PMID- 9418856
OWN - NLM
STAT- MEDLINE
DCOM- 19980122
LR  - 20210526
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 18
IP  - 1
DP  - 1998 Jan
TI  - A farnesyltransferase inhibitor induces tumor regression in transgenic mice 
      harboring multiple oncogenic mutations by mediating alterations in both cell 
      cycle control and apoptosis.
PG  - 85-92
AB  - 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.
FAU - Barrington, R E
AU  - Barrington RE
AD  - Department of Medicine, The University of Texas Health Science Center at San 
      Antonio, 78284, USA.
FAU - Subler, M A
AU  - Subler MA
FAU - Rands, E
AU  - Rands E
FAU - Omer, C A
AU  - Omer CA
FAU - Miller, P J
AU  - Miller PJ
FAU - Hundley, J E
AU  - Hundley JE
FAU - Koester, S K
AU  - Koester SK
FAU - Troyer, D A
AU  - Troyer DA
FAU - Bearss, D J
AU  - Bearss DJ
FAU - Conner, M W
AU  - Conner MW
FAU - Gibbs, J B
AU  - Gibbs JB
FAU - Hamilton, K
AU  - Hamilton K
FAU - Koblan, K S
AU  - Koblan KS
FAU - Mosser, S D
AU  - Mosser SD
FAU - O'Neill, T J
AU  - O'Neill TJ
FAU - Schaber, M D
AU  - Schaber MD
FAU - Senderak, E T
AU  - Senderak ET
FAU - Windle, J J
AU  - Windle JJ
FAU - Oliff, A
AU  - Oliff A
FAU - Kohl, N E
AU  - Kohl NE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (L 744832)
RN  - AE28F7PNPL (Methionine)
RN  - EC 2.5.- (Alkyl and Aryl Transferases)
RN  - EC 2.5.1.29 (Farnesyltranstransferase)
SB  - IM
MH  - Alkyl and Aryl Transferases/*antagonists & inhibitors
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Apoptosis/*drug effects
MH  - Carcinoma/drug therapy/*genetics/pathology
MH  - Cell Cycle/drug effects
MH  - Enzyme Inhibitors/*pharmacology/therapeutic use
MH  - Farnesyltranstransferase
MH  - Female
MH  - Genes, ras
MH  - Humans
MH  - Mammary Neoplasms, Experimental/drug therapy/*genetics/pathology
MH  - Mammary Tumor Virus, Mouse
MH  - Methionine/*analogs & derivatives/pharmacology/therapeutic use
MH  - Mice
MH  - Mice, Transgenic
MH  - Salivary Gland Neoplasms/drug therapy/*genetics/pathology
PMC - PMC121456
EDAT- 1998/01/07 00:00
MHDA- 1998/01/07 00:01
PMCR- 1998/01/01
CRDT- 1998/01/07 00:00
PHST- 1998/01/07 00:00 [pubmed]
PHST- 1998/01/07 00:01 [medline]
PHST- 1998/01/07 00:00 [entrez]
PHST- 1998/01/01 00:00 [pmc-release]
AID - 1234 [pii]
AID - 10.1128/MCB.18.1.85 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1998 Jan;18(1):85-92. doi: 10.1128/MCB.18.1.85.