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Action of topoisomerase targeting drugs on Non-Hodgkin's lymphoma and leukemia: Correlation of clinical and cell culture studies.

机译：拓扑异构酶靶向药物对非霍奇金淋巴瘤和白血病的作用：临床和细胞培养研究的相关性。

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摘要

In two different phase I clinical studies, Non-Hodgkin's lymphoma patients were treated with combination of topotecan (SKF 104864, Hycamptamine) and etoposide (VP16) while acute leukemia patients were treated with combination of topotecan and Ara-C. Peripheral blood samples were withdrawn from patients immediately after administration of topotecan or VP16, and mixed with Sarkosyl to trap the topoisomerase-DNA covalent complexes for the In Vivo Link assay (Topogen). Blood samples were collected in EDTA at the same time were used for preparation of leukocyte RNA. Semi-quantitative cDNA-PCR was performed to examine the levels of mRNA corresponding to topoisomerase I, topoisomerase II α and II β over the course of therapy. The formation of covalent topoisomerase-DNA complexes was found to vary between patients. There was a significant correlation between the clinical response and the formation of drug induced covalent complex in NHL patients. All patients with complete and partial remission formed drug induced covalent complex, while some of the patients with stable or progression of disease also formed the complex. The formation of protein-DNA covalent complex appeared to be necessary but not sufficient for clinical response. A consistent decline in the level of topoisomerase II α mRNA in the peripheral blood leukocytes of both NHL and leukemia were observed over the course of the treatments.;Based on the decrease in the mRNA level of topoisomerase II α, we hypothesized that increase in p53 level in response to drug induced DNA damage led to decreased topo II α mRNA level. In order to test this hypothesis two leukemic cell lines: ML-1 (wild type p53) and HL-60 (p53 null) were treated with camptothecin and the expression levels of topo II α mRNA and protein were determined by northern and western blot analyzes respectively. In ML-1 cell line p53 protein was induced while both topo II α mRNA and protein levels decreased below the pre-treatment level. In HL-60 cell line both topo II α mRNA and protein levels remained relatively the same. Thus it is highly probable that the decrease in topo II α mRNA in both NHL and leukemia patients after treatment with topotecan were due to the increase in p53 level. This should be considered in designing schedule for combination therapy using inhibitors of both topoisomerase I and II.
机译：在两项不同的第一阶段临床研究中，非霍奇金淋巴瘤患者接受了拓扑替康（SKF 104864，海马胺）和依托泊苷（VP16）的联合治疗，而急性白血病患者则接受了拓扑替康和Ara-C的联合治疗。给予拓扑替康或VP16后立即从患者中抽取外周血样品，并与Sarkosyl混合以捕获拓扑异构酶-DNA共价复合物，以用于体内连接测定（Topogen）。同时在EDTA中收集血样用于制备白细胞RNA。进行半定量cDNA-PCR以检查在治疗过程中对应于拓扑异构酶I，拓扑异构酶IIα和IIβ的mRNA水平。发现患者之间共价拓扑异构酶-DNA复合物的形成有所不同。 NHL患者的临床反应与药物诱导的共价复合物的形成之间存在显着相关性。所有完全缓解和部分缓解的患者形成药物诱导的共价复合物，而某些疾病稳定或进展的患者也形成复合物。蛋白质-DNA共价复合物的形成似乎是必需的，但不足以实现临床反应。在治疗过程中，NHL和白血病的外周血白细胞中拓扑异构酶IIαmRNA水平持续下降。基于拓扑异构酶IIαmRNA水平的降低，我们推测p53升高药物诱导的DNA损伤引起的TNF-α水平降低导致topo IIαmRNA水平下降。为了检验该假设，用喜树碱处理了两种白血病细胞系：ML-1（野生型p53）和HL-60（p53无效），并通过Northern和Western印迹分析确定了topo IIαmRNA和蛋白的表达水平。分别。在ML-1细胞系中，诱导了p53蛋白，而topo IIαmRNA和蛋白水平均降至治疗前水平以下。在HL-60细胞系中，topo IIαmRNA和蛋白质水平均保持相对相同。因此，在使用拓扑替康治疗后，NHL和白血病患者中topo IIαmRNA的降低很可能是由于p53水平的升高所致。在设计使用拓扑异构酶I和II抑制剂的联合治疗方案时应考虑到这一点。

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  • 作者

    Nair, Jayasree S.;

  • 作者单位

    New York Medical College.;

  • 授予单位 New York Medical College.;
  • 学科 Biology Molecular.;Health Sciences Oncology.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2000
  • 页码 136 p.
  • 总页数 136
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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