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Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: HYPOXIA‐ACTIVATED PRODRUGS AS ANTITUMOUR AGENTS: STRATEGIES FOR MAXIMIZING TUMOUR CELL KILLING
Author(s) -
Wilson William R.,
Pruijn Frederik B.
Publication year - 1995
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.1995.tb01956.x
Subject(s) - prodrug , hypoxia (environmental) , pharmacology , drug , tirapazamine , cytotoxic t cell , chemistry , cancer research , cytotoxicity , medicine , biology , biochemistry , oxygen , in vitro , organic chemistry
SUMMARY 1. Hypoxia arises in solid tumour because of inefficient blood supply. While hypoxic cells are resistant to radiotherapy and probably to many chemotherapeutic drugs they can, in principle, be turned to advantage through the development of hypoxia‐activated cytotoxic drugs (bioreductive drugs). 2. Three general approaches to exploiting tumour hypoxia are discussed. The first relies on fluctuating blood flow in tumours and the consequent cycling of cells through the hypoxic compartment. The second incorporates a prodrug approach in which drug activation gives rise to cytotoxic metabolites which diffuse out of hypoxic zones. The third utilizes selective inhibitors of tumour blood flow to induce additional hypoxia and thus enhance bioreductive drug activation. 3. The latter two approaches are illustrated by recent studies with the dinitrobenzamide nitrogen mustard class of bioreductive drugs and their combination with the tumour blood flow inhibitor 5,6‐dimethylxanthenone‐4‐acetie acid.