Charcosset J Y, Soues S, Laval F
Laboratoire de pharmacologie et de toxicologie fondamentales, CNRS, Toulouse, France.
Bull Cancer. 1993 Nov;80(11):923-54.
Over the past decade, DNA topoisomerase I and II appeared to be the targets of some antitumor agents: CPT-11 and Topotecan derived from Camptothecin which interact with topoisomerase I; Actinomycin D, Adriamycin and Daunorubicin, Elliptinium Acetate, Mitoxantrone, Etoposide and Teniposide, Amsacrine which interact with topoisomerase II. The multiple functions of these enzymes are important as they play a role during replication, transcription, recombination, repair and chromatine organisation. Particularly, they relax torsional constraints which appear when intertwined DNA strands are separated while replication fork or RNA polymerases are moving. To some extent, topoisomerase I and II are structurally and functionally different. Moreover, topoisomerase I is not indispensable for a living cell whereas topoisomerase II is. Drug-topoisomerase interaction which probably leads to antitumoral effect of the compounds studied in this review is not a trivial inhibition of the enzyme but rather a poisoning due to stabilization of cleavable complexes between the enzyme and DNA. These stabilized complexes are likely to induce apoptosis-like programmed cell death, which is characterised by DNA fragmentation. However, it appears that it is the collision of the replication fork with the drug-stabilized cleavable complex that is responsible for the cytotoxicity of the drug: poisoning of topoisomerases by antitumor agents leads to a new concept of "dynamic toxicity". Although they interact with a common target, topoisomerase II poisons have differential effects on macromolecules syntheses, cell cycle and chromosome fragmentation; a few compounds may produce free radicals. Because of these differential effects in addition to quantitative and qualitative variations of stabilized cleavable complexes, in particular DNA sequences on which topoisomerase II is stabilized, these antitumor agents do not resemble each other. Cellular resistance to topoisomerases poisons results of two principal types of alteration: target and/or drug transport modification. Decreased ability to form the cleavable complex in resistant cells may be the consequence of both decreased amount of topoisomerase or altered enzyme. On the other hand, overexpression of membrane P-glycoprotein, which pumps drugs out of the cell by an energy dependent process provokes a decreased accumulation of these drugs. Cross resistances to other drugs are mainly under control of these two different mechanisms of resistance. A complete knowledge of their individual effects and mechanisms of resistance would allow a better clinical use of topoisomerases poisons, especially when administered in combination chemotherapy.
在过去十年中，DNA拓扑异构酶I和II似乎是某些抗肿瘤药物的作用靶点：源自喜树碱的CPT-11和拓扑替康与拓扑异构酶I相互作用；放线菌素D、阿霉素、柔红霉素、醋酸椭圆玫瑰树碱、米托蒽醌、依托泊苷和替尼泊苷、安吖啶与拓扑异构酶II相互作用。这些酶的多种功能很重要，因为它们在复制、转录、重组、修复和染色质组织过程中发挥作用。特别是，当复制叉或RNA聚合酶移动时，缠绕的DNA链分开会产生扭转张力，而它们能缓解这种张力。在某种程度上，拓扑异构酶I和II在结构和功能上有所不同。此外，拓扑异构酶I对活细胞并非不可或缺，而拓扑异构酶II则是。本文所研究化合物的药物-拓扑异构酶相互作用可能导致抗肿瘤作用，这并非对酶的简单抑制，而是由于酶与DNA之间可裂解复合物的稳定化导致的中毒。这些稳定化复合物可能诱导类似凋亡的程序性细胞死亡，其特征是DNA片段化。然而，似乎是复制叉与药物稳定化的可裂解复合物的碰撞导致了药物的细胞毒性：抗肿瘤药物对拓扑异构酶的中毒导致了“动态毒性”这一新概念。尽管它们与共同靶点相互作用，但拓扑异构酶II中毒药物对大分子合成、细胞周期和染色体片段化有不同影响；一些化合物可能产生自由基。由于这些不同影响，以及稳定化可裂解复合物的数量和质量变化，特别是拓扑异构酶II在其上稳定化的DNA序列的变化，这些抗肿瘤药物彼此并不相似。细胞对拓扑异构酶中毒的抗性源于两种主要类型的改变：靶点和/或药物转运修饰。耐药细胞中形成可裂解复合物的能力降低可能是拓扑异构酶数量减少或酶改变的结果。另一方面，膜P-糖蛋白的过度表达通过能量依赖过程将药物泵出细胞，导致这些药物的积累减少。对其他药物的交叉抗性主要受这两种不同抗性机制的控制。全面了解它们各自的作用和抗性机制将有助于更好地临床使用拓扑异构酶中毒药物，尤其是在联合化疗中使用时。
