Dw. End et al., Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro, CANCER RES, 61(1), 2001, pp. 131-137
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.