talaporfin and Glioma

The objective of the present study was to perform a prospective evaluation of the potential efficacy and safety of intraoperative photodynamic therapy (PDT) using talaporfin sodium and irradiation using a 664-nm semiconductor laser in patients with primary malignant parenchymal brain tumors.. In 27 patients with suspected newly diagnosed or recurrent primary malignant parenchymal brain tumors, a single intravenous injection of talaporfin sodium (40 mg/m(2)) was administered 1 day before resection of the neoplasm. The next day after completion of the tumor removal, the residual lesion and/or resection cavity were irradiated using a 664-nm semiconductor laser with a radiation power density of 150 mW/cm(2) and a radiation energy density of 27 J/cm(2). The procedure was performed 22-27 hours after drug administration. The study cohort included 22 patients with a histopathologically confirmed diagnosis of primary malignant parenchymal brain tumor. Thirteen of these neoplasms (59.1%) were newly diagnosed glioblastomas multiforme (GBM).. Among all 22 patients included in the study cohort, the 12-month overall survival (OS), 6-month progression-free survival (PFS), and 6-month local PFS rates after surgery and PDT were 95.5%, 91%, and 91%, respectively. Among patients with newly diagnosed GBMs, all these parameters were 100%. Side effects on the skin, which could be attributable to the administration of talaporfin sodium, were noted in 7.4% of patients and included rash (2 cases), blister (1 case), and erythema (1 case). Skin photosensitivity test results were relatively mild and fully disappeared within 15 days after administration of photosensitizer in all patients.. Intraoperative PDT using talaporfin sodium and a semiconductor laser may be considered as a potentially effective and sufficiently safe option for adjuvant management of primary malignant parenchymal brain tumors. The inclusion of intraoperative PDT in a combined treatment strategy may have a positive impact on OS and local tumor control, particularly in patients with newly diagnosed GBMs. Clinical trial registration no.: JMA-IIA00026 (https://dbcentre3.jmacct.med.or.jp/jmactr/App/JMACTRS06/JMACTRS06.aspx?seqno=862).

Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Female; Glioma; Humans; Laser Therapy; Lasers, Semiconductor; Male; Middle Aged; Photochemotherapy; Photosensitizing Agents; Porphyrins; Treatment Outcome

To investigate the safety and efficacy of photodynamic therapy (PDT) using talaporfin sodium in patients with surgically, completely unresectable malignant gliomas with invasion into the eloquent areas of the brain associated with language and motor functions.. Subjects consisted of consecutive 14 adult patients with malignant gliomas that were shown on preoperative diagnostic imaging to have invaded the eloquent areas of the brain. Of these, 6 patients had newly diagnosed tumors and 8 patients had recurrent tumors. In 15 craniotomy and tumor resection procedures, PDT was used as additional intraoperative treatment 24 h after 40 mg/m(2) of talaporfin sodium had been injected intravenously. After the tumor bulk had been resected as extensively as possible either 1 or 2 sites of probable tumor invasion in the bottom of resection cavity were irradiated superficially with a 664-nm diode laser for 180 s (27 J/cm(2)) at a power density of 150 mW/cm(2).. PDT achieved a response rate of 80% at the treated sites in the 6 patients with newly diagnosed malignant gliomas. In these patients, the median progression-free survival time was 23 months. The median survival time in 3 patients who died was 26 months, and the remaining 3 patients survived for more than 3 years with a good Karnofsky Performance Scale (KPS). In the 8 patients with recurrent tumors who received PDT, their response rate was low (25.0%), their gliomas recurred 3 months after PDT, and their survival time was only 9 months following PDT. No adverse events directly attributable to PDT occurred in any patients. Protection against light was only required for approximately 3 days after PDT.. We examined the safety and efficacy of PDT using talaporfin sodium as an additional intraoperative treatment for malignant glioma. PDT in addition to surgical resection achieved better therapeutic results than conventional protocols, especially in patients with newly diagnosed malignant gliomas. However, the current methodology has some limitations with respect to patients with recurrent tumors. Larger-scale studies are required to confirm the clinical feasibility of PDT plus surgery.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Brain Neoplasms; Female; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Pilot Projects; Porphyrins; Treatment Outcome

The study aim to demonstrate the therapeutic tissue depth of photodynamic therapy (PDT) using the photosensitizer talaporfin sodium and semiconductor laser for malignant glioma from an autopsy finding. Three patients diagnosed with glioblastoma by pre-operative imaging (1 newly diagnosed patient and 2 patients with recurrence) were treated with intra-operative additional PDT and adjuvant therapy such as post-operative radiotherapy or chemotherapy. All three patients died of brain stem dysfunction owing to cerebrospinal fluid dissemination or direct invasion of the tumor cells from 13, 18, or 20 months after PDT. Antemortem magnetic resonance images demonstrated no tumor recurrence in the site of PDT, and autopsy was performed for the pathological analysis. Macroscopic observation demonstrated no tumor recurrence in two patients, but one patient demonstrated tumor recurrence in the therapeutic depth of PDT. Microscopic analysis demonstrated histopathological changes reaching depths of 9, 11, and 18 mm (mean: 12.7 mm) from the surface of the cavity of tumor resection, suggesting the therapeutic tissue depth of PDT to be in this range. This region demonstrated glial scarring with infiltration of T lymphocytes and macrophages, with slight degeneration of small vessel walls. However, viable tumor tissues were observed beyond or around the therapeutic tissue depth of PDT in two patients. PDT for glioblastoma prevented early local recurrence, which suggests the possibility that activation of the immune mechanisms was involved. The therapeutic tissue depth was suggested to be 9-18 mm from the surface of the cavity of tumor resection; however, the viable tumor tissues were demonstrated beyond this therapeutic range.

Topics: Adult; Autopsy; Female; Glioblastoma; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Porphyrins; Retrospective Studies; Treatment Outcome

Photodynamic therapy (PDT) induces selective cell death of neoplastic tissue and connecting vasculature by combining photosensitizers with light. We have previously reported that PDT induces apoptotic cell death in glioma cells when the photosensitizer talaporfin sodium (NPe6) is used. Here, we investigated the combined effect of NPe6-PDT with temozolomide, a DNA-alkylating drug used in glioma therapy.. Human glioblastoma T98G cells and human glioma U251 cells were used as glioma cells. Cell viability was evaluated by WST-8 assay. Apoptosis was evaluated by measurement of caspase-3 activity and DNA-fragmentation. Intracellular reactive oxygen species were evaluated by dihydrorhodamine assay.. While the degree of NPe6-PDT induced cell death unchanged in T98G and U251 cells when temozolomide treatment was adjuvant, it was dose-dependently increased by concomitant treatment with temozolomide. Further, concomitantly administered temozolomide dose-dependently increased caspase-3 activity and DNA-fragmentation, while adjuvant-temozolomide did not. These results are suggesting that concomitantly administered temozolomide potentiates the effect of NPe6-PDT to facilitate apoptotic cell death. Additionally, concomitantly administered temozolomide increased intracellular NPe6-fluorescence and reactive oxygen species, suggesting that the augmentation effect of combined treatment may be due to increased intracellular accumulation of NPe6.. These results suggest that concomitant treatment with NPe6-PDT and temozolomide is a potentially useful therapy for glioma.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Dacarbazine; Drug Therapy, Combination; Glioma; Humans; Photochemotherapy; Photosensitizing Agents; Porphyrins; Temozolomide; Treatment Outcome

To investigate the kinetics of cell death in human glioma cell lines induced by photodynamic therapy (PDT) with the second-generation photosensitizer talaporfin sodium (TS) and a 664-nm diode laser.. Three human glioma cell lines (T98G, A172, U251) were studied. After incubation of the cell lines with various concentrations of TS for 4 h, PDT using diode laser irradiation at 33 mW/cm² and 10 J/cm² was performed. Cell viability and changes in cell morphology were examined by the Cell Counting Kit-8 assay and phase-contrast microscopy, respectively. In addition, to evaluate the pathology of cell death, changes in cell viability after treatment with a caspase activation inhibitor and an autophagy inhibitor were also examined.. In all 3 human glioma cell lines, TS induced dose-dependent cell death. However, the 50% lethal dose of TS varied among these cell lines. The main morphological feature of cell death was shrinkage of the cell body, and the number of cells with this morphological change increased in a time-dependent manner, resulting in cell death. In addition, a dose-dependent improvement in cell viability by the caspase inhibitor Z-VAD-fmk was observed.. PDT with TS induces dose-dependent apoptosis in human glioma cell lines. However, the sensitivity to PDT varied among the cell lines, indicating a possible difference in the intracellular content of TS, or a difference in the susceptibility to the intracellular oxidative stress caused by PDT.

Topics: Apoptosis; Cell Line, Tumor; Dose-Response Relationship, Drug; Glioma; Humans; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents; Treatment Outcome

Photodynamic therapy (PDT) induces selective cell death of neoplastic tissue and connecting vasculature by combining photosensitizers with light. Here we clarified the types of cell death induced by PDT in combination with the photosensitizer talaporfin sodium (mono-L-aspartyl chlorine e6, NPe6) in order to evaluate the potential of this therapy as a treatment for glioma. PDT with NPe6 (NPe6-PDT) induces dose-dependent cell death in human glioblastoma T98G cells. Specifically, cell death modalities were observed in NPe6-PDT treated T98G cells, including signs of apoptosis (activation of caspase-3, expression of phosphatidylserine, and DNA fragmentation) and necrosis (stainability of propidium iodide). In addition, high doses of NPe6-PDT decreased the proportion of apoptotic cell death, while increasing necrosis. Closer examination of apoptotic characteristics revealed release of cytochrome-c from mitochondria as well as activation of both caspse-9 and caspase-3 in cells treated with low doses of NPe6-PDT. Benziloxycarbonyl-Leu-Gln(OMe)-His-Asp(OMe)-fluoromethyl-ketone (Z-LEHD-fmk), a caspase-9 specific inhibitor, and benziloxycarbonyl-Asp(OMe)-Gln-Met-Asp(OMe)-fluoromethyl-ketone (Z-DQMD-fmk), a caspase-3 specific inhibitor, showed dose-dependent prevention of cell death in NPe6-PDT treated cells, indicating that mitochondrial apoptotic pathway was a factor in the observed cell death. Further, the cell morphology was observed after PDT. Time- and NPe6-dose dependent necrotic features were increased in NPe6-PDT treated cells. These results suggest that NPe6-PDT could be an effective treatment for glioma if used in mild doses to avoid the increased necrosis that may induce undesirable obstacles.

Topics: Antineoplastic Agents; Brain Neoplasms; Caspase 3; Cell Death; Cell Line, Tumor; Cytochromes c; DNA Fragmentation; Glioma; Humans; Mitochondria; Necrosis; Photochemotherapy; Photosensitizing Agents; Porphyrins

The usefulness of photodynamic therapy (PDT) as a local therapy for malignant glioma was evaluated by investigating histological changes in a rat C6 glioma model treated with a combination of talaporfin sodium, a water-soluble photosensitizer derived from chlorophyll and exposure to a diode laser.. Glioma cells (C6) at the confluence stage were transplanted stereotactically into the right frontal lobe of SD rats. Five days later, the rats underwent right frontal craniotomy and intravenous administration of talaporfin sodium. One hour after talaporfin sodium administration, each rat was irradiated by a 664 nm diode laser beam. The brain was removed 1, 3 or 6h after laser irradiation for histological examination of tumor-affected brain tissue and surrounding normal brain tissue.. In addition to the tumor mass, tumor cells invading surrounding edematous brain tissue were seen in untreated rats, ranging from the brain surface to a depth of 2mm. One hour after PDT, coagulation necrosis as well as disappearance of indication of cell viability such as disappearance of tumor cell processes and foamy changes of cytoplasm were noted in the tumor tissue at a depth of 0.5mm, accompanied by reduction of cytoplasmic glial fibrillary acidic protein (GFAP) expression and appearance of granular M30 cytodeath positivity. Three hours later, the cytoplasm of the residual tumor cells showed disappearance of GFAP expression and increased expression of M30 cytodeath. Six hours later, the foamy cytoplasm of swollen tumor cells demonstrated strong positivity for M30 cytodeath.. PDT using talaporfin sodium induced coagulation necrosis and apoptosis in rats with C6 glioma.

Topics: Animals; Brain; Cell Line, Tumor; Glioma; Male; Photochemotherapy; Photosensitizing Agents; Porphyrins; Rats; Rats, Sprague-Dawley

The objective of the study was to investigate the potential of mono-L-aspartyl chlorine e6 (NPe6), a water-soluble photosensitizer derived from chlorophyll, for use in photodynamic diagnosis (PDD) of malignant brain tumor. A C6 glioma cell line was transplanted in the SD rat brain to create a brain tumor model. Five days after transplantation, NPe6 was administrated via the tail vein at concentrations ranging from 1.25 to 10 mg/kg; then the skull was opened in the rat brain, the site of tumor transplant was irradiated with a diode laser beam at 664 nm, and the time-course intensity and distribution of emerging fluorescence were observed. Furthermore, the correlation between fluorescence distribution and histopathological findings was investigated in the removed brain. Fluorescence was observed in the site of brain tumor transplant from 5 min after injection, and stable fluorescence was recognized at the site until 4 h after administration. No differences were noted in fluorescence intensity at NPe6 doses of 2.5 mg/kg or more; therefore, it was possible to estimate the optimal dose range. Fluorescence distribution had a clear correlation with tumor cell density, and it was possible to capture the margin of tumor cell invasion with fluorescence. The photosensitizer NPe6 is capable of assessing tumor cell density in malignant glioma tissue in terms of differences in fluorescence intensity. The usefulness of PDD using 5-aminoleveulinic acid during surgery for malignant glioma has been recognized in recent years. The results of the present study suggested the potential of NPe6 as a promising photosensitizer for use in PDD for accurate grasp of the extent of removal during the course of malignant glioma surgery.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Glioma; Lasers; Male; Neoplasm Transplantation; Photosensitizing Agents; Porphyrins; Rats; Rats, Sprague-Dawley