title: Stereoisomers in clinical oncology: why it is important to know what the right and left hands are doing.
abstract: BACKGROUND
  In the past few years it has become clear that the individual stereoisomers, especially the enantiomers, of a biologically active chiral molecule may differ in potency, pharmacological action, metabolism, toxicity, plasma disposition and urine excretion kinetics. The situation exists in all classes of therapeutically active agents including chiral agents used in clinical oncology. Chiral anticancer agents which exist as a pair of enantiomers are commonly administered as racemic (50:50) mixtures of the two isomers. The possibility exists that only one of the enantiomers possesses the desired pharmacological activity while the other is responsible for part or all of the observed toxicity. The toxicity due to the non-efficacious isomer may be the difference between a clinically useful anticancer drug and one which is too toxic to use.
  
  
  RESULTS
  The chiral compounds used in standard and experimental cancer chemotherapy include leucovorin, ifosfamide and verapamil. Only one stereoisomer of leucovorin, (6S)-leucovorin is active and data suggests that the administration of just the single isomer may enhance the activity of the agent as well as improve therapeutic monitoring. Both enantiomers of verapamil, (R)-verapamil and (S)-verapamil, are active in reversing adriamycin resistance in some tumor lines. The standard clinical formulation of verapamil is a mixture of the two isomers and cannot be used in clinical treatment of resistant disease due to the cardiotoxicity of the (S)-isomer. (S)-verapamil is the active calcium channel blocking agent while (R)-verapamil has no effect in this area. Thus, an effective anticancer drug would be (R)-verapamil. Data also exists which suggests that the use of a single isomer of ifosfamide may reduce dose limiting CNS toxicity.
  
  
  CONCLUSIONS
  The existence of stereoisomeric forms of a chemical has been a recognized fact for almost 150 years. However, the clinical consequences of symmetry and asymmetry are only just beginning to be considered. Within the three-dimensional structures of the human body lie tremendous potentials for differential drug actions and, perhaps, new keys to the treatment of cancer and other diseases. The next few years should see the end to the two-dimensional clinical pharmacology we are accustomed to and the growth of stereochemical clinical pharmacology; where we always know what the right and left hands are doing.
authors.affiliation: Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: I W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007069:Ifosfamide / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002955:Leucovorin / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013237:Stereoisomerism; D014700:Verapamil / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D014700:Verapamil; D002955:Leucovorin; D007069:Ifosfamide