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PMID: 8512801 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S. Review

SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours.

British journal of cancer ·Vol. 67 ·No. 6 ·1993-06-00 ·Pages 1163-70

Brown JM

Abstract

SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide, WIN 59075, tirapazamine) is the lead compound in a new class of bioreductive anticancer drugs, the benzotriazine di-N-oxides. It is currently undergoing Phase I clinical testing. The preferential tumour cell killing of SR 4233 is a result of its high specific toxicity to cells at low oxygen tensions. Such hypoxic cells are a common feature of solid tumours, but not normal tissues, and are resistant to cancer therapies including radiation and some anticancer drugs. The killing of these tumour cells by SR 4233, particularly when given on multiple occasions, can increase total tumour cell killing by fractionated irradiation by several orders of magnitude without increasing toxicity to surrounding normal tissues. Topics covered in this review include the rationale for developing a hypoxic cytotoxic agent, the cytotoxicity of SR 4233 as a function of oxygen concentration, the mechanism of action of the drug and its intracellular target and the in vivo evidence that the drug may be useful as an adjunct both to radiotherapy and chemotherapy. Finally, the major unanswered questions on the drug are outlined.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Cell Hypoxia/drug effects,physiology Humans Mice Neoplasms, Experimental/drug therapy,metabolism Tirapazamine Triazines/pharmacology
Chemicals
Antineoplastic Agents Triazines Tirapazamine
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Brown J M
Department of Radiation Oncology, Stanford University, California 94305.
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63 references, click to expand
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Article Info
Journal
British journal of cancer
Abbr.
Br J Cancer
ISSN
0007-0920
DOI
10.1038/bjc.1993.220
Published
1993-06-00
Pages
1163-70
Language
English
Region
England
NLM ID
0370635
PMCID
PMC1968495
Subset
IM
Grants
NCI NIH HHS · CA 15201 · United States
External Links
PubMed source DOI: 10.1038/bjc.1993.220 PMC Full Text View journal details
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