The retinoids play a key role in differentiation, proliferation and apoptosis and as a result over 30 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market. The focus of retinoid attention has been skin conditions and cancer, however although efficacy has been demonstrated in acute promyelocytic leukemia and various skin cancers, the extension of therapeutic benefit to other cancers has been limited. In our recent dossier “Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development” we set out to offer a full and up to date insight into the complexities of the retinoids. Furthermore we describe how these complexities relate to the limited therapeutic potential of the retinoids and strategies for overcoming these limitations.

The potential of the retinoids to prevent breast cancer was noted almost 20 years ago. One retinoid that has attracted particular attention with respect to breast cancer is 4-HPR (retinamide; fenretinide). Initial preclinical studies indicated that 4-HPR can suppress carcinogen-induced mammary cancer in rats; subsequent phase III trials demonstrated that 4-HPR can prevent second breast malignancies in premenopausal women with early breast cancer. In contrast 4-HPR is ineffective in patients with advanced disease. Breast cancer, like many other cancers is characterized by the absence and abnormal regulation of RAR beta receptors and expression of the RAR beta gene restores retinoic acid sensitivity to breast cancer cells. Understanding the mechanisms responsible for loss of receptor activity should facilitate the therapeutic use of the retinoids. Our recent dossier repeatedly underlines the importance that histone acetylation/methylation plays in the biology of the retinoid.

The concept that chromatin structure is plastic and that this represents a key mechanism in the regulation of transcriptional control is now generally accepted. This plasticity is regulated by histone (de)acetylation (Click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer") and methylation. Correspondingly, defects in acetylation and/or methylation have been proposed to play a central role in cancer, while on the other hand therapeutics that modulate histone deacetylase or methylase activity hold considerable potential for the treatment of cancer. CpG island hypermethylation is known to be associated with gene silencing in cancer, and these silenced genes can be reactivated by 5-aza-2'-deoxycytidine (5-Aza-CdR), a potent inhibitor of DNA methylation. Japanese researchers have recently reported that 5-Aza-CdR treatment resulted in complete demethylation of the RAR beta 2 gene in a breast cancer cell line and that this was accompanied by cell cycle arrest and time-dependent growth inhibition. This finding therefore brings together the two cutting edge fields of histone plasticity and retinoid biology and perhaps more importantly demonstrates how the tumor suppressive effects of the retinoids can be reintroduced into cancer cells through the inhibition of DNA methylation.

Entry date March, 2003

Adapted from Yang et al, Anticancer Res 2002 Sep-Oct;22(5):2753-6 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk