Modulation of purine analogs- 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 chlorambucil (CLB), fludarabine (FAMP) and 2-chlorodeoxy-adenosine (CDA) on peripheral lymphocytes from 49 untreated CLL patients was investigated by the MTT colorimetric assay. The effects of recombinant-interleukin (r-IL)-2 and alpha-interferon (alpha-IFN) on drug-induced cell death were evaluated. r-IL-2 significantly increased in vitro resistance to CLB, while purine analog cytotoxicity was slightly reduced by the cytokine. The potential in vivo significance of r-IL-2, acting as a survival signal on CLB-induced cell death, is supported by the correlation between the lowest IL-2 serum levels, the highest in vitro sensitivity 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 samples, respectively; conversely, alpha-IFN showed a synergism with both CLB and FAMP in six samples and with CDA in four. These results correlate with immunoenzymatic assay data showing that alpha-IFN either up- or down-regulates tumor necrosis factor and IL-1 levels in supernatants of some CLL samples. Apparently, alpha-IFN plays a dual role in regulating drug-induced cell death, while IL-2 seems to solely favor cell survival in CLL.
Morabito
F
F
Centro Trapianti di Midollo Osseo A Neri, Dipartimento di Ematologia, Reggio Calabria, Italy.
Callea
I
I
Rodinò
A
A
Messina
G
G
Callea
V
V
Iacopino
P
P
Nobile
F
F
Brugiatelli
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002699:Chlorambucil / Q000494:pharmacology*; D017338:Cladribine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007375:Interleukin-1 / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000473:pathology* / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D016898:Interferon-alpha; D007375:Interleukin-1; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D002699:Chlorambucil; D017338:Cladribine; D014740:Vidarabine; C024352:fludarabine