Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia.

Abstract:

:Preclinical models in vitro and in vivo have shown that tumor hypoxia alters the malignant cell phenotype, selecting for p53 mutations, stimulating angiogenesis and metastasis, and markedly reducing the efficacy of both radiotherapy and chemotherapy. Similarly, clinical studies measuring pretreatment tumor oxygen status confirm that the presence of hypoxia confers a negative impact on local control, disease-free survival, and overall survival. Despite these data and extensive past research efforts, the promise of developing selective hypoxic-cell sensitizers has been largely unfulfilled. In contrast, tirapazamine is the rationally designed prototype for a new class of therapeutic agents targeting tumor hypoxia: hypoxic cytotoxins. Tirapazamine is bioreductively activated in hypoxic cells and has been shown to potentiate the cytotoxicity of radiation and a number of chemotherapeutic drug classes, in particular platinum compounds and taxanes. This article reviews the preclinical and clinical development of tirapazamine, as well as current trials in non-small cell lung cancer designed to provide proof of principle for this new category of cancer therapeutics.

journal_name

Semin Oncol

journal_title

Seminars in oncology

authors

Gandara DR,Lara PN Jr,Goldberg Z,Le QT,Mack PC,Lau DH,Gumerlock PH

doi

10.1053/sonc.2002.31531

subject

Has Abstract

pub_date

2002-02-01 00:00:00

pages

102-9

issue

1 Suppl 4

eissn

0093-7754

issn

1532-8708

pii

S0093-7754(02)50117-2

journal_volume

29

pub_type

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