13-cis retinoic acid and isomerisation in paediatric oncology--is changing shape the key to success? |
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Authors: | Armstrong Jane L Redfern Christopher P F Veal Gareth J |
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Institution: | 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 |
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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. |
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Keywords: | AHR aryl hydrocarbon receptor APL acute promyelocytic leukaemia ATRA all-trans retinoic acid CEPT cholesteryl ester transfer protein CRABP cellular retinoic acid binding protein GST glutathione S-transferase IGFBP-3 insulin-like growth factor binding protein-3 LRAT lecithin-retinol acyltransferase M6P mannose-6-phosphate MTD maximum tolerated dose PGP P-glycoprotein RAG retinoyl β-glucuronide 13cisRA 13-cis retinoic acid 9cisRA 9-cis retinoic acid RA retinoic acid RAR retinoic acid receptor RARE retinoic acid response element RXR retinoid X receptor |
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