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.