Preclinical & clinical pharmacology of agents in GI malignancies: topoisomerase I

喜树碱类药物是一类以DNA松弛酶拓扑异构酶I为靶点的新型抗癌药物。这些药物包括伊立替康（CPT-11）、拓扑替康和9-氨基喜树碱。喜树碱通过与拓扑异构酶I结合并使酶稳定在与DNA的共价复合物中而起作用。这导致单链DNA断裂的积累，当DNA复制四遇到这些损伤时，单链DNA断裂可以转化为双链断裂。迄今为止，CPT-11和托泊替康已显示出对实体瘤包括结肠癌和卵巢癌的有希望的抗癌活性，并且9-氨基喜树碱目前处于II期临床测试中。正在进行的临床试验试图在分子水平上监测靶组织（如肿瘤和骨髓细胞）中的特定药物作用，以便更好地了解这些药物如何引起其临床作用。这一小瓶信息将有望允许设计更好的喜树碱与其他活性剂的组合，用于治疗人类癌症。我们还在研究这些药物的代谢和活化，以试图预测它们在个体患者中的临床效果和毒性。- 人体受试者&人体组织、体液、细胞等

The camptothecins are a new class of anticancer agents which target the DNA relaxing enzyme, topoisomerase I. These agents include irinotecan (CPT-11), topotecan and 9-aminocamptothecin. The camptothecins act by binding to topoisomerase I and stabilizing the enzyme in a covalent complex with DNA. This leads to the accumulation of single-strand DNA break which can be converted into double strand breaks when a DNA replication four encounters these lesions. To date, CPT-11 and topotecan have demonstrating promising anticancer activity against solid tumors including colon and ovarian cancer and 9-aminocamptothecin is currently in phase II clinical testing. Ongoing clinical trials are attempting to monitor specific drug effects at the molecular level in target tissues such as tumors and bone marrow cells in order to better understand how these agents cause their clinical effects. This vial information will hopefully allow for the design of better combinations of camptothecins with other active agents for the treatment of human cancers. We are also studying the metabolism and activation of these agents in order to try to predict their clinical effects and toxicities in individual patients. - Human Subjects & Human Tissues, Fluids, Cells, etc.