DT-diaphorase: a target for new anticancer drugs.
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.
Danson
S
S
Paterson Institute for Cancer Research, Manchester, UK. sdanson@fsmail.net
Ward
T H
TH
Butler
J
J
Ranson
M
M
D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D002986:Clinical Trials as Topic; D004351:Drug Resistance; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016685:Mitomycin / Q000378:metabolism* / Q000494:pharmacology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011110:Polymorphism, Genetic; D011809:Quinones / Q000378:metabolism* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53
C117776:2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone; D000903:Antibiotics, Antineoplastic; D001388:Aziridines; D016227:Benzoquinones; D011809:Quinones; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D016660:NAD(P)H Dehydrogenase (Quinone)