Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy.
Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy.
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发表时间：
1998-12
期刊：
影响因子：
11.2
通讯作者：
N. Keshelava;R. Seeger;S. Groshen;P. Reynolds
中科院分区：
文献类型：
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作者：
N. Keshelava;R. Seeger;S. Groshen;P. Reynolds
为了确定神经母细胞瘤是否因体内暴露于给予患者的化疗药物而获得持续的耐药表型，我们研究了在不同治疗时间点建立的神经母细胞瘤细胞系：治疗前诊断时（DX）6个，诱导治疗期间疾病进展时6个（PD-Ind），强化放化疗和骨髓移植（PD-BMT）后复发时5个。在没有药物选择压力的情况下维持细胞。通过使用96孔板数字成像显微镜（DIMSCAN）微量测定法测量细胞毒性，确定美法仑、顺铂、卡铂、阿霉素和依托泊苷对细胞系组的剂量-反应曲线。细胞系的耐药性随着体内递送的治疗强度而逐渐增加。在PD-BMT细胞系中观察到最大的耐药性：PD-BMT细胞系中的IC 90值比临床可达到的药物水平高1-37倍（美法仑）、1-9倍（卡铂）、25-78倍（顺铂）、6-719倍（多柔比星）和3-52倍（依托泊苷）。MYCN基因组扩增与抗性无关。Pearson相关分析（r ≥ 0.6）显示：（a）顺铂+多柔比星;（B）卡铂+顺铂、依托泊苷或美法仑;（c）依托泊苷+顺铂、美法仑或多柔比星之间存在交叉耐药。这些数据表明，在治疗过程中，神经母细胞瘤可以获得对细胞毒性药物的耐药性，因为肿瘤细胞的群体扩增具有稳定的遗传或表观遗传改变，赋予耐药性。
To determine whether neuroblastomas acquire a sustained drug-resistant phenotype from exposure to chemotherapeutic agents given to patients in vivo, we studied neuroblastoma cell lines established at different points of therapy: six at diagnosis before therapy (DX), six at progressive disease during induction therapy (PD-Ind), and five at relapse after intensive chemoradiotherapy and bone marrow transplantation (PD-BMT). Cells were maintained in the absence of drug selective pressure. Dose-response curves of melphalan, cisplatin, carboplatin, doxorubicin, and etoposide for the cell line panel were determined by measuring cytotoxicity with a 96-well-plate digital imaging microscopy (DIMSCAN) microassay. Drug resistance of cell lines progressively increased with the intensity of therapy delivered in vivo. The greatest resistance was seen in PD-BMT cell lines: IC90 values in PD-BMT cell lines were higher than clinically achievable drug levels by 1-37 times for melphalan, 1-9 times for carboplatin, 25-78 times for cisplatin, 6-719 times for doxorubicin, and 3-52 times for etoposide. Genomic amplification of MYCN did not correlate with resistance. Cross-resistance by Pearson correlation (r > or = 0.6) was observed between: (a) cisplatin + doxorubicin; (b) carboplatin + cisplatin, etoposide, or melphalan; (c) etoposide + cisplatin, melphalan, or doxorubicin. These data indicate that during therapy, neuroblastomas can acquire resistance to cytotoxic drugs because of the population expansion of tumor cells possessing stable genetic or epigenetic alterations that confer resistance.