| ZD9331: discovery to clinical development. | |
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MedLine Citation:
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PMID: 15613898 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Thymidylate synthase (TS) has been targeted in cancer therapy for many years. As a result of a prolonged and extensive drug development program specific TS inhibitors have come into clinical practice. Following on from the development of the polyglutamatable TS inhibitor raltitrexed (Tomudex, ZD1694), ZD9331 is a rationally designed third-generation specific inhibitor of TS that does not require polyglutamation for its activity. Its development was based on the dual rationale of increased efficacy, by overcoming the potential for resistance due to reduced expression of folylpolyglutamate synthetase (FPGS), whilst potentially reducing the toxicities associated with polyglutamation and drug retention in normal tissues. Preclinical studies have shown it to be transported by the ubiquitously expressed reduced folate carrier as well as the alpha-folate receptor which is overexpressed in some cancers, especially ovarian. In vivo studies demonstrated a broad range of activity, leading to an extensive phase I program with several administration schedules. Whilst not being targeted to any individual tumor type, a large number of phase I, II, monotherapy and combination studies have been undertaken, and overall activity has been most promising, particularly in platinum-refractory relapsed ovarian, pancreatic and gastric cancers. Its role in the treatment of these diseases may be important, especially if patients were to be selected on the basis of their folate transport and FPGS status. The true potential of the drug remains to be determined. |
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Authors:
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T S Benepal; I Judson |
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Publication Detail:
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Type: Journal Article; Review |
Journal Detail:
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Title: Anti-cancer drugs Volume: 16 ISSN: 0959-4973 ISO Abbreviation: Anticancer Drugs Publication Date: 2005 Jan |
Date Detail:
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Created Date: 2004-12-22 Completed Date: 2005-06-28 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9100823 Medline TA: Anticancer Drugs Country: England |
Other Details:
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Languages: eng Pagination: 1-9 Citation Subset: IM |
Affiliation:
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Royal Marsden Hospital NHS Trust, Sutton, Surrey UK. tim.benepal@rmh.nthames.nhs.uk |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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therapeutic use* Clinical Trials as Topic Drug Evaluation Female Humans Neoplasms / drug therapy* Ovarian Neoplasms / drug therapy Quinazolines / therapeutic use* Thymidylate Synthase / antagonists & inhibitors* |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Quinazolines; 0/ZD 9331; EC 2.1.1.45/Thymidylate Synthase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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