Preclinical Activity of R115777

A potent and selective inhibitor of FTase, R115777 inhibited farnesylation of lamin-B and K-RasB peptides with IC50 values of0.86 nM and 7.9 nM, respectively. By contrast, inhibition of geranylgeranylation occurred only at concentrations > 50 pM. In cell proliferation assays, growth of T24 bladder carcinoma (H-ras mutant), MCF-7 breast carcinoma, pancreatic CAPAN-2 (K-rasB mutation), and colon LoVo tumor cells (K-RasB) were inhibited with IC50s ranging from 1.7-22 nM. Similar to other inhibitors of FTase, inhibition of K-Ras mutant cells required approx 10-fold higher concentrations of the drug. Growth delay rather than tumor regression was observed in T24, LoVo, and CAPAN-2 xenografts (Janssen Research Foundation, unpublished reports). Toxicity studies in beagle dogs showed that maximum tolerated dose (MTD) was dependent on duration of treatment. Myelosuppression affecting granulocytes and platelets was reversible after 4 and 7 d of treatment at 40 mg/kg, whereas doses exceeding 10 mg/kg were not tolerated on longer dosing schedules. Renal and gastrointestinal toxic effects were also observed, more severe with higher doses and longer duration of treatment.

From: Farnesyltransferase Inhibitors in Cancer Therapy Edited by: S. M. Sebti and A. D. Hamilton © Humana Press Inc., Totowa, NJ

Based on these data, the initial Phase I clinical trial employed a 5-d on, 9-d off schedule, with cycles repeated every 2 wk (3). While this trial was in progress, additional Phase I trials employing continuous oral dosing were initiated in the US and Europe.

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