A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis.
The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultured cells expressing a mutated H-ras gene and induces dramatic regression of mammary and salivary carcinomas in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice. To better understand how the farnesyltransferase inhibitors might be used in the treatment of human tumors, we have further explored the mechanisms by which L-744,832 induces tumor regression in a variety of transgenic mouse tumor models. We assessed whether L-744,832 induces apoptosis or alterations in cell cycle distribution and found that the tumor regression in MMTV-v-Ha-ras mice could be attributed entirely to elevation of apoptosis levels. In contrast, treatment with doxorubicin, which induces apoptosis in many tumor types, had a minimal effect on apoptosis in these tumors and resulted in a less dramatic tumor response. To determine whether functional p53 is required for L-744,832-induced apoptosis and the resultant tumor regression, MMTV-v-Ha-ras mice were interbred with p53(-/-) mice. Tumors in ras/p53(-/-) mice treated with L-744,832 regressed as efficiently as MMTV-v-Ha-ras tumors, although this response was found to be mediated by both the induction of apoptosis and an increase in G1 with a corresponding decrease in the S-phase fraction. MMTV-v-Ha-ras mice were also interbred with MMTV-c-myc mice to determine whether ras/myc tumors, which possess high levels of spontaneous apoptosis, have the potential to regress through a further increase in apoptosis levels. The ras/myc tumors were found to respond nearly as efficiently to L-744,832 treatment as the MMTV-v-Ha-ras tumors, although no induction of apoptosis was observed. Rather, the tumor regression in the ras/myc mice was found to be mediated by a large reduction in the S-phase fraction. In contrast, treatment of transgenic mice harboring an activated MMTV-c-neu gene did not result in tumor regression. These results demonstrate that a farnesyltransferase inhibitor can induce regression of v-Ha-ras-bearing tumors by multiple mechanisms, including the activation of a suppressed apoptotic pathway, which is largely p53 independent, or by cell cycle alterations, depending upon the presence of various other oncogenic genetic alterations.
Barrington
R E
RE
Department of Medicine, The University of Texas Health Science Center at San Antonio, 78284, USA.
Subler
M A
MA
Rands
E
E
Omer
C A
CA
Miller
P J
PJ
Hundley
J E
JE
Koester
S K
SK
Troyer
D A
DA
Bearss
D J
DJ
Conner
M W
MW
Gibbs
J B
JB
Hamilton
K
K
Koblan
K S
KS
Mosser
S D
SD
O'Neill
T J
TJ
Schaber
M D
MD
Senderak
E T
ET
Windle
J J
JJ
Oliff
A
A
Kohl
N E
NE
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051231:Farnesyltranstransferase; D005260:Female; D011905:Genes, ras; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C096898:L 744832; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase