Antiangiogenic, bioreductive and gene therapy approaches to the treatment of hypoxic tumours.
Quinone based bioreductive drugs have, potentially, a very versatile use in cancer chemotherapy. They can be activated by DT-diaphorase and hence can be used to target tumour types rich in this (O2)-independent reductase enzyme. Small molecular modifications can substantially reduce specificity for DT-diaphorase and under these circumstances the quinones become much less toxic in air but retain their potent cytotoxic effects under hypoxic conditions. Our understanding of the reductive (bio) chemistry of indolequinones, in particular, has subsequently allowed us to develop a platform technology where almost any therapeutic entity can potentially be delivered, selectively, to hypoxic tumours. Antiangiogenic approaches are currently receiving a substantial amount of attention and this review brings their development into context in view of the hypoxia dependence for neovascularization. Lastly, the use of bioreductive drugs when combined with hypoxia-mediated gene therapy is described. Such an approach provides a unique dual level of specificity for targeting hypoxic tumours and potentially can provide substantial therapeutic benefit.
McNally
Virginia A
VA
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
Patterson
Adam V
AV
Williams
Kaye J
KJ
Cowen
Rachel L
RL
Stratford
Ian J
IJ
Jaffar
Mohammed
M
D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects* / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000098:blood supply* / Q000628:therapy*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011355:Prodrugs; D011809:Quinones