Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of human farnesyltransferase, BIM‐46228

• Published in: International journal of cancer 2001-03, Vol.91 (5), p.718-722
• Main Authors: Prevost, Grégoire P., Pradines, Anne, Brezak, Marie‐Christine, Lonchampt, Marie‐Odile, Viossat, Isabelle, Ader, Isabelle, Toulas, Christine, Kasprzyk, Philip, Gordon, Thomas, Favre, Gilles, Morgan, Barry
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Alkyl and Aryl Transferases - antagonists & inhibitors; Animals; Anti-Bacterial Agents - therapeutic use; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Phytogenic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; BIM‐46228; bioavailability; Biological and medical sciences; Blotting, Western; Cell Division; Chemotherapy; Combined Modality Therapy; Dimethylallyltranstransferase - metabolism; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Enzyme Inhibitors - therapeutic use; farnesyltransferase; Farnesyltranstransferase; Female; Genes, ras - genetics; HeLa Cells; Humans; Imidazoles - chemistry; Imidazoles - therapeutic use; Inhibitory Concentration 50; Lovastatin - analogs & derivatives; Lovastatin - therapeutic use; Medical sciences; Mice; Mice, Nude; Models, Chemical; Neoplasm Transplantation; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - radiotherapy; Nitriles - chemistry; Nitriles - therapeutic use; Paclitaxel - therapeutic use; Peptides - therapeutic use; Pharmacology. Drug treatments; radio sensitizer; ras oncogene; Time Factors; Tumor Cells, Cultured
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/1097-0215(200002)9999:9999<::AID-IJC1104>3.0.CO;2-S

Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a wide spectrum of human cancers (pancreas, thyroid, colon, non‐small‐cell lung cancer). Membrane anchorage of Ras, required for functional activity in signal transduction, is facilitated by post‐translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C‐terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel FTase inhibitor, BIM‐46228, which showed (i) specific inhibition of purified human FTase enzyme, (ii) inhibition of proliferation in vitro in a large spectrum of human tumor cell lines, (iii) inhibition of growth of human tumor xenografts in athymic nude mice treated by per os administration and (iv) the benefits of in vitro combination of its activity with chemotherapy or radiotherapy. © 2001 Wiley‐Liss, Inc.