We review the therapeutic and preventive applications of a
retinoid analog (
vitamin A and its derivatives) for human
cancers.
Chemoprevention of
cancer is an intervention in the carcinogenic process by chemical agents that block or reverse the malignant transformation of cells.
Retinoids are prime candidates for
cancer chemoprevention since
cancer is characterized by abnormal growth with a lack of differentiation, which could be modified by
retinoids.
Retinoids exert their
biological functions through
nuclear receptors,
retinoic acid receptor (RAR) and
retinoid X receptor (RXR). A number of experimental and clinical studies have been performed in the past two decades with
retinoids showing that they inhibit or reverse the carcinogenic process in some organs, including
hematological malignancy as well as premalignant and malignant lesions in the oral cavity, head and neck, breast, skin and liver. We particularly focus upon the therapeutic application of all-trans RA (atRA) to
acute promyelocytic leukemia (APL) and on the preventive approach to
hepatocellular carcinoma (HCC) by a synthetic
retinoid analog,
acyclic retinoid. In both
malignancies, malfunction of
retinoid nuclear receptors is closely related to their carcinogenic process. In APL, a
chromosomal translocation produces a chimeric
protein between RAR alpha and a
protein called promyelocyte
leukemia protein (PML). PML-RAR alpha works as a dominant negative receptor in the leukemic cells, interfering with the normal function of RAR alpha and/or PML, which in turn results in the arrest of cell maturation at the stage of promyelocytes.
Oral administration of atRA induces differentiation of promyelocytic leukemic cells to mature neutrophils, and leads to a high rates (over 90%) of complete remission. AtRA
therapy has become standard in the treatment of APL. In the case of HCC, post-translational modification of RXR by phosphorylation impairs its function, which leads to uncontrolled cell growth.
Acyclic retinoid suppresses the phosphorylation of RXR alpha, restores its function in the presence of its endogenous
ligand, 9-cis RA, and thereby induces apoptosis of the
cancer cells.
Acyclic retinoid given orally successfully suppresses the development of second primary
tumors in cirrhotic patients who undergo curative removal of preceding HCC. Eradication of (pre)malignant clones ('clonal deletion') from the liver is suggested as a mechanism of the chemopreventive effect. Further development of more effective
retinoids as well as their use in combination with other classes of
anticancer agents including immunopreventive drugs like
interferons may provide strategies for
cancer prevention.