Lonafarnib is an orally bioavailable farnesyl protein transferase (FPTase) inhibitor for H-ras, K-ras and N-ras with IC₅₀ of 1.9 nM, 5.2 nM and 2.8 nM, respectively. Lonafarnib has anti-hepatitis delta virus (HDV) activities. IC50 & Target: IC50: 1.9 nM (H-ras), 5.2 nM (K-ras), 2.8 nM (N-ras)^[1] In Vitro: Lonafarnib (Sch66336) potently inhibits Ha-Ras processing in whole cells and blocks the trans formed growth properties of fibroblasts and human tumor cell lines expressing activated Ki-Ras proteins^[1]. All treatment groups containing Lonafarnib (10 µM) show a significantly higher level of unfarnesylated H-Ras (116-137%) compared to control treatment^[2]. In Vivo: In mouse, rat, and monkey systems, Lonafarnib (Sch66336) has excellent oral bioavailability and pharmacokinetic properties. In the nude mouse, Lonafarnib demonstrates potent oral activity in a wide array of human tumor xenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin^[1]. Lonafarnib alone (80 mg/kg by oral gavage, once daily) has limited ability to inhibit orthotopic U87 tumors compared to vehicle treated control animals (T/C of 0.67). The combination of XRT/Tem (2.5Gy/day for 2 days; 5 mg/kg by oral gavage 90 min prior to XRT) is designed to produce modest tumor growth inhibition in vivo(T/C of 0.42). Concurrent Lonafarnib/XRT/Tem (Lonafarnib 80 mg/kg by oral gavage, once daily, XRT 2.5Gy/day for 2 days, and Tem 5 mg/kg by oral gavage 90 min prior to XRT) provides the strongest growth reduction (T/C of 0.02) and is significantly more effective than XRT/Tem (p<0.04), with the majority of animals demonstrating a decrease in tumor volume (p<0.05) after two weeks and persisting after 4 weeks (p<0.05)^[2].