Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia.
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.
Gandara
David R
DR
Division of Hematology-Oncology and the Department of Radiation Oncology, University of California, Sacramento, CA 95817, USA.
Lara
Primo N
PN
Goldberg
Zelanna
Z
Le
Quynh T
QT
Mack
Phillip C
PC
Lau
Derick H M
DH
Gumerlock
Paul H
PH
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000860:Hypoxia; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D010641:Phenotype; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*
D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine