Uggla Bertil, Tina Elisabet, Nahi Hareth, Paul Christer, Höglund Martin, Sirsjö Allan, Tidefelt Ulf
Department of Medicine, Orebro University Hospital, 701 85 Orebro, Sweden.
Int J Oncol. 2007 Jul;31(1):153-60.
The objective of this study was to correlate the expression of topoisomerase (topo) IIalpha to in vitro drug sensitivity and to the clinical outcome in patients with acute leukaemia. Leukaemic cells were isolated from bone marrow or blood from 94 patients. Topo IIalpha mRNA (n=58) and protein (n=60) expression was determined by real-time RT-PCR and flow cytometry, respectively. In both groups, chemosensitivity testing by a bioluminescence ATP assay was performed to a variable extent for both topo IIalpha poisons and non-topo IIalpha targeting drugs. Topo IIalpha mRNA expression varied with relative values ranging from 0.03 to 14.20 (median 1.10). The median value for topo IIalpha protein-positive cells was 23% (range 0-99%). Cell samples from patients with a high (>median value) percentage of topo IIalpha-positive cells were significantly more sensitive to the topo IIalpha active drugs etoposide and daunorubicin, and showed a borderline value for idarubicin (p=0.08), while there was no difference for non-topo IIalpha targeting drugs. However, we did not find any significant differences in mRNA expression or the percentage of topo IIalpha-positive cells in patients who achieved complete remission after at most two induction courses compared with those who did not, nor did we find any difference in survival when patients with high mRNA expression/percentage of topo IIalpha-positive cells were compared with patients with low values. We conclude that expression of topo IIalpha, determined as percentage of topo IIalpha-positive cells, in leukaemic cells correlates to chemosensitivity in vitro against topoisomerase poisons but that it does not predict clinical outcome in acute leukaemia.
本研究的目的是将拓扑异构酶（topo）IIα的表达与急性白血病患者的体外药物敏感性及临床结局相关联。从94例患者的骨髓或血液中分离白血病细胞。分别通过实时逆转录聚合酶链反应（RT-PCR）和流式细胞术测定topo IIα信使核糖核酸（mRNA）（n = 58）和蛋白（n = 60）的表达。在两组中，对topo IIα毒药和非topo IIα靶向药物均不同程度地进行了生物发光ATP检测法的化学敏感性测试。topo IIα mRNA表达的相对值范围为0.03至14.20（中位数为1.10）。topo IIα蛋白阳性细胞的中位数为23%（范围为0至99%）。topo IIα阳性细胞百分比高（>中位数）的患者的细胞样本对topo IIα活性药物依托泊苷和柔红霉素明显更敏感，对伊达比星显示临界值（p = 0.08），而对非topo IIα靶向药物则无差异。然而，我们并未发现最多经过两个诱导疗程后达到完全缓解的患者与未达到完全缓解的患者在mRNA表达或topo IIα阳性细胞百分比方面存在任何显著差异，将topo IIα mRNA高表达/topo IIα阳性细胞百分比高的患者与低表达/低百分比的患者进行生存比较时也未发现差异。我们得出结论，白血病细胞中以topo IIα阳性细胞百分比确定的topo IIα表达与体外对拓扑异构酶毒药的化学敏感性相关，但不能预测急性白血病的临床结局。
