Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro

R115777 {(B)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)-methyl]-4- (3-chlorophenyl)-1-methyl-2(1H )-quinolinone} is a potent and selective inh ibitor of farnesyl protein transferase with significant antitumor effects i n vivo subsequent to oral administration in mice. In vitro, using isolated human farnesyl protein transferase, R115777 competitively inhibited the far nesylation of lamin B and K-RasB peptide substrates, with IC(50)s of 0.86 n M and 7.9 nM, respectively. In a panel of 53 human tumor cell lines tested for growth inhibition, similar to 75% were found to be sensitive to R115777 , The majority of sensitive cell, lines had a wild-type ras gene. Tumor cel l lines bearing H-ras or N-ras mutations were among the most sensitive of t he cell lines tested, with responses observed at nanomolar concentrations o f R115777. Tumor cell lines bearing mutant K-ras genes required higher conc entrations for inhibition of cell growth, with 50 % of the cell lines resis tant to R115777 up to concentrations of 500 nM. Inhibition of H-Ras, N-Ras, and lamin B protein processing was observed at concentrations of R115777 t hat inhibited cell proliferation. However, inhibition of K-RasB protein-pro cessing could not be detected. Oral administration b.i.d. of R115777 to nud e mice bearing s.c. tumors at doses ranging from 6.25-100 mg/kg inhibited t he growth of tumors bearing mutant H-ras, mutant K-ras, and wild-type ras g enes. Histological evaluations revealed heterogeneity in tumor responses to R115777. In LoVo human colon tumors, treatment with R115777 produced a pro minent antiangiogenic response. In CAPAN-2 human pancreatic tumors, an anti proliferative response predominated, whereas in C32 human melanoma, marked induction of apoptosis was observed. The heterogeneity of histological chan ges associated with antitumor effects suggested that R115777, and possibly farnesyl protein transferase inhibitors as a class, alter processes of tran sformation related to tumor-host interactions in addition to inhibiting tum or-cell proliferation.