Epithelial cancer, retinoids

Certain retinoids may prove of value in the treatment of epithelial cancers [cancers in body cavities], although vitamin A itself may never be useful as it only slowly converts to the more bioactive retinoic acid. Beyond this is the fact that vitamin A can accumulate in toxic levels in the liver, a problem avoided with retinoic acid [Chaney, in Devlin, 1986, p. 1203].)... 

Hembree JR, Agarwal C, Beard RL, Chandraratna RA, and Eckert R [1996] Retinoid X receptor-specific retinoids inhibit the ability of retinoic acid receptor-specific retinoids to increase the level of insulin-like growth factor binding protein-3 in human ectocervical epithelial cells. Cancer Res 56 1794-1799... 

Agarwal C, Rorke EA, Irwin JC, and Eckert RL [1991] Immortalization by human papillomavirus type 16 alters retinoid regulation of human ectocervical epithelial cell differentiation. Cancer Res 51 3982-3989... 

In addition to the regression of established tumors, a number of retinoids show apparent inhibition of the chemical induction of the bladder and other epithelial tumors in experimental animals. The effect is not in fact inhibition of carcinogenesis, but rather a lengthening of the latent period between the initiation step of carcinogenesis and the development of mmors. Although perhaps not as exciting as compounds that prevent the development of cancers, such a delaying action may be usefitl. If the results can be scaled from... 

The potential of retinoic acid and other retinoids in the treatment of epithelial disorders and cancer has been the driving force in much of the work with retinoids. Already all-trons retinoic acid (Tretinoin) and 13-m-retinoic acid (Isotretinoin/Accutane) are approved in Europe and the United States for clinical use in the treatment of different forms of acne while Acitretin (R26) and its ethyl ester (etretinate) are used in the treatment of psoriasis. The use of retinoids in the treatment of photodamaged skin is also being investigated [19]. 

Jetten, A. M, Nervi, C, and Vollberg, T M (1992) Control of squamous differentiation in tracheobronchial and epidermal epithelial cells, role of retinoids J. Natl, Cancer Inst Monog. 13, 93-100. 

One of the most exciting potential uses for the retinoids lies in the area of cancer prevention. The rationale for the use of retinoids in cancer prevention derives from their ability to control normal differentiation in many epithelial tissues. Animal studies that document the efficacy of retinoids in cancer prevention have been reviewed in detail earlier in this chapter. To date, clinical trials have concentrated primarily on the reversal of premalignant conditions or the prevention of recurrent lesions in patients with certain malignant diagnoses. 

RA and its isomers inhibit prostate epithelial cell growth [54]. Inhibition of RA metabolism raises plasma RA and inhibits relapse in the rat Dunning prostate cancer model [55]. RA decreases the concentrations of dihydrotestosterone, 3a-adiol and androsterone in serum, seems to cause a metabolic deviation away from the 5a-reductase path in liver [56], and causes a three-fold decrease in androgen receptor binding capacity [57]. Conversely, androgens affect the actions of retinoids by decreasing the mRNA of RARa approximately five-fold in prostate epithelia and 15 to 20-fold in seminal vesicles, while increasing it two-fold in kidney [58]. 

Malignant ER breast cancer cells, which generally fail to express RARp but retain high levels of RARa, are probably unable to respond to retinoids like the normal mammary epithelial cells only in terms of a proliferation inhibition. Therefore other mechanisms have to take place. 

---