Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice.
For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.
Kohl
N E
NE
Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Omer
C A
CA
Conner
M W
MW
Anthony
N J
NJ
Davide
J P
JP
deSolms
S J
SJ
Giuliani
E A
EA
Gomez
R P
RP
Graham
S L
SL
Hamilton
K
K
D019883:Alkyl and Aryl Transferases; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D011905:Genes, ras; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D012468:Salivary Gland Neoplasms / Q000188:drug therapy*; D014166:Transferases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C096898:L 744832; D008715:Methionine; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase