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22 janvier 2013 2 22 /01 /janvier /2013 07:48
Lonafarnib for cancer and progeria. AuthorsWong NS, et al. Show all Journal Expert Opin Investig Drugs. 2012 Jul;21(7):1043-55. doi: 10.1517/13543784.2012.688950. Epub 2012 May 24. Affiliation National Cancer Centre Singapore, Department of Medical Oncology, Singapore. Abstract INTRODUCTION: Lonafarnib is a non-peptidomimetic inhibitor of farnesyl transferase, an enzyme responsible for the post-translational lipid modification of a wide variety of cellular proteins that are involved in the pathogenic pathways of various diseases including cancer and progeria. Although extensive clinical research indicates limited activity of lonafarnib in solid tumors, there is recent interest in combinations of farnesyl transferase inhibitors with imatinib or bortezomib in hematological malignancies and to investigate the role of lonafarnib in progeria. AREAS COVERED: This review examines the in vitro and in vivo pharmacology of lonafarnib and the available clinical data for lonafarnib monotherapy and combination therapy in the treatment of solid and hematological malignancies as well as progeria, using studies identified from the PubMed database supplemented by computerized search of relevant abstracts from major cancer and hematology conferences. EXPERT OPINION: There is no evidence to support the use of lonafarnib in solid tumors. There is ongoing interest to explore lonafarnib for progeria and to investigate other farnesyl transferase inhibitors for chronic and acute leukemias. PMID 22620979 [PubMed - indexed for MEDLINE] Full text: Informa Healthcare Related CitationsShow all Combining the farnesyltransferase inhibitor lonafarnib with paclitaxel results in enhanced growth inhibitory effects on human ovarian cancer models in vitro and in vivo. Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function. Lonafarnib in cancer therapy. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Continuous and intermittent dosing of lonafarnib potentiates the therapeutic efficacy of docetaxel on preclinical human prostate cancer models. Lonafarnib in cancer therapy. AuthorsMorgillo F, et al. Show all Journal Expert Opin Investig Drugs. 2006 Jun;15(6):709-19. Affiliation M. D. Anderson Cancer Center, Department of Thoracic/Head & Neck Medical Oncology, Houston, TX, USA. Abstract Farnesyl transferase inhibitors (FTIs) are anticancer agents that were designed to block the post-translational attachment of the prenyl moiety to C-terminal cysteine residue of Ras and thus inactivate it. Because Ras plays an important role in tumour progression and the ras mutation is one of the most frequent aberrations in cancer, FTIs have been expected to exert excellent therapeutic activities. Phase I and II clinical trials confirmed relevant antitumour activity and low toxicity; however, no improvement in overall survival has been reported in Phase III trials. The exact mechanism of action of this class of agents is currently unknown. Increasing lines of evidence indicate that the cytotoxic actions of FTIs are not due to the inhibition of Ras proteins exclusively, but to the modulation of other targets, including RhoB, the centromere-binding proteins and other proteins that have not yet been identified. This review describes the pharmacological and clinical data as well as mechanisms of action of FTIs, especially lonafarnib (SCH-66336), a non-peptidomimetic inhibitor that has shown anticancer activity. PMID 16732721 [PubMed - indexed for MEDLINE]

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