The farnesyl transferase inhibitor SCH 66336 induces a G(2) --> M or G(1) pause in sensitive human tumor cell lines.
SCH 66336 is a potent farnesyl transferase inhibitor (FTI) in clinical development. It efficiently prevents the membrane association of H-ras, but not K- or N-ras. Yet, in soft agar, it reverts the anchorage-independent growth of human tumor cell lines (hTCLs) harboring H-ras, K-ras, and N-ras mutations, implying that blocking farnesylation of proteins besides ras may be responsible for this effect. Experiments show that SCH 66336 altered the cell cycle distribution of sensitive human tumor cells in two distinct ways. Most sensitive hTCLs accumulated in the G(2)-->M phase after the FTI treatment, but those with an activated H-ras accumulated in G(1) phase, suggesting that the biological effects induced by FTIs in cells with an activated H-ras are distinct from other sensitive cells. A careful genotypic comparison of the hTCLs revealed that those cells with wild-type p53 are especially sensitive to the FTIs. In these cells p53 and its downstream target gene p21(Cip1) are induced after treatment with SCH 66336 for 24 h. These data suggest that cell cycle effects, either G(1) or G(2)-->M accumulation, and p53 status are important for mediating the effects of FTIs on tumor cells.
Ashar
H R
HR
Department of Tumor Biology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey, 07033, USA.
James
L
L
Gray
K
K
Carr
D
D
McGuirk
M
M
Maxwell
E
E
Black
S
S
Armstrong
L
L
Doll
R J
RJ
Taveras
A G
AG
Bishop
W R
WR
Kirschmeier
P
P
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051231:Farnesyltranstransferase; D016193:G1 Phase; D016195:G2 Phase; D006801:Humans; D020014:K562 Cells; D007700:Kinetics; D051379:Mice; D008938:Mitosis; D015394:Molecular Structure; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D015689:Oncogene Protein p21(ras); D010880:Piperidines; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C115354:lonafarnib; D003986:Dibenzocycloheptenes