Mode of cytostatic action of mesoionic oxatriazole nitric oxide donors in proliferating human hematopoietic cells.
The cytopathological effects of the novel nitric oxide (NO)-releasing, mesoionic 3-aryl-substituted oxatriazole-5-imine derivatives GEA 3162 and GEA 3175, and a reference NO donor SIN-1 were investigated in proliferating human hematopoietic cells. The GEA compounds (10-50 microM) induced rapid surface changes, which progressed as peculiar deep indentations and strictures in human leukemic T cells (MOLT-3) in 30 min. An excess of red cells partially prevented these surface changes. GEA 3162-treated MOLT-3 cells became permeable to ethidium bromide and lost their ability to be stained by acridine orange after 5 h of exposure. GEA 3162 and GEA 3175 suppressed thymidine and uridine incorporation in a dose-dependent manner, reflecting the inhibition of DNA and RNA synthesis respectively. In addition, the GEA compounds inhibited the growth of human bone marrow stem cells, CFU-GM colonies being more susceptible to the cytostatic action than BFU-E. The reference compound SIN-1 had comparative cytostatic effects at ten times greater concentrations (500 microM). We conclude that NO-releasing mesoionic oxatriazole derivatives have cytostatic action against human malignant and non-malignant hematopoietic cells, supporting the value of NO-releasing and NO-inducing compounds as anti-cancer agents.
Vilpo
J A
JA
Department of Clinical Chemistry, Tampere University Hospital, Finland.
Vilpo
L M
LM
Vuorinen
P
P
Moilanen
E
E
Metsä-Ketelä
T
T
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009569:Nitric Oxide / Q000493:pharmacokinetics / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C093084:GEA 3175; D009363:Neoplasm Proteins; D010975:Platelet Aggregation Inhibitors; D012334:RNA, Neoplasm; D014230:Triazoles; D009569:Nitric Oxide; C002385:linsidomine; C082874:GEA 3162; D008981:Molsidomine