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Induction of apoptosis by
flavopiridol (FP) independent of a cell cycle arrest in germ cell tumor (GCT)
cell lines
F. Mayer, S. Koch, E. Malenke, C. Bokemeyer
University of Tuebingen Medical Center, Tuebingen, Germany
Background.
GCTs are highly sensitive to cisplatin-based
chemotherapy.
The inability to arrest the cell cycle at the G1/S-check-point due to a lack of
retinoblastoma gene product (RB) has been suggested as an explanation.
FP, an inhibitor of cyclin dependent kinases, causes cell cycle arrest or
apoptosis depending on the relation of transcription factor E2F1 to RB.
Methods.
The effect of FP was evaluated in GCT-derived cell lines 2102EP,
NT2, and NCCIT in comparison with other solid tumor cell lines (SKOV, MCF7,
HeLa) using the MTT-assay.
Cell cycle progression and induction of apoptosis were followed by flow
cytometry and immunoblot analysis of PARP-cleavage.
Results.
FP did not affect cell cycle and proliferation of GCT cell lines
at sublethal doses.
Cell death occurred independent of cell cycle progression at doses well beneath
plasma concentrations in clinical studies.
The IC50 was 5fold lower for the GCT cell lines (60/60/70 nM) than for the other
cell lines tested (350/280/300 nM).
Sensitivity for FP did not correlate with that for cisplatin.
Flow cytometry and immunoblot for PARP indicated apoptotic cell death induced by
FP.
Synergism between cisplatin or paclitaxel and FP was not observed.
Conclusion.
The data suggest significant antitumor activity of FP in
GCT.
GCT derived cell lines were far more responsive of FP than the cells derived
from other solid tumor models.
No cross resistance between FP and cisplatin was observed.
In contrast to other cell lines tested, GCT derived cell lines did not show cell
cycle arrest after exposure to FP, possibly due to the lack of
RB-expression.
However, already at low concentrations, apoptosis was induced unrelated to cell
cycle progression.
A clinical trial evaluating the single agent activity of FP in patients with
cisplatin-refractory GCTs would be warranted.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-003331,00.asp
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