Enzyme prodrug therapy of cancer

Abstract

Tumour therapy may be greatly improved if an enzyme is used to activate a relatively non-toxic prodrug into a potent cytotoxic drug locally at the tumour site, since this should result in increased drug delivery to the tumour and reduced drug levels in critical normal tissues. Antibody-directed enzyme prodrug therapy (ADEPT) utilises the specificity of tumour selective monoclonal antibodies to achieve selective enzyme delivery to the tumour. Viral-directed enzyme prodrug therapy (VDEPT) and gene-directed enzyme prodrug therapy (GDEPT) utilise promoter regulated enzyme gene expression to achieve similar selectivity. Both approaches have been shown to be capable of achieving major improvements in tumour therapy in animal tumour models when compared with conventional systemic delivery of cytotoxic drugs. Early clinical trials with first generation ADEPT and VDEPT/GDEPT systems suggest that the effects achieved in animal tumours will translate well into the clinic. This article describes the development of these approaches over the last 10 years, reviewing both primary and patent literature.