DNA TOPOISOMERASE ACTIVITY AND CANCER THERAPY

多种抗肿瘤药物，包括嵌入剂和 表鬼臼毒素通过抑制细胞外信号转导途径发挥细胞毒作用。 核酶、DNA拓扑异构酶II.耐药细胞的研究 几位研究人员的研究成果帮助定义了 对拓扑异构酶II活性药物的耐药性。这两个方面都是 靶向酶(拓扑异构酶II)，当细胞进展到 静止，以及酶本身的变化，导致 药物不敏感，已被证明会导致耐药性。一个角色是 拓扑异构酶II活性在耐药中的调节改变 也有人建议。下面的研究可能会进一步定义 拓扑异构酶II抑制剂的耐药机制。多面性 中国仓鼠卵巢(CHO)-16C2细胞的耐药性 到目前为止，似乎还存在定义不明确的核因素。这间牢房 LINE在控制拓扑异构酶II活性方面可能有变化， 对这些核因子的阐明将有助于定义“正常”的酶 控制以及这些细胞的阻力。另外三个 耐药CHO细胞株，与-16C2细胞相似 在VP-16在场的情况下被选中，也将接受他们的评估 抗性机制。关于基础的信息很少 米托蒽醌耐药是存在的。获得抗药性的CHO细胞系 这种新的抗肿瘤药物将被分离出来，并在努力 为了确定拓扑异构酶II的扰动在 对米托蒽醌耐药。除了这些关于药物的研究 多发性骨髓瘤细胞对拓扑异构酶II的耐药反应 将在几个层面上对抑制剂进行调查。抗药性 将评估RPMI8226 DOX 1V人骨髓瘤细胞的耐药性 似乎是由于拓扑异构酶II活性降低所致。那 拓扑异构酶II是几种抗肿瘤药物的靶点， 细胞毒性与靶标酶含量相关，提示 IL-6刺激的人骨髓瘤ILKM3细胞对 VP-16在细胞增殖增强时的细胞毒作用 拓扑异构酶II。同样的方法将被用来试图清除 这种疾病患者骨髓中的骨髓瘤细胞。在……里面 简而言之，本文描述的研究致力于阐明 拓扑异构酶II抑制剂的抗药性及其应用 该酶介导的细胞毒性的临床观察 范例。

Numerous antineoplastic agents, including intercalators and epipodophyllotoxins, exert their cytotoxic effect via inhibition of the nuclear enzyme, DNA topoisomerase II. Studies of drug-resistant cell lines by several investigators have helped define mechanisms of resistance to topoisomerase II-active drugs. Both a decrease in the target enzyme (topoisomerase II) which occurs when cells progress to quiescence, as well as alterations in the enzyme itself which result in drug insensitivity, have been shown to result in resistance. A role for altered modulation of topoisomerase II activity in drug resistance has also been suggested. The following studies are likely to further define mechanisms of resistance to topoisomerase II inhibitors. The multiple drug resistance of the Chinese hamster ovary (CHO) TAM-16C2 cell fine appears to reside in, as yet, poorly defined nuclear factors. This cell line may have an alteration in the control of topoisomerase II activity, and elucidation of these nuclear factors will help define "normal" enzyme control as well as the resistance of these cells. Three other drug-resistant CHO cell lines, similar to TAM-16C2 cells in that they were selected in the presence of VP-l6, will also be evaluated for their mechanisms of resistance. A paucity of information concerning the basis for mitoxantrone resistance exists. CHO cell lines made resistant to this new antitumor agent, will be isolated and characterized in an effort to define the possible role of perturbations of topoisomerase II in resistance to mitoxantrone. In addition to these studies on drug resistance, the response of multiple myeloma cells to topoisomerase II inhibitors will be investigated at several levels. The drug resistance of RPMI 8226 DOX 1 V human myeloma cells will be evaluated; resistance appears to result from diminished topoisomerase II activity. That topoisomerase II is the target of several antitumor drugs and that cytotoxicity correlates with the content of target enzyme, suggests that IL-6-stimulated human myeloma ILKM3 cells will be hypersensitive to the cytotoxic effects of VP-16 if the increased proliferation augments topoisomerase II. This same approach will be used in an attempt to purge myeloma cells from the bone marrow of patients with this disease. In short, the research described herein endeavors to elucidate mechanisms of resistance to topoisomerase II inhibitors and to apply recent observations regarding cytotoxicity mediated by this enzyme in a clinical paradigm.