Department of Paediatric Medicine, Neuro-oncology Unit, Anna Meyer Children's University Hospital Florence, Italy.
Am J Cancer Res. 2013 Aug 14;3(4):424-32. eCollection 2013.
Our group recently demonstrated in a rat model that pretreatment with morphine facilitates doxorubicin delivery to the brain in the absence of signs of increased acute systemic toxicity. Morphine and other drugs such as dexamethasone or ondansetron seem to inhibit MDR proteins localized on blood-brain barrier, neurons and glial cells increasing the access of doxorubicin to the brain by efflux transporters competition. We explored the feasibility of active modification of the blood-brain barrier protection, by using morphine dexamethasone or ondansetron pretreatment, to allow doxorubicin accumulation into the brain in a rodent model. Rats were pretreated with morphine (10 mg/kg, i.p.), dexamethasone (2 mg/kg, i.p.) or ondansetron (2 mg/kg, i.p.) before injection of doxorubicin (12 mg/kg, i.p.). Quantitative analysis of doxorubicin was performed by mass spectrometry. Acute hearth and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels. The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated with morphine (P < 0.001) or ondansetron (P < 0.05) than in control tissues. The concentration of doxorubicin was significantly higher in cerebral hemispheres and brainstem (P < 0.05) but not in cerebellum of rats pretreated with dexamethasone than in control tissues. Pretreatment with any of these drugs did not increase LDH activity or lipid peroxidation compared to controls. Our data suggest that morphine, dexamethasone or ondansetron pretreatment is able to allow doxorubicin penetration inside the brain by modulating the BBB. This effect is not associated with acute cardiac or renal toxicity. This finding might provide the rationale for clinical applications in the treatment of refractory brain tumors and pave the way to novel applications of active but currently inapplicable chemotherapeutic drugs.
我们的小组最近在大鼠模型中证明，吗啡预处理可促进阿霉素向大脑输送，而不会增加急性全身毒性的迹象。吗啡和其他药物，如地塞米松或昂丹司琼，似乎抑制了位于血脑屏障、神经元和神经胶质细胞上的多药耐药蛋白，通过外排转运蛋白竞争增加阿霉素进入大脑的机会。我们探索了通过使用吗啡、地塞米松或昂丹司琼预处理来主动修饰血脑屏障保护的可行性，以使阿霉素在啮齿动物模型中积聚到大脑中。大鼠在注射阿霉素（12 mg/kg，ip）前用吗啡（10 mg/kg，ip）、地塞米松（2 mg/kg，ip）或昂丹司琼（2 mg/kg，ip）预处理。通过质谱分析法对阿霉素进行定量分析。通过测量阿霉素积累、LDH 活性和丙二醛血浆水平来分析急性心脏和肾脏损伤。与对照组组织相比，用吗啡（P < 0.001）或昂丹司琼（P < 0.05）预处理的大鼠所有脑区的阿霉素浓度均显著升高。与对照组组织相比，用地塞米松预处理的大鼠大脑半球和脑干（P < 0.05）但小脑的阿霉素浓度显著升高。与对照组相比，用这些药物中的任何一种预处理均未增加 LDH 活性或脂质过氧化作用。我们的数据表明，吗啡、地塞米松或昂丹司琼预处理能够通过调节血脑屏障使阿霉素渗透到大脑中。这种作用与急性心脏或肾脏毒性无关。这一发现可能为治疗难治性脑肿瘤的临床应用提供了依据，并为活性但目前无法应用的化疗药物的新应用铺平了道路。
