Ribizzi I, Darnowski J W, Goulette F A, Akhtar M S, Chatterjee D, Calabresi P
Department of Medicine, Division of Clinical Pharmacology, Brown University and RI Hospital, Providence, RI, USA.
Bone Marrow Transplant. 2002 Feb;29(4):313-9. doi: 10.1038/sj.bmt.1703359.
Taurolidine has been shown to have remarkable cytotoxic activity against selected human tumor cells at concentrations that spare normal cells. In this study we have extended this observation and assessed the ability of Taurolidine to purge tumor cells from chimeric mixtures of bone marrow (BM) and neoplastic cells. Normal murine BM and human leukemic (HL-60) or ovarian (PA-1) tumor cell lines were used as models. Exposure of tumor cells to 2.5 mM Taurolidine for 1 h resulted in the complete elimination of viable cells. In contrast, exposure of BM to 5 mMTaurolidine for 1 h reduced CFU-GM, BFU-E and CFU-GEEM colony formation by only 23.0%, 19.6% and 25.2%, respectively. Inhibition of long-term BM culture (LTBMC) growth following a 1 h exposure to 5 mM Taurolidine also was approximately 20% compared to untreated LTBMC. Finally, chimeric cultures were generated from BM and HL-60GR or PA-1GR cells (tumor cells transfected with the geneticin resistance gene). Exposure of these chimeric cultures to 5 mM Taurolidine for 1 h totally eliminated viable cancer cells while minimally reducing viable BM cells. This finding was confirmed by subsequent positive selection for surviving tumor cells with geneticin. These findings reveal that Taurolidine holds promise for use in BM purging.
已证明牛磺罗定在不损伤正常细胞的浓度下，对特定人类肿瘤细胞具有显著的细胞毒性活性。在本研究中，我们扩展了这一观察结果，并评估了牛磺罗定从骨髓（BM）和肿瘤细胞的嵌合混合物中清除肿瘤细胞的能力。使用正常小鼠骨髓和人类白血病（HL-60）或卵巢（PA-1）肿瘤细胞系作为模型。将肿瘤细胞暴露于2.5 mM牛磺罗定1小时可导致活细胞完全消除。相比之下，将骨髓暴露于5 mM牛磺罗定1小时，CFU-GM、BFU-E和CFU-GEEM集落形成仅分别减少23.0%、19.6%和25.2%。与未处理的长期骨髓培养（LTBMC）相比，暴露于5 mM牛磺罗定1小时后对LTBMC生长的抑制也约为20%。最后，从骨髓和HL-60GR或PA-1GR细胞（转染了遗传霉素抗性基因的肿瘤细胞）生成嵌合培养物。将这些嵌合培养物暴露于5 mM牛磺罗定1小时可完全消除活的癌细胞，同时使活的骨髓细胞减少到最低程度。这一发现通过随后用遗传霉素对存活肿瘤细胞进行阳性选择得到了证实。这些发现表明牛磺罗定在骨髓净化方面具有应用前景。
