9-cis retinoic acid

Retinoic acid (RA) describes a group of vitamin A acid (synonym Vitamin A1 acid) derivatives such as all-irans-retinoic acid (tretinoin), 9-cis-retinoic acid and 13-cis retinoic acid (isotretinoin). Retinoic acids act through binding to retinoic acid and retinoid X response elements. 

Among retinoids, 13-cis-retinoic acid is known to have not only anti-inflammatory but also sebostatic effects. Therefore it is one of the most potent topical and also systemic agents for therapy of acne. 

Currently, 13-cis-retinoic acid is the most studied chemopreventive agent that decreases the incidence of second primary tumors in patients with head-and-neck cancer, reverses premalignant lesions, and reduces appearance of nonmelanoma skin cancer in patients with xeroderma pigmentosum. Unfortunately, this vitamin A derivative has a significant clinical toxicity, which limits its utility in a practice setting. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

Systemic treatment of 13-cis retinoic acid frequently leads to cheilitis and eye irritations (e.g., unspecific cornea inflammation). Also other symptoms such as headache, pruritus, alopecia, pains of joints and bone, and exostosis formation have been reported. Notably, an increase of very low density lipoproteins and triglycerides accompanied by a decrease of the high density lipoproteins has been reported in 10-20% of treated patients. Transiently, liver function markers can increase during oral retinoid therapy. Etretinate causes the side effects of 13-cis retinoid acid at lower doses. In addition to this, generalized edema and centrilobulary toxic liver cell necrosis have been observed. 

Oral Isotretinoin (13-cis-retinoic acid) efficacy is based on its specific actions against all four factors implicated in acne pathogenesis. Isotretinoin targets are 1) sebum suppression ... 

The title compound, 88, the main metabolite of 13-cis-retinoic acid in mammals, has been synthesized27 as before via condensation of acetone-1,2,3-13C3 with 3,7-dimethyl-2,6-octadienal (citral), 89 (equation 33). 

Cis retinoic acid 185, labelled with carbon-14 at the 14 position, has been obtained27,100 in the reaction of 14C-labelled butenolide 186 with C-15 Wittig reagent 187 (equation 67). 

This reaction was also used in a synthesis of 13-cis-retinoic acid.2 Thus reduction of 3 under the same conditions gives the triethylsilyl ether (4) of 13-cis-retinol, with retention of the geometry of the terminal double bond. This product can be converted to 13-cis-retinoic acid by deprotection and oxidation (60% yield). 

There are many retinol containing preparations to treat vitamin deficiency states. Retinoids are also used to treat dermatological diseases like acne, psoriasis, Darier s disease, and ichthyosis. Tretinoin, all-trans-retinoic acid, is a topical preparation while isotretinoin or 13-cis-retinoic acid, and etretinate are available for oral administration. 

DeYoimg DJ, Bande JA, Eort DJ (1991) Assessment of the developmental toxicity of ascorbic acid, sodium selenate, comnarin, serotonin, and 13-cis retinoic acid using FETAX. Drug Chem Toxicol 14 127-141... 

Much recent interest has been aroused by the fact that retinoid compounds, including both retinol and retinoic acid, reduce the incidence of experimentally induced cancer. In addition, 13-czs-retinoic acid taken orally is remarkably effective in treatment of severe cystic acne. s However, both vitamin A and retinoic acid in large doses are teratogenic, i.e., they cause fetal abnormalities. The use of 13-cis-retinoic acid during early phases of pregnancy led to a high incidence of major malformations in infants born.1 11 1... 

Table IV. Tumor Incidence Induced by MBN in Rats Deficient in Zinc and Given Ethyl Alcohol and 13-cis Retinoic Acid...

Table XVII. Effects of 13-cis Retinoic Acid on DMH-Induced Tumors...

It is widely accepted that retinoids inhibit tumor growth and development, or the promotional phase of tumorigenesis (1J5) since it is well known that vitamin A plays a marked, as yet ill-defined, role in controlling the growth and differentiation of epidermis and epidermally-derived structures (16-18). Experimental evidence for this hypothesis rests primarily on the observation that conditions of hypervitaminosis A significantly inhibit tumor production even when initiated after application of the carcinogenic insult. Thus, 13-cis-retinoic acid inhibits the induction of transitional cell... 

Modulation of Mutagenesis by 3-carotene and 13-cis-Retinoic Acid. The provitamin 3-carotene, and a synthetic derivative of vitamin A, 13-cis-retinoic acid, were examined with respect to their capacity to modulate 2-fluorenamine-induced mutagenicity in Salmonella. These studies were carried out since dietary and serum levels of 3-carotene vary widely among humans. Also, there is considerable interest in the anti-tumor activity of 13-cis-retinoic acid and other synthetic retinoids. 

When carcinogen activation was mediated by S9, high concentrations of 13-cis-retinoic acid were slightly inhibitory toward mutagenicity in Salmonella (Table V), while 13-cis-retinoic acid was extremely inhibitory to mutagenesis induced by 2-fluorenamine when carcinogen activation was carried out by microsomes (Table VI). 

Table V. Effect of retinol, 13-cis-retinoic acid and 3-carotene on 2-FA-induced mutagenesis in J5. typhimurium (TA98) mediated...

Modulation of Mutagenicity by the Intestinal Carcinogen 3,21-Dimethyl-4-Aminobiphenyl. We wished to examine the effect of retinol, 3-carotene and 13-cis-retinoic acid on yet another aromatic amine,... 

Table VIII. Effect of 13-cis-retinoic acid, 3-carotene and retinol on...

Similar effects were observed with the synthetic retinoid 13-cis-retinoic acid, while 3-carotene was without effect in modulating the mutagenicity of aromatic amines in Salmonella. 

In experiments on animals, it was possible to show that all-trans retinoic acid and 13-cis retinoic acid, and derivatives of these acids, can prevent the development of... 

Grubbs CJ, Moon RC, Squire RA, Farrow GM, Stinson SF, Goodman DG, Brown CC, Sporn MB. 13-cis-retinoic acid inhibition of bladder carcinogenesis induced in rats by A-butyl-A-(4-hydroxybutyl)nitrosamine. Science 1977 198 743-4. 

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