Ahmad Mobasher
University College of Pharmacy, University of the Punjab (Old Campus), the Mall, Lahore, Pakistan.
Sci Pharm. 2011 Oct-Dec;79(4):921-35. doi: 10.3797/scipharm.1106-18. Epub 2011 Aug 12.
The relative lack of clinical success with conventional anticancer agents may be due in part to the traditional concept of cancer being a biological state rather than a dynamic process. Redefining cancer as a dynamic disease commencing with carcinogenesis introduces the possibility of chemoprevention. Retinoids offer the promise of a therapeutic option based on differentiation of premalignant as well as malignant cells. Research to date has concentrated on the use of exogenous retinoids in cancer. Although this research continues with new retinoid derivatives, an alternative 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 which increase the level of endogenous retinoic acid (RA) within the tumor cells by blocking their metabolism. This approach presents several theoretic advantages.In the present study a wide range of established P-450 inhibitors has been screened to examine their inhibitory activity on all-trans-Retinoic acid (ATRA) metabolism. Forty-one known P450 inhibitors were tested for their inhibitory activity against RA metabolism. Most of them are nitrogen-containing compounds. The results showed that among these compounds only six compounds (N-benzyl-2-phenylethanamine, itraconazole, chlorpromazine, 5-chloro-1,3-benzoxazol-2-amine, proadifen and furazolidone) showed inhibition of RA metabolism which was > 50%. Ketoconazole and liarozole were also screened as standard potent inhibitors in the same system and gave 87.5% and 89% inhibition, respectively. The results indicate that mostly azoles with substituents in positions other than the 1-position on the ring are very weak inhibitors of RA metabolism. The most effective inhibitors (ketoconazole, itraconazole, bifonazole and clotrimazole) are 1-substituted and possess relatively large aromatic groups in the molecule. 1-Substituted imidazoles bind to cytochrome P-450 with a very high affinity but substitution in the other position of the imidazole decreases the binding affinity.
传统抗癌药物在临床上相对缺乏成功可能部分归因于癌症是一种生物学状态而非动态过程的传统观念。将癌症重新定义为始于致癌作用的动态疾病引入了化学预防的可能性。视黄酸基于癌前细胞和恶性细胞的分化提供了一种治疗选择的前景。迄今为止的研究集中在外源性视黄酸在癌症中的应用。尽管这项研究随着新的视黄酸衍生物仍在继续，但克服与外源性视黄酸相关缺点的另一种方法是使用一类称为视黄酸代谢阻断剂（RAMBAs）的新型药物来抑制细胞色素P450介导的视黄酸分解代谢，从而提高内源性视黄酸（RA）的水平，这些药物通过阻断肿瘤细胞内视黄酸的代谢来提高内源性视黄酸（RA）的水平。这种方法具有几个理论优势。在本研究中，已筛选了多种已确立的P-450抑制剂，以检查它们对全反式维甲酸（ATRA）代谢的抑制活性。测试了41种已知的P450抑制剂对RA代谢的抑制活性。它们中的大多数是含氮化合物。结果表明，在这些化合物中，只有六种化合物（N-苄基-2-苯乙胺、伊曲康唑、氯丙嗪、5-氯-1,3-苯并恶唑-2-胺、普罗地芬和呋喃唑酮）显示出对视黄酸代谢的抑制率>50%。酮康唑和利阿唑也作为同一系统中的标准强效抑制剂进行了筛选，抑制率分别为87.5%和89%。结果表明，大多数在环上1位以外位置有取代基的唑类对视黄酸代谢的抑制作用非常弱。最有效的抑制剂（酮康唑、伊曲康唑、联苯苄唑和克霉唑）是1-取代的，并且分子中具有相对较大的芳基。1-取代的咪唑以非常高的亲和力与细胞色素P-450结合，但咪唑其他位置的取代会降低结合亲和力。
