The influence of farnesyl protein transferase inhibitor R115777 (Zarnestra) alone and in combination with purine nucleoside analogs on acute myeloid leukemia progenitors in vitro.
R115777 (Tipifarnib, Zarnestra)-farnesyl transferase inhibitor belongs to the new class of signal transduction inhibitors which seems to be yielding results in the treatment of patients with solid tumors. Recently it has also been considered as a drug of promise in hematologic malignancies such as acute myeloid leukemia (AML), especially in older patients, in chronic myelogenous leukemia (CML) as well as myelodysplastic syndromes (MDS). The aim of our study was to evaluate the influence of R115777 used alone or with purine nucleoside analogs (PNA): cladribine (2-CdA) and fludarabine (F-ara-A) on leukemic progenitors [colony-forming unit-leukemia (CFU)-L] from AML patients. Our studies were based on the methods of semisolid leukemic CFU-L and normal granulocyte-macrophage progenitor (CFU-GM) cultures in vitro. R115777 was added to the culture alone or in combinations with PNA. We showed that R115777 used alone or together with PNA at all combinations significantly inhibited the colony growth of AML CFU-L, when compared with normal CFU-GM (P < 0.01). In addition, the drugs used in combinations of two higher concentrations in significantly higher degree inhibited CFU-L colony growth, when compared either with R115777 or with any of PNA used alone (P < 0.04). IC(50) for R115777 were 67.1 and 121.9 nm for AML CFU-L and normal CFU-GM, respectively. Furthermore, in the case of AML the combination index was 0.89 and 1.16, respectively, for the combination of R115777 with 2-CdA and R115777 with F-ara-A. An additive effect on AML CFU-L cells and subadditive effect on normal CFU-GM were seen. To assess a proapoptotic effect, the drugs were added to the liquid cultures at the same concentrations as for clonogenic assays. A significant increase in the rate of apoptosis induced by combinations of drugs in comparison with single agents was observed. In conclusion, the combination of R115777 with both PNA could be more effective than the drugs used alone. However, further experimental studies on the usefulness of these combinations in the treatment of myeloid leukemia patients are warranted.
Korycka
Anna
A
Department of Hematology, Medical University of Lodz, Lodz, Poland.
Smolewski
Piotr
P
Robak
Tadeusz
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D017338:Cladribine / Q000008:administration & dosage / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007951:Leukemia, Myeloid / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D015363:Quinolones; D017338:Cladribine; D014740:Vidarabine; C402769:tipifarnib; C024352:fludarabine