Retinoids as preventive and therapeutic anticancer agents (Part I).

Retinoids, the synthetic and natural analogs of vitamin A, frequently block the phenotypic expression of cancer in vitro; they also inhibit growth and induce differentiation in many animal and human malignant cell types. Only recently has it become possible to propose a unifying mechanism of retinoid action, which involves the protein kinase-C cascade system. This system may mediate retinoids' many diverse actions, including their effects on enzyme synthesis, membrane properties, growth factors, binding proteins, genomic and postgenomic expression, the extracellular matrix, and immunologic responses. Ongoing in vitro studies of retinoid structure-activity relationships, effects on oncogene expression, reversal of drug-resistance, and, especially, the protein kinase-C cascade system should help clarify the precise mechanism of their anticancer action. Many in vitro and in vivo assay systems are available for testing the 2000 + synthetic retinoids. These assays indicate specific drug sensitivities, which may help focus future clinical trials. In human cancer prevention, retinoids have been most effective for skin diseases, including actinic keratosis, keratoacanthoma, and basal cell carcinoma; however, nondermatologic premalignancies, such as oral leukoplakia, bronchial metaplasia, laryngeal papillomatosis, cervical dysplasia, myelodysplastic syndromes, and the urinary bladder, also respond to retinoid therapy. Significant therapeutic advances are also occurring with this class of drugs in refractory malignancies, including advanced cutaneous squamous and basal cell cancer, mycosis fungoides, and acute promyelocytic leukemia. Newer third-generation retinoids, such as the highly potent retinoidal benzoic acid derivatives, are demonstrating therapeutic indexes far higher than earlier-generation retinoids. Current in vitro testing is also demonstrating that retinoids have synergistic activity in combination with other agents (eg, biologic modifiers, hormones, and DNA synthesis inhibitors) and treatment modalities (eg, irradiation). Notwithstanding the progress already made with retinoids in human cancer, many in vitro questions remain, and clinical work is just beginning.

Effects of retinoid deficiency on the development of the heart and vascular system of the quail embryo.

The regulatory role of retinoids in growth and differentiation has been examined in vitro and in vivo by light and scanning electron microscopy using retinoid-deficient and control quail embryos between the 5-15 somite stage, as well as 2- and 2.5-day-old embryos. Fertile, retinoid-deficient eggs were obtained from flocks of quail maintained on a retinoid- and carotenoid-deficient diet, supplemented only with small amounts of retinoic acid methyl ester as described by Thompson et al. 1969. As described previously, retinoid deprivation during embryonal development causes abnormalities in organs of epithelial and mesenchymal origin, most dramatically preventing the formation of the extraembryonal circulatory system in the avian embryo. Our in vivo studies show that the basis for the latter defect is the failure of the primitive heart tubes to open at their posterior end, thus preventing the formation of omphalomesenteric veins normally connecting the embryonal with the extraembryonal circulatory system. Early manifestation of the retinoid-deficient defect may result also in formation of a cardia bifida, late manifestation in development of a single dilated ventricle. In contrast, the extraembryonal vascular system of blood islands is well developed. Heart function as shown by the rate of heart beat is reduced in deficient embryos. Our in vitro studies demonstrate similar defects in the development of the circulatory system by culture of normal 24-h embryos on retinoid-deficient agar medium; conversely, normal development is observed upon culture of retinoid-deficient embryos on retinoid-containing agar medium.