Drug resistance is one of the important factors that determine tumor response to chemotherapy. Several candidates for resistance to various chemotherapeutic agents have been elucidated. O6-methylguanine-DNA methyltransferase (MGMT) removes methylation damage induced by nitrosourea from the O6 position of DNA guanines before cell injury. Glutathione-S-transferase (GST) pi is also involved in nitrosourea resistance. We examined the expression of MGMT and GST pi in 18 glioblastomas (GBM) using immunohistochemistry and compared the results with patients' survival after administration of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU)-based chemotherapy. According to the Kaplan-Meier's method, although median progression free survival (PFS) of eight patients whose tumors retained high MGMT (3+ approximately 2+), and 10 patients whose tumors showed low MGMT expression (1+ approximately 0) were nine and 15 months, respectively (p = 0.09), median overall survival (OS) of the two groups were 12 and 22 months, respectively, which were significantly different (p = 0.01). GST pi expression in GBM was not a prognostic factor. It is suggested that GBM with strong staining of MGMT activity may show more resistance to ACNU-based chemotherapy compared to that with low MGMT. The simple immunohistochemical analysis of MGMT in GBM can be a useful method to determine whether ACNU or another treatment regimen should be recommended.
Although malignant gliomas are highly invasive tumors, a characteristic that contributes to the commonly observed therapeutic failures and local disease recurrences, the molecular events that regulate invasion in these tumors remain poorly understood. Because the transcription factor RelA/NF-kappaB has been shown to regulate invasion during several cellular processes, we have examined immunohistochemically expression of the constitutively activated RelA/NF-kappaB in tissues obtained from 49 astrocytic tumors [8 diffuse astrocytomas, 9 anaplastic astrocytomas (AAs) and 32 glioblastomas (GBMs)]. In addition, we examined the in vitro effects of antisense oligonucleotides and curcumin on the expression and activation of RelA/NF-kappaB, urokinase-type plasminogen activator (u-PA) expression, migration, and invasion in the T98G glioma cell line. Expression of the constitutively activated RelA/NF-kappaB was observed in 2 (25%) of 8 cases of diffuse astrocytomas, 5 (55.6%) of 9 cases of AAs, and 30 (93.8%) of 32 cases of GBMs. This expression was significantly correlated with the malignant potential in astrocytic tumors (P < 0.001). Moreover, antisense oligonucleotides and curcumin inhibited phorbol-12-myristate-13-acetate (PMA)-induced RelA/NF-kappaB expression or activation (or both), down-regulated u-PA expression, and reduced the migration and invasive potentials of T98G glioma cells. Thus, the expression of constitutively activated RelA/NF-kappaB is associated with malignancy potential in astrocytic tumors and may play a critical role in the regulation of u-PA expression and invasiveness in gliomas. RelA/NF-kappaB may therefore be an intriguing candidate for studies aimed at understanding and prevention of the invasiveness of gliomas.
The adhesion molecule E-cadherin has been shown to influence malignant transformation of tumors, including local and distant metastases. We examined the expression of E-cadherin to determine its relationship to the development of metastasis in metastatic brain tumors. Immunohistochemistry for E-cadherin and Ki-67 was carried out in 76 formalin-fixed, paraffin-embedded archival specimens of metastatic brain tumors and in 14 corresponding available primary tumors from patients who received treatment for metastatic brain tumors. The primary tumors were mainly lung cancers (51.3%), followed by gastrointestinal tumors (28.9%). E-cadherin was expressed in 62 (81.5%) of 76 cases examined. In metastatic adenocarcinomas, a consistent tendency for E-cadherin expression was noted, regardless of the degree of differentiation or the extent of spread of the disease (P = 0.04). There was a direct correlation between E-cadherin expression and high MIB-1 index in all metastatic brain tumors (P = 0.0007). Pairwise analysis in 14 primary tumors and the corresponding metastatic specimens revealed high E-cadherin and MIB-1 staining in metastatic brain tumors. These results provide a unique association between E-cadherin, systemic metastasis, and proliferation potential in metastatic brain tumors.
OBJECTIVERegional ischemic vulnerability of the brain reportedly differs between the cortex and basal ganglia and has been poorly assessed in the setting of endovascular mechanical thrombectomy. This study was conducted to determine the fate of an ischemic basal ganglia and its contribution to the clinical outcome after successful endovascular recanalization for acute ischemic stroke with large vessel occlusion involving the lenticulostriate arteries.METHODSClinical and radiological findings were retrospectively analyzed in consecutive patients with acute ischemic stroke characterized by large vessel occlusion involving the lenticulostriate arteries. Mechanical thrombectomy was performed in all patients using a stent retriever. The fate of ischemic basal ganglia based on location (lentiform nucleus, caudate nucleus, and internal capsule) and insular cortex was assessed according to the Alberta Stroke Programme Early CT Score (ASPECTS).RESULTSOf 170 patients with large intracranial vessel occlusion who achieved successful endovascular recanalization, defined as a thrombolysis in cerebral infarction grade of ≥ 2B, involvement of the lenticulostriate arteries was seen in 55 patients (internal carotid artery, n = 35; proximal middle cerebral artery, n = 20). Preoperative infarction was detected in the lentiform nucleus (66.7%), internal capsule (11.1%), and caudate nucleus (33.3%), all of which showed secondary advancement despite successful recanalization (85.4%, 27.3%, and 54.5%, respectively; p < 0.05). Lenticulostriate arteries with a lateral proximal and/or medial proximal origin significantly affected the development of mature infarction in the lentiform nucleus. Postoperative hemorrhagic transformation was detected in 25 of 55 patients, mostly in the lentiform nucleus. Involvement of insular ribbon infarction was significantly high in patients with hemorrhagic transformation in the basal ganglia. Age, initial National Institutes of Health Stroke Scale (NIHSS) score, initial ASPECTS, postoperative ASPECTS, postoperative infarction in the insular ribbon, and lesions in the middle cerebral artery area (M1–M6) were significantly different between patients with good and poor modified Rankin Scale scores. Interestingly, no differences were detected in postoperative infarction or hemorrhagic transformation in the basal ganglia. Multivariate analysis showed that only age (p = 0.02, OR 0.88) and the initial NIHSS score (p = 0.01, OR 0.86) independently affected favorable clinical outcomes.CONCLUSIONSThe basal ganglia are vulnerable and readily develop secondary infarction and hemorrhagic transformation despite successful recanalization. However, this does not have a significant impact on the clinical outcome of acute ischemic stroke with large vessel occlusion involving the lenticulostriate arteries.
Simultaneous brain microdialysis in tumour and non-tumour tissues has been used for kinetic determination of the local distribution of an anticancer agent, cisplatin, in rats. Rat brain was implanted with 9L malignant glioma and cisplatin (3.5 mg kg-1) was administered as a selective intracarotid infusion for 30 min to rats prepared for brain microdialysis. The amount of platinum in the dialysate collected from tumour and non-tumour brain tissues was determined by atomic absorption spectrophotometry, as representative of cisplatin. Total and free platinum concentrations in plasma were also measured. Free platinum is accumulated preferentially in the tumour tissue and the brain tumour distribution coefficient (the ratio of brain tumour platinum AUC to plasma free platinum AUC, where AUC is the area under the platinum concentration-time curve) was 0.69, although there was little distribution into normal brain tissue. Drug binding to plasma proteins was 65%. It is concluded that simultaneous microdialysis is an easy and available method for assessing in-vivo local pharmacokinetics and distribution of cisplatin in tumour and non-tumour tissues of the brain.
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