Rooprai H K, Kandanearatchi A, Maidment S L, Christidou M, Trillo-Pazos G, Dexter D T, Rucklidge G J, Widmer W, Pilkington G J
Department of Neuropathology, Institute of Psychiatry, King's College London, UK.
Neuropathol Appl Neurobiol. 2001 Feb;27(1):29-39. doi: 10.1046/j.0305-1846.2000.00298.x.
Although intrinsic tumours of the brain seldom metastasize to distant sites, their diffuse, infiltrative-invasive growth within the brain generally precludes successful surgical and adjuvant therapy. Hence, attention has now focused on novel therapeutic approaches to combat brain tumours that include the use of anti-invasive and anti-proliferative agents. The effect of four anti-invasive agents, swainsonine (a locoweed alkaloid), captopril (an anti-hypertensive drug), tangeretin and nobiletin (both citrus flavonoids), were investigated on various parameters of brain tumour invasion such as matrix metalloproteinase (MMP) secretion, migration, invasion and adhesion. A standard cytotoxicity assay was used to optimize working concentrations of the drugs on seven human brain tumour-derived cell lines of various histological type and grade of malignancy. A qualitative assessment by gelatin zymography revealed that the effect of these agents varied between the seven cell lines such that the low grade pilocytic astrocytoma was unaffected by three of the agents. In contrast, downregulation of the two gelatinases, MMP-2 and MMP-9 was seen in the grade 3 astrocytoma irrespective of which agent was used. Generally, swainsonine was the least effective whereas the citrus flavonoids, particularly nobiletin, showed the greatest downregulation of secretion of the MMPs. Furthermore, captopril and nobiletin were most efficient at inhibiting invasion, migration and adhesion in four representative cell lines (an ependymoma, a grade II oligoastrocytoma, an anaplastic astrocytoma and a glioblastoma multiforme). Yet again, the effects of the four agents varied between the four cell lines. Nobiletin was, nevertheless, the most effective agent used in these assays. In conclusion, the differential effects seen on the various parameters studied by these putative anti-invasive agents may be the result of interference with MMPs and other mechanisms underlying the invasive phenotype. From these pilot studies, it is possible that these agents, especially the citrus flavonoids, could be of future therapeutic value. However, further work is needed to validate this in a larger study.
尽管脑内原发性肿瘤很少转移至远处，但它们在脑内呈弥漫性、浸润性生长，这通常使手术及辅助治疗难以成功。因此，目前的注意力已集中在对抗脑肿瘤的新型治疗方法上，其中包括使用抗侵袭和抗增殖药物。研究了四种抗侵袭药物——苦马豆素（一种疯草生物碱）、卡托普利（一种抗高血压药物）、橘红素和川陈皮素（均为柑橘类黄酮）对脑肿瘤侵袭的各种参数的影响，如基质金属蛋白酶（MMP）分泌、迁移、侵袭和黏附。采用标准细胞毒性试验来优化这些药物在七种不同组织学类型和恶性程度等级的人脑肿瘤衍生细胞系上的工作浓度。通过明胶酶谱法进行的定性评估显示，这些药物在七种细胞系中的作用各不相同，低级别毛细胞型星形细胞瘤不受其中三种药物的影响。相反，无论使用哪种药物，在三级星形细胞瘤中均可见到两种明胶酶MMP - 2和MMP - 9的下调。一般来说，苦马豆素效果最差，而柑橘类黄酮，尤其是川陈皮素，对MMPs分泌的下调作用最大。此外，在四种代表性细胞系（室管膜瘤、二级少突星形细胞瘤、间变性星形细胞瘤和多形性胶质母细胞瘤）中，卡托普利和川陈皮素在抑制侵袭、迁移和黏附方面最为有效。这四种药物在这四种细胞系中的作用再次各不相同。不过，川陈皮素是这些试验中最有效的药物。总之，这些假定的抗侵袭药物对所研究的各种参数产生的不同作用可能是由于干扰了MMPs以及侵袭表型背后的其他机制。从这些初步研究来看，这些药物，尤其是柑橘类黄酮，有可能具有未来的治疗价值。然而，需要进一步开展工作，在更大规模的研究中对此进行验证。
