Ochiai Hidenobu, Pernell Chris T, Archer Gary E, Chewning Tracy A, McLendon Roger E, Friedman Henry S, Sampson John H
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
Neurol Med Chir (Tokyo). 2006 Oct;46(10):485-9; discussion 489-90. doi: 10.2176/nmc.46.485.
The topoisomerase I inhibitor, 9-nitro-camptothecin (9NC), is highly tumoricidal against glioblastoma multiforme (GBM) in vitro. However, systemic administration of 9NC has not shown the expected efficacy in clinical trials. This failure may be due to the rapid hydrolysis of 9NC in plasma from the active form to the inactive and myelosuppressive form in the presence of human albumin at physiologic pH. Concurrent treatment with anticonvulsants and dexamethasone, drugs indispensable for the supportive therapy of patients with GBM, has also been shown to decrease plasma concentrations of these drugs. Intrathecal drug delivery circumvents the blood-brain barrier and minimizes systemic toxicity. Intrathecal delivery of 9NC may also have the more specific advantage of significantly reducing the hydrolysis of 9NC that occurs after systemic delivery due to the more favorable pH and reduced albumin content in cerebrospinal fluid. The present study evaluated the toxicity and efficacy of intrathecal delivery of 9NC in an athymic rat model of neoplastic meningitis. Toxicity tests showed that 0.3 micromol (5000 microM), 0.03 micromol (500 microM), 0.003 micromol (50 microM), or 0.0003 micromol (5 microM) of 9NC administered intrathecally to the athymic rats caused no evidence of clinical or histological toxicity. Intrathecal administration of 0.3 micromol (5000 microM) of 9NC twice a week for three doses to athymic rats with neoplastic meningitis induced by the GBM cell line, U87MGDeltaEGFR, resulted in a 26% increase of median survival compared to the control group (p < 0.005). These results suggest that intrathecal treatment with 9NC may be useful for patients with GBM neoplastic meningitis.
拓扑异构酶I抑制剂9-硝基喜树碱（9NC）在体外对多形性胶质母细胞瘤（GBM）具有高度杀肿瘤活性。然而，9NC的全身给药在临床试验中并未显示出预期的疗效。这种失败可能是由于在生理pH值下，9NC在人白蛋白存在的情况下，在血浆中从活性形式迅速水解为无活性和骨髓抑制性形式。同时使用抗惊厥药和地塞米松（GBM患者支持治疗中不可或缺的药物）也已证明会降低这些药物的血浆浓度。鞘内给药可绕过血脑屏障并将全身毒性降至最低。鞘内注射9NC还可能具有更特殊的优势，即由于脑脊液中更有利的pH值和更低的白蛋白含量，可显著减少全身给药后发生的9NC水解。本研究评估了鞘内注射9NC在无胸腺大鼠肿瘤性脑膜炎模型中的毒性和疗效。毒性试验表明，向无胸腺大鼠鞘内注射0.3微摩尔（5000微摩尔/升）、0.03微摩尔（500微摩尔/升）、0.003微摩尔（50微摩尔/升）或0.0003微摩尔（5微摩尔/升）的9NC未显示出临床或组织学毒性迹象。每周两次向由GBM细胞系U87MGDeltaEGFR诱导的肿瘤性脑膜炎无胸腺大鼠鞘内注射0.3微摩尔（5000微摩尔/升）的9NC，共注射三剂，与对照组相比，中位生存期增加了26%（p < 0.005）。这些结果表明，鞘内注射9NC可能对GBM肿瘤性脑膜炎患者有用。
