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ABSTRACT: Clinical studies have indicated that photodynamic therapy (PDT) significantly prolonged the median survival of patients with gliomas. Experimental studies demonstrate that increasing optical energy and photosensitizer dose leads to increased volume of tumor necrosis. However, increasing the light dose delivered to the tumor may increase the risks of inducing permanent neurological deficits. In the current study, we sought to test the behavioral deficits induced in normal rats by brain PDT and the neurorestorative effects of atorvastatin on PDT-induced behavioral deficits. Considering its potential as a combination treatment of brain tumors, we investigated both in vitro and in vivo whether atorvastatin treatment promotes brain tumor growth. Non-tumored Fischer rats received PDT (n=18). Nine of the PDT-treated animals were treated with atorvastatin. Control animals underwent the same surgical procedure, but did not receive Photofrin and laser light. PDT-treated animals had significant behavioral deficits on days 2, 5, 7, 9 and 14 after PDT, compared with surgery controls. PDT-treated animals receiving atorvastatin displayed significantly ameliorated behavioral deficits on days 7, 9 and 14 after PDT, compared to PDT-treated rats. In vitro tumor cell viability and growth were evaluated. Atorvastatin did not affect the growth of glioma cells. Fischer rats with intracranial 7-day-old 9L glioma tumor cell implantation were randomly subjected to no treatment, PDT alone, atorvastatin alone, or combined treatment with atorvastatin and PDT (6 rats/group). Our data indicate that atorvastatin did not promote tumor growth in either PDT treated and non-treated rats. However, atorvastatin significantly reduced the cell damage caused by PDT. To further test the mechanisms underlying the atorvastatin-mediated reduction of functional deficits, we investigated the effects of atorvastatin on angiogenesis and synaptogenesis. Our data demonstrate that atorvastatin significantly induced angiogenesis and synaptogenesis in the PDT-damaged brain tissue. Our data indicate that PDT induces functional deficits. Atorvastatin treatment promotes functional restoration after PDT, but does not promote glioma growth in vitro and in vivo. Atorvastatin reduces astrocyte and endothelial cell damage caused by PDT and induces angiogenesis and synaptogenesis after PDT. Thus consideration and further testing of the combination of atorvastatin and PDT for the treatment of glioma is warranted.
International Journal of Oncology 08/2011; 39(5):1133-41. · 2.40 Impact Factor
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ABSTRACT: The objective of the present study was to investigate the treatment of 9L gliosarcoma brain tumor in the rat with the combination of surgical resection and photodynamic therapy (PDT). Nude rats with intracranial 7-day-old 9L gliomas were randomly subjected to no treatment, PDT alone (Photofrin®: 2 mg kg-1, optical: 80 J cm-2), surgical resection alone or resection combined with 2 mg kg-1Photofrin®-mediated PDT at an optical dose of 80 J cm-2. All animals were sacrificed 14 days after tumor implantation. Hematoxylin-and-eosin and immunohistochemical stainings were performed to assess the tumor volume and the expression of vascular endothelial growth factor (VEGF) in the brain adjacent to the tumor (BAT) as well as the tumor cell apoptosis and proliferation. Our data show that both surgical resection alone and PDT alone significantly decreased tumor volume, but furthermore, surgical resection combined with PDT significantly reduced the tumor volume and reduced local tumor infiltration compared to either surgical resection or PDT treatment alone. PDT treatment with or without resection increased tumor apoptosis, but resection alone did not alter the tumor cell apoptosis compared with a nontreatment control group. Both surgical resection alone and PDT alone induced a significant increase in VEGF expression in the BAT; however intraoperative PDT did not further increase VEGF expression, compared with surgery alone or PDT alone. No significant differences were found in tumor cell proliferation as indicated by Ki67 immunoreactivity among the four groups. Our results suggest that PDT enhances the efficacy of surgical resection in the management of malignant gliomas without increasing VEGF expression in the BAT.
Photochemistry and Photobiology 06/2008; 82(6):1704 - 1711. · 2.41 Impact Factor
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ABSTRACT: The objective of this study was to investigate functional deficits and reactive peri-tumoral brain plasticity events in glioma-bearing rats. 9L gliosarcoma cells were implanted into the forelimb region of the sensorimotor cortex in Fischer rats. Control animals underwent the same operation without tumor implantation. Sensitive tests for detecting sensorimotor dysfunction, including forelimb-use asymmetry, somatosensory asymmetry, and vibrissae-evoked forelimb placing tests, were conducted. We found that tumor-bearing animals exhibited significant composite behavioral deficits on day 14 post-tumor injection compared to surgical controls. With the assistance of magnetic resonance imaging, we demonstrated a significant correlation between tumor volume and magnitude of somatosensory asymmetry, indicating that the somatosensory asymmetry test can provide an effective and efficient means to measure and predict tumor progression. Histopathological assessments were performed after the rats were sacrificed 14 days following tumor implantation. Immunostaining revealed that densities of microtubule-associated protein 2, glial fibrillary acid protein, von Willebrand factor, and synaptophysin were all significantly upregulated in the peri-tumoral area, compared to the corresponding region in surgical controls, suggesting synaptic plasticity, astrocyte activation and angiogenesis in response to tumor insult. Understanding the behavioral and bystander cellular events associated with tumor progression may lead to improved evaluation and development of new brain tumor treatments that promote, or at least do not interfere with, functional adaptation.
Experimental Neurology 11/2007; 207(2):357-67. · 4.70 Impact Factor
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ABSTRACT: The objective of this study is to measure the chronic responses of 9L glioma and normal brain to photodynamic therapy (PDT). Tumor size, proliferation activity of glioma cells, and vascular endothelial growth factor (VEGF) expression in both the tumor area and the brain adjacent to tumor (BAT) were observed 7 days after clinically relevant doses of PDT treatment. 9L Gliosarcoma cells were implanted into the brain of 20 athymic nude mice. Fifteen mice were injected intraperitoneally with Photofrin at a dose of 2 mg/kg on day 6 after tumor implantation and were treated with laser at different optical doses of 40 J/cm(2) (n = 5), 80 J/cm(2) (n = 5), and 120 J/cm(2) (n = 5) at 24 h after Photofrin injection, respectively. The remaining five tumor-bearing mice served as a tumor-only control. All animals were killed 14 days after tumor implantation. Hematoxylin and eosin and immunostaining were performed to assess tumor volume, VEGF expression in the tumor and the BAT, as well as Ki67 expression in the tumor area. The tumor volume of the mice receiving 80 or 120 J/cm(2) group was significantly smaller than the control group (p < 0.01). VEGF immunoreactivity in the BAT was significantly increased in the 120 J/cm(2) PDT-treated mice (p < 0.001), compared with the immunoreactivity seen in untreated mice and those receiving Photofrin and lower optical doses. No significant differences were detected in the proliferation of glioma cells and VEGF expression in the tumor area between these groups. These data indicate that PDT can shrink tumor, especially at the high light dose, and that PDT induces expression of VEGF in the BAT, which is associated with tumor recurrence. Therefore, PDT combined with anti-angiogenic agents may be an effective treatment strategy for glioma.
Lasers in Medical Science 11/2007; 22(4):253-9. · 2.00 Impact Factor
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ABSTRACT: The objective of this study was to evaluate the effects of combination therapy with photodynamic therapy (PDT) and a novel antiangiogenic regimen using monoclonal antibodies against both vascular endothelial growth factor receptors (VEGFR)-1 (MF1) and VEGFR-2 (DC101) on intracranial glioblastoma xenografts in nude mice. Nude mice bearing intracerebral U87 glioblastoma were treated with PDT and the antiangiogenic regimen (MF1 and DC101) either alone or in combination, while those left untreated served as tumor controls. Tumor volume and animal survival time were analyzed to evaluate the outcome of different treatment modalities. In addition, the immunohistochemical expression of VEGF in the brain adjacent to the tumor, von Willebrand factor (vWF), apoptotic, and proliferative markers in the tumor area were examined. PDT or MF1 + DC101 alone significantly reduced the tumor volume and prolonged the survival time of glioma-implanted animals. Combined therapy markedly reduced tumor volume and increased survival time with significantly better outcomes than both monotherapies. Both vWF and VEGF levels significantly increased after PDT while they both significantly decreased after antiangiogenic treatment, compared with no treatment. PDT plus antiangiogenic treatment led to significant decreases in both vWF and VEGF expression, compared with PDT alone. Either PDT or antiangiogenic treatment alone significantly increased tumor cell apoptosis compared with no treatment, while combination therapy resulted in further augmentation of apoptosis. Antiangiogenic treatment with or without PDT significantly decreased tumor cell proliferation, compared with either no treatment or PDT alone. In summary, we demonstrate both significant inhibition of tumor growth and extended survival of mice treated by the combination therapy with PDT and antiangiogenic agents, compared with each single treatment, suggesting that the combination therapy may be a promising strategy to improve clinical outcomes in glioblastoma.
Photochemistry and Photobiology 10/2007; 84(1):128-37. · 2.41 Impact Factor
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ABSTRACT: The objective of the current study was to investigate the behavioral changes of glioma-bearing nude mice and functional outcome from treatment with a novel antiangiogenesis regimen, which is a combination of monoclonal antibodies against both vascular endothelial growth factor receptor (VEGFR)-1 (MF1) and VEGFR-2 (DC101). The reliability and responsiveness of behavioral measurement with the rearing test were first examined in nude mice bearing two kinds of gliomas--9L gliosarcoma and U87 human glioma, which have different growth rates. Using immunohistochemical staining and fluorescent imaging techniques, upregulation of the angiogenesis marker VEGF, coincident with the abnormal neovascular architecture, was confirmed in the human U87 glioma model. The behavioral measurement was then applied to assess functional outcome with the combination antibody treatment in the orthotopic mouse model of human U87 glioma. The combination antibody therapy retarded tumor progression and delayed the onset of significant behavioral deficits. Histologically, tumor necrosis and apoptosis were increased and tumor cell proliferation was decreased after treatment. In clinical trials for novel interventions, functional end points typically are included in the assessment of potential efficacy. Because certain interventions that successfully treat tumor progression in animal models might interfere with compensatory neuroplasticity, functional measurement may be valuable for improving the clinical relevance of translational brain tumor research.
Behavioural Brain Research 09/2007; 182(1):42-50. · 3.42 Impact Factor
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ABSTRACT: The membrane-anchored metalloproteinase tumor necrosis factor-alpha-converting enzyme (TACE/a disintegrin and metalloproteinase [ADAM] 17) is key in proteolytic ectodomain shedding of several membrane-bound growth factors, cytokines and receptors. The expression and activity of ADAM17 increases under some pathological conditions including stroke, and promotes neural progenitor cell migration and contributes to stroke-induced neurogenesis. Hypoxia initiates cellular invasive processes that occur under both physiological and pathological conditions such as invasion and metastasis of some tumors. In the present study, we sought to elucidate whether ADAM17 contributes to brain tumor invasion. To this end, we examined the role of ADAM17 in the invasiveness of two different brain tumor cell lines, 9L rat gliosarcoma and U87 human glioma, under normoxic and hypoxic conditions. Additionally, we tested the effects of ADAM17 suppression on in vitro tumor cell invasion by means of ADAM17 proteolytic inhibitors and specific small interfering RNA. We found that tumor cells upregulated ADAM17 expression under hypoxia, and that ADAM17 activity correlated with increased tumor cell invasion. Conversely, suppression of ADAM17 proteolysis decreased invasiveness induced by hypoxia in 9L and U87 cells. Furthermore, the contribution of ADAM17 to tumor invasion was independent of matrix metalloproteinase (MMP)-2 and MMP-9 activity. ADAM17 was also found to activate the epidermal growth factor/phosphoinositide-3 kinase/serine/threonine kinase signal transduction pathway. Our data suggest that hypoxia-induced ADAM17 contributes to glioma cell invasiveness through activation of the EGFR signal pathway.
Cancer Science 06/2007; 98(5):674-84. · 3.33 Impact Factor
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ABSTRACT: In this study, we investigated the impact of intracerebral delivery of chemotherapy on functional recovery from focal cortical tissue displacement, characteristic of brain tumors. Unilateral focal brain compression was induced by epidural implantation of an inverted hemisphere-shaped bead over the sensorimotor cortex. Microinjections of a total of 1mg chemoagent fluorouracil or the same volume of saline were made into the compressed cortex. Behavioral tests of forelimb sensorimotor function were conducted during 4 weeks' observation. Rats subjected to any of the three types of lesions, saline microinjection plus cortical compression, chemoagent microinjection alone, or chemoagent microinjection combined with cortical compression, demonstrated significant behavioral deficits in several sensorimotor tasks, compared with saline-microinjected control animals. In placing tests, behavioral deficits elicited by each single treatment were worsened by combined treatment with chemoagent microinjection and focal cortical compression. Concurrently, local delivery of chemoagent into the compressed cortex induced increased cortical tissue loss, necrosis and apoptosis. These data indicate that local chemotherapy exacerbates compression-induced neurological impairment, and a model of controlled focal cortical compression may provide a valuable means to improve anti-cancer therapeutic designs with reduced deterioration of brain function.
Behavioural Brain Research 10/2006; 172(1):80-9. · 3.42 Impact Factor
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ABSTRACT: Glutamate antagonists have recently been shown to limit tumor growth, providing potential new therapeutic targets and strategies against brain tumors. Here, we demonstrate that the glutamate NMDA receptor antagonist MK801, after a delay, adversely reverses functional recovery in rats with compressive mass lesions of the sensorimotor cortex. Our data suggest that the controlled focal cortical compression model may be a valuable pre-clinical tool to screen compounds for the treatment of brain tumors. It may be possible to use this model to develop interventions that maintain anti-cancer effects but with diminished harm to bystander tissue and brain plasticity.
Experimental Neurology 08/2006; 200(1):262-6. · 4.70 Impact Factor
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ABSTRACT: In this study, we focused on a preclinical model of brain compression injury that has relevance to pathological conditions such as tumor, hematoma, blood clot, and intracerebral bony fragment. We investigated behavioral impairment as a result of rapid-onset small mass, and the factors involved in lesion formation and neuroplasticity. An epidural bead implantation method was adopted. Two sizes (1.5 mm and 2.0 mm thick) of hemisphere-shaped beads were used. The beads were implanted into various locations over the sensorimotor cortex (SMC--anterior, middle and posterior). The effects of early versus delayed bead removal were examined to model clinical neurosurgical or other treatment procedures. Forelimb and hind-limb behavioral deficits and recovery were observed, and histological changes were quantified to determine brain reaction to focal compression. Our results showed that the behavioral deficits of compression were influenced by the location, timing of compression release, and magnitude of compression. Even persistent compression by the thicker bead (2.0 mm) caused only minor behavioral deficits, followed by fast recovery within a week in most animals, suggesting a mild lesion pattern for this model. Brain tissue was compressed into a deformed shape under pressure with slight tissue damage, evidenced by pathological evaluation on hematoxylin and eosin (H&E)- and TUNEL-stained sections. Detectable but not severe behavioral dysfunction exhibited by this model makes it particularly suitable for direct assessment of adverse effects of interventions on neuroplasticity after brain compression injury. This model may permit development of treatment strategies to alleviate brain mass effects, without disrupting neuroplasticity.
Journal of Neurotrauma 06/2006; 23(5):721-32. · 3.65 Impact Factor
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ABSTRACT: We tested whether low-dose photodynamic therapy (PDT) induces an angiogenic response in the normal brain of nude mice (n=20). Normal brains of nude mice were subjected to PDT at low doses (Photofrin: 2 mg/kg; optical: 2 J/cm(2) and 4 J/cm(2)). BrdU (50 mg/kg) was injected (intraperitoneally, i.p.) daily from PDT treatment to sacrifice (1 and 2 weeks after PDT). Laser scanning confocal microscopy, immunohistochemistry, and immunofluorescence staining were performed to assay angiogenic response. Morphological results show no significant tissue damage induced by PDT and two- and three-dimensional image analyses revealed no significant difference in vascular structure between the areas of exposure to PDT and contralateral areas in all mice. However, the number of BrdU immunoreactive cells were significantly increased in the areas of PDT treatment compared with contralateral hemisphere in both groups, and the number of BrdU-positive cells increased in a PDT-dose-dependent manner. Furthermore, immunohistochemical data indicate that PDT at these low doses significantly induces the expression of the vascular endothelial growth factor (VEGF) in PDT-treated regions in the 1-week group, but not in the 2-week group. These data indicate that low-dose PDT results in increased VEGF expression and endothelial cell proliferation in normal brains.
Lasers in Medical Science 10/2005; 20(2):74-9. · 2.00 Impact Factor
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ABSTRACT: The objective of the present study was to investigate the treatment of 9L gliosarcoma brain tumor in the rat with the combination of surgical resection and photodynamic therapy (PDT). Nude rats with intracranial 7-day-old 9L gliomas were randomly subjected to no treatment, PDT alone (Photofrin: 2 mg kg(-1), optical: 80 J cm(-2)), surgical resection alone or resection combined with 2 mg kg(-1) Photofrin-mediated PDT at an optical dose of 80 J cm(-2). All animals were sacrificed 14 days after tumor implantation. Hematoxylin-and-eosin and immunohistochemical stainings were performed to assess the tumor volume and the expression of vascular endothelial growth factor (VEGF) in the brain adjacent to the tumor (BAT) as well as the tumor cell apoptosis and proliferation. Our data show that both surgical resection alone and PDT alone significantly decreased tumor volume, but furthermore, surgical resection combined with PDT significantly reduced the tumor volume and reduced local tumor infiltration compared to either surgical resection or PDT treatment alone. PDT treatment with or without resection increased tumor apoptosis, but resection alone did not alter the tumor cell apoptosis compared with a nontreatment control group. Both surgical resection alone and PDT alone induced a significant increase in VEGF expression in the BAT; however intraoperative PDT did not further increase VEGF expression, compared with surgery alone or PDT alone. No significant differences were found in tumor cell proliferation as indicated by Ki67 immunoreactivity among the four groups. Our results suggest that PDT enhances the efficacy of surgical resection in the management of malignant gliomas without increasing VEGF expression in the BAT.
Photochemistry and Photobiology 82(6):1704-11. · 2.41 Impact Factor
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ABSTRACT: In this study, we focused on a preclinical model of brain compression injury that has relevance to pathological conditions such as tumor, hematoma, blood clot, and intracerebral bony fragment. We investigated behavioral impairment as a result of rapid-onset small mass, and the factors involved in lesion formation and neuroplasticity. An epidural bead implantation method was adopted. Two sizes (1.5 mm and 2.0 mm thick) of hemisphere-shaped beads were used. The beads were implanted into various locations over the sensorimotor cortex (SMC—anterior, middle and posterior). The effects of early versus delayed bead removal were examined to model clinical neurosurgical or other treatment procedures. Forelimb and hind-limb behavioral deficits and recovery were observed, and histological changes were quantified to determine brain reaction to focal compression. Our results showed that the behavioral deficits of compression were influenced by the location, timing of compression release, and magnitude of compression. Even persistent compression by the thicker bead (2.0 mm) caused only minor behavioral deficits, followed by fast recovery within a week in most animals, suggesting a mild lesion pattern for this model. Brain tissue was compressed into a deformed shape under pressure with slight tissue damage, evidenced by pathological evaluation on hematoxylin and eosin (H&E)– and TUNEL–stained sections. Detectable but not severe behavioral dysfunction exhibited by this model makes it particularly suitable for direct assessment of adverse effects of interventions on neuroplasticity after brain compression injury. This model may permit development of treatment strategies to alleviate brain mass effects, without disrupting neuroplasticity. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/63138/1/neu.2006.23.721.pdf
