Farnesyltransferase Inhibitors as Potential Anticancer Agents

2001 ◽  
pp. 190-198
Author(s):  
J. B. Gibbs ◽  
N. J. Anthony ◽  
I. Bell ◽  
C. A. Buser ◽  
J. P. Davide ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Farnesyltransferase Inhibitors

Design of peptidomimetic farnesyltransferase inhibitors as anticancer agents

2002 ◽  
pp. 461-462
Author(s):  
Seonggu Ro ◽  
Jinho Lee ◽  
Seon-Goan Baek ◽  
Hae Yeon Cho ◽  
Jong Hyun Kim ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Farnesyltransferase Inhibitors

scholarly journals Structure-Based Design and Synthesis of Potent, Ethylenediamine-Based, Mammalian Farnesyltransferase Inhibitors as Anticancer Agents

2010 ◽  
Vol 53 (19) ◽  
pp. 6867-6888 ◽  
Author(s):  
Steven Fletcher ◽  
Erin Pusateri Keaney ◽  
Christopher G. Cummings ◽  
Michelle A. Blaskovich ◽  
Michael A. Hast ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Farnesyltransferase Inhibitors ◽  
Design And Synthesis

Treatment of Imatinib-Sensitive and -Resistant Chronic Myelogenous Leukemia Cells with a Combination of Imatinib and Farnesyltransferase Inhibitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4881-4881 ◽  
Author(s):  
Aleksandar Radujkovic ◽  
Julian Topaly ◽  
W. Jens Zeller ◽  
Anthony D. Ho ◽  
Stefan Fruehauf
Keyword(s):  
Cell Line ◽  
Anticancer Agents ◽  
Apoptotic Cell ◽  
Synergistic Effects ◽  
Myelogenous Leukemia ◽  
Strong Increase ◽  
Imatinib Treatment ◽  
Farnesyltransferase Inhibitors ◽  
Sensitive Cell ◽  
Sensitive Cell Line

Abstract Farnesyl protein transferase inhibitors (FTIs) represent a new class of anticancer agents. We were interested whether the farnesyltransferase inhibitors L-744,832 and LB42918 alone and in combination with imatinib are active in imatinib-sensitive and -resistant CML cells. LB42918 was more potent with ED50 = 4 ± 1 μM (mean ± S.D., n = 3) in the BCR-ABL+ imatinib-sensitive cell line EM-3 vs. ED50 = 25 ± 2 μM for L-744,832 after 48 hrs of treatment and assessment by MTT assay. The growth of imatinib-sensitive K562 and LAMA84 cells was not measurably inhibited by L-744,832 doses up to 25 μM. Similarly, the growth of K562 was not affected by 25 μM of LB42918. However, for LB42918 in LAMA84 cells an ED50 value of 30 ± 11 μM could be determined. In the imatinib-sensitive cell line EM-3, combination index values (CI) obtained using the method of Chou and Talalay indicated synergistic effects following simultaneous treatment with imatinib and FTI (CI = 0.5 ± 0.2 and 0.7 ± 0.2 at ED75 for imatinib + L-744,832 and imatinib + LB42918 respectively). In the cell imatinib-sensitive and -resistant lines K562 and LAMA84 a trend to lower ED50 values of imatinib was determined when up to 16 μM of L-744,832 or LB42918 were added, indicating potentiation of imatinib activity. Annexin V / propidium showed a strong increase of the apoptotic cell fraction in all imatinib-sensitive and an increase in the imatinib-resistant cells treated for 48 hrs by the combination imatinib + L-744,832 or imatinib + LB42918 as compared to treatment with each drug alone. Growth inhibition of CFU-GM colonies of primary imatinib-sensitive CML cells obtained from 4 patients is stronger after treatment with different concentrations of the combination of both drugs than after monotherapy with either imatinib or L-744,832. On the basis of the observed potentiation effects FTIs may find their place as supplement for CML patients on imatinib treatment.

scholarly journals Pharmacotherapy of Hematologic Malignancies with Tipifarnib

2009 ◽  
Vol 1 ◽  
pp. CMT.S1097
Author(s):  
Ioannis Kotsianidis ◽  
Evangelia Nakou ◽  
Irene Bouchliou
Keyword(s):  
Anticancer Agents ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Specific Inhibitor ◽  
Hematologic Malignancies ◽  
Farnesyltransferase Inhibitors ◽  
Cellular Processes ◽  
Predictors Of Response ◽  
Inhibition Of Tumor Growth ◽  
Molecular Aberrations

The illumination of cellular processes in cancer has revolutionized oncology drug development leading to a shift from non-specific chemotherapy to the selective targeting of tumorigenic signal transduction pathways. Farnesyltransferase inhibitors (FTIs) target proteins needing prenylation for functioning, thus inhibiting a wide variety of molecular targets crucial for cell proliferation and survival. Tipifarnib (R115777, Zarnestra®), a potent and specific inhibitor of Farnesyltransferase, can attain strong inhibition of tumor growth in preclinical models. As a single agent, tipifarnib has demonstrated activity in several hematologic malignancies, namely acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and multiple myeloma. However, considering the complexity of the molecular aberrations implicated in the pathogenesis of hematologic neoplasms, it is rather unlikely that monotherapy with tipifarnib will serve as a stand-alone treatment approach. Indeed, improved results have been achieved by combining tipifarnib with other anticancer agents, whereas the first efforts for the identification of molecular predictors of response are reporting intriguing results. Ongoing trials are anticipated to define the exact role of tipifarnib in the treatment of hematologic malignancies.

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