In vitro effects of the farnesyltransferase inhibitor tipifarnib on myelodysplastic syndrome progenitors.
BACKGROUND
Farnesyltransferase inhibitors (FTIs) target proteins needing prenylation for functioning. Tipifarnib (Zarnestra), a potent and specific inhibitor of farnesyltransferase, showed considerable activity in phase I and II studies in myelodysplastic syndrome (MDS), but the optimal regimen achieving high response rates with minor myelosuppression remains to be determined. Additionally, a direct effect on purified human MDS progenitors has not yet been shown.


METHODS
MDS and normal CD34+ cells isolated by using immunomagnetic beads were plated for short-term cultures in semisolid media or liquid cultures for flow-cytometric assessment of apoptosis in the presence of either DMSO or various FTI concentrations.


RESULTS
Tipifarnib exerted selective in vitro toxicity against clonal MDS hematopoiesis at concentrations less than 10 nM the effect being more prominent in white cell progenitors. This action was not due to apoptosis induction as both normal and MDS progenitors displayed equivalent DiOC3 and annexin V expression up to 72 h after exposure to tipifarnib.


CONCLUSIONS
The leukemic clone is more susceptible in tipifarnib than normal progenitors. Since myelosuppression represents the main obstacle in the clinical use of tipifarnib in MDS, further reduction of the currently employed dose will potentially result in a more tolerable regimen without compromising its antileukemic action.
Kotsianidis
Ioannis
I
Department of Haematology, Democritus University of Thrace, Medical School, Alexandroupolis, Greece. ikotsian@med.duth.gr
Bazdiara
Ioanna
I
Anastasiades
Athanasios
A
Spanoudakis
Emmanouil
E
Pantelidou
Despoina
D
Margaritis
Dimitrios
D
Bourikas
George
G
De Coster
Roland
R
De Porre
Peter
P
Tsatalas
Costas
C
D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D018189:Immunomagnetic Separation; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000187:drug effects* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D015363:Quinolones / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D015363:Quinolones; D051231:Farnesyltranstransferase; C402769:tipifarnib