Vilpo J A, Vilpo L M, Vuorinen P, Moilanen E, Metsä-Ketelä T
Department of Clinical Chemistry, Tampere University Hospital, Finland.
Anticancer Drug Des. 1997 Mar;12(2):75-89.
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.
研究了新型释放一氧化氮（NO）的中氮茚3-芳基取代的恶二唑-5-亚胺衍生物GEA 3162和GEA 3175以及参考NO供体SIN-1在增殖的人造血细胞中的细胞病理学效应。GEA化合物（10 - 50 microM）诱导迅速的表面变化，30分钟内在人白血病T细胞（MOLT-3）中进展为特殊的深度凹陷和狭窄。过量的红细胞部分阻止了这些表面变化。暴露5小时后，经GEA 3162处理的MOLT-3细胞对溴化乙锭变得通透，并失去了被吖啶橙染色的能力。GEA 3162和GEA 3175以剂量依赖的方式抑制胸苷和尿苷掺入，分别反映了对DNA和RNA合成的抑制。此外，GEA化合物抑制人骨髓干细胞的生长，CFU-GM集落比BFU-E对细胞抑制作用更敏感。参考化合物SIN-1在浓度高十倍（500 microM）时具有相当的细胞抑制作用。我们得出结论，释放NO的中氮茚恶二唑衍生物对人恶性和非恶性造血细胞具有细胞抑制作用，支持释放NO和诱导NO的化合物作为抗癌剂的价值。
