Glantz M J, Choy H, Kearns C M, Mills P C, Wahlberg L U, Zuhowski E G, Calabresi P, Egorin M J
Department of Medicine, Brown University School of Medicine, Providence, RI, USA.
J Natl Cancer Inst. 1995 Jul 19;87(14):1077-81. doi: 10.1093/jnci/87.14.1077.
Paclitaxel (Taxol) has been shown to sensitize some malignant cells to the effects of radiation. A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to exploit this phenomenon. The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissue being radiated. Paclitaxel is known to have limited access to the central nervous system (CNS) of rats and mice, but its ability to penetrate malignant tissue in the CNS is inadequately documented.
Our purpose was to examine the concentrations of paclitaxel in the cerebrospinal fluid (CSF) of patients with CNS malignancies and in normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concomitant paclitaxel concentrations in the plasma of those same patients and animals.
Four patients were treated with 3-hour infusions of paclitaxel at doses between 90 and 200 mg/m2. Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of the paclitaxel infusion. Four Fischer rats had 20,000 C6 glioma cells stereotactically implanted into their right frontal lobes; 28 days later, they were given 3-hour infusions of paclitaxel at 10 mg/kg. Plasma was sampled during the paclitaxel infusion. At the completion of the infusion, rats were killed, and portions of their normal and malignant CNS tissues were removed for histologic assessment. Concentrations of paclitaxel in plasma, CSF, and brain tissue were determined with high-pressure liquid chromatography.
Plasma pharmacokinetics of paclitaxel in patients with brain tumors were comparable to those previously described in patients with other malignancies. Paclitaxel could be measured in CSF of all patients, but concentrations were very low. Peak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occurred between 3.25 and 5 hours after initiation of the paclitaxel infusion. Peak paclitaxel concentrations in CSF were between 0.12% and 8.3% of those present in concomitant plasma samples. Paclitaxel was not detectable in the normal or malignant CNS tissue of any rat, despite the fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 microM.
Paclitaxel has only limited access to the CSF of patients with CNS malignancies and to normal and malignant CNS tissues of rats bearing brain tumors.
The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.
已证明紫杉醇（泰素）可使某些恶性细胞对辐射作用敏感。已设计了许多将紫杉醇与放射治疗相结合的临床方案来利用这一现象。紫杉醇的辐射增强作用可能取决于该药物穿透受辐射组织的能力。已知紫杉醇进入大鼠和小鼠中枢神经系统（CNS）的能力有限，但其穿透CNS中恶性组织的能力尚无充分记录。
我们的目的是检测中枢神经系统恶性肿瘤患者脑脊液（CSF）中以及携带C6大鼠胶质瘤的Fischer大鼠脑的正常和恶性组织中紫杉醇的浓度，然后将这些紫杉醇浓度与相同患者和动物血浆中的紫杉醇浓度进行比较。
4例患者接受了3小时的紫杉醇输注，剂量为90至200mg/m²。在紫杉醇输注开始后的0.33、1.5、3.25、5、6和24小时采集血浆和CSF样本。4只Fischer大鼠通过立体定向将20000个C6胶质瘤细胞植入其右额叶；28天后，它们接受了10mg/kg的3小时紫杉醇输注。在紫杉醇输注期间采集血浆样本。输注结束后，处死大鼠，并取出其正常和恶性中枢神经系统组织的部分进行组织学评估。用高压液相色谱法测定血浆、CSF和脑组织中紫杉醇的浓度。
脑肿瘤患者中紫杉醇的血浆药代动力学与先前在其他恶性肿瘤患者中描述的相似。所有患者的CSF中均可检测到紫杉醇，但浓度非常低。CSF中紫杉醇的峰值浓度在5至83nM之间，出现在紫杉醇输注开始后的3.25至5小时之间。CSF中紫杉醇的峰值浓度为同期血浆样本中浓度的0.12%至8.3%。尽管在采集组织时血浆中紫杉醇浓度范围为0.62至153μM，但在任何大鼠的正常或恶性中枢神经系统组织中均未检测到紫杉醇。
紫杉醇进入中枢神经系统恶性肿瘤患者的CSF以及携带脑肿瘤大鼠的正常和恶性中枢神经系统组织的能力有限。
鉴于已证明紫杉醇进入中枢神经系统的能力有限，应考虑将紫杉醇与放射治疗联合用于治疗中枢神经系统恶性肿瘤的效用。
