Retinoic acid metabolism blocking agents (RAMBAs) for treatment of cancer and dermatological diseases

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• 作者：Vincent C.O. Njar ; Lalji Gediya ; Puranik Purushottamachar ; Pankaj Chopra ; Tadas Sean Vasaitis ; Aakanksha Khandelwal ; Jhalak Mehta ; Carlic Huynh ; Aashvini Belosay and Jyoti Patel
• 关键词：All-trans retinoic acid (ATRA) ; Retinoic acid (RA) ; CYP26 ; Retinoic acid metabolism blocking agents (RAMBAs) ; Differentiation ; Retinoid resistance ; Cancer ; Dermatology
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2006
• 出版时间：1 July 2006
• 年：2006
• 卷：14
• 期：13
• 页码：4323-4340
• 全文大小：926 K

文摘

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.