Mechanisms regulating resistance to inhibitors of topoisomerase II.
Mechanisms regulating resistance to inhibitors of topoisomerase II.
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DOI：
10.3389/fphar.2013.00089
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发表时间：
2013
影响因子：
5.6
通讯作者：
Ganapathi MK
中科院分区：
文献类型：
--
作者：
Ganapathi RN;Ganapathi MK
拓扑异构酶II抑制物(Topo II)在血液系统恶性肿瘤和实体瘤的治疗中具有临床疗效。针对Topo II的抗肿瘤药物的疗效往往受到耐药性的限制，体外细胞培养模型的研究为潜在的机制提供了几点见解。多药转运体参与了多种抗肿瘤药物的外排，从而降低了细胞毒性，这表明它们在临床活性药物的耐药性中发挥了重要作用。然而，在临床试验中，用抑制外排泵的药物调节多药耐药表型并没有产生影响。由于药物累积减少本身不足以解释肿瘤细胞对Topo II抑制剂的耐药性，一些研究集中在以该酶为靶点的药物对DNA损伤的影响机制上。哺乳动物的TOPO IIα和TOPO IIβ同工酶具有相似的催化活性，但具有不同的生物学活性。Topo IIα与细胞分裂有关，Topo IIβ参与细胞分化。除了可以影响药物诱导的Topo II介导的DNA损伤的位点特异性突变外，主要通过磷酸化的Topo II翻译后修饰可能会影响酶介导的DNA损伤和针对Topo II的药物的下游细胞毒性反应。影响磷酸化的信号通路以及细胞内钙水平/钙依赖信号的变化可以调节Topo II抑制剂的下游细胞毒性效应。总体而言，肿瘤细胞对Topo II抑制剂的耐药性是一个复杂的过程，不仅受细胞药代动力学的影响，更重要的是受控制内在药物敏感性的酶变化的影响。
Inhibitors of topoisomerase II (topo II) are clinically effective in the management of hematological malignancies and solid tumors. The efficacy of anti-tumor drugs targeting topo II is often limited by resistance and studies with in vitro cell culture models have provided several insights on potential mechanisms. Multidrug transporters that are involved in the efflux and consequently reduced cytotoxicity of diverse anti-tumor agents suggest that they play an important role in resistance to clinically active drugs. However, in clinical trials, modulating the multidrug-resistant phenotype with agents that inhibit the efflux pump has not had an impact. Since reduced drug accumulation per se is insufficient to explain tumor cell resistance to topo II inhibitors several studies have focused on characterizing mechanisms that impact on DNA damage mediated by drugs that target the enzyme. Mammalian topo IIα and topo IIβ isozymes exhibit similar catalytic, but different biologic, activities. Whereas topo IIα is associated with cell division, topo IIβ is involved in differentiation. In addition to site specific mutations that can affect drug-induced topo II-mediated DNA damage, post-translation modification of topo II primarily by phosphorylation can potentially affect enzyme-mediated DNA damage and the downstream cytotoxic response of drugs targeting topo II. Signaling pathways that can affect phosphorylation and changes in intracellular calcium levels/calcium dependent signaling that can regulate site-specific phosphorylation of topoisomerase have an impact on downstream cytotoxic effects of topo II inhibitors. Overall, tumor cell resistance to inhibitors of topo II is a complex process that is orchestrated not only by cellular pharmacokinetics but more importantly by enzymatic alterations that govern the intrinsic drug sensitivity.
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影响因子：
2.4
作者：
Carlson, Robert W.;O'Neill, Anne M.;Wood, William C.
通讯作者：
Wood, William C.
影响因子：
5.8
作者：
BERTRAND, R;KERRIGAN, D;POMMIER, Y
通讯作者：
POMMIER, Y
DOI：
10.1073/pnas.86.23.9431
发表时间：
1989-12-01
影响因子：
11.1
作者：
CHUNG, TDY;DRAKE, FH;MIRABELLI, CK
通讯作者：
MIRABELLI, CK
影响因子：
51.1
作者：
Di Leo, Angelo;Desmedt, Christine;Buyse, Marc
通讯作者：
Buyse, Marc
影响因子：
4.8
作者：
Chikamori, K;Grabowski, DR;Ganapathi, MK
通讯作者：
Ganapathi, MK