Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
PLoS One. 2010 Apr 19;5(4):e10108. doi: 10.1371/journal.pone.0010108.
Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment.
METHODOLOGY/PRINCIPAL FINDINGS: We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [(14)C]dextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu) by cultured mouse brain endothelial cells (MBEC). The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [(14)C]dextran (2.6-fold increase) and to Herceptin (2-fold increase). Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p<0.01). Log-rank survival analysis of mice bearing HER2-positive intracranial breast tumor also showed a significant survival increase (p<0.02) in the group treated with Herceptin plus vardenafil as compared to other groups. However, vardenafil did not exert any beneficial effect on survival of mice bearing intracranial breast tumor with low HER2 expression and co-treated with Herceptin (p>0.05).
CONCLUSIONS/SIGNIFICANCE: These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.
化疗药物和新开发的治疗性单克隆抗体能够充分输送到大多数实体瘤和全身性肿瘤。然而，血脑肿瘤屏障（BTB）阻碍了药物进入原发性脑肿瘤和转移灶，这极大地限制了这些药物在脑癌治疗中的应用。
方法/主要发现：我们研究了磷酸二酯酶 5（PDE5）抑制剂在裸鼠中的作用，这些裸鼠颅内植入了人肺癌和乳腺癌肿瘤，作为最常见的形成脑转移的原发性肿瘤，并研究了药物转运的潜在机制。体外实验表明，PDE5 抑制剂增强了培养的小鼠脑内皮细胞（MBEC）对[(14)C]葡聚糖和曲妥珠单抗（赫赛汀，一种针对 HER2/neu 的人源化单克隆抗体）的摄取。使用小窝介导的内吞、巨胞饮和有被小窝/网格蛋白内吞抑制剂来研究药物输送的机制。抑制剂分析强烈表明 PDE5 抑制剂增强 MBEC 摄取曲妥珠单抗涉及小窝和巨胞饮内吞途径。PDE5 抑制剂伐地那非口服给予颅内荷 HER2 阳性肺癌肿瘤的小鼠，导致肿瘤对高分子量[(14)C]葡聚糖（增加 2.6 倍）和曲妥珠单抗（增加 2 倍）的通透性增加。与未治疗、伐地那非或曲妥珠单抗治疗的小鼠相比，用曲妥珠单抗联合伐地那非治疗颅内肺癌荷瘤小鼠的存活时间显著延长（p<0.01）。HER2 阳性颅内乳腺癌荷瘤小鼠的对数秩生存分析也显示，与其他组相比，用曲妥珠单抗联合伐地那非治疗的组生存时间显著延长（p<0.02）。然而，伐地那非对 HER2 表达低且与曲妥珠单抗联合治疗的颅内乳腺癌荷瘤小鼠的存活没有任何有益影响（p>0.05）。
结论/意义：这些发现表明，PDE5 抑制剂可能有效地调节 BTB 的通透性，并增强不同原发性脑转移瘤（已转移至大脑）中单克隆抗体的输送和治疗效果。
