Hypoxia: targeting the tumour

Anticancer Agents Med Chem. 2006 Jul;6(4):281-6. doi: 10.2174/187152006777698169.

Abstract

Solid tumours contain regions of very low oxygen concentrations that are said to be hypoxic. Hypoxia is a natural phenotype of solid tumours resulting from an imperfect vascular network. There are a number of consequences associated with tumour hypoxia including: resistance to ionising radiation, resistance to chemotherapy and the magnification of mutated p53. In addition tissue hypoxia has been regarded as a key factor for tumour aggressiveness and metastasis by activation of signal transduction pathways and gene regulatory mechanisms. It is clear that hypoxia in solid tumours promotes a strong oncogenic phenotype and is a phenomenon that occurs in all solid tumours. As such this provides a significant target for drug discovery particularly for tumour-targeting agents. A range of chemical classes (N-oxides, quinones, nitro-aromatics) have been explored as bioreductive agents that target tumour hypoxia. The most advanced agent, tirapazamine, is in phase III clinical trials in combination with cis-platin. The aim of this review is to give a brief overview of the current molecules and strategies being explored for targeting tumour hypoxia.

Publication types

  • Review

MeSH terms

  • Anthraquinones / pharmacokinetics
  • Anthraquinones / therapeutic use
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Aziridines / pharmacokinetics
  • Aziridines / therapeutic use
  • Benzoquinones / pharmacokinetics
  • Benzoquinones / therapeutic use
  • Cell Hypoxia / drug effects*
  • Clinical Trials, Phase III as Topic
  • Drug Screening Assays, Antitumor
  • Humans
  • Imidazoles / pharmacokinetics
  • Imidazoles / therapeutic use
  • Indolequinones / pharmacokinetics
  • Indolequinones / therapeutic use
  • Neoplasms / blood supply
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Prodrugs / pharmacokinetics
  • Prodrugs / therapeutic use
  • Quinolines / pharmacokinetics
  • Quinolines / therapeutic use
  • Radiation-Sensitizing Agents / pharmacokinetics
  • Radiation-Sensitizing Agents / therapeutic use*
  • Tirapazamine
  • Triazines / pharmacokinetics
  • Triazines / therapeutic use

Substances

  • 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone
  • 4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride
  • Anthraquinones
  • Antineoplastic Agents
  • Aziridines
  • Benzoquinones
  • Imidazoles
  • Indolequinones
  • Prodrugs
  • Quinolines
  • Radiation-Sensitizing Agents
  • Triazines
  • Tirapazamine
  • AQ4N
  • tretazicar
  • apaziquone