ANTITUMOR-ACTIVITY OF SCH-66336, AN ORALLY BIOAVAILABLE TRICYCLIC INHIBITOR OF FARNESYL-PROTEIN TRANSFERASE, IN HUMAN TUMOR XENOGRAFT MODELS AND WAP-RAS TRANSGENIC MICE
M. Liu et al., ANTITUMOR-ACTIVITY OF SCH-66336, AN ORALLY BIOAVAILABLE TRICYCLIC INHIBITOR OF FARNESYL-PROTEIN TRANSFERASE, IN HUMAN TUMOR XENOGRAFT MODELS AND WAP-RAS TRANSGENIC MICE, Cancer research, 58(21), 1998, pp. 4947-4956
We have been developing a series of nonpeptidic, small molecule farnes
yl protein transferase inhibitors that share a common tricyclic nucleu
s and compete with peptide/protein substrates for binding to farnesyl
protein transferase. Here, we report on pharmacological and in vivo st
udies with SCH 66336, a lead compound in this structural class. SCH 66
336 potently inhibits Ha-Pas processing in whole cells and blocks the
transformed growth properties of fibroblasts and human tumor cell line
s expressing activated Ki-Ras proteins. The anchorage-independent grow
th of many human tumor Lines that lack an activated ras oncogene is al
so blocked by treatment with SCH 66336. In mouse, rat, and monkey syst
ems, SCH 66336 has excellent oral bioavailability and pharmacokinetic
properties. In the nude mouse, SCH 66336 demonstrated potent oral acti
vity in a wide array of human tumor xenograft models including tumors
of colon, lung, pancreas, prostate, and urinary bladder origin, Enhanc
ed in vivo efficacy was observed when SCH 66336 was combined with vari
ous cytotoxic agents (cyclophosphamide, 5-fluorouracil, and vincristin
e). In a Ha-Pas transgenic mouse model, prophylactic treatment with SC
H 66336 delayed tumor onset, reduced the average number of tumors/mous
e, and reduced the average tumor weight/animal. In a therapeutic mode
in which gavage treatment was initiated after the transgenic mice had
developed palpable tumors, significant tumor regression was induced by
SCH 66336 in a dose-dependent fashion. This was associated with incre
ased apoptosis and decreased DNA synthesis in tumors of animals treate
d with SCH 66336. Enhanced efficacy was also observed in this model wh
en SCH 66336 was combined with cyclophosphamide. SCH 66336 is presentl
y being evaluated in Phase I clinical trials.