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ABSTRACT: Direct evidence of the anatomical localization of brain function is provided by functional neurological changes during awake surgery combined with data from preoperative functional magnetic resonance imaging and diffusion tensor imaging studies. The goal of the present study was to analyze the etiology and mechanism of motor hemineglect using these techniques. Of 29 patients with brain tumors within and near the primary motor area (M1) in whom awake surgery was employed from April 2004 through March 2007, 2 patients evinced motor hemineglect of the left hand during awake surgery. The brain tumors in these 2 cases alone were located just beside the hand area of M1 and the primary sensory area (S1) in the right hemisphere. In case 1, the U fibers that connected the areas activated by hand clenching in M1 with S1 were compressed by the brain tumor. These results suggest that the combination of damage to the right hemispheric hand area in M1 and S1 plays a critical role in the development of motor hemineglect.
European Neurology 11/2009; 63(1):17-23. · 1.81 Impact Factor
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ABSTRACT: Changes in motor function in response to lesions in the premotor area (PM) and the primary motor area (M1) are difficult to predict. The goal of the present study was to use awake surgery to characterize the functional property of the PM or the M1 in patients with brain tumors. Neurological change before, during and after awake surgery was compared among 8 cases of patients with brain tumors located in the PM or M1. Degree of recovery after awake surgery was better for those with brain tumors in the PM (average motor strength, 2.3) when compared with those with brain tumors in the M1 (average motor strength, 1.0). Mean duration until recovery of motor strength after awake surgery was significantly shorter for those with brain tumors in the PM (4.3 days) when compared with those with brain tumors in the M1 (7.8 days) (p < 0.05). Since the degree of removal of brain tumors was greater in those with tumors in the PM when compared with those with tumors in the M1, and because the size of brain tumors in both areas were comparable, the marked and rapid recovery of motor strength after awake surgery for those with brain tumors in PM was likely related to the specific neurological properties of PM such as the redundant network of the secondary motor area. Recovery of motor strength after awake surgery for those with brain tumors located in PM was relatively marked and rapid when compared with those with brain tumors in the M1.
British Journal of Neurosurgery 06/2009; 23(3):309-14. · 0.88 Impact Factor
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ABSTRACT: Functional neurological changes after surgery combined with data from diffusion tensor imaging (DTI) studies can provide direct evidence of anatomical localization of brain function. The goal of the present study was to characterize mechanisms of spatial neglect using these techniques by analyzing two patients with development or worsening of left neglect after surgery at our hospital in 2008. In both cases, the surgical approach was via the right inferior parietal lobes, and damage to the superior longitudinal fasciculus (SLF) was demonstrated after surgery by DTI tractography. By contrast, neither the inferior longitudinal fasciculus (ILF) nor the inferior fronto-occipital fasciculus (IFOF) was damaged. These results suggest that damage to the right SLF in the inferior parietal lobe plays a critical role in the development of spatial neglect.
Neuropsychologia 06/2009; 47(12):2600-3. · 3.64 Impact Factor
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ABSTRACT: Cortical mapping during awake surgery assesses intraoperative neurological change in response to electrical stimulation to provide direct information regarding the anatomical localization of the primary motor area (M1). The goal of the present study was to analyze the reliability of the identification of the precentral knob in the axial image of magnetic resonance imaging or functional MRI (fMRI) for the detection of M1.
Among patients with brain tumors within or near M1 in whom awake surgery was employed from April 2004 through March 2007, 14 cases were analyzed in which either the M1 or premotor area (PMA) was successfully detected by mapping during awake surgery.
The precentral knob was localized to the PMA in 4 cases and to M1 in 10 cases. By contrast, the gyrus activated by hand clenching in fMRI on the affected side at least partially corresponded to M1 in all cases, while those on the unaffected side corresponded to M1 in 12 of 12 cases.
These results indicate that the precentral knob corresponds to PMA as well as to M1, whereas the gyrus activated in fMRI corresponds to M1 on the affected and unaffected side.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 04/2009; 36(2):227-33. · 0.97 Impact Factor
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ABSTRACT: Ommaya reservoirs are commonly used in the diagnosis and management of leptomeningeal metastases (LM) from malignant tumors. The present study investigates the utility of an intraoperative navigation-guided technique for Ommaya reservoir placement. Between March 2004 and December 2005, 85 navigation-guided Ommaya reservoir placements were performed in 77 patients with intracranial malignancies at the Komagome Metropolitan Hospital. Anterior horn puncture and posterior horn puncture were used for 59 and 26 procedures, respectively. A slit ventricle was present in 6 cases. All procedures were performed under assistance from the Medtronic STEALTH STATION TRIA navigation system. Computed tomographic (CT) scans were routinely obtained just after completion of the procedure. Patients diagnosed with LM received subsequent treatment. An Ommaya catheter was applied to the ventricular puncture needle registered in the navigation system and was inserted into the lateral ventricle. Using the real-time "Guidance View", the surgeon was able to verify the catheter position continuously during the procedure. Postoperative CT scan revealed an appropriate catheter position in all except for one case. Complications (catheter malposition) occurred in only one case (complication rate, 1.2%). None of the patients experienced hemorrhage or infection. In conclusion, navigation-guided Ommaya reservoir placement was associated with a very low incidence of complications. This method appears to be safe and effective when employed in patients with intracranial malignancy.
min - Minimally Invasive Neurosurgery 01/2008; 50(6):340-5. · 0.70 Impact Factor
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ABSTRACT: The accurate localization of the primary motor cortex (M1) is critical for the preservation of motor function during resection of brain tumors in and around the M1. The goal of the present study was to determine which technique provided the most accurate localization of M1. The accuracy of preoperative functional magnetic resonance imaging (fMRI), intraoperative somatosensory evoked potential (SEP) and cortical mapping for the localization of M1 was determined in 17 patients with brain tumors in and around the M1. Because localization of the M1 is typically symmetrical in the cerebral hemispheres, the M1 on the affected side was localized by determination of the M1 location on the unaffected side using fMRI with patient hand clenching. The location of M1 was successfully determined by SEP in 5 of 11 cases. In the remainder of cases, the sulcus at which phase reversal occurred during SEP was shifted 1 or 2 gyri rostral to the central sulcus. The location of M1 was successfully determined by brain mapping in 9 of 15 cases. In the remainder of cases, stimulation failed to elicit a motor response. Finally, the location of M1 was successfully determined by fMRI in 16 of 17 cases. These data indicate that fMRI was more reliable than SEP or brain mapping for the detection of M1 in proximity to a tumor.
Stereotactic and Functional Neurosurgery 02/2007; 85(2-3):99-105. · 1.85 Impact Factor
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ABSTRACT: Resection of tumors involving the motor area frequently results in postoperative motor deficits. In an attempt to prevent poor motor outcomes, our institution has utilized preoperative fMRI and tractography as well as intraoperative cortical mapping and continuous motor tasks during awake surgery in patients with motor area tumors. In one case, a patient demonstrated deterioration in continuous motor task performance before initiation of tumor resection. Thus, the goal of this study was to evaluate the relationship between head position and development of intraoperative or postoperative motor deficits in five patients with motor area tumors.
In four cases, the patient's head was rotated 60 degrees from the supine position. In two cases, in which the tumor was located relatively medially, deterioration in continuous motor task function was noted prior to resection of the tumor. In the two other cases, in which the tumor was located relatively laterally, there was no deterioration of continuous motor task performance until resection of the tumor. Another patient, in whom the tumor was located relatively medially, underwent surgery with the head positioned straight and with the patient in a half-sitting position. This patient did not experience deterioration of continuous motor task performance during the surgery.
These data suggest that head positioning can have a significant impact on motor function in patients with motor area tumors. Furthermore, the straight head position may be the preferred positioning, particularly for patients with tumors located on the medial side of motor area.
min - Minimally Invasive Neurosurgery 01/2006; 48(6):315-21. · 0.70 Impact Factor
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ABSTRACT: The goal of the present study was to determine the efficacy of preoperative fMRI, tractography, and intraoperative continuous task during awake surgery in preserving postoperative motor function in patients undergoing resection of metastatic brain tumors in or near the primary motor area. Three patients with metastatic brain tumors in the primary motor area elected to undergo surgical treatment. Preoperative fMRI and tractography were performed, and various primary motor areas (e. g., hand, arm, face and leg) were identified and confirmed by cortical mapping or by the outcome of awake surgery. Cortical mapping and continuous appropriate task were performed during awake surgery. Preoperative fMRI and tractography correctly identified the primary motor area. In contrast, cortical mapping identified the gyrus of the primary motor area but was unable to identify specific primary motor areas, such as those for the hand or arm, which were compressed by the tumor. Tumor resection was terminated when any deterioration in continuous task performance was observed during awake surgery. Paresis was transient and resolved within one week in all cases. The combination of preoperative fMRI, tractography and continuous task during awake surgery helped to maintain motor function following surgical management of metastatic brain tumors of the primary motor cortex.
min - Minimally Invasive Neurosurgery 05/2005; 48(2):85-90. · 0.70 Impact Factor
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ABSTRACT: Six patients with brain tumors within or near the primary motor cortex underwent preoperative functional magnetic resonance imaging (fMRI) and intraoperative cortical mapping, and the accuracy of those techniques for localization of the primary motor cortex and motor function beside the tumor were determined by comparison against neuroanatomical correlates from pre-, intra- and postoperative neurological observations. The location of the primary motor cortex was detected by intraoperative cortical mapping in 5 of 6 cases and by fMRI in all 6 cases. Brain mapping provided equivocal information on the cortical representation of motor territories, and with the technique used in close proximity to the tumor, the motor territories were not detected in all but 1 case. In contrast, the areas controlling motor function in close proximity to the tumor were detected by fMRI in 4 of 6 cases. These data indicate that intraoperative cortical mapping has a low sensitivity for the detection of motor function in the area beside the tumor. Therefore, this technique may not be sufficient to prevent compromise of motor areas during tumor resection.
Stereotactic and Functional Neurosurgery 02/2005; 83(4):135-41. · 1.85 Impact Factor
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ABSTRACT: Reliably predicting infection soon after craniotomies would prevent infection and reduce treatment costs and hospitalization expenses. Therefore we analysed potential risk factors and blood count data after craniotomies for brain tumours in order to predict infection as soon as possible after surgery. We analysed 139 patients who underwent craniotomies for brain tumours from January 1997 to December 2001, and divided them into four categories (Types A to D) according to the following: increase in their white blood counts (WBCs) from Day 0 to Day 1, maximum WBC between Day 0 and Day 2, and maximum c-reactive protein (CRP) between Day 0 and Day 4 after surgery. We evaluated potential risk factors and the blood count data for infections via logistic regression analysis. Type D patients had a significantly higher rate of infection (p = 0.0123) than the other Types, while Type B patients had the lowest rate among the four groups (p = 0.0006). When Type A patients suffered CSF leakages, they had a significantly higher possibility of meningitis (p < 0.0001) or scalp infection (p = 0.012). In those Type A or D patients who were male, more than 70 years old, and suffered from metastases from primary lung cancer lesions, the possibility of pneumonia was significantly higher (p = 0.0178). In conclusion, we are able to predict infection within four days after craniotomies for brain tumours according to standard blood count data and certain risk factors. This possibility allows for improved care and better clinical outcomes in patients that undergo craniotomies for brain tumours.
British Journal of Neurosurgery 12/2004; 18(6):598-603. · 0.88 Impact Factor
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ABSTRACT: Mutation of the p53 gene plays a critical role in the development of cancer and response to cancer therapy. To analyze the mechanism of cancer development and to improve cancer therapy, it is important to assess which genes are downstream components of p53 in cancers, and whether the expression levels of these genes affect p53-mediated apoptosis. In this study, we transduced the wild type p53 gene along with the Apaf-1 and caspase-9 genes via adenovirus vectors into U251 and U-373MG glioma cells harbouring a mutated p53, and evaluated the degree of apoptosis. Co-induction of Apaf-1 and caspase-9 genes highly enhanced p53-mediated apoptosis in glioma cells. Induction of wild type p53 enhanced the expression levels of Bax, p21/WAF1, and Fas protein. To determine which gene is activated by wild type p53 induction and, in turn, activates Apaf-1 and caspase-9, we transduced the Bax, p21/WAF1 or Fas gene via adenovirus vector to U251 cells to achieve a similar expression level as that induced by the Adv for p53 in U251 cells. U251 cells transduced with Fas concomitant with the Apaf-1 and caspase-9 genes underwent drastic apoptosis. This suggests that induction of wild type p53 upregulates Fas, which in turn may play a role in the activation of Apaf-1 and caspase-9. These results are important for analyzing the mechanism of tumour development and for predicting the therapeutic effect of p53 replacement gene therapy in a particular patient.
British Journal of Cancer 03/2002; 86(4):587-95. · 5.04 Impact Factor
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ABSTRACT: The p53 tumor-suppressor gene plays a critical role in radiation-induced apoptosis. Several genes, including Bax and Fas, are involved in p53-mediated apoptosis, and their over-expression enhances the degree of radiation-induced apoptosis. Apaf-1 and caspase-9 have been reported to be downstream components of p53-mediated apoptosis, suggesting that these genes play a role in radiation-induced apoptosis. In this study, we transduced U-373MG cells harboring mutant p53 with the Apaf-1 and/or caspase-9 genes via adenoviral (Adv) vectors concomitant with X-ray irradiation and evaluated the degree of apoptosis. The percentage of apoptotic cells in U-373MG cells co-infected with the Adv for Apaf-1 (Adv-APAF-1) and that for caspase-9 (Adv-Casp9) and treated with irradiation (24%) was much higher than that in cells co-infected with Adv-APAF-1 and Adv-Casp9 and not treated with irradiation (0.86%) and that in cells infected with either Adv-APAF-1 or Adv-Casp9 and treated with irradiation (2.0% or 2.6%, respectively). The apoptosis induced by co-transduction of Apaf-1 and caspase-9 and irradiation was repressed in cells that were co-infected with the Adv for Bcl-X(L) but not in cells co-infected with the Adv for Bcl-2. These results indicate that Apaf-1 and caspase-9 play a role in radiation-induced apoptosis in cancer cells harboring mutant p53. Bcl-X(L) may be critically involved in the radioresistance of cancer cells by repressing Apaf-1- and caspase-9-mediated apoptosis. Expression of Apaf-1 and caspase-9 in tumors may be an important determinant of the therapeutic effect of irradiation in cancer treatment.
International Journal of Cancer 08/2001; 93(2):252-61. · 5.44 Impact Factor
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ABSTRACT: Conflicting reports have been published with regard to the relationship between the efficacy of p53 gene therapy and the p53 status of gliomas. In this study, we evaluated whether U-87MG glioma cells harboring wild-type p53 and U251 and U-373MG glioma cells harboring mutated p53 demonstrate different sensitivities to p53-induced apoptosis. In addition, we tested whether transduction of Bax or caspase-9, which are downstream components of p53-induced apoptosis, can override the resistance mechanism of U-87MG cells to apoptosis.
We transduced U-87MG, U251, and U-373MG glioma cells with p53, Bax, or caspase-9 genes via adenovirus (Adv) vectors, to induce the same level of respective proteins, and evaluated the degree of apoptosis.
U-87MG cells were highly resistant to Adv for p53 (Adv-p53)-mediated apoptosis, whereas U251 and U-373 cells underwent extensive apoptosis after Adv-p53 infection. In U-87MG cells, the elevation of Bax and Fas was not as marked as that observed in U251 and U-373MG cells after Adv-p53 infection. Endogenous expression of Bcl-XL and Bcl-2 in U-87MG cells was greater than that in U251 and U-373MG cells. U-87MG cells were more resistant to Bax-mediated apoptosis than were U251 or U-373MG cells. In contrast, U-87MG cells were more sensitive to caspase-9-mediated apoptosis than were U251 or U-373MG cells, suggesting that transduction of caspase-9 may override the resistance mechanism of U-87MG to p53-mediated apoptosis.
These results demonstrate that proapoptotic function induced by p53 transduction in U-87MG cells was repressed at several steps and that induction of caspase-9 may circumvent this resistance mechanism.
Neurosurgery 08/2001; 49(1):177-86; discussion 186-7. · 2.79 Impact Factor
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ABSTRACT: Hyperthermia kills glioma cells by inducing apoptosis and is thereby an effective therapeutic modality for the treatment of malignant gliomas. However, cells harboring mutated p53 are refractory to hyperthermia-induced apoptosis. In this study, we assessed whether or not adenovirus (Adv)-mediated transduction of p53 overrides this resistant mechanism.
We transduced the p53 wild-type tumor suppressor gene into U251 glioma cells harboring mutated p53 using Adv vectors in combination with hyperthermia (43, 44.5 degrees C), and evaluated the degree of cell death and apoptosis.
The percentage of cells that had died, as measured by trypan blue staining, among U251 cells infected with the Adv for p53 (Adv-p53) and treated with hyperthermia, was significantly higher than the percentage of cells that had died among U251 cells infected with Adv-p53 and not treated with hyperthermia, or those infected with the control Adv for dE (Adv-dE) and treated with hyperthermia. The degree of apoptosis, measured at 24 h after treatment, in hyperthermia-treated U251 cells infected with Adv-p53 (43 degrees C, 73%; 44.5 degrees C, 92%) was much higher than that infected with Adv-p53 (41%), or that infected with control Adv-dE and treated with hyperthermia (43 degrees C, 1.3%; 44.5 degrees C, 19%). Treatment with combined hyperthermia and Adv-p53 infection induced cleavage of caspase-3 in U251 cells.
These results indicate that Adv-mediated transduction of p53 would render glioma cells highly sensitive to hyperthermia.
International Journal of Radiation OncologyBiologyPhysics 07/2001; 50(2):525-31. · 4.11 Impact Factor
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ABSTRACT: Several apoptosis-related genes have been reported to be involved in chemotherapy-induced apoptosis in cancers. An assessment of the relationship between expression of those genes and the degree of chemotherapy-induced apoptosis may be useful in improving the efficacy of cancer therapy. We transduced Apaf-1 (apoptotic protease-activating factor-1) and caspase-9 into U-373MG glioma cells using adenovirus (Adv) vectors in the presence of etoposide and evaluated the degree of apoptosis. The degree of apoptosis in etoposide-treated U-373MG cells infected with Adv for Apaf-1 (Adv-APAF1) was higher (27%) than that in cells infected with control Adv (14%), that in cells infected with Adv for caspase-9 (Adv-Casp9) was higher (34%) than that in cells infected with Adv-APAF1, and that in cells infected with both Adv-APAF1 and Adv-Casp9 was the highest (41%). Treatment with etoposide increased expression of p53 and decreased expression of Bcl-X(L) in U-373MG cells which harbored mutant p53. These results indicate that the expression of Apaf-1 and caspase-9 may be important determinants in predicting the sensitivity of cancers to chemotherapy. Adv-mediated co-transduction of Apaf-1 and caspase-9 should render cancer cells highly sensitive to chemotherapy.
Japanese journal of cancer research: Gann 05/2001; 92(4):467-74.
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ABSTRACT: It has been reported that U-87MG glioma cells with wild-type p53 are resistant to p53 replacement gene therapy. As some gliomas harbor wild-type p53, it would be important to override the resistance mechanism due to wild-type p53 in glioma gene therapy. In this study, we transduced U-87MG cells or U251 glioma cells harboring mutated p53 with the p53 or p73alpha gene (a homologue of p53, that differently induces some p53-responsive genes) via adenovirus vectors (Advs) at same multiplicities of infection (MOIs) into respective cells (U-87MG: MOI 1000, U251: MOI 100), and evaluated the degree of apoptosis. The results demonstrate that the degree of apoptosis induced by Adv-mediated transduction of p53 in U-87MG cells was lower than that in U251 cells, whereas that induced by Adv-mediated transduction of p73alpha in U-87MG cells was higher than that in U251 cells. Bax expression in U-87MG and U251 cells induced by Adv-mediated transduction of p53 was almost the same as that of p73alpha. On the other hand, Adv-mediated transduction of p73alpha induced caspase-9 at higher levels than that of p53 in both cells. The results indicate that Adv-mediated transduction of p73alpha might be beneficial to overcome the resistance mechanism of glioma cells harboring wild-type p53.
Cancer Letters 12/2000; 160(1):67-73. · 4.24 Impact Factor
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ABSTRACT: Most malignant astrocytomas (gliomas) express a high level of Fas, whereas the surrounding normal tissues such as neurons and astrocytes express a very low level of Fas. Thus, transduction of Fas ligand would selectively kill malignant astrocytoma cells. On the other hand, glioma cells harboring p53 mutation have been reported to be resistant to conventional therapies including radiation. To override the resistance mechanism of glioma cells with p53 mutation to radiation, we transduced U-373MG malignant astrocytoma (glioma) cells harboring mutant p53 with Fas ligand via an adenovirus (Adv) vector in combination with X-ray irradiation, and evaluated the degree of apoptosis. The degree of apoptosis in U-373MG cells infected with the Adv for Fas ligand (Adv-FL) and treated with irradiation (81%) was much higher than that in U-373MG cells infected with Adv-FL and not treated with irradiation (0.8%) or that in U-373MG cells infected with the control Adv for lacZ and treated with irradiation (5.0%). In U-373MG cells infected with Adv-FL, irradiation increased the expression of Fas ligand. Coincident with the increase in Fas ligand, there was a marked reduction in the caspase-3 level and a marked increase in the cleaved form of poly(ADP-ribose) polymerase (PARP), which are downstream components of Fas ligand-mediated apoptosis. This suggests that the enhanced activation of caspase-3 by the transduction of Fas ligand combined with irradiation, induced extensive apoptosis in U-373MG cells. In summary, transduction of Fas ligand may override the resistance mechanism to radiotherapy in glioma cells harboring p53 mutation.
Japanese journal of cancer research: Gann 11/2000; 91(10):1044-50.
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ABSTRACT: Suicide gene therapy utilizing the herpes simplex thymidine kinase (HSVtk) / ganciclovir (GCV) system has been performed to kill cancer cells. However, the low transduction efficiency of HSVtk gene into cancer cells critically limits its efficacy in cancer treatment in clinical situations. To improve delivery of the HSVtk gene into cancer cells, we transduced U-87MG and U-373MG glioma cells with adenovirus (Adv) vectors with a fiber mutant, F / K20, which has a stretch of 20 lysine residues added at the C-terminus of the fiber, for the HSVtk gene (Adv-TK-F / K20), and compared the cytopathic effect of Adv-TK-F / K20 with that of the Adv for HSVtk with wild-type fiber (Adv-TK). The cytopathic effect of Adv-TK-F / K20 in U-87MG and U-373MG cells was approximately 140 and 40 times, respectively, stronger than that of Adv-TK. At the same multiplicity of infection (MOI) in each cell line, Adv-TK-F / K20 induced a higher degree of apoptosis (U-87MG, 35%; U-373MG, 77%) than Adv-TK (U-87MG, 0.11%; U-373MG, 27%) in U-87MG (MOI 0.03) and U-373MG cells (MOI 0.1). Cleavage of poly(ADP-ribose)polymerase (PARP) was more marked in the cells that were infected with Adv-TK-F / K20 than in cells that were infected with Adv-TK. These results indicate that gene therapy utilizing Adv-TK-F / K20 may be a promising therapeutic modality for the treatment of gliomas.
Japanese journal of cancer research: Gann 11/2000; 91(10):1028-34.
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ABSTRACT: p53 replacement gene therapy has been carried out clinically for cancers with p53 mutations; however, some cancers are resistant to p53 gene therapy. In this study, we transduced A-172 and U251 cells harboring p53 mutations with wild-type p53 using adenovirus vectors to induce wild-type p53 protein at similar expression levels. A-172 cells did not undergo apoptosis after p53 transduction, whereas U251 cells were markedly sensitive to p53-mediated apoptosis. A-172 cells showed higher endogenous expression of Bcl-X(L) than U251, and transduction of Bcl-X(L) repressed p53-mediated apoptosis in U251 cells, suggesting that high endogenous expression of Bcl-X(L) renders A-172 cells, at least in part, resistant to p53-mediated apoptosis. We transduced A-172 cells and U251 cells with the Apaf-1 or caspase-9 genes; both are downstream components of p53-mediated apoptosis. We found that A-172 cells were highly sensitive to Apaf-1- and caspase-9-mediated apoptosis. The results indicate that A-172 cells harboring mutant p53 were not susceptible to p53-mediated apoptosis, possibly due to high endogenous expression of Bcl-X(L). Transduction of Apaf-1 or caspase-9 would override the resistance mechanism of apoptosis in A-172 cells. These findings provide potentially a novel approach in killing cancers that are resistant to p53 replacement gene therapy.
Biochemical and Biophysical Research Communications 07/2000; 272(3):667-73. · 2.48 Impact Factor
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ABSTRACT: Impaired function of apoptosis-related genes is deeply involved in oncogenesis and the progression of cancers, and caspase-3 plays a critical role as an executioner of apoptosis. We introduced the caspase-3 gene via an adenovirus (Adv) vector into Alexander hepatoma cells, MCF-7 breast cancer cells, and U251 and U-373MG glioma cells which have different endogenous levels of caspase-3 expression. None of the cell lines underwent apoptosis by overexpression of caspase-3, indicating that induction of caspase-3 alone is not applicable for cancer gene therapy. Next, we investigated whether overexpression of caspase-3 could enhance Fas ligand-mediated apoptosis in these four cell lines. In U-373MG cells, which showed the highest level of expression of surface Fas among the four cell lines, coinfection of the Adv for caspase-3 (Adv-caspase-3) and the Adv for Fas ligand (Adv-FL) induced a remarkably increased degree of apoptosis compared with that induced by the single infection of either Adv-caspase-3 or Adv-FL. Similar results were obtained by cotreatment with anti-Fas antibody in U-373MG cells. These data suggest that when strong proapoptotic upstream stimuli are induced, the level of caspase-3 expression determines the degree of apoptosis in cancer cell lines. In conclusion, overexpression of caspase-3 alone did not induce apoptosis in cancer cells. Both a strong proapoptotic signal and a high expression of caspase-3 were required to induce drastic apoptosis in cancers. This strategy would be highly beneficial for selected cancer patients.
Experimental Cell Research 06/2000; 256(2):423-33. · 3.58 Impact Factor
