Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia.
BCR/ABL, the oncoprotein responsible for chronic myeloid leukemia (CML), transforms hematopoietic cells through both Ras-dependent and -independent mechanisms. Farnesyl protein transferase inhibitors (FTIs) were designed to block mutant Ras signaling, but they also inhibit the growth of transformed cells with wild-type Ras, implying that other farnesylated targets contribute to FTI action. In the current study, the clinical candidate FTI SCH66336 was characterized for its ability to inhibit BCR/ABL transformation. When tested against BCR/ABL-BaF3 cells, a murine cell line that is leukemogenic in mice, SCH66336 potently inhibited soft agar colony formation, slowed proliferation, and sensitized cells to apoptotic stimuli. Quantification of activated guanosine triphosphate (GTP)-bound Ras protein and electrophoretic mobility shift assays for AP-1 DNA binding showed that Ras effector pathways are inhibited by SCH66336. However, SCH66336 was more inhibitory than dominant-negative Ras in assays of soft agar colony formation and cell proliferation, suggesting activity against targets other than Ras. Cell cycle analysis of BCR/ABL-BaF3 cells treated with SCH66336 revealed G2/M blockade, consistent with recent reports that centromeric proteins that regulate the G2/M checkpoint are critical farnesylated targets of FTI action. Mice injected intravenously with BCR/ABL-BaF3 cells developed acute leukemia and died within 4 weeks with massive splenomegaly, elevated white blood cell counts, and anemia. In contrast, nearly all mice treated with SCH66336 survived and have remained disease-free for more than a year. Furthermore, SCH66336 selectively inhibited the hematopoietic colony formation of primary human CML cells. As an oral, nontoxic compound with a mechanism of action distinct from that of ABL tyrosine kinase inhibition, FTI SCH66336 shows promise for the treatment of BCR/ABL-induced leukemia.
Peters
D G
DG
Whitehead Institute, Cambridge, MA; Division of Hematology/ Oncology, Massachusetts General Hospital, Boston, MA 02142, USA.
Hoover
R R
RR
Gerlach
M J
MJ
Koh
E Y
EY
Zhang
H
H
Choe
K
K
Kirschmeier
P
P
Bishop
W R
WR
Daley
G Q
GQ
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism*; D051231:Farnesyltranstransferase; D016313:Genes, abl / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D015996:Survival Rate; D014170:Transformation, Genetic; D014407:Tumor Cells, Cultured; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes