Hypoxia-activated prodrugs as antitumour agents: strategies for maximizing tumour cell killing

Clin Exp Pharmacol Physiol. 1995 Nov;22(11):881-5. doi: 10.1111/j.1440-1681.1995.tb01956.x.

Abstract

1. Hypoxia arises in solid tumour because of inefficient blood supply. While hypoxic cells are resistant to radiotherapy and probably to many chemotherapeutic drugs they can, in principle, be turned to advantage through the development of hypoxia-activated cytotoxic drugs (bioreductive drugs). 2. Three general approaches to exploiting tumour hypoxia are discussed. The first relies on fluctuating blood flow in tumours and the consequent cycling of cells through the hypoxic compartment. The second incorporates a prodrug approach in which drug activation gives rise to cytotoxic metabolites which diffuse out of hypoxic zones. The third utilizes selective inhibitors of tumour blood flow to induce additional hypoxia and thus enhance bioreductive drug activation. 3. The latter two approaches are illustrated by recent studies with the dinitrobenzamide nitrogen mustard class of bioreductive drugs and their combination with the tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aniline Mustard / analogs & derivatives*
  • Aniline Mustard / metabolism
  • Animals
  • Antineoplastic Agents / metabolism*
  • Cell Hypoxia*
  • Mice
  • Neoplasms / metabolism*
  • Nitrogen Mustard Compounds / metabolism*
  • Prodrugs / metabolism*
  • Xanthenes / metabolism*
  • Xanthones*

Substances

  • Antineoplastic Agents
  • Nitrogen Mustard Compounds
  • Prodrugs
  • Xanthenes
  • Xanthones
  • vadimezan
  • 5-(N,N-bis(2-chloroethyl)amino)-2,4-dinitrobenzamide
  • Aniline Mustard