CLONAL VARIABILITY OF RADIATION-INDUCED CISPLATIN-RESISTANT HELA-CELLS

Low-dose fractionated gamma-irradiation (3 cycles of 5x2 Gy) induces m oderate cisplatin resistance in HeLa cells which is associated with al terations of the caspase-dependent apoptotic pathway (2). There is a c onsiderable heterogeneity in cell survival among isolated resistant cl ones (R-f values between 1.4 to 2.4) and in the propensity of the cell s to enter apoptosis. These variations are associated with altered act ivation of the apoptotic pathway by members of the TNF family. The mem brane receptor CD95 (Apo-1/Fas), which is upregulated immediately afte r cisplatin exposure in parental HeLa cells, is expressed at various l evels in the resistant clones. There are also changes in the formation of the inhibitor protein I kappa B, which regulates the antiapoptotic transcription factor NF kappa B. Since the response to radiation is u nchanged, the results collectively suggest that changes in the activat ion of the caspase-dependent signalling cascade are involved in the de ath pathway initiated by cisplatin but not by radiation damage.