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

Biochemical pharmacology (2005-04-14)
Jane L Armstrong, Christopher P F Redfern, Gareth J Veal
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Isotretinoin, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
13-cis-Retinoic acid, ≥98% (HPLC)
USP
Isotretinoin, United States Pharmacopeia (USP) Reference Standard
Isotretinoin, European Pharmacopoeia (EP) Reference Standard