Department of Onco-Hematology and Neuro-Surgery Units, A Meyer Children's Hospital, viale G Pieraccini 24, 50139 Florence, Italy.
Cancer Chemother Pharmacol. 2011 Jun;67(6):1333-40. doi: 10.1007/s00280-010-1429-3. Epub 2010 Aug 25.
The blood-brain barrier discriminates the access of several molecules to the brain. This hampers the use of some drugs, as doxorubicin, potentially active for treatment of brain tumors. We explored the feasibility of active modification of the blood-brain barrier protection, by using morphine pretreatment, to allow doxorubicin accumulation in the brain in an animal model.
Rats were pretreated with different doses of intraperitoneal morphine before injection of doxorubicin (12 mg/kg). Quantitative analysis of doxorubicin was performed by mass spectrometry. Acute heart 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 than in control tissues (P < 0.001). This was evident only at therapeutic morphine dose (10 mg/kg, three times over 24 h), while lower doses (2.5 and 5 mg/kg) were not associated with doxorubicin accumulation. Pretreatment with morphine did not induce an elevation of LDH activity or of lipid peroxidation compared to controls.
Our data suggest that morphine pretreatment is able to allow doxorubicin penetration inside the brain, by modulating the blood-brain barrier. This is not associated with acute cardiac or renal toxicity. These preliminary results will enable us to generate novel therapeutic approaches to refractory or recurrent brain tumors, and might be useful in other human diseases of the central nervous system in which molecules usually stopped by the blood-brain barrier may have a therapeutic impact.
血脑屏障限制了许多分子进入大脑，这阻碍了一些药物的使用，如多柔比星，其具有治疗脑肿瘤的潜力。我们通过使用吗啡预处理来探索主动改变血脑屏障保护的可行性，以允许多柔比星在动物模型中积累到大脑中。
在注射多柔比星（12mg/kg）之前，大鼠通过腹腔内给予不同剂量的吗啡预处理。通过质谱法对多柔比星进行定量分析。通过测量多柔比星积累、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，吗啡预处理的大鼠所有脑区的多柔比星浓度均明显更高（P<0.001）。这仅在治疗剂量的吗啡（10mg/kg，24 小时内三次）时明显，而较低剂量（2.5 和 5mg/kg）与多柔比星积累无关。与对照组相比，吗啡预处理并未引起 LDH 活性或脂质过氧化的升高。
我们的数据表明，吗啡预处理能够通过调节血脑屏障使多柔比星穿透进入大脑。这与急性心脏或肾脏毒性无关。这些初步结果将使我们能够为难治性或复发性脑肿瘤生成新的治疗方法，并且可能对其他中枢神经系统的人类疾病有用，因为通常被血脑屏障阻止的分子可能具有治疗作用。
