molecular Structure NAD(P)H Dehydrogenase (Quinone) - chemistry NAD(P)H Dehydrogenase (Quinone) - pharmacology Neoplasms - drug therapy Neoplasms - pathology Nitrogen Mustard Compounds - chemistry Nitrogen Mustard Compounds - pharmacology Nitroimidazoles - chemistry Nitroimidazoles - pharmacology Phosphoramide Mustards - chemistry Phosphoramide Mustards - pharmacology Prodrugs - chemistry Prodrugs - pharmacology Review Tirapazamine Triazines - chemistry Triazines - pharmacology 前体药物 生物还原 癌症治疗 硝基化合物 细胞毒素 缺氧 肿瘤 药物前体 |
| title | Bioreductive prodrugs as cancer therapeutics： targeting tumor hypoxia |
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