13-cis retinoic acid and isomerisation in paediatric oncology--is changing shape the key to success?
Retinoic acid isomers have been used with some success as chemotherapeutic agents, most recently with 13-cis retinoic acid showing impressive clinical efficacy in the paediatric malignancy neuroblastoma. The aim of this commentary is to review the evidence that 13-cis retinoic acid is a pro-drug, and consider the implications of retinoid metabolism and isomerisation for the further development of retinoic acid for cancer therapy. The low binding affinity of 13-cis retinoic acid for retinoic acid receptors, low activity in gene expression assays and the accumulation of the all-trans isomer in cells treated with 13-cis retinoic acid, coupled with the more-favourable pharmacokinetic profile of 13-cis retinoic acid compared to other isomers, suggest that intracellular isomerisation to all-trans retinoic acid is the key process underlying the biological activity of 13-cis retinoic acid. Intracellular metabolism of all-trans retinoic acid by a positive auto-regulatory loop may result in clinical resistance to retinoic acid. Agents that block or reduce the metabolism of all-trans retinoic acid are therefore attractive targets for drug development. Devising strategies to deliver 13-cis retinoic acid to tumour cells and facilitate the intracellular isomerisation of 13-cis retinoic acid, while limiting metabolism of all-trans retinoic acid, may have a major impact on the efficacy of 13-cis retinoic acid in paediatric oncology.
Armstrong
Jane L
JL
Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, University of Newcastle Upon Tyne, Newcastle Upon Tyne NE2 4HH, UK. j.l.armstrong@ncl.ac.uk
Redfern
Christopher P F
CP
Veal
Gareth J
GJ
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002648:Child; D006801:Humans; D015474:Isotretinoin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015394:Molecular Structure; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism*; D012177:Retinol-Binding Proteins / Q000378:metabolism; D013237:Stereoisomerism; D014212:Tretinoin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D012177:Retinol-Binding Proteins; D014212:Tretinoin; D015474:Isotretinoin