Lamond J P, Mehta M P, Boothman D A
Department of Human Oncology, University of Wisconsin-Madison, USA.
J Neurooncol. 1996 Oct;30(1):1-6. doi: 10.1007/BF00177437.
Despite innovations in imaging, surgery, and radiation therapy, local failure remains the principle clinical problem in most CNS malignancies. To date, chemotherapy has not major impact in the treatment of most adult CNS tumors. The inroads made by chemotherapy in pediatric CNS malignancies suggest that novel drugs, or drug combinations, may improve therapy. Topoisomerase I (Topo I) inhibitors are a relatively new group of chemotherapy drugs with a novel mechanism of action. Drugs in this group currently undergoing clinical trials are the Camptothecin analogues Topotecan, CPT-11, and 9-aminocamptothecin. There is substantial preclinical and some clinical evidence to suggest that these drugs could be useful in the treatment of CNS malignancies. Preclinical studies with the water soluble Topo I inhibitor, Topotecan, demonstrate antineoplastic activity in a variety of CNS malignancies. In addition, Topotecan has good CNS penetration in primates, and recent preliminary phase I and II clinical trials of Topotecan in pediatric and adult CNS malignancies have been promising. In this paper, we describe the unique mechanism of action, antineoplastic activity, and radiosensitizing properties of Topo I inhibitors. We present the first report demonstrating potentiation of radiation lethality by Topotecan in a human glioma (D54) cell line. The dose enhancement ratio was 3.2 at 10% survival. Thus, there is evidence to suggest that Topo I inhibitors may be beneficial in the treatment of CNS neoplasms on the basis of their antineoplastic activity alone, as well as their radiosensitizing effects. Two clinical trials which utilize concurrent Topotecan and radiation in the treatment of pediatric and adult CNS malignancies are discussed.
尽管在成像、手术和放射治疗方面有所创新，但局部复发仍是大多数中枢神经系统恶性肿瘤的主要临床问题。迄今为止，化疗对大多数成人中枢神经系统肿瘤的治疗没有重大影响。化疗在儿童中枢神经系统恶性肿瘤治疗中取得的进展表明，新型药物或药物组合可能会改善治疗效果。拓扑异构酶I（Topo I）抑制剂是一类作用机制新颖的相对较新的化疗药物。目前正在进行临床试验的该类药物有喜树碱类似物拓扑替康、CPT-11和9-氨基喜树碱。有大量临床前和一些临床证据表明这些药物可用于治疗中枢神经系统恶性肿瘤。对水溶性Topo I抑制剂拓扑替康的临床前研究表明，它在多种中枢神经系统恶性肿瘤中具有抗肿瘤活性。此外，拓扑替康在灵长类动物中具有良好的中枢神经系统穿透力，最近拓扑替康在儿童和成人中枢神经系统恶性肿瘤中的I期和II期初步临床试验前景良好。在本文中，我们描述了Topo I抑制剂独特的作用机制、抗肿瘤活性和放射增敏特性。我们首次报告了拓扑替康在人胶质瘤（D54）细胞系中增强辐射致死性的情况。在10%存活率时剂量增强比为3.2。因此，有证据表明，Topo I抑制剂可能因其单独的抗肿瘤活性以及放射增敏作用而对中枢神经系统肿瘤的治疗有益。本文还讨论了两项在儿童和成人中枢神经系统恶性肿瘤治疗中同时使用拓扑替康和放疗的临床试验。
