MODULATION OF PURINE ANALOGS-INDUCED AND CHLORAMBUCIL-INDUCED CYTOTOXICITY BY ALPHA-INTERFERON AND INTERLEUKIN-2 IN CHRONIC LYMPHOCYTIC-LEUKEMIA

The decrease in cell viability observed in vitro from the effect of ch lorambucil (CLB), fludarabine (FAMP) and 5-chlorodeoxyadenosine (CDA) on peripheral lymphocytes from 49 untreated CLL patients was investiga ted by the MTT colorimetric assay. The effects of recombinant-interleu kin (r-IL)-2 and alpha-interferon (alpha-IFN) on drug-induced cell dea th were evaluated. r-IL-2 significantly increased in vitro resistance to CLB, while purine analog cytotoxicity was slightly reduced by the c ytokine. The potential in vivo significance of r-IL-2, acting as a sur vival signal on CLB-induced cell death, is supported by the correlatio n between the lowest IL-2 serum levels, the highest in vitro sensitivi ty to CLB and a major clinical response after CLB treatment in six out of eight CLL patients. Using 25 samples, alpha-IFN enabled CLL cells to increase resistance to CLB, CDA and FAMP In 14, eight and seven sam ples, respectively; conversely, alpha-IFN showed a synergism with both CLB and FAMP in six samples and with CDA in four. These results corre late with immunoenzymatic assay data showing that alpha-IFN either up- or down-regulates tumor necrosis factor and IL-1 levels in supernatan ts of some CLL samples. Apparently, alpha-IFN plays a dual role in reg ulating drug-induced cell death, while IL-2 seems to solely favor cell survival in CLL.