THE EMERGING ROLE OF RETINOIDS AND RETINOIC ACID METABOLISM BLOCKING-AGENTS IN THE TREATMENT OF CANCER

BACKGROUND. Although significant advances have been made in the treatm ent of some malignancies, the prognosis of patients with metastatic tu mors remains poor. Differentiating agents redirect cells toward their normal phenotype and therefore may reverse or suppress evolving malign ant lesions or prevent cancer invasion. In addition, they offer a pote ntial alternative to the classic cytostatic drugs. METHODS. The purpos e of this review was to examine the current and potential future roles of differentiating agents in the treatment of cancer. RESULTS, Initia l studies with differentiating agents focused on retinoid therapy. Alt hough retinoids have shown some clinical success, their widespread use has been limited by resistance and, in the chemopreventive setting, t oxicity. This has led to the synthesis of a number of new retinoids th at currently are undergoing clinical investigation. A further approach to overcoming the drawbacks associated with exogenous retinoids has b een to increase the levels of endogenous retinoic acid (RA) by inhibit ing the cytochrome P450-mediated catabolism of RA using a novel class of agents known as retinoic acid metabolism blocking agents (RAM-BAs). Liarozole, the first RAMBA to undergo clinical investigation, prefere ntially increases intratumor levels of endogenous RA resulting in anti tumor activity. CONCLUSIONS. Although studies using exogenous retinoid s in this setting have not yet fulfilled their initial promise, studie s with a growing set of synthetic retinoids are ongoing. Furthermore, modulation of endogenous retinoids may offer a significant new potenti al treatment for cancer. Cancer 1998;83:1471-82. (C) 1998 American Can cer Society.