Prospects for hypoxia-activated anticancer drugs.
The occurrence of hypoxic cells in solid tumors, and their resistance to radiotherapy and many chemotherapeutic drugs, has engendered an interest in non-toxic prodrugs that can be activated selectively under hypoxic conditions. Despite this, no such compounds are yet registered for clinical use, due to the difficulty of their design and of measuring the extent of hypoxia clinically, and the failure of early examples. A new appreciation of the critical importance of the extravascular diffusion of the parent prodrug from the blood vessels to the remote hypoxic cells, and the back-diffusion of the activated cytotoxin from the hypoxic cells to surrounding tumor cells, is now guiding drug design in this area. New principles for the selective activation of prodrugs have also been reported, including using the reducing species generated in cells by radiotherapy itself, and using non-pathogenic anaerobic bacteria as a hypoxia-dependent vector for the delivery of prodrug-activating enzymes in a suicide gene therapy context.
Denny
William A
WA
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 90219, Auckland, New Zealand. b.denny@auckland.ac.nz
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004058:Diffusion; D015195:Drug Design; D006801:Humans; D000860:Hypoxia; D008954:Models, Biological; D008956:Models, Chemical; D011355:Prodrugs / Q000494:pharmacology; D000077704:Tirapazamine; D014227:Triazines / Q000627:therapeutic use
D000970:Antineoplastic Agents; D011355:Prodrugs; D014227:Triazines; D000077704:Tirapazamine