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首页> 外文期刊>Fluids and Barriers of the CNS >Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas
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Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas

机译：脑脊液基质金属蛋白酶9在复发性恶性神经胶质瘤的治疗过程中增加

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Background Matrix metalloproteinases (MMPs) are enzymes that promote tumor invasion and angiogenesis by enzymatically remodeling the extracellular matrix. MMP-2 and MMP-9 are the most abundant forms of MMPs in malignant gliomas, while a 130 kDa MMP is thought to be MMP-9 complexed to other proteinases. This study determined whether doxycycline can block MMP activity in vitro. We also measured MMP-2 and MMP-9 levels in cerebrospinal fluid (CSF) from patients with recurrent malignant gliomas. Methods To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition in vitro using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m2/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI). Results Doxycyline in vitro completely abolished MMP-9 activity at 500 μg/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI. Conclusion Doxycycline can block MMP-2 and MMP-9 activities from glioma cells in vitro. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.
机译：背景基质金属蛋白酶（MMP）是通过酶促重塑细胞外基质来促进肿瘤侵袭和血管生成的酶。 MMP-2和MMP-9是恶性神经胶质瘤中MMP的最丰富形式，而130 kDa的MMP被认为与其他蛋白酶复合。这项研究确定了强力霉素是否可以在体外阻断MMP活性。我们还测量了复发性恶性神经胶质瘤患者脑脊液（CSF）中的MMP-2和MMP-9水平。方法为了确定强力霉素是否可以阻断MMP活性，我们使用表皮生长因子受体（EGFR）转染的U251胶质瘤细胞系测量了强力霉素介导的MMP-2和MMP-9体外抑制程度。使用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳（SDS-PAGE）酶谱法测量MMP活性。此外，患者在基线，6周（1个周期）和12周（2个周期）之后接受腰穿CSF采样，同时接受伊立替康，沙利度胺和强力霉素的新型化疗方案治疗，以阻止生长/增殖，血管生成和侵袭。伊立替康以125 mg / m2 /周的剂量连续6周给药，持续4周，在第1天每天两次，连续100毫克强力霉素，此后每天两次，连续50毫克。我们队列中的沙利度胺的每日剂量为400 mg。通过磁共振成像（MRI）监测肿瘤的进展。结果在体外，强力霉素在500μg/ ml时完全废除了MMP-9活性，而对MMP-2活性的抑制作用仅为30％至50％。四名患者分别完成了伊立替康，沙利度胺和强力霉素的4、3、1和2个周期。一名患者出现放射学确定的肺栓塞，另一名患者可能发生了肺栓塞后，终止患者入组。尽管CSF MMP-2和130 kDa MMP水平稳定，但尽管MRI稳定，但在治疗过程中MMP-9水平逐渐升高。结论强力霉素可体外阻断神经胶质瘤细胞的MMP-2和MMP-9活性。脑脊液MMP-9活性升高可能是恶性神经胶质瘤患者疾病活动的生物标志，而在MRI上未发现任何变化。

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