Wierenga P K, Setroikromo R, Vellenga E, Kampinga H H
Department of Radiation and Stress Cell Biology, University of Groningen, Groningen, The Netherlands.
Br J Haematol. 2000 Dec;111(4):1145-52. doi: 10.1046/j.1365-2141.2000.02469.x.
Hyperthermia has been shown to be a potential purging modality in autologous stem cell transplantation settings owing to its selective toxicity towards leukaemic cells. We describe two approaches to further increase the therapeutic index of the hyperthermic purging modality by using normal murine bone marrow cells and a murine model for acute myeloid leukaemia. First, the tetrapeptide AcSDKP was used to protect the normal haematopoietic progenitor cells against hyperthermic damage. Pretreatment for 8 h at 37 degrees C with 1 x 10(-9) mol/l AcSDKP resulted in a decrease in hyperthermic sensitivity of only normal haematopoietic progenitor cells. This combined treatment protocol revealed a therapeutic index (ratio of surviving fractions of normal vs. leukaemic cells) of > 500, which was considered to be sufficient for purging. This was confirmed in vivo by the survival of lethally irradiated recipients transplanted with purged simulated remission bone marrow (1 x 10(6) normal bone marrow cells and 5 x 10(4) leukaemic cells). A further increase of the therapeutic index cells was achieved by the alkyl-lysophospholipid ET-18-OCH(3). An incubation for 4 h at 37 degrees C with 25 microg/ml in the presence of 5% fetal calf serum preferentially enhanced the cytotoxic effect towards the leukaemic stem cell. The combination of AcSDKP and ET-18-OCH(3) with hyperthermia resulted in a therapeutic index of > 5000. This enabled a reduction of the hyperthermic treatment and will further minimize the toxicity to normal haematopoietic stem cell subsets, while a therapeutic index far above the required value is achieved. This tripartite purging treatment therefore offers a safe and fast purging protocol for the elimination of residual leukaemic cells in autografts.
由于热疗对白血病细胞具有选择性毒性，它已被证明是自体干细胞移植环境中的一种潜在净化方式。我们描述了两种方法，通过使用正常小鼠骨髓细胞和急性髓性白血病小鼠模型来进一步提高热疗净化方式的治疗指数。首先，使用四肽AcSDKP保护正常造血祖细胞免受热损伤。在37℃下用1×10⁻⁹mol/L AcSDKP预处理8小时，仅导致正常造血祖细胞的热敏感性降低。这种联合治疗方案显示治疗指数（正常细胞与白血病细胞存活分数之比）>500，这被认为足以进行净化。通过移植经净化的模拟缓解期骨髓（1×10⁶个正常骨髓细胞和5×10⁴个白血病细胞）的致死性照射受体的存活情况在体内得到了证实。通过烷基溶血磷脂ET-18-OCH₃进一步提高了治疗指数。在5%胎牛血清存在下，于37℃用25μg/ml孵育4小时，优先增强了对白血病干细胞的细胞毒性作用。AcSDKP和ET-18-OCH₃与热疗联合使用导致治疗指数>5000。这使得热疗治疗得以减少，并将进一步使对正常造血干细胞亚群的毒性降至最低，同时实现远高于所需值的治疗指数。因此，这种三方净化治疗为消除自体移植物中残留的白血病细胞提供了一种安全、快速的净化方案。
