13- cis Retinoic acid and isomerisation in paediatric oncology—is changing shape the key to success?

Abstract

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.