title: Continuous and intermittent dosing of lonafarnib potentiates the therapeutic efficacy of docetaxel on preclinical human prostate cancer models.
abstract: Lonafarnib is a potent, selective farnesyltransferase inhibitor (FTI) undergoing clinical studies for the treatment of solid tumors and hematological malignancies. Preclinically, a number of FTIs, including lonafarnib, interact with taxanes to inhibit cancer cell growth in an additive/synergistic manner. These observations provided rationale for investigating the effects of combining lonafarnib and docetaxel on preclinical prostate cancer models. To date, docetaxel is the only chemotherapeutic agent in clinical use for hormone-refractory prostate cancer. In vitro experiments with 22Rv1, LNCaP, DU-145, PC3 and PC3-M prostate cancer cell lines showed significantly enhanced inhibition of cell proliferation and apoptosis when lonafarnib was added to docetaxel. In human tumor xenograft models, continuous coadministration of lonafarnib with docetaxel caused marked tumor regressions (24-47%) in tumors from all of the cell types as well as parental CWR22 xenografts. Intermittent dosing of lonafarnib (5 days on then 5 days off) coadministered with docetaxel produced similar regressions in hormone-refractory 22Rv1 tumors. 22Rv1 tumors progressing on docetaxel treatment also responded to treatment with intermittent lonafarnib (5 days on then 5 days off). Moreover, animals did not exhibit any signs of toxicity during coadministration of lonafarnib and docetaxel. In conclusion, coadministration of continuous and intermittent lonafarnib enhanced the antitumor activity of docetaxel in a panel of prostate cancer models. An intermittent dosing schedule of lonafarnib coadministered with docetaxel may allow enhanced efficacy to that of continuous dosing by improving the tolerability of higher doses of lonafarnib.
authors.affiliation: Schering-Plough Research Institute, Biological Research - Oncology, Kenilworth, NJ 07033, USA.
authors.forename: Gongjie
authors.initials: G
authors.lastname: Liu
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Taylor
authors.forename: Cindy H
authors.initials: CH
authors.lastname: Marrinan
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.forename: Paul
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Long
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043823:Taxoids / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D003986:Dibenzocycloheptenes
chemical_list: D000970:Antineoplastic Agents; D000077143:Docetaxel; D010880:Piperidines; D011725:Pyridines; D043823:Taxoids; C115354:lonafarnib; D003986:Dibenzocycloheptenes