Cytochrome P450 Retinoic Acid 4-Hydroxylase Inhibitors: Potential Agents for Cancer Therapy

Author: Njar V.C.O.

Source: Mini Reviews in Medicinal Chemistry, Volume 2, Number 3, June 2002 , pp. 261-269(9)

Publisher: Bentham Science Publishers

Abstract:

Retinoids play a crucial role in cellular differentiation and proliferation of epithelial tissue and their utility in oncology and dermatology is well documented. This mini review focuses on the role of all-trans-retinoic acid (ATRA or RA), the principal endogenous retinoid and its metabolism in cancer therapy.

ATRA has been used successfully in differentiating therapy of acute promyelecytic leukemia and other types of cancers. However, its usefulness is limited by the rapid emergence of ATRA resistance due (in part) to ATRA - induced acceleration of ATRA metabolism. A novel strategy to subjugate 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 enzyme(s) 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 since 1987. Major emphasis is given to liarozole, the most studied and only RAMBA to undergo clinical investigation and also the recently developed novel and highly potent 4-azoly retinoids. The potential role of a new family of cytochrome P450 enzymes, CYP26, with specificity towards ATRA is also discussed.

Keywords: liarozole; atra-hydroxylase inhibitor; rambas; 4-azoye retinoids

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389557023406223

Publication date: 2002-06-01

• The aim of Mini-Reviews in Medicinal Chemistry is to publish short reviews on the important recent developments in medicinal chemistry and allied disciplines.
  
  The scope of Mini-Reviews in Medicinal Chemistry will cover all areas of medicinal chemistry including developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, drug targets, and natural product research and structure-activity relationship studies.
  
  Mini-Reviews in Medicinal Chemistry is an essential journal for every medicinal and pharmaceutical chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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