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 treatment of some malignancies, the prognosis of patients with metastatic tumors remains poor. Differentiating agents redirect cells toward their normal phenotype and therefore may reverse or suppress evolving malignant lesions or prevent cancer invasion. In addition, they offer a potential alternative to the classic cytostatic drugs.


METHODS
The purpose of this review was to examine the current and potential future roles of differentiating agents in the treatment of cancer.


RESULTS
Initial studies with differentiating agents focused on retinoid therapy. Although retinoids have shown some clinical success, their widespread use has been limited by resistance and, in the chemopreventive setting, toxicity. This has led to the synthesis of a number of new retinoids that currently are undergoing clinical investigation. A further approach to overcoming the drawbacks associated with exogenous retinoids has been to increase the levels of endogenous retinoic acid (RA) by inhibiting the cytochrome P450-mediated catabolism of RA using a novel class of agents known as retinoic acid metabolism blocking agents (RAMBAs). Liarozole, the first RAMBA to undergo clinical investigation, preferentially increases intratumor levels of endogenous RA resulting in antitumor activity.


CONCLUSIONS
Although studies using exogenous retinoids in this setting have not yet fulfilled their initial promise, studies with a growing set of synthetic retinoids are ongoing. Furthermore, modulation of endogenous retinoids may offer a significant new potential treatment for cancer.
Lady Davis Institute for Medical Research and SMBD Jewish General Hospital, Department of Oncology, McGill University, Montreal, Quebec, Canada.
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D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D018890:Chemoprevention; D065607:Cytochrome P-450 Enzyme Inhibitors; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology; D012176:Retinoids / Q000009:adverse effects / Q000627:therapeutic use*; D014212:Tretinoin / Q000378:metabolism*
D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014212:Tretinoin; C061121:liarozole