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Selection for drug resistance results in resistance to Fas-mediated
apoptosis
TH Landowski, MC Gleason-Guzman and WS Dalton
Department of Medicine, University of Arizona, Tucson, USA.
Recent evidence has supported the hypothesis that chemotherapeutic drugs
and radiation induce an apoptotic pathway that requires the active
participation of the cell. One pathway of apoptosis in malignant lymphoid
cells is mediated by the Fas antigen. We studied the human myeloma (8226)
and T-cell leukemia (CEM) cell lines selected for resistance to the
anthracenes, doxorubicin or mitoxantrone, by continuous culture in the
presence of either agent. We found that these drug-resistant cell lines
were also resistant to Fas-mediated apoptosis in a dose-dependent manner.
The degree of resistance to Fas-mediated apoptosis correlated directly with
the level of resistance to chemotherapeutic drugs. These observations
indicate that, as cancer cell lines develop mechanisms of drug resistance,
they may also develop mechanisms of resistance to physiologic signals of
apoptosis. Two mechanisms of resistance to Fas-mediated apoptosis were
observed in these cell lines. One mechanism was associated with a
dose-dependent reduction in the surface expression of Fas antigen. Analysis
of RNA by reverse transcriptase-polymerase chain reaction assays showed
that the reduction of Fas antigen expression occurred at the level of
transcription. A second mechanism of drug resistance showed no decrease of
Fas antigen expression; however, the apoptotic response was diminished. In
this situation, removal of the chemotherapeutic agent resulted in a partial
reversion to chemosensitivity and re-expression of the Fas antigen, but
these cell lines did not regain the ability to undergo apoptosis in
response to cross-linking by anti-Fas antibody. These findings support the
hypothesis that apoptosis mediated by both chemotherapeutic agents and
physiologic stimuli may share a common downstream effector. The
demonstration that selection for drug resistance in hematopoietic cell
lines results in a simultaneous resistance to Fas-mediated apoptosis may
have clinical implications in the development of strategies for the
treatment of resistant disease. Further analysis of the molecular
mechanisms of Fas expression and function will facilitate the design of
biological response modifying agents for the treatment of malignancy.
Volume 89,
Issue 6,
pp. 1854-1861,
03/15/1997
Copyright © 1997 by The American Society of Hematology
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