Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis.
Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30% of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma membrane and thereby prevent activity of these prenylation-dependent proteins, but their mechanism of tumor suppression remains unknown. Many patients receiving FTIs do experience myelosuppression. In this work, the in vitro effects of the FTI, R115777 on normal and leukemic hematopoiesis have been examined as have its effects on apoptosis induction and cell cycle profile in both leukemic blasts and normal CD34+ cells. R115777 was inhibitory to normal CD34+ cell proliferation and to leukemic blast cells, but did not affect long-term culture initiating cell frequency nor NOD-SCID reconstituting capacity. No induction of apoptosis or cell cycle changes were noted in AML blasts. These data suggest that myelosuppression with R115777 occurs largely at the intermediate to late progenitor stage of hematopoiesis and that cyclic use might avoid long-term marrow suppression.
Liesveld
J L
JL
James P Wilmot Cancer Center and the Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
Lancet
J E
JE
Rosell
K E
KE
Menon
A
A
Lu
C
C
McNair
C
C
Abboud
C N
CN
Rosenblatt
J D
JD
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000637:transplantation
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D011065:Poly(ADP-ribose) Polymerases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C402769:tipifarnib