Retinoic acid metabolism blocking agents (RAMBAs) for treatment of cancer and dermatological diseases.
The naturally occurring retinoids and their synthetic analogs play a key role in differentiation, proliferation, and apoptosis, and their use/potential in oncology, dermatology and a variety of diseases are well documented. This review focuses on the role of all-trans-retinoic acid (ATRA), the principal endogenous metabolite of vitamin A (retinol) and its metabolism in oncology and dermatology. ATRA has been used successfully in differentiated therapy of acute promyelocytic leukemia, skin cancer, Kaposi's sarcoma, and cutaneous T-cell lymphoma, and also in the treatment of acne and psoriasis. However, its usefulness is limited by the rapid emergence of acquired ATRA resistance involving multifactoral mechanisms. A key mechanism of resistance involves ATRA-induced catabolism of ATRA. Thus, a novel strategy to overcome the limitation associated with exogenous ATRA therapy has been to modulate and/or increase the levels of endogenous ATRA by inhibiting the cytochrome P450-dependent ATRA-4-hydroxylase enzymes (particularly CYP26s) responsible for ATRA metabolism. These inhibitors are also referred to as retinoic acid metabolism blocking agents (RAMBAs). This review highlights development in the design, synthesis, and evaluation of RAMBAs. Major emphasis is given to liarozole, the most studied and only RAMBA in clinical use and also the new RAMBAs in development and with clinical potential.
Njar
Vincent C O
VC
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, 21201-1559, USA. vnjar001@umaryland.edu
Gediya
Lalji
L
Purushottamachar
Puranik
P
Chopra
Pankaj
P
Vasaitis
Tadas Sean
TS
Khandelwal
Aakanksha
A
Mehta
Jhalak
J
Huynh
Carlic
C
Belosay
Aashvini
A
Patel
Jyoti
J
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003879:Dermatologic Agents / Q000737:chemistry* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000072516:Retinoic Acid 4-Hydroxylase; D012871:Skin Diseases / Q000188:drug therapy* / Q000201:enzymology; D014212:Tretinoin / Q000378:metabolism* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D003879:Dermatologic Agents; D004791:Enzyme Inhibitors; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase