Zamboni W C, Lüftner D I, Egorin M J, Schweigert M, Sezer O, Richter T, Natale J J, Possinger K
Program of Molecular Therapeutics and Drug Discovery, University of Pittsburgh, Cancer Institute, Pennsylvania 15213, USA.
Ann Oncol. 2001 Jan;12(1):119-22. doi: 10.1023/a:1008369615016.
The development of metastatic disease throughout the neuroaxis from primary central nervous system (CNS) tumors and non-CNS tumors suggests the cerebrospinal fluid (CSF) is an important source of exposure for chemotherapeutic agents. In non-human primates, a 4-hour, as compared to a 30-minute, topotecan (TPT) infusion prolonged TPT exposure in the CSF.
We evaluated this approach in a 51-year-old woman with breast cancer metastatic to the CNS. TPT was administered at 1.5 mg/m2/day (cycle 1) and 1.0 mg/m2/day (cycles 2 and 3) as a 30-minute infusion on days 0-4, and as a 4-hour infusion on day 5. Cycles were repeated every 21 days. Plasma, lateral ventricular CSF, and lumbar CSF samples were obtained after 30-minute and 4-hour infusions, and assayed for TPT lactone and total by HPLC. A three-compartment model was used to calculate area under the plasma (AUCplasma) and lateral ventricular CSF (AUCCSF) concentation-time curves. TPT CSF penetration was calculated as the ratio of AUCCSF to AUCplasma.
Mean +/- SD values for TPT total CSF penetration in lateral CSF after 30-minute and 4-hour infusions were 0.25 +/- 0.15 and 0.29 +/- 0.02, respectively. TPT total lumbar CSF concentration was 3-fold greater after a 4-hour as compared to a 30-minute infusion. For TPT lactone and TPT total, time > 1 ng/ml in lateral CSF was 1.8- and 1.7-fold greater, respectively, for a 4-hour as compared to a 30-minute infusion.
Prolonging TPT infusion from 30 minute to 4 hours increases the duration of exposure in the CSF. This study demonstrates the ability to develop treatment strategies of systemically administered chemotherapy to enhance cytotoxic exposure in the CSF.
原发性中枢神经系统（CNS）肿瘤和非CNS肿瘤在整个神经轴上发生转移性疾病，这表明脑脊液（CSF）是化疗药物暴露的重要来源。在非人灵长类动物中，与30分钟的拓扑替康（TPT）输注相比，4小时的输注延长了CSF中TPT的暴露时间。
我们对一名患有CNS转移的51岁乳腺癌女性患者采用了这种方法。TPT在第0 - 4天以1.5 mg/m²/天（第1周期）和1.0 mg/m²/天（第2和3周期）进行30分钟输注，在第5天进行4小时输注。每21天重复一个周期。在30分钟和4小时输注后采集血浆、侧脑室CSF和腰段CSF样本，通过高效液相色谱法测定TPT内酯和总量。使用三室模型计算血浆浓度 - 时间曲线下面积（AUCplasma）和侧脑室CSF浓度 - 时间曲线下面积（AUCCSF）。TPT的CSF渗透以AUCCSF与AUCplasma的比值计算。
30分钟和4小时输注后侧脑室CSF中TPT总CSF渗透的平均值±标准差分别为0.25±0.15和0.29±0.02。与30分钟输注相比，4小时输注后腰段CSF中TPT总浓度高3倍。对于TPT内酯和TPT总量，与30分钟输注相比，4小时输注后侧脑室CSF中时间>1 ng/ml分别高出1.8倍和1.7倍。
将TPT输注时间从30分钟延长至4小时可增加CSF中的暴露持续时间。本研究证明了制定全身化疗治疗策略以增强CSF中细胞毒性暴露的能力。
