Selective antagonism of anticancer drugs for side-effect removal

Trends Pharmacol Sci. 2009 Aug;30(8):403-10. doi: 10.1016/j.tips.2009.06.001.

Abstract

By interfering with signal transduction events that control cell proliferation and fate, kinase inhibitors (KIs) hold promise as anticancer agents. Nevertheless, the functional role of a kinase depends on the cellular context and hence kinase inhibition in off-target cells could lead to side effects. For instance, this context dependence renders many KIs potentially cardiotoxic since inhibition of primary cancer targets such as ABL, RAF1 or AMPK recruits pro-apoptotic pathways in cardiomyocytes. Motivated by these observations, we propose a mode of 'therapeutic editing' where one drug (the editor) suppresses the side effect promoted by the primary drug as it impacts off-target cells. Editor and primary drug have overlapping therapeutic impact, and the editor suppresses the downstream propagation of toxicity-related signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / antagonists & inhibitors*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cardiotoxins / antagonists & inhibitors
  • Drug Delivery Systems
  • Humans
  • Models, Biological
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Organ Specificity
  • Protein Kinase Inhibitors / adverse effects*
  • Protein Kinase Inhibitors / antagonists & inhibitors*
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Cardiotoxins
  • Protein Kinase Inhibitors