Bioreductive therapies: an overview of drugs and their mechanisms of action.
OBJECTIVE
Bioreductively activated drugs have been used as antimicrobials, chemotherapeutic agents, and radiation sensitizers. The present paper is an overview of their mechanism of action and application in the treatment of cancer.


METHODS
Drugs such as nitroimidazoles, mitomycins, and benzotriazine di-N-oxides were a focus of this research. Studies have ranged from the chemistry of the reductive process of activation to in vitro and in vivo studies in rodent and human cells, through to clinical testing. The variety of techniques and test systems brought to bear on these compounds is a strength of this field of research.


RESULTS
A detailed chemical understanding of the mechanism of action of a variety of bioreductives is now available. The enzymatic processes by which these drugs are activated and the cofactors involved in this activation are becoming well understood. Recent advances have been made in the design and use of dual-function bioreductives, bioreductive triggers of drug activation, and DNA-targeted bioreductives. Significant success has been demonstrated clinically with bioreductive drugs, used in combination with radiation and front-line chemotherapeutic agents. The areas of antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT) are identified as new directions for bioreductive therapy.


CONCLUSIONS
The use of bioreductively-activated drugs for the treatment of cancer has made steady progress. The success obtained clinically and the new molecular approaches currently being implemented promise significant advances in the future.
Rauth
A M
AM
Division of Experimental Therapeutics, Ontario Cancer Institute, Toronto, Canada.
Melo
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Misra
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D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001388:Aziridines / Q000378:metabolism / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D005544:Forecasting; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D008920:Misonidazole / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D016685:Mitomycin / Q000378:metabolism / Q000494:pharmacology; D009581:Nitrofurans / Q000378:metabolism / Q000494:pharmacology; D009593:Nitroimidazoles / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000077704:Tirapazamine; D014227:Triazines / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D001388:Aziridines; D004273:DNA, Neoplasm; D045563:Indolequinones; D007211:Indoles; D009581:Nitrofurans; D009593:Nitroimidazoles; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D016685:Mitomycin; C100099:tretazicar; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole; C060817:apaziquone