2.50
Hdl Handle:
http://hdl.handle.net/10541/78144
Title:
DT-diaphorase: a target for new anticancer drugs.
Authors:
Danson, Sarah; Ward, Timothy H; Butler, John; Ranson, Malcolm R
Abstract:
DT-diaphorase (DTD) is an obligate two-electron reductase which bioactivates chemotherapeutic quinones. DTD levels are elevated in a number of tumour types, including non-small cell lung carcinoma, colorectal carcinoma, liver cancers and breast carcinomas, when compared to the surrounding normal tissue. The differential in DTD between tumour and normal tissue should allow targeted activation of chemotherapeutic quinones in the tumour whilst minimising normal tissue toxicity. The prototypical bioreductive drug is Mitomycin C (MMC) which is widely used in clinical practice. However, MMC is actually a relatively poor substrate for DTD and its metabolism is pH-dependent. Other bioreductive drugs have failed because of poor solubility and inability to surpass other agents in use. RH1, a novel diaziridinylbenzoquinone, is a more efficient substrate for DTD. It has been demonstrated to have anti-tumour effects both in vitro and in vivo and demonstrates a relationship between DTD expression levels and drug response. RH1 has recently entered a phase I clinical trial in solid tumours under the auspices of Cancer Research UK. Recent work has demonstrated that DTD is present in the nucleus and is associated with both p53 and the heat shock protein, HSP-70. Furthermore, DTD is inducible by several non-toxic compounds and therefore much interest has focussed on increasing the differential in DTD levels between tumour and normal tissues.
Affiliation:
Paterson Institute for Cancer Research, Manchester, UK. sdanson@fsmail.net
Citation:
DT-diaphorase: a target for new anticancer drugs. 2004, 30 (5):437-49 Cancer Treat. Rev.
Journal:
Cancer Treatment Reviews
Issue Date:
Aug-2004
URI:
http://hdl.handle.net/10541/78144
DOI:
10.1016/j.ctrv.2004.01.002
PubMed ID:
15245776
Type:
Article
Language:
en
ISSN:
0305-7372
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorDanson, Sarah-
dc.contributor.authorWard, Timothy H-
dc.contributor.authorButler, John-
dc.contributor.authorRanson, Malcolm R-
dc.date.accessioned2009-08-21T11:08:05Z-
dc.date.available2009-08-21T11:08:05Z-
dc.date.issued2004-08-
dc.identifier.citationDT-diaphorase: a target for new anticancer drugs. 2004, 30 (5):437-49 Cancer Treat. Rev.en
dc.identifier.issn0305-7372-
dc.identifier.pmid15245776-
dc.identifier.doi10.1016/j.ctrv.2004.01.002-
dc.identifier.urihttp://hdl.handle.net/10541/78144-
dc.description.abstractDT-diaphorase (DTD) is an obligate two-electron reductase which bioactivates chemotherapeutic quinones. DTD levels are elevated in a number of tumour types, including non-small cell lung carcinoma, colorectal carcinoma, liver cancers and breast carcinomas, when compared to the surrounding normal tissue. The differential in DTD between tumour and normal tissue should allow targeted activation of chemotherapeutic quinones in the tumour whilst minimising normal tissue toxicity. The prototypical bioreductive drug is Mitomycin C (MMC) which is widely used in clinical practice. However, MMC is actually a relatively poor substrate for DTD and its metabolism is pH-dependent. Other bioreductive drugs have failed because of poor solubility and inability to surpass other agents in use. RH1, a novel diaziridinylbenzoquinone, is a more efficient substrate for DTD. It has been demonstrated to have anti-tumour effects both in vitro and in vivo and demonstrates a relationship between DTD expression levels and drug response. RH1 has recently entered a phase I clinical trial in solid tumours under the auspices of Cancer Research UK. Recent work has demonstrated that DTD is present in the nucleus and is associated with both p53 and the heat shock protein, HSP-70. Furthermore, DTD is inducible by several non-toxic compounds and therefore much interest has focussed on increasing the differential in DTD levels between tumour and normal tissues.en
dc.language.isoenen
dc.subjectCanceren
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAntibiotics, Antineoplastic-
dc.subject.meshAziridines-
dc.subject.meshBenzoquinones-
dc.subject.meshClinical Trials as Topic-
dc.subject.meshDrug Resistance-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshHumans-
dc.subject.meshMitomycin-
dc.subject.meshNAD(P)H Dehydrogenase (Quinone)-
dc.subject.meshNeoplasms-
dc.subject.meshPolymorphism, Genetic-
dc.subject.meshQuinones-
dc.subject.meshTumor Suppressor Protein p53-
dc.titleDT-diaphorase: a target for new anticancer drugs.en
dc.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research, Manchester, UK. sdanson@fsmail.neten
dc.identifier.journalCancer Treatment Reviewsen

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