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

Lookup NU author(s): Dr Jane Renwick, Dr Chris RedfernORCiD, Professor Gareth Veal


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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. © 2005 Elsevier Inc. All rights reserved.

Publication metadata

Author(s): Armstrong, J.L., Redfern, C.P.F., Veal, G.J.

Publication type: Review

Publication status: Published

Journal: Biochemical Pharmacology

Year: 2005

Volume: 69

Issue: 9

Pages: 1299-1306

Print publication date: 01/05/2005

ISSN (print): 0006-2952

ISSN (electronic): 1873-2968


DOI: 10.1016/j.bcp.2005.02.003

PubMed id: 15826600