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Supplement

Advances in the Development of Retinoids as Chemopreventive Agents¹

Departments of Clinical Cancer Prevention and Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

²To whom correspondence should be addressed.

	ABSTRACT

TOP ABSTRACT INTRODUCTION Retinoids as chemopreventive... Retinoids as chemopreventive... Retinoid mechanism of action:... REFERENCES

 
With the inclusion of brief discussions of retinoid drug development in animal carcinogenesis models (e.g., skin, breast, oral cavity, lung, prostate or bladder) and clinical trials (e.g., head and neck or cervix), this review will focus on recent advances in retinoid molecular targeting studies designed primarily to develop retinoids with reduced toxicity, while maintaining or enhancing activity in the context of chemoprevention. Major current retinoid molecular targets include the six known nuclear retinoid receptors (RAR and RXR). Receptor numbers, distinct functions, tissue-expression patterns, ligand specificities, functional redundancy and regulation of multiple pathways make retinoid signaling highly complex. Development of receptor-selective synthetic retinoids is a major focus of molecular retinoid development. RAR heterodimerize with RXR and mediate classic retinoid activity/toxicity. RXR are more promiscuous, heterodimerizing with several other members of the steroid receptor superfamily [e.g., peroxisome proliferator-activated receptors (PPAR) or vitamin D receptors]. RXR-selective ligands are less toxic and more active in animal breast cancer prevention studies and less toxic than RAR ligands in clinical trials. Other new avenues of retinoid molecular drug development include newly identified retinoid-regulated genes, orphan-receptor ligands/functions, novel retinoid mechanisms involving potent receptor-independent apoptosis-inducing activity (e.g., 4-HPR or anhydroretinol), synergistic combinations [e.g., RXR agonists plus selective estrogen receptor modulators (SERM)], activity in other diseases and novel delivery systems.

KEY WORDS: • retinoids • chemoprevention • molecular targeting

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Retinoids as chemopreventive... Retinoids as chemopreventive... Retinoid mechanism of action:... REFERENCES

 
Although significant progress has been made in the therapy of certain malignancies over the last decade, there are still many types of cancer for which survival rates are discouragingly low (e.g., lung cancer). One approach to address this major problem is to develop novel strategies for cancer prevention. Besides the avoidance of or reduction in exposure to carcinogenic insults, cancer prevention includes intervention in the metabolism and function of carcinogens to inhibit the initiation of carcinogenesis as well as preventing the progression of precancerous lesions to invasive cancer. Recent advances in the molecular biology of carcinogenesis and drug mechanisms and the parallel advances in clinical/translational research, including molecular targeting, have accelerated the rational development of chemopreventive agents (Davies and Lippman 1996 , Lippman et al. 1998 , Lotan 1996 ). One of the goals of molecular targeting approaches is to retain or enhance chemopreventive activity while reducing known toxic effects. Recent clinical trials have demonstrated that certain agents that act along selective molecular pathways are less toxic. Examples of such agents include vitamin A derivatives and synthetic analogs known as retinoids, along with selective estrogen receptor modulators (SERM),³ polyamine biosynthesis inhibitors (e.g., difluoromethylornithine), cyclooxygenase-2 inhibitors (e.g., celecoxib) and several other agent classes (Hong and Sporn, 1997 , Lippman et al. 1998 ). The mechanistic approach to chemopreventive development of retinoids, which encompasses a large diversity of positive and toxic effects, is facilitated by the recent advances in the understanding of the complex molecular pathways of retinoid signaling (Chambon 1996 ). This brief review highlights recent advances in understanding the molecular mechanism of the action of retinoids in the context of chemoprevention.

	Retinoids as chemopreventive agents in animal models

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Retinoids have been found to be effective in suppressing tumor development in several carcinogenesis models, including those of the skin, breast, oral cavity, lung, prostate, bladder, liver, bladder and pancreas (Kelloff et al. 1996 , Lotan 1996 , Moon et al. 1994 ). Administered either topically or systemically, in the diet or intragastrically, and before, concurrently or after a carcinogen or a tumor-promoting agent, certain retinoids were found to possess antipromotion activity. In some studies, retinoids administered in an "adjuvant setting" were found to suppress the development of second primary tumors after the first tumor had already appeared and been excised (Moon et al. 1994 ). The effects of retinoids were reversible when retinoid treatment was started after the carcinogenic insult and discontinued after a few weeks. This finding has led to the conclusion that retinoids may have to be used continuously to achieve long-term suppression of carcinogenesis. Initial studies used naturally occurring retinoids such as retinyl palmitate, all-trans retinoic acid (ATRA) or 13-cis-retinoic acid (13-cis-RA). However, with the increase in the availability of synthetic retinoids, more active compounds that have lower toxicity and/or improved pharmacokinetics than the natural retinoids have been identified (Davies and Lippman 1996 ). Some retinoids were found to be active in certain animal models of carcinogenesis but not in others. The effect of retinoids was not restricted to a specific carcinogen but rather to the type of tissue involved, suggesting that some retinoids exhibit tissue selectivity, possibly because of differences in pharmacokinetics (Davies and Lippman 1996 , Lotan 1996 , Moon et al. 1994 ).

	Retinoids as chemopreventive agents in clinical trials

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Most clinical trials for chemoprevention with retinoic acids or synthetic retinoids have targeted individuals at an increased risk of developing cancer such as patients who have premalignant lesions (Hong and Itri 1994 , Lippman et al. 1994 and 1998 , Lotan 1996 ). Certain retinoids (e.g., ATRA, 13-cis-RA, fenretinide or etretinate) have shown activity in suppressing precancerous lesions including cutaneous actinic keratoses (Bavinck et al. 1995 , Moon et al. 1997a , Rook et al. 1995 ), dysplastic nevi (Edwards and Jaffe 1990 , Halpern et al. 1994 ), oral premalignant lesions such as leukoplakias (Chiesa et al. 1993 , Hong et al. 1986 , Hong and Itri 1994 , Lippman et al. 1993 and 1995 ) and moderate cervical dysplasia (Meyskens et al. 1994 ).

Another group targeted for chemoprevention with retinoids are patients who had been treated for an early-stage cancer but remained at high risk to develop a second primary cancer. Certain retinoids showed some efficacy in inhibiting the development of second primary cancers including skin cancers in xeroderma pigmentosum patients (Peck and DiGiovanna, 1994 ), patients with previous actinic keratoses or squamous cell carcinoma of skin (Moon et al. 1997a and 1997b ), patients with basal cell carcinomas (Peck and DiGiovanna, 1994 ), patients after surgery and/or radiotherapy of stage I-IV head and neck cancer (Hong et al. 1990 and 1995 , Hong and Itri 1994 ), patients who had undergone resection of stage I nonsmall cell lung cancer (Pastorino et al. 1993 ), prevention of second primary tumors in patients with hepatocellular cancer (Muto et al. 1996 ), patients with surgically removed early stage breast cancer and, treated for prevention of contralateral breast cancer, showed suppression of development of breast cancer in premenopausal women (Veronesi et al. 1999 ) and patients with superficial papillary bladder tumors stages T-a and T-1 (Studer et al. 1995 ).

	Retinoid mechanism of action: nuclear receptors

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Retinoids have been shown to modulate fundamental physiologic processes, including embryonal development, cellular proliferation, differentiation and apoptosis. These effects are mediated by changes in gene expression or function. A major breakthrough in the understanding of the mechanism by which retinoids exert their effects on gene expression was the discovery that certain members of the large steroid hormone receptor superfamily can bind retinoic acids (Chambon 1996 ). There are six human nuclear retinoid receptors–two functionally distinct receptor classes retinoic acid (RA) receptors (RAR) and retinoid X receptors (RXR). Each of these includes three subtypes designated , ß and , which are encoded by distinct genes. The RAR, RARß and RAR genes have been localized to chromosomes 17q21, 3p24 and 12q13, respectively. The RXR, RXRß and RXR genes have been mapped to chromosomes 9q34.3, 6p21.3 and 1q22–23, respectively (Chambon 1996 ). The RAR bind both ATRA and 9-cis-RA, whereas the RXR bind only 9-cis-RA. These receptors also bind a variety of synthetic retinoids, some of which exhibit preferential binding to specific subtypes. These receptors are the key molecular targets of current retinoid drug development. RAR can form heterodimers with RXR, and RXR can also form homodimers and bind to specific segments of DNA, called retinoic acid response elements (RARE) and retinoid X response elements (RXRE), respectively; these are embedded within the promoters of retinoid-regulated genes. These elements consist of PuG(G/T)TCA(X)_nPuG(G/T)TCA or closely degenerate motifs of direct repeats with intervening nucleotides (X) numbering 1 or 5, although more complex motifs have also been identified in certain gene promoters. Transcription regulation by retinoid receptors requires cofactors of two types, i.e., corepressors and coactivators. The complexes formed by nuclear retinoid receptors and DNA response elements are recognized by corepressors and other nuclear factors. Ligand binding can alter the conformation of retinoid receptors such that the corepressors dissociate, and coactivators associate with the receptors and form a bridge to the basic transcriptional machinery (Chambon 1996 , Torchia et al. 1998 ).

Retinoid signaling is highly complex for the following reasons: the number of receptors; distinct receptor functions, tissue expression patterns (in normal and tumor tissue) and ligand specificities; functional redundancy; and the ability to regulate other pathways [e.g., activator protein 1 (AP-1)] (Kamei et al. 1996 , Pfahl 1993 , Zhou et al. 1999 ). Ligand/receptor diversity accounts for the finding that the same ligand can produce very different effects, depending in part on the nuclear receptor pairing. Also, the same receptor pair can mediate very different effects, depending in part on the ligand specificity (Chen et al. 1996 ; Perlmann and Evans 1997 ).

To date, most clinical work has involved the natural retinoids/ligands, i.e., 13-cis-RA, ATRA and 9-cis-RA, all having considerable toxicity (Davies and Lippman 1996 ). Although, ATRA binds molecularly only with RAR, and 9-cis-RA binds with both RAR and RXR, all three natural ligands activate RAR-RXR as a result of in vivo interconversion via isomerization. It is noteworthy that 13-cis-RA does not bind directly to either receptor class, but converts to ATRA in cells and thereby activates the receptor pathway.

Because the natural retinoic acids are panagonists (nonselective), there is intense interest in developing synthetic retinoid ligands with greater selectivity than that of the natural ligands. These selective retinoids are designed to increase the therapeutic index by, for example, "dialing out" specific toxicities. Many structurally diverse synthetic ligands have been developed. Development of receptor-selective retinoid ligands is elucidating the great complexity of ligand/receptor pharmacology. Synthetic ligands in or near clinical testing include selective agonists for RAR-/ß/ (e.g., LGD1550), -ß/ (e.g., tazarotene), or - (e.g., AM80), and RXR-/ß/ (e.g., LGD1069).

RAR usually forms a heterodimer with RXR. RAR mediate classic retinoid toxicities. RAR- is associated with skin, bone and teratogenic toxicity, and RAR- with triglyceride elevation. Therefore, substantial toxicity may be avoided by selective ligands that activate RAR-ß but do not activate RAR- or - or by use of RAR- and - selective antagonists in combination with retinoids that activate RAR-ß/ or –/ß. Receptor activity varies with the specific system. RAR- is the key player (differentiation inducer) in acute promyelocytic leukemia; RAR-–selective ligands have a high therapeutic index in preclinical and early clinical leukemia studies. RAR-ß appears to be relevant to epithelial carcinogenesis and chemoprevention and is transcriptionally regulated by retinoic acids (Lotan et al. 1995 ). RAR also have been shown to transrepress AP-1 signaling (Kamei et al. 1996 , Pfahl 1993 , Zhou et al. 1999 ).

In contrast to RAR, RXR are promiscuous in that they can form heterodimers with different partners, which are members of the steroid hormone receptor superfamily including thyroid hormone receptors (TR), vitamin D receptor (VDR), peroxisome proliferator-activated receptors (PPAR), and a number of orphan receptors, such as LXR, PXR and FXR (Chambon 1996 , Davies and Lippman 1996 , Lala et al. 1996 , Mukherjee et al. 1997 , Perlmann and Evans 1997 ). RXR are important in controlling apoptosis and can function in a ligand-dependent or -independent manner (Nagy et al. 1998 ). RXR-selective ligands have produced less skin toxicity in clinical studies. Animal model studies of breast cancer prevention strongly support retinoid molecular targeting approaches, i.e., RXR agonists are more active and less toxic than are RAR agonists (Bischoff et al. 1998 , Gottardis et al. 1996 ). RXR subtype–selective ligands have been difficult to synthesize because of striking similarities in ligand binding sites.

The name "rexinoids" was coined recently for RXR-selective ligands to reflect their unique activity as dimer-specific "modulators" of other endocrine signaling pathways. Rexinoids can synergize with VDR and PPAR ligands (in RXR-VDR and -PPAR heterodimers) to modulate vitamin D analog (deltanoid) and PPAR drug activity (Chambon 1996 , Davies and Lippman,1996 , Mukherjee et al. 1998 , Perlmann and Evans 1997 ). Certain rexinoids are active in animals in tamoxifen-resistant breast cancer (Bischoff et al. 1999 ). The molecular basis of this effect, however, is unclear because, in contrast to the VDR and PPAR, no RXR-estrogen receptor heterodimer has been identified. RXR interactions with endocrine pathways have important activity/toxicity implications.

Retinoid drug development is proceeding along several other novel avenues. New retinoid-regulated genes (e.g., retinoid response element identified in HoxA-1 and Stat1 promoters) are being identified as potential downstream molecular drug targets (Langston et al. 1997 ). Retinoid regulation of Stat1 provides a molecular basis for RA potentiation of interferon signaling and clinical chemopreventive activity of RA-interferon combinations (Lingen et al. 1998 , Weihua et al. 1997 ). Other novel avenues include identification of orphan-receptor ligands/functions, elucidation of the mechanism of novel retinoids (e.g., CD437, anhydroretinol or 4-HPR) with potent receptor-independent apoptosis-inducing activity (Clifford et al. 1999 , Oridate et al. 1997 ), retinoid activity in other diseases, such as diabetes (Mukherjee et al. 1997 ) and emphysema, and novel retinoid delivery systems (liposomal, aerosolized) (Mulshine et al. 1998 ).

	FOOTNOTES

 
¹ Presented at the symposium entitled "Diet, Natural Products and Cancer Prevention: Progress and Promise" as part of the Experimental Biology 99 meeting held April 17–21 in Washington, DC. This symposium was sponsored by the American Society for Nutritional Sciences and was supported in part by an educational grant from the American Institute for Cancer Research. The proceedings of this symposium are published as a supplement to The Journal of Nutrition. Guest editor for the symposium publication was Keith Singletary, University of Illinois, Urbana, IL.

³ Abbreviations used: AP-1, activator protein 1; ATRA, all-trans-retinoic acid; 13-cis-RA, 13-cis-retinoic acid; PPAR, peroxisome proliferator activated receptors; RAR, retinoic acid receptors; RARE, retinoic acid response elements; RXR, retinoid X receptors; RXRE, retinoid X response elements; SERM, selective estrogen receptor modulators; TR, thyroid hormone receptor; VDR, vitamin D receptor.

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