Killing of target cells by cytotoxic T cells is mediated by induction of ap
optosis requiring functional death pathways. Kill is mediated either by the
CD95 or the perforin/granzyme pathway. We found that SH-EP neuroblastoma c
ells are preferentially kilted via CD95, while in the T leukemia cell line
CEM CD95 and perforin/granzyme are involved. In both types of cell lines, c
ells resistant to CD95- and drug-induced apoptosis are cross-resistant to c
ytotoxic T cell kill. Resistant cells show decreased apoptosis and deficien
t activation of caspases indicated by decreased cleavage of the prototype c
aspase substrate PARP. Preincubation with the caspase inhibitor zVAD-fmk st
rongly decreased LAK cell kill in sensitive cells. Although parental CEM ce
lls could be sensitized for LAK kill by preincubation with doxorubicin, res
istance could not be reverted in doxorubicin or CD95 resistant CEM cells. T
hese data demonstrate the crossresistance in induction of apoptosis by diff
erent cytotoxic regimens in tumor cells and may have implications for the i
mmunotherapy of tumors in which apoptosis resistance was induced by previou
s chemotherapy.