Elsevier

Drug Discovery Today

Volume 7, Issue 23, 1 December 2002, Pages 1165-1174
Drug Discovery Today

Review
Selective retinoids and rexinoids in cancer therapy and chemoprevention

https://doi.org/10.1016/S1359-6446(02)02526-6Get rights and content

Abstract

Natural and synthetic retinoids are effective inhibitors of tumor cell growth in vitro and in vivo. However, the toxicity of natural derivatives of vitamin A limits their therapeutic use. Recently, synthetic compounds selective for the different retinoid receptor isotypes have been generated that circumvent pan-retinoid toxicity. The tumor-suppressive activity of selective retinoid and/or rexinoid ligands has been established preclinically, and emerging clinical trials are supportive of the chemotherapeutic and chemopreventive potential of these compounds in multiple oncology indications, with reduced toxicity. Moreover, the combination of retinoids and/or rexinoids with chemotherapeutic agents for the synergistic modulation of specific pathways could also be of benefit in cancer therapy.

Section snippets

Diversity and mechanisms-of-action of the retinoid receptors

The retinoid signal is mediated in target cells through RARs and RXRs, each of which comprise three isotypes designated α, β and γ as well as several isoforms generated by alternative splicing or promoter use [9]. Retinoic acid receptors and RXRs are divergent in their ligand specificity; ATRA can bind and activate only RAR receptors, with a similar affinity for all three isotypes. By contrast, 9cRA binds and activates all three RARs and RXRs, but with different affinities [10]. Retinoic acid

Why is selectivity needed for retinoid-based therapies?

The beneficial therapeutic potential of retinoids is counterbalanced by their toxicity. Taken together, studies on vitamin A deficiency (VAD) and genetic inactivation of the retinoid receptors indicate that vitamin A is essential during pre- and post-natal development, as well as in adult life, and that the retinoid receptors are responsible for mediating the physiological functions of retinoic acids derived from vitamin A. Indeed, similar abnormalities in fetal development of the respiratory

General background

Synthetic retinoids have been the subject of chemical investigation since the early 1960s. Early attempts to overcome the air-, light- and metabolic-instability of retinoic acid led to the replacement of the polyene chain in the natural vitamin with aromatic groups (Fig. 2). Discovery of the individual retinoic acid receptors spurred further successful investigations into modifications conferring binding specificity. Several reviews of retinoid structural evolution have been published 35., 36.,

Activity of selective retinoids for tumor growth inhibition

The use of RARα-selective agonists in the treatment of APL is a very attractive therapeutic approach because the underlying pathology involves oncogenic fusion proteins with the α-isotype of RAR. Accordingly, the selective RARα agonists, AM80, AM580 and BMS194753, were shown to induce differentiation of the acute promyelocytic leukemia cell lines HL60 and NB4, and this effect was reversed by the selective RARα antagonist BMS195614 18., 48.. Furthermore, AM80 successfully induced complete

Activity of rexinoids

Retinoid X receptors are promiscuous dimerization partners for a large number of nuclear hormone receptors; rexinoid ligands therefore have the potential to affect multiple signal transduction pathways. One of these ligands, the RXR agonist LGD1069 (Targretin; Fig. 5), was shown to prevent the formation and progression of primary and secondary N-nitroso-N-methylurea (NMU)-induced rat mammary carcinomas. These effects of LGD1069 were also observed in tamoxifen refractory breast tumors of the NMU

The future of selective retinoids in cancer therapy and chemoprevention

Development of the natural vitamin A derivatives, including ATRA, 9cRA and 13cRA, as oral chemotherapeutic agents has been compromised by the severe adverse toxicities they generate through regulation of multiple receptor isotypes. The generation of retinoids and rexinoids with restricted selectivity has opened new avenues for cancer therapy and chemoprevention. However, instead of a broad use, these compounds should be restricted to particular malignancies, such as the use of RARα agonists in

Acknowledgements

We are extremely grateful to Hinrich Gronemeyer and Nature Reviews for permission to use Fig. 1, originally published in [13]. We also thank Marco Gottardis for helpful discussion and support.

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