van der Hem K G, Schuurhuis G J, Dräger A M, Odding J H, Huijgens P C
Department of Hematology, Free University Hospital, Amsterdam, The Netherlands.
Leuk Res. 1996 Sep;20(9):743-50. doi: 10.1016/0145-2126(96)00031-8.
The potent anti-neoplastic actions displayed in vitro by bryostatins have led to the introduction of short-term bryostatin-1 infusions in phase I clinical trials. Because bryostatin (bryo) undergoes a rapid clearance in vivo, we were interested in its scheduling effects on acute myeloid leukemia (AML) clonogenicity. Therefore, we assessed the primary plating efficiency (PE1) of AML samples in response to several bryo concentrations after various preincubation periods in a semi-solid colony forming assay. Whereas continuous exposure to 10 nM bryo during the assay period reduced the PE1 in nearly all samples tested, preincubation of eight AML patients' specimens for 1, 2, 3 or 4 days with bryo in a dose range of 0.1-10 nM showed a heterogenous PE1 response. Stimulatory as well as inhibitory effects on leukemic clonogenic growth were seen within individual specimens depending on dose and preincubation time with no single incubation time or concentration that caused unequivocal common overall inhibition of clonogenic growth in most or all of the samples. Higher doses of bryo also failed to result in specific inhibition of leukemic cells: 4/8 samples showed an increased clonogenic response to 250 nM bryo whereas normal bone marrow progenitor cells were consistently inhibited in their clonogenicity at this dose. A marked similarity, i.e. undulatory effects with increasing bryo concentrations, was found for HL60 leukemic cells. In conclusion, the effects of bryo on clonogenic leukemia cell growth are strongly dependent on scheduling and dose varying between and within individual AML samples. These results caution against in vivo bryo pulse therapy, as currently applied, for treatment of AML.
苔藓抑素在体外所展现出的强大抗肿瘤作用，已促使其在I期临床试验中采用短期输注苔藓抑素-1的方式。由于苔藓抑素（bryo）在体内清除迅速，我们对其给药方案对急性髓系白血病（AML）克隆形成能力的影响很感兴趣。因此，我们在半固体集落形成试验中，评估了AML样本在不同预孵育时间后对几种苔藓抑素浓度的原发性接种效率（PE1）。在试验期间持续暴露于10 nM苔藓抑素会使几乎所有测试样本中的PE1降低，而将8例AML患者的标本在0.1 - 10 nM剂量范围内用苔藓抑素预孵育1、2、3或4天，结果显示出异质性的PE1反应。根据剂量和预孵育时间，在单个标本中观察到对白血病克隆生长既有刺激作用也有抑制作用，没有单一的孵育时间或浓度能在大多数或所有样本中明确导致对克隆生长的普遍抑制。较高剂量的苔藓抑素也未能特异性抑制白血病细胞：4/8的样本对250 nM苔藓抑素表现出克隆形成反应增加，而在此剂量下正常骨髓祖细胞的克隆形成能力始终受到抑制。对于HL60白血病细胞，发现了一个显著的相似性，即随着苔藓抑素浓度增加呈现波动效应。总之，苔藓抑素对白血病克隆细胞生长的影响强烈依赖于给药方案和剂量，在个体AML样本之间以及样本内部存在差异。这些结果警示了目前应用的体内苔藓抑素脉冲疗法治疗AML的可行性。
