Abstract
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.
Highlights
Significant advances have been made in the treatment of some malignancies, the prognosis of patients with metastasis tumors remains poor
It has been suggested that the therapeutic effects of All-trans-retinoic acid (ATRA) are undermined by its rapid in vivo metabolism and catabolism by cytochrome P450 enzyme (CYPs) [13, 14]
Forty-one known P450 inhibitors belonging to antifungal, analgesic, anticoagulant, anticonvulsants, antineoplastics, histamine, antihistamines and some miscellaneous drug classes were tested for their inhibitory activity against Retinoic acid (RA) metabolism
Summary
Significant advances have been made in the treatment of some malignancies, the prognosis of patients with metastasis tumors remains poor. Differentiating agents redirect cells toward their normal phenotype and may reverse or suppress evolving malignant lesions or prevent cancer invasion. They offer a potential alternative to the classic cytostatic drugs and represent an attractive target for medicinal intervention. Several experiments in animals have demonstrated that ATRA inhibited the induction and caused the disappearance of prostate tumors [11]. In spite of these encouraging results, the effects of prolonged ATRA therapy on human cancers in the clinic has been scarce and disappointing [12]. It has been suggested that the therapeutic effects of ATRA are undermined by its rapid in vivo metabolism and catabolism by cytochrome P450 enzyme (CYPs) [13, 14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
