RADIATION-INDUCED APOPTOSIS IN HUMAN TUMOR-CELL LINES - ADAPTIVE RESPONSE AND SPLIT-DOSE EFFECT

Irradiation of human ovarian carcinoma cells (OVCAR 3) and myeloma cel ls (RPMI 8226) with graded doses of' Cs-137-gamma-rays led to a 35-40% increase in time-dependent apoptosis 72 hr after 6-8 Gy irradiation. Large individual variations in sensitivity to radiation-induced apopto sis were noted in human lymphocytes obtained from 5 donors. Pretreatme nt of OVCAR 3 and RPMI 8226 cells with 0.01 Gy increased their resista nce to apoptosis after subsequent 6 Gy irradiation several hours or 48 and 72 hr later. A dose of 4 or 8 Gy given in 2 equal fractions at an interval of a few hours produced a raw level of apoptosis compared to that resulting from a single administration of the same total dose. A daptive response was demonstrated in 2 out of 3 samples of human lymph ocytes isolated from different donors, and no split-dose effect for ap optosis was noted in 2 other donors, In split-dose experiments, there was no correlation between the sensitivity of cells to apoptosis and t heir position in the cell cycle, after the first: half-dose. No G(1) b lock was observed in irradiated cell lines. Adaptive response and spli t-dose effect were prevented by 3-aminobenzamide and okadaic acid whic h inhibit poly(ADP-ribose)polymerase and protein phosphatase, respecti vely. These results imply a common mechanism for acquired resistance t o radiation-induced apoptosis in adaptive response and the split-dose effect. (C) 1998 Wiley-Liss, Inc.