Carboxypeptidase-G2-based gene-directed enzyme-prodrug therapy: a new weapon in the GDEPT armoury.
Gene-directed enzyme-prodrug therapy (GDEPT) aims to improve the therapeutic ratio (benefit versus toxic side-effects) of cancer chemotherapy. A gene encoding a 'suicide' enzyme is introduced into the tumour to convert a subsequently administered non-toxic prodrug into an active drug selectively in the tumour, but not in normal tissues. Significant effects can now be achieved in vitro and in targeted experimental models, and GDEPT therapies are entering the clinic. Our group has developed a GDEPT system that uses the bacterial enzyme carboxypeptidase G2 to convert nitrogen mustard prodrugs into potent DNA crosslinking agents, and a clinical trial of this system is pending.
Hedley
Douglas
D
Institute of Cancer Research Haddow Laboratories, 15, Cotswold Road, Sutton, Surrey, UK.
Ogilvie
Lesley
L
Springer
Caroline
C
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000493:pharmacokinetics*; D001419:Bacteria; D001711:Biotransformation; D024201:Bystander Effect; D017321:Clinical Trials, Phase I as Topic; D003432:Cross-Linking Reagents / Q000009:adverse effects / Q000493:pharmacokinetics*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005813:Genes, Synthetic; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009588:Nitrogen Mustard Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000502:physiology; D014780:Viruses; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics / Q000502:physiology*
D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D011623:gamma-Glutamyl Hydrolase