Antiangiogenic, bioreductive and gene therapy approaches to the treatment of hypoxic tumours

Virginia A. McNally, Adam V. Patterson, Kaye J. Williams, Rachel L. Cowen, Ian J. Stratford, Mohammed Jaffar

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)1319-1333
    Number of pages14
    JournalCurrent Pharmaceutical Design
    Volume8
    Issue number15
    DOIs
    Publication statusPublished - 2002

    Keywords

    • Angiogenesis
    • Angiogenic inhibitors
    • Bioreductive prodrugs
    • GDEPT
    • Gene delivery
    • Hypoxia
    • Indolequinone
    • Nitric oxide synthase (NOS)
    • P450 reductase
    • VEGF

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