Unexpected neurotoxicity of etoposide phosphate administered in combination with other chemotherapeutic agents after blood-brain barrier modification to enhance delivery, using propofol for general anesthesia, in a rat model
Unexpected neurotoxicity of etoposide phosphate administered in combination with other chemotherapeutic agents after blood-brain barrier modification to enhance delivery, using propofol for general anesthesia, in a rat model
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DOI：
10.1097/00006123-200007000-00041
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发表时间：
2000-07-01
期刊：
影响因子：
4.8
通讯作者：
Neuwelt, EA
中科院分区：
文献类型：
--
作者：
Fortin, D;McCormick, CI;Neuwelt, EA
目的：渗透性血脑屏障破坏（BBBD）增加了化疗剂的脑和脑肿瘤递送，这导致针对脑肿瘤的功效增加。我们以前注意到，使用丙泊酚麻醉BBBD增加了成功中断的百分比，导致化疗药物的输送量增加。方法：Long-Evans大鼠在异氟醚（n = 11）或丙泊酚（n = 90）麻醉下进行渗透BBBD。卡铂和/或美法仑，甲氨蝶呤，或磷酸依托泊苷动脉内（IA）后BBBD使用丙泊酚麻醉。评估动物的全身和神经毒性。结果：在异丙酚或异氟醚麻醉下，BBBD单独给药无全身或神经毒性。当IA与BBBD联合给药时，单药相对无神经毒性，卡铂或美法仑与甲氨蝶呤联合给药也是如此。观察到，如果在BBBD后同时给予磷酸依托泊苷和任何其他药物，则这两种药物具有高度神经毒性。给予依托泊苷磷酸盐之前BBBD完全消除神经毒性，虽然发生急性肺毒性与任何组合的依托泊苷磷酸盐和甲氨蝶呤，无论时间administration.CONCLUSION：神经毒性显着增加的依托泊苷磷酸盐组合组，特别是当这两种药物在BBBD后IA。这种神经毒性的增加可能反映了丙泊酚麻醉中观察到的药物输送增加。在BBBD和丙泊酚麻醉下IA给予磷酸依托泊苷的神经毒性可通过BBBD前IA给予磷酸依托泊苷和BBBD后IA给予卡铂或美法仑而最小化。
OBJECTIVE: Osmotic blood-brain barrier disruption (BBBD) increases brain and brain tumor delivery of chemotherapeutic agents, which results in increased efficacy against brain tumors. We previously noted that the use of propofol anesthesia for BBBD increased the percentage of successful disruptions, resulting in delivery of increased amounts of chemotherapeutic drugs. This study evaluated the neurotoxicity of combination chemotherapeutic administration with this enhanced delivery system.METHODS: Osmotic BBBD was performed in Long-Evans rats with isoflurane (n = 11) or propofol (n = 90) anesthesia. Carboplatin and/or melphalan, methotrexate, or etoposide phosphate was administered intraarterially (IA) after BBBD using propofol anesthesia. Animals were assessed for systemic and neurological toxicity. Animals were killed for neuropathological evaluation 30 days after treatment.RESULTS: With propofol or isoflurane anesthesia, BBBD alone produced no systemic or neurological toxicity. Single agents were relatively non-neurotoxic when administered IA with BBBD, as were the combinations of carboplatin or melphalan with methotrexate. Etoposide phosphate in combination with any other agent was observed to be highly neurotoxic if both agents were administered after BBBD. Administration of etoposide phosphate before BBBD completely eliminated neurotoxicity, although acute pulmonary toxicity occurred with any combination of etoposide phosphate and methotrexate, regardless of the timing of administration.CONCLUSION: Neurotoxicity was significantly increased for etoposide phosphate combination groups, particularly when both drugs were administered IA after BBBD. This increase in neurotoxicity may reflect on increase in drug delivery observed with propofol anesthesia. The neurotoxicity of IA administered etoposide phosphate with BBBD and propofol anesthesia could be minimized by administering etoposide phosphate IA before BBBD and administering carboplatin or melphalan IA after BBBD.