ANTITUMOR-ACTIVITY OF SCH-66336, AN ORALLY BIOAVAILABLE TRICYCLIC INHIBITOR OF FARNESYL-PROTEIN TRANSFERASE, IN HUMAN TUMOR XENOGRAFT MODELS AND WAP-RAS TRANSGENIC MICE

Citation
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
Citations number
45
Categorie Soggetti
Oncology
Journal title
ISSN journal
00085472
Volume
58
Issue
21
Year of publication
1998
Pages
4947 - 4956
Database
ISI
SICI code
0008-5472(1998)58:21<4947:AOSAOB>2.0.ZU;2-4
Abstract
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.