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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.
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
html.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.


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