Hypoxia: targeting the tumour.
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.
Boyle
Robert George
RG
Sentinel Oncology Ltd., Cambridge, UK. bob.boyle@sentineloncology.com
Travers
Stuart
S
D000880:Anthraquinones / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001388:Aziridines / Q000493:pharmacokinetics / Q000627:therapeutic use; D016227:Benzoquinones / Q000493:pharmacokinetics / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000187:drug effects*; D017326:Clinical Trials, Phase III as Topic; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D045563:Indolequinones / Q000493:pharmacokinetics / Q000627:therapeutic use; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use; D011804:Quinolines / Q000493:pharmacokinetics / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077704:Tirapazamine; D014227:Triazines / Q000493:pharmacokinetics / Q000627:therapeutic use
C117776:2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone; C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D000880:Anthraquinones; D000970:Antineoplastic Agents; D001388:Aziridines; D016227:Benzoquinones; D007093:Imidazoles; D045563:Indolequinones; D011355:Prodrugs; D011804:Quinolines; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; C094428:AQ4N; C100099:tretazicar; C060817:apaziquone