Comparative activity of melarsoprol and arsenic trioxide in chronic B-cell leukemia lines.
Inorganic arsenic trioxide (As2O3) was recently shown to induce apoptosis in NB4 promyelocytic leukemic cells. We have investigated the effects of the organic arsenical, melarsoprol (a drug used for treatment of trypanosomiasis), upon induction of apoptosis in cell lines representative of chronic B-cell lymphoproliferative disorders. An Epstein-Barr virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), an EBV-transformed B-cell chronic lymphocytic leukemia (B-CLL) cell line (I83CLL), and one non-EBV-transformed B-CLL cell line (WSU-CLL) were used as targets. Dose-response experiments with melarsoprol (10(-7) to 10(-9) mol/L) were performed over 96 hours. Unexpectedly, we found that melarsoprol caused a dose- and time-dependent inhibition of survival and growth in all three cell lines. In contrast, As2O3 at similar concentrations had no effect on either viability or growth. After 24 hours, all three cell lines treated with melarsoprol (10(-7) mol/L) exhibited morphologic characteristics of apoptosis. We also observed prominent concentration-dependent downregulation of bcl-2 mRNA after 24 hours of exposure to melarsoprol in WSU-CLL, I83CLL, and JVM-2 cells. Decrease of bcl-2 protein expression was also observed in all three cell lines, whereas As2O3 had no effect on this parameter. We conclude that melarsoprol may inhibit the growth of lymphoid leukemic cell by promoting programmed cell death. Results of these studies suggest that melarsoprol shows promising therapeutic activity in these diseases, and a study to evaluate clinical effects of this drug has been initiated.
König
A
A
Sloan-Kettering Institute, the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Wrazel
L
L
Warrell
R P
RP
Rivi
R
R
Pandolfi
P P
PP
Jakubowski
A
A
Gabrilove
J L
JL
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D020261:Arsenic Poisoning; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D053938:DNA Fragmentation; D004354:Drug Screening Assays, Antitumor; D004854:Herpesvirus 4, Human; D006801:Humans; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008549:Melarsoprol / Q000633:toxicity*; D010087:Oxides / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D000077237:Arsenic Trioxide; D008549:Melarsoprol