Primary intracranial aggressive fibromatosis arising in sella turcica: illustrative case.

BACKGROUND: Aggressive fibromatosis is a rare histologically benign but locally infiltrative myofibroblastic tumor. Primary intracranial aggressive fibromatosis (IAF) can exhibit a clinically malignant course. OBSERVATIONS: A 22-year-old otherwise healthy woman presented with left painful ophthalmoplegia. Magnetic resonance imaging (MRI) revealed a left sellar tumor with cavernous sinus invasion. Endoscopic transsphenoidal surgery was performed. The lesion could not be totally resected. An inflammatory myofibroblastic tumor was suspected, so steroid pulse therapy was introduced, but it was ineffective. The tumor recurred after a few months, and she complained of visual acuity loss, abducens nerve palsy, trigeminal neuralgia, and panhypopituitarism. The lesion was diagnosed as primary IAF by a pathological review. Gamma Knife radiosurgery was performed, and chemotherapies were introduced but ineffective. Her consciousness was disturbed, and MRI showed hypothalamic invasion of the tumor, occlusion and stenosis of carotid arteries, and cerebral stroke. Palliative care was introduced, and she died 32 months after the onset. The autopsy revealed tumor invasion to the cavernous sinus, optic nerve, hypothalamus, pituitary, and tonsillar herniation due to massive cerebral stroke. LESSONS: Radical resection can be impossible in patients with IAF. Radiotherapy and chemotherapy are not always effective for residual lesions. Adjuvant therapy for IAF remains to be explored.

[Surgery for a Refractory Chronic Subdural Hematoma Using an Exoscope:A Technical Case Report].

Burr hole irrigation and drainage is effective in most cases of chronic subdural hematoma(CSDH). However, we sometimes encounter refractory cases that need further procedures or other interventions. Here we report a case with a disturbance of consciousness and left hemiparesis. CT of the head showed a right CSDH, which recurred three times in spite of repeated burr-hole irrigation surgeries. We performed a mini-craniotomy and evacuation of the hematoma under the exoscope to remove the hematoma effectively. The post-operative course was uneventful and no recurrence was found at the last follow up. A mini-craniotomy with an exoscope might be a useful option for treating cases of refractory CSDH.

[A Case of Slowly Progressive Brain Metastasis with Minor Bleeding after Removal of and Chemotherapy for Non-Small Cell Lung Cancer].

Of all brain metastases, the most common primary lesion is derived from the lung. These types of metastases enlarge aggressively with unfavorable prognoses. We report the case of a 75-year-old male patient who had a history of pulmonary resection for Stage IA non-small cell lung cancer(NSCLC), and received chemotherapy. One year after NSCLC surgery, he experienced a cardiogenic cerebral infarction, and anticoagulant therapy was initiated. Mass lesions with hemorrhage were detected bilaterally in the frontal lobes through magnetic resonance imaging three years after the NSCLC surgery. The lesions slowly enlarged during follow-up. However, there were no clinical symptoms. There was no finding indicating a local recurrence or metastasis through positron emission tomography(PET). Two and a half years after the detection of the lesion, left hemiplegia was observed. Massive hemorrhage from the right frontal lobe lesion was observed on computed tomography(CT). Craniotomy and evacuation of the hematoma were performed. The histopathological findings showed adenocarcinoma and the diagnosis was brain metastasis of the lung cancer. This case reveals brain metastasis of lung cancer that progressed without extracranial metastases for three years. The brain tumor enlarged, accompanied by hemorrhage, extremely slowly without any symptoms. It was difficult to differentiate between metastasis and cavernous hemangioma, considering the extremely slow progress and image analyses. Of the reported prognostic factors associated with postoperative brain metastasis from surgically resected NSCLC, three factors were applicable to this case:adenocarcinoma, a small number of brain metastases, and the absence of extracranial metastases at the diagnosis of brain metastasis. We should consider the possibility of a metastatic brain tumor secondary to lung cancer even long after thoracic surgery.

Hyperglycemia is associated with poor survival in primary central nervous system lymphoma patients.

PURPOSE: Primary central nervous system lymphoma (PCNSL) is a type of non-Hodgkin lymphoma (NHL), and it has been postulated that metabolic disorder may contribute to NHL etiology. We retrospectively investigated the prognostic significance of hyperglycemia in patients with PCNSL. We evaluated glucose transporter type 1 (GLUT1) expression by immunohistochemistry and analyzed its association with hyperglycemia and survival. METHODS: The medical and neuroradiologic records of 50 patients with PCNSL at our institution over the past 15 years were analyzed. Patients were divided into 3 groups based on mean fasting plasma glucose (FPG) levels: normal (<110 mg/dL), prediabetes (110-125 mg/dL), and diabetes (≥126 mg/dL). We defined prediabetes and diabetes groups as hyperglycemia. RESULTS: Forty-four percent of patients were in the prediabetes and diabetes groups. One-year survival rates were 73%, 66%, and 43% in normal, prediabetes, and diabetes groups, respectively. Univariate analysis revealed that high age, female sex, poor performance status, high mean FPG, and monotherapy were associated with shorter survival. Multivariable Cox regression analyses showed that high mean FPG and monotherapy were significant predictors of shorter survival (p = 0.036 and p = 0.000, respectively). The GLUT1 immunohistopathologic staining was performed in 34 cases, 20 of which (58%) showed variable levels of GLUT1 expression at the cell membrane and/or cytoplasm. Prediabetes and diabetes groups had a higher percentage of GLUT1-positive cells compared with the normal group (p = 0.015). CONCLUSIONS: These findings indicate that hyperglycemia is associated with poor survival. The putative biological mechanism might involve differential GLUT1 expression between hyperglycemic and normal states in patients with PCNSL.

Long-term follow-up results of linear accelerator-based radiosurgery for vestibular schwannoma using serial three-dimensional spoiled gradient-echo MRI.

We examined the characteristic changes in vestibular schwannoma (VS) volume after treatment with linear accelerator-based radiosurgery (LBRS) and the long-term therapeutic effects, by performing three-dimensional (3D) MRI evaluations of tumor volumes. We included 44 patients in whom tumor volume changes could be observed using 3D-spoiled gradient-echo MRI for at least 5 years. Examinations were performed every 3-4 months for the first 2 years after treatment and every 6-12 months thereafter. Enlargement or shrinkage was determined as a change of at least 20% from the volume at the time of treatment. The median observation period was 13.8 years (range, 5.5-19.5 years). The tumor control rates at 5 and 10 years after treatment and at the final MRI were 90.9%, 90.0%, and 88.6%, respectively. Tumor volume changes were categorized into the following four patterns: enlargement, five patients (11.4%); stable, three patients (6.8%); transient enlargement, 24 patients (54.5%); and direct shrinkage, 12 patients (27.3%). Bimodal peaks were observed in three of the 24 patients with transient enlargement. Tumor volume changes from 5 and 10 years post-LBRS to the final observation point were observed in 27 (64.2%) and 10 patients (33.3%), respectively. The long-term tumor volume changes observed after LBRS suggest that radiation exerts long-term effects on tumors. Furthermore, while transient enlargements in tumor volume were characteristic, true tumor enlargements should be characterized by increased volumes of more than two-fold and continued growth for at least 2 years.

Indication and limitations of endoscopic extended transsphenoidal surgery for craniopharyngioma.

The transsphenoidal approach has been utilized in intrasellar craniopharyngioma surgeries. However, the advent of endoscopic extended transsphenoidal approach (EETSA) has expanded its indication to suprasellar craniopharyngiomas. We compared the indication and limitations of EETSA to those of unilateral basal interhemispheric approach (UBIHA), which presents similar indications for surgery. We analyzed 30 patients with tumors located below the foramen of Monro and the lateral boundary extending slightly beyond the internal carotid artery (UBIHA: N = 18; EETSA: N = 12). Postoperative magnetic resonance imaging (MRI) revealed gross total resection in 10 patients in the EETSA group (83.3%) and 12 in the UBIHA group (66.7%). Postoperative MRI in the EETSA group revealed residual tumor at the cavernous sinus in one patient, at the prepontine in one; in the UBIHA group, residual tumors were located in the retrochiasmatic area in two patients, infundibulum-hypothalamus in one, on the stalk in one, and in the intrasellar region in two. No intergroup differences were observed in the preservation of pituitary function and postoperative improvement of visual function. The extent of resection was better with EETSA than with UBIHA. EETSA is considered the first-line therapy because the distance between the optic chiasm and the superior border of the pituitary is large; the lateral extension does not go beyond the internal carotid artery; and the tumor does not extend inferiorly beyond the posterior clinoid process. However, in patients showing poorly developed sphenoid sinuses or pituitary stalks anterior to the tumor, surgery is difficult regardless of the selection criteria.

Linear accelerator-based radiosurgery alone for arteriovenous malformation: more than 12 years of observation.

PURPOSE: Although radiosurgery is an accepted treatment method for intracranial arteriovenous malformations (AVMs), its long-term therapeutic effects have not been sufficiently evaluated, and many reports of long-term observations are from gamma-knife facilities. Furthermore, there are few reported results of treatment using only linear accelerator (LINAC)-based radiosurgery (LBRS). METHODS AND MATERIALS: Over a period of more than 12 years, we followed the long-term results of LBRS treatment performed in 51 AVM patients. RESULTS: The actuarial obliteration rates, after a single radiosurgery session, at 3, 5, 10, and 15 years were 46.9%, 54.0%, 64.4%, and 68.0%, respectively; when subsequent radiosurgeries were included, the rates were 46.9%, 61.3%, 74.2%, and 90.3%, respectively. Obliteration rates were significantly related to target volumes ≥4 cm(3), marginal doses ≥12 Gy, Spetzler-Martin grades (1 vs other), and AVM scores ≥1.5; multivariate analyses revealed a significant difference for target volumes ≥4 cm(3). The postprocedural actuarial symptomatic radiation injury rates, after a single radiation surgery session, at 5, 10, and 15 years were 12.3%, 16.8%, and 19.1%, respectively. Volumes ≥4 cm(3), location (lobular or other), AVM scores ≥1.5, and the number of radiosurgery were related to radiation injury incidence; multivariate analyses revealed significant differences associated with volumes ≥4 cm(3) and location (lobular or other). CONCLUSIONS: Positive results can be obtained with LBRS when performed with a target volume ≤4 cm(3), an AVM score ≤1.5, and ≥12 Gy radiation. Bleeding and radiation injuries may appear even 10 years after treatment, necessitating long-term observation.

Cyst formation after linac-based radiosurgery for arteriovenous malformation: examination of predictive factors using magnetic resonance imaging.

OBJECTIVE: Cyst formation is a well-known complication following radiosurgery for arteriovenous malformations (AVMs). In this retrospective study, the authors studied predictors for AVMs using magnetic resonance imaging (MRI) to assess the mechanism of cyst formation after linac-based radiosurgery (LBRS). METHODS: From April 1993 to April 2008, LBRS was performed on 109 patients with cerebral AVMs at our institution. Six patients (5.5%) were diagnosed with cyst formation after LBRS, and 5 of them underwent regular MRI follow-up every 3-4 months for 2 years post-LBRS, and every 6-12 months thereafter. RESULTS: Time from initial LBRS until cyst formation ranged from 8 months to 10.5 years. MRI showed contrast changes at the irradiated site and its periphery within a period of 4 months to 7 years after the initial LBRS. Moreover, the emergence of a high-intensity area (HIA) was observed on T2-weighted MRI (T2W-MRI) during the same period when changes were found on contrast-enhanced imaging. The emergence of a low-intensity area on T2W-MRI was observed prior to cyst formation or expansion, which was believed to be due to a subclinical hemorrhage near the irradiated region in all patients. Histological examination of the cyst nodule revealed hemosiderin deposits and microbleeding. CONCLUSIONS: Future cyst formation was suggested by the emergence of subclinical hemorrhage (microbleeding) in an irradiated field after gadolinium-enhanced MRI showed contrast changes and T2W-MRI showed a HIA around the irradiated field. MRI follow-up should be conducted on a regular basis in such patients, even after a complete occlusion has been diagnosed.

Unilateral Basal interhemispheric approach through the sphenoid sinus to retrochiasmatic and intrasellar craniopharyngiomas: surgical technique and results.

OBJECTIVE: In the treatment of craniopharyngioma, complete surgical removal offers the best chance of cure and recurrence prevention. The basal interhemispheric approach involves problems with difficulty resecting tumors in the retrochiasmatic space located behind the optic chiasm and inability to resect, under direct view, tumors extending into the sella turcica. We report our approach via the sphenoid sinus devised to resolve these problems. METHODS: A unilateral basal interhemispheric approach is planned for tumor resection. In cases in which the prechiasmatic space is too narrow to be utilized or the tumor has extended into the sella turcica, the prechiasmatic space is expanded by shaving the sphenoid surface and the tuberculum sellae. If the tumor inside the sella turcica needs to be removed, the anterior wall of the sella turcica also is shaved to permit tumor resection. RESULTS: This technique was applied to 7 cases in total (in 3 cases to achieve prechiasmatic space expansion and in 4 cases for intrasellar tumor resection). Gross total removal was achieved in 6 cases and subtotal removal in 1. Of the 6 cases with preoperative visual field defects, 5 showed alleviation of these defects. The 5 patients with partial hypopituitarism developed complete panhypopituitarism postoperatively. All 7 patients have not suffered from postoperative cerebrospinal fluid leakage and meningitis. CONCLUSIONS: This approach allowed a working space to be secured even in cases with a narrow prechiasmatic space, allowing tumor freeing from the lower plane of the optic nerve and safe resection of the intrasellar tumor.

Indication and limitations of endoscopic extended transsphenoidal surgery for craniopharyngioma.

The transsphenoidal approach has been utilized in intrasellar craniopharyngioma surgeries. However, the advent of endoscopic extended transsphenoidal approach (EETSA) has expanded its indication to suprasellar craniopharyngiomas. We compared the indication and limitations of EETSA to those of unilateral basal interhemispheric approach (UBIHA), which presents similar indications for surgery. We analyzed 30 patients with tumors located below the foramen of Monro and the lateral boundary extending slightly beyond the internal carotid artery (UBIHA: N=18; EETSA: N=12). Postoperative magnetic resonance imaging (MRI) revealed gross total resection in 10 patients in the EETSA group (83.3%) and 12 in the UBIHA group (66.7%). Postoperative MRI in the EETSA group revealed residual tumor at the cavernous sinus in one patient, at the prepontine in one; in the UBIHA group, residual tumors were located in the retrochiasmatic area in two patients, infundibulum-hypothalamus in one, on the stalk in one, and in the intrasellar region in two. No intergroup differences were observed in the preservation of pituitary function and postoperative improvement of visual function. The extent of resection was better with EETSA than with UBIHA. EETSA is considered the first-line therapy because the distance between the optic chiasm and the superior border of the pituitary is large; the lateral extension does not go beyond the internal carotid artery; and the tumor does not extend inferiorly beyond the posterior clinoid process. However, in patients showing poorly developed sphenoid sinuses or pituitary stalks anterior to the tumor, surgery is difficult regardless of the selection criteria.

Initial contact of glioblastoma cells with existing normal brain endothelial cells strengthen the barrier function via fibroblast growth factor 2 secretion: a new in vitro blood-brain barrier model.

Glioblastoma multiforme (GBM) cells invade along the existing normal capillaries in brain. Normal capillary endothelial cells function as the blood-brain barrier (BBB) that limits permeability of chemicals into the brain. To investigate whether GBM cells modulate the BBB function of normal endothelial cells, we developed a new in vitro BBB model with primary cultures of rat brain endothelial cells (RBECs), pericytes, and astrocytes. Cells were plated on a membrane with 8 µm pores, either as a monolayer or as a BBB model with triple layer culture. The BBB model consisted of RBEC on the luminal side as a bottom, and pericytes and astrocytes on the abluminal side as a top of the chamber. Human GBM cell line, LN-18 cells, or lung cancer cell line, NCI-H1299 cells, placed on either the RBEC monolayer or the BBB model increased the transendothelial electrical resistance (TEER) values against the model, which peaked within 72 h after the tumor cell application. The TEER value gradually returned to baseline with LN-18 cells, whereas the value quickly dropped to the baseline in 24 h with NCI-H1299 cells. NCI-H1299 cells invaded into the RBEC layer through the membrane, but LN-18 cells did not. Fibroblast growth factor 2 (FGF-2) strengthens the endothelial cell BBB function by increased occludin and ZO-1 expression. In our model, LN-18 and NCI-H1299 cells secreted FGF-2, and a neutralization antibody to FGF-2 inhibited LN-18 cells enhanced BBB function. These results suggest that FGF-2 would be a novel therapeutic target for GBM in the perivascular invasive front.

Repeated delayed onset cerebellar radiation injuries after linear accelerator-based stereotactic radiosurgery for vestibular schwannoma: case report.

A 63-year-old woman presented with right hearing disturbance and vertigo. Magnetic resonance (MR) imaging revealed the presence of right vestibular schwannoma (VS). Stereotactic radiosurgery (SRS) was performed with a tumor marginal dose of 14 Gy using two isocenters. She was followed up clinically and neuroradiologically using three-dimensional spoiled gradient-echo MR imaging. She experienced temporal neurological deterioration due to peritumoral edema in her right cerebellar peduncle and pons for a few months beginning 1.5 years after SRS, when she experienced transient right facial dysesthesia and hearing deterioration. Ten years after SRS, the patient presented with sudden onset of vertigo, gait disturbance, diplopia, dysarthria, and nausea. MR imaging demonstrated a new lesion in the right cerebellar peduncle, which was diagnosed as radiation-induced stroke. The patient was followed up conservatively and her symptoms disappeared within a few months. Multiple delayed onset radiation injuries are possible sequelae of SRS for VS.

A case of multinodular high-grade neuroepithelial tumor with ependymal differentiation.

We describe a rare case of multinodular cerebral neuroepithelial tumor with ependymal differentiation. A 65-year-old man experienced loss of consciousness with an obscure episode of seizure attack. Magnetic resonance images disclosed a lesion located in the left temporal lobe and the insular cortex. The tumor was partially removed. Histologically, the tumor showed infiltrating multinodular tumor nodules in the cerebrum. Each nodule was well demarcated and composed of clear cells with perinuclear halos, intermingled fibrillary cells, and poorly differentiated neuroepithelial cells with mitotic activity. Immunohistochemically, clear cells showed dot-like positivity for epithelial membrane antigen. Fibrillary cells were positive for vimentin and nestin, whereas only a few glial fibrillary acidic protein-immunopositive cells were seen. We conclude that this tumor, being microscopically characterized by multinodular tumor nodules, was a high-grade neuroepithelial tumor with ependymal differentiation.

miR-195, miR-455-3p and miR-10a( *) are implicated in acquired temozolomide resistance in glioblastoma multiforme cells.

To identify microRNAs (miRNAs) specifically involved in the acquisition of temozolomide (TMZ) resistance in glioblastoma multiforme (GBM), we first established a resistant variant, U251R cells from TMZ-sensitive GBM cell line, U251MG. We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a( *) were the three most up-regulated miRNAs in the resistant cells. To investigate the functional role of these miRNAs in TMZ resistance, U251R cells were transfected with miRNA inhibitors consisting of DNA/LNA hybrid oligonucleotides. Suppression of miR-455-3p or miR-10a( *) had no effect on cell growth, but showed modest cell killing effect in the presence of TMZ. On the other hand, knockdown of miR-195 alone displayed moderate cell killing effect, and combination with TMZ strongly enhanced the effect. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs. In conclusion, our findings suggest that those miRNAs may play a role in acquired TMZ resistance and could be a novel target for recurrent GBM treatment.

[Radiation injury after stereotactic irradiaton: especially long-term follow-up benign of targets].

OBJECTIVE: To analyses the result of linac radiosurgery (LRS) for the treatment of intracranial benign lesions and to assess possible factors related to complications. METHODS: The authors retrospectively reviewed 204 patients treated with LRS between May, 1993 and December, 2003. The study determined the correlation between radiosurgical complications including imaging changes after LRS and multiple factors such as radiosurgical parameters, location, volume and shape. We divided the patients into three groups by MRI imaging changes and clinical symptoms. Group 1 (Gr. 1): Imaging change only. Group 2 (Gr. 2): Imaging change with transient symptoms. Group 3 (Gr.3): Imaging change with permanent symptoms. RESULT: Ninty-three patient with AVM: Gr. 1, 8 cases (8.6%), Gr. 2, 1 case (1.1%), Gr. 3, 2 cases (2.1%). A significantly higher incidence of imaging change was noted in patients with arteriovenous malformation (AVM) volumes greater than 10 cc, irregular shape of the nidus and deep location. Fifty-eight patients with vestibulan schwannoma (VS): Gr. 1, 6 cases (10.3%), Gr. 2, 1 case (1.8%), Gr. 3, 2 cases (3.4%). Imaging changes were seen mostly in cases with tumor volume greater than 5 cc. Fifty-three patients with meningioma: Gr. 1, 4 cases (7.5%), Gr.2, 2 cases (3.7%), Gr.3, 0 case. Imaging changes were seen mostly in convexity, parasaggital, and falx meningiomas that were deeply embedded in the cortex. The symptom continued the until last serial observation in four cases. We used various interventions in these patients including steroid, anticoagulant, surgical removal, and hyperbaric oxygen therapy; but these therapies were not effective. CONCLUSION: LRS for each disease seems to be a safe and effective treatment. However, once serious radiation injuries occur there is no effective therapy, so it is important to make appropriate selection of patients for radiosurgery.

Aneurysmal embolization of a blisterlike aneurysm of the internal carotid artery: a case report and review of the literature.

BACKGROUND: Little is known regarding the optimal management of a ruptured blisterlike aneurysm of the ICA. Because of the high risk for intraoperative bleeding, direct surgical treatments of these fragile lesions have generally been associated with a poor outcome. We herein report a very rare case of a ruptured blisterlike aneurysm that was successfully treated with coil embolization in the late period. CASE DESCRIPTION: The patient was 21 years old when he had a Hunt and Hess grade IV subarachnoid hemorrhage. At the time of the hemorrhage, 3D-CTA demonstrated a minimal aneurysmal enlargement located in the left C2 portion of the ICA. Because of his poor neurological condition and the risk for a premature rupture during early surgery, delayed surgery was thus scheduled. Cerebral angiography, 13 days later, revealed the shape and size of the aneurysm to have changed in form from a blisterlike aneurysm to a saccular-type one. Initially, we planned to treat the aneurysm by trapping with bypass surgery on the 15th day. However, we instead performed coil embolization on the 19th day because a thick thrombus was found to cover the aneurysm at the time of surgery on the 15th day. CONCLUSION: This is the first report of a ruptured blisterlike aneurysm that was successfully treated with coil embolization in the late period of a subarachnoid hemorrhage after operative confirmation of thrombus formation around the aneurysm. Our findings suggest that coil embolization in the late period appears to be an effective option in the management of selective cases of ruptured blisterlike aneurysms.

Factors affecting rapid growth of unruptured cerebral aneurysms during the acute stage of subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Several unruptured cerebral aneurysms have been reported to grow and rupture. To determine which factors affect the growth of these aneurysms during the acute stage of subarachnoid hemorrhage (SAH), a retrospective review was performed. METHODS: Between January 2000 and January 2003, 130 patients with angiographically proven ruptured cerebral aneurysms were treated at our institution. Of these patients, 32 also had simultaneous unruptured aneurysms, and the total number of the unruptured aneurysms was 40, including two neck remnants which had remained since the past clipping. Seventeen patients had 17 unruptured aneurysms and two neck remnants. The unruptured aneurysms were not treated during the acute stage of SAH but had received a complete short term follow-up. RESULTS: The rapid growth of one unruptured aneurysm and two neck remnants was confirmed by a second angiogram performed on average 40 days after the first angiogram. Several candidate factors responsible for the growth of aneurysm were selected, and the results of a statistical analysis indicate that a systolic blood pressure above 200 mmHg during the acute stage of SAH and vasospasm, confirmed by transcranial Doppler ultrasound (TCD) or neurological examination, and neck remnants, are risk factors that affect the growth. CONCLUSIONS: Short term follow-up angiography is thus important for patients with untreated unruptured cerebral aneurysms after the acute stage of SAH.

Nuclear glutathione S-transferase pi prevents apoptosis by reducing the oxidative stress-induced formation of exocyclic DNA products.

We previously found that nuclear glutathione S-transferase pi (GSTpi) accumulates in cancer cells resistant to anticancer drugs, suggesting that it has a role in the acquisition of resistance to anticancer drugs. In the present study, the effect of oxidative stress on the nuclear translocation of GSTpi and its role in the protection of DNA from damage were investigated. In human colonic cancer HCT8 cells, the hydrogen peroxide (H(2)O(2))-induced increase in nuclear condensation, the population of sub-G(1) peak, and the number of TUNEL-positive cells were observed in cells pretreated with edible mushroom lectin, an inhibitor of the nuclear transport of GSTpi. The DNA damage and the formation of lipid peroxide were dependent on the dose of H(2)O(2) and the incubation time. Immunological analysis showed that H(2)O(2) induced the nuclear accumulation of GSTpi but not of glutathione peroxidase. Formation of the 7-(2-oxo-hepyl)-substituted 1,N(2)-etheno-2'-deoxyguanosine adduct by the reaction of 13-hydroperoxyoctadecadienoic acid (13-HPODE) with 2'-deoxyguanosine was inhibited by GSTpi in the presence of glutathione. The conjugation product of 4-oxo-2-nonenal, a lipid aldehyde of 13-HPODE, with GSH in the presence of GSTpi, was identified by LS/MS. These results suggested that nuclear GSTpi prevents H(2)O(2)-induced DNA damage by scavenging the formation of lipid-peroxide-modified DNA.

Significance of nuclear glutathione S-transferase pi in resistance to anti-cancer drugs.

Recent study has shown that nuclear glutathione S-transferase (GST) pi accumulates in cancer cells resistant to doxorubicin hydrochloride (DOX) and may function to prevent nuclear DNA damage caused by DOX (Goto et al., FASEB J., 15, 2702 - 2714 (2001)). It is not clear if the amount of nuclear GSTpi increases in response to other anti-cancer drugs and if so, what is the physiological significance of the nuclear transfer of GSTpi in the acquisition of drug-resistance in cancer cells. In the present study, we employed three cancer cell lines, HCT8 human colonic cancer cells, A549 human lung adenocarcinoma cells, and T98G human glioblastoma cells. We estimated the nuclear transfer of GSTpi induced by the anti-cancer drugs cisplatin (CDDP), irinotecan hydrochloride (CPT-11), etoposide (VP-16) and 5-fluorouracil (5-FU). It was found that: (1) Nuclear GSTpi accumulated in these cancer cells in response to CDDP, DOX, CPT-11, VP-16 and 5-FU. (2) An inhibitor of the nuclear transport of GSTpi, edible mushroom lectin (Agaricus bisporus lectin, ABL), increased the sensitivity of the cancer cells to DOX and CDDP, and partially to CPT-11. Treatment with ABL had no apparent effect on the cytotoxicity of VP-16 and 5-FU. These results suggest that inhibitors of the nuclear transfer of GSTpi have practical value in producing an increase of sensitivity to DOX, CDDP and CPT-11.

Hammerhead ribozyme against gamma-glutamylcysteine synthetase attenuates resistance to ionizing radiation and cisplatin in human T98G glioblastoma cells.

Glioblastoma cells are highly malignant and show resistance to ionizing radiation, as well as anti-cancer drugs. This resistance to cancer therapy is often associated with a high concentration of glutathione (GSH). In this study, the effect of continuous down-regulation of gamma-glutamylcysteine synthetase (gamma-GCS) expression, a rate-limiting enzyme for GSH synthesis, on resistance to ionizing radiation and cisplatin (CDDP) was studied in T98G human glioblastoma cells. We constructed a hammerhead ribozyme against a gamma-GCS heavy subunit (gamma-GCSh) mRNA and transfected it into T98G cells. (1) The transfection of the ribozyme decreased the concentration of GSH and resulted in G1 cell cycle arrest of T98G cells. (2) The transfection of the ribozyme increased the cytotoxicity of ionizing radiation and CDDP in T98G cells. Thus, hammerhead ribozyme against gamma-GCS is suggested to have potential as a cancer gene therapy to reduce the resistance of malignant cells to ionizing radiation and anti-cancer drugs.