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Photochemistry and Photobiology Jul 2017This preclinical study examines light fluence, photodynamic therapy (PDT) dose and "apparent reacted singlet oxygen," [ O ] , to predict local control rate (LCR) for... (Comparative Study)
Comparative Study
This preclinical study examines light fluence, photodynamic therapy (PDT) dose and "apparent reacted singlet oxygen," [ O ] , to predict local control rate (LCR) for Photofrin-mediated PDT of radiation-induced fibrosarcoma (RIF) tumors. Mice bearing RIF tumors were treated with in-air fluences (50-250 J cm ) and in-air fluence rates (50-150 mW cm ) at Photofrin dosages of 5 and 15 mg kg and a drug-light interval of 24 h using a 630-nm, 1-cm-diameter collimated laser. A macroscopic model was used to calculate [ O ] and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [ O ] were defined as a temporal integral of drug concentration and fluence rate, and singlet oxygen concentration consumed divided by the singlet oxygen lifetime, respectively. LCR was stratified for different dose metrics for 74 mice (66 + 8 control). Complete tumor control at 14 days was observed for [ O ] ≥ 1.1 mm or PDT dose ≥1200 μm J cm but cannot be predicted with fluence alone. LCR increases with increasing [ O ] and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [ O ] outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR.
Topics: Animals; Dihematoporphyrin Ether; Dose-Response Relationship, Drug; Female; Fibrosarcoma; Mice, Inbred C3H; Neoplasms, Radiation-Induced; Photochemotherapy; Photosensitizing Agents; Singlet Oxygen
PubMed: 28083883
DOI: 10.1111/php.12719 -
Photochemistry and Photobiology Mar 2017In prior studies, we have identified the ability of low-level lysosomal photodamage to potentiate the phototoxic effect of subsequent photodamage to mitochondria. The...
In prior studies, we have identified the ability of low-level lysosomal photodamage to potentiate the phototoxic effect of subsequent photodamage to mitochondria. The mechanism involves calpain-mediated cleavage of the autophagy-associated protein ATG5 to form a proapoptotic fragment (tATG5). In this report, we explore the permissible time lag between the two targeting procedures along with the effect of simultaneously targeting both lysosomes and mitochondria. This was found to be as effective as the sequential protocol with no gap between the irradiation steps. Inhibition of calpain reversed the enhanced efficacy of the "simultaneous" protocol. It appears that even a minor level of lysosomal photodamage can have a significant effect on the efficacy of subsequent mitochondrial photodamage. We propose that these results may explain the efficacy of Photofrin, a photosensitizing product that also targets both lysosomes and mitochondria for photodamage.
Topics: Animals; Autophagy-Related Protein 5; Cell Line, Tumor; Dihematoporphyrin Ether; Light; Lysosomes; Mice; Mitochondria; Photochemotherapy; Photosensitizing Agents; Spectrum Analysis
PubMed: 27935055
DOI: 10.1111/php.12692 -
Journal of Biomedical Optics Aug 2016Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account...
Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account for the differences in PDT oxygen consumption for different fluence rates ( ? ). A macroscopic model was adopted to evaluate using calculated reacted singlet oxygen concentration ( [ O 2 1 ] rx ) to predict Photofrin-PDT outcome in mice bearing radiation-induced fibrosarcoma tumors, as singlet oxygen is the primary cytotoxic species responsible for cell death in type II PDT. Using a combination of fluences (50, 135, 200, and 250 ?? J / cm 2 ) and ? (50, 75, and 150 ?? mW / cm 2 ), tumor regrowth rate, k , was determined for each condition. A tumor cure index, CI = 1 ? k / k control , was calculated based on the k between PDT-treated groups and that of the control, Available on the SPIE Digital Library.
Topics: Animals; Dihematoporphyrin Ether; Female; Mice; Mice, Inbred C3H; Models, Biological; Neoplasms, Experimental; Photochemotherapy; Photosensitizing Agents; Radiation Dosage; Singlet Oxygen; Xenograft Model Antitumor Assays
PubMed: 27552311
DOI: 10.1117/1.JBO.21.8.088002 -
Oncology Reports Jun 2016Photodynamic therapy (PDT) exerts direct cytotoxic effects on tumor cells, destroys tumor blood and lymphatic vessels and induces local inflammation. Although PDT...
Photodynamic therapy (PDT) exerts direct cytotoxic effects on tumor cells, destroys tumor blood and lymphatic vessels and induces local inflammation. Although PDT triggers the release of immunogenic antigens from tumor cells, the degree of immune stimulation is regimen-dependent. The highest immunogenicity is achieved at sub-lethal doses, which at the same time trigger cytoprotective responses, that include increased expression of glucose-regulated protein 78 (GRP78). To mitigate the cytoprotective effects of GRP78 and preserve the immunoregulatory activity of PDT, we investigated the in vivo efficacy of PDT in combination with EGF-SubA cytotoxin that was shown to potentiate in vitro PDT cytotoxicity by inactivating GRP78. Treatment of immunocompetent BALB/c mice with EGF-SubA improved the efficacy of PDT but only when mice were treated with a dose of EGF-SubA that exerted less pronounced effects on the number of T and B lymphocytes as well as dendritic cells in mouse spleens. The observed antitumor effects were critically dependent on CD8+ T cells and were completely abrogated in immunodeficient SCID mice. All these results suggest that GRP78 targeting improves in vivo PDT efficacy provided intact T-cell immune system.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Combined Modality Therapy; Dihematoporphyrin Ether; Endoplasmic Reticulum Chaperone BiP; Epidermal Growth Factor; Escherichia coli Proteins; Female; Heat-Shock Proteins; Humans; Liver; Mice; Mice, Inbred BALB C; Mice, SCID; Photochemotherapy; Photosensitizing Agents; Recombinant Fusion Proteins; Subtilisins; Xenograft Model Antitumor Assays
PubMed: 27035643
DOI: 10.3892/or.2016.4723 -
Journal of Thoracic Oncology : Official... Feb 2016We report a phase I trial of photodynamic therapy (PDT) of carcinoma in situ (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS)...
A Phase I Study of Light Dose for Photodynamic Therapy Using 2-[1-Hexyloxyethyl]-2 Devinyl Pyropheophorbide-a for the Treatment of Non-Small Cell Carcinoma In Situ or Non-Small Cell Microinvasive Bronchogenic Carcinoma: A Dose Ranging Study.
INTRODUCTION
We report a phase I trial of photodynamic therapy (PDT) of carcinoma in situ (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH). HPPH has the advantage of minimal general phototoxicity over the commonly used photosensitizer porfimer sodium (Photofrin; Pinnacle Biologics, Chicago, IL).
METHODS
The objectives of this study were (1) to determine the maximally tolerated light dose at a fixed photosensitizer dose and (2) to gain initial insight into the effectiveness of this treatment approach. Seventeen patients with 21 CIS/MIC lesions were treated with HPPH with light dose escalation starting from 75 J/cm2 and increasing to 85, 95,125, and 150 J/cm2 respectively. Follow-up bronchoscopy for response assessment was performed at 1 and 6 months, respectively.
RESULTS
The rate of pathological complete response (CR) was 82.4% (14 of 17 evaluable lesions; 14 patients) at 1 month and 72.7% (8/11 evaluable lesions; 8 patients) at 6 months. Only four patients developed mild skin erythema. One of the three patients in the 150 J/cm2 light dose group experienced a serious adverse event. This patient had respiratory distress caused by mucus plugging, which precipitated cardiac ischemia. Two additional patients treated subsequently at this light dose had no adverse events. The sixth patient in this dose group was not recruited and the study was terminated because of delays in HPPH supply. However, given the observed serious adverse event, it is recommended that the light dose does not exceed 125 J/cm2.
CONCLUSIONS
PDT with HPPH can be safely used for the treatment of CIS/MIC of the airways, with potential effectiveness comparable to that reported for porfimer sodium in earlier studies.
Topics: Aged; Aged, 80 and over; Carcinoma in Situ; Carcinoma, Bronchogenic; Carcinoma, Non-Small-Cell Lung; Chlorophyll; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Middle Aged; Photochemotherapy; Photosensitizing Agents
PubMed: 26718878
DOI: 10.1016/j.jtho.2015.10.020 -
International Journal of Molecular... Nov 2015Hilar cholangiocarcinoma (CC) is non-resectable in the majority of patients often due to intrahepatic extension along bile duct branches/segments, and even after...
Hilar cholangiocarcinoma (CC) is non-resectable in the majority of patients often due to intrahepatic extension along bile duct branches/segments, and even after complete resection (R0) recurrence can be as high as 70%. Photodynamic therapy (PDT) is an established palliative local tumor ablative treatment for non-resectable hilar CC. We report the long-term outcome of curative resection (R0) performed after neoadjuvant PDT for downsizing of tumor margins in seven patients (median age 59 years) with initially non-resectable hilar CC. Photofrin(®) was injected intravenously 24-48 h before laser light irradiation of the tumor stenoses and the adjacent bile duct segments. Major resective surgery was done with curative intention six weeks after PDT. All seven patients had been curatively (R0) resected and there were no undue early or late complications for the neoadjuvant PDT and surgery. Six of seven patients died from tumor recurrence at a median of 3.2 years after resection, the five-year survival rate was 43%. These results are comparable with published data for patients resected R0 without pre-treatment, indicating that neoadjuvant PDT is feasible and could improve overall survival of patients considered non-curatively resectable because of initial tumor extension in bile duct branches/segments--however, this concept needs to be validated in a larger trial.
Topics: Adult; Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Dihematoporphyrin Ether; Female; Humans; Injections, Intravenous; Klatskin Tumor; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Palliative Care; Photochemotherapy; Photosensitizing Agents; Pilot Projects; Recurrence; Survival Analysis
PubMed: 26561801
DOI: 10.3390/ijms161125978 -
The Journal of Surgical Research Jan 2016There is a need to develop novel therapies for non-small cell lung cancer (NSCLC). Photodynamic therapy has been used successfully for endobronchial palliation of NSCLC,... (Comparative Study)
Comparative Study
BACKGROUND
There is a need to develop novel therapies for non-small cell lung cancer (NSCLC). Photodynamic therapy has been used successfully for endobronchial palliation of NSCLC, and its role in early stages of disease is being explored. We hypothesized that a novel photosensitizer, PS1, would be more effective than the standard agent, porfimer sodium (Photofrin or PFII), in treating human lung cancer xenografts in mice.
MATERIALS AND METHODS
Patient-derived NSCLC xenografts were established subcutaneously in severe combined immune deficiency mice. Two groups of five mice were injected with PS1 (3-[1'-m-iodobenzyloxy]ethyl-3-devinylpyropheophorbide-a), a chlorophyll-a derivative, or PFII (a purified version of hematoporphyrin derivative) and then treated with nonthermal laser light. Four mice were treated with laser light without photosensitizer and six mice received no treatment at all. All mice were then observed for tumor growth. The tumor growth end point, time-to-1000 mm(3), was evaluated using standard Kaplan-Meier methods and the log-rank test. Tumor hematoxylin and eosin and caspase 3 staining was done to evaluate necrosis and apoptosis.
RESULTS
The median time-to-1000 mm(3) was 12, 12, 26, and 52 d for the control, light only, PFII, and PS1 groups. There was a significant association between the tumor growth end point and treatment (P < 0.05). Hematoxylin and eosin staining revealed <1%, 0%, 67%, and 80% necrosis, and caspase 3 positivity was 2%, <1%, 17%, and 39%, respectively, in the same four groups.
CONCLUSIONS
The mice treated with PS1 exhibited a longer time for tumor regrowth and showed more tumor necrosis and apoptosis compared with the other treatment groups. Thus, the novel photosensitizer, PS1, was demonstrated to be more effective than porfimer sodium in this preclinical pilot study.
Topics: Animals; Carcinoma, Non-Small-Cell Lung; Chlorophyll; Dihematoporphyrin Ether; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Mice; Mice, SCID; Neoplasm Transplantation; Photochemotherapy; Photosensitizing Agents; Pilot Projects; Transplantation, Heterologous; Treatment Outcome
PubMed: 26494011
DOI: 10.1016/j.jss.2015.07.024 -
International Journal of Molecular... Aug 2015Photofrin/photodynamic therapy (PDT) at sub-lethal doses induced a transient stall in proteasome activity in surviving A549 (p53(+/+)) and H1299 (p53(-/-)) cells as...
Photofrin/photodynamic therapy (PDT) at sub-lethal doses induced a transient stall in proteasome activity in surviving A549 (p53(+/+)) and H1299 (p53(-/-)) cells as indicated by the time-dependent decline/recovery of chymotrypsin-like activity. Indeed, within 3 h of incubation, Photofrin invaded the cytoplasm and localized preferentially within the mitochondria. Its light activation determined a decrease in mitochondrial membrane potential and a reversible arrest in proteasomal activity. A similar result is obtained by treating cells with Antimycin and Rotenone, indicating, as a common denominator of this effect, the ATP decrease. Both inhibitors, however, were more toxic to cells as the recovery of proteasomal activity was incomplete. We evaluated whether combining PDT (which is a treatment for killing tumor cells, per se, and inducing proteasome arrest in the surviving ones) with Bortezomib doses capable of sustaining the stall would protract the arrest with sufficient time to induce apoptosis in remaining cells. The evaluation of the mitochondrial membrane depolarization, residual proteasome and mitochondrial enzymatic activities, colony-forming capabilities, and changes in protein expression profiles in A549 and H1299 cells under a combined therapeutic regimen gave results consistent with our hypothesis.
Topics: Antineoplastic Agents; Apoptosis; Bortezomib; Cell Line, Tumor; Dihematoporphyrin Ether; Humans; Intracellular Space; Membrane Potential, Mitochondrial; Microscopy, Confocal; Mitochondria; Neoplasms; Photochemotherapy; Photosensitizing Agents; Proteasome Endopeptidase Complex; Reactive Oxygen Species
PubMed: 26343643
DOI: 10.3390/ijms160920375 -
Redox Biology Dec 2015Intracellular singlet oxygen generation in photofrin-loaded cells caused cell death without discrimination between nonmalignant and malignant cells. In contrast,...
Singlet oxygen treatment of tumor cells triggers extracellular singlet oxygen generation, catalase inactivation and reactivation of intercellular apoptosis-inducing signaling.
Intracellular singlet oxygen generation in photofrin-loaded cells caused cell death without discrimination between nonmalignant and malignant cells. In contrast, extracellular singlet oxygen generation caused apoptosis induction selectively in tumor cells through singlet oxygen-mediated inactivation of tumor cell protective catalase and subsequent reactivation of intercellular ROS-mediated apoptosis signaling through the HOCl and the NO/peroxynitrite signaling pathway. Singlet oxygen generation by extracellular photofrin alone was, however, not sufficient for optimal direct inactivation of catalase, but needed to trigger the generation of cell-derived extracellular singlet oxygen through the interaction between H2O2 and peroxynitrite. Thereby, formation of peroxynitrous acid, generation of hydroxyl radicals and formation of perhydroxyl radicals (HO2(.)) through hydroxyl radical/H2O2 interaction seemed to be required as intermediate steps. This amplificatory mechanism led to the formation of singlet oxygen at a sufficiently high concentration for optimal inactivation of membrane-associated catalase. At low initial concentrations of singlet oxygen, an additional amplification step needed to be activated. It depended on singlet oxygen-dependent activation of the FAS receptor and caspase-8, followed by caspase-8-mediated enhancement of NOX activity. The biochemical mechanisms described here might be considered as promising principle for the development of novel approaches in tumor therapy that specifically direct membrane-associated catalase of tumor cells and thus utilize tumor cell-specific apoptosis-inducing ROS signaling.
Topics: Animals; Apoptosis; Caspase 8; Catalase; Cell Line; Cell Line, Tumor; Dihematoporphyrin Ether; Enzyme Inhibitors; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; Hydrogen Peroxide; Hypochlorous Acid; Light; Metalloporphyrins; Mice; NADPH Oxidases; Nitric Oxide; Peroxynitrous Acid; Photosensitizing Agents; Signal Transduction; Singlet Oxygen; Sulfones; Taurine; fas Receptor
PubMed: 26225731
DOI: 10.1016/j.redox.2015.07.006 -
Cellular Physiology and Biochemistry :... 2015Photodynamic therapy (PDT) is a promising noninvasive technique, which has been successfully applied to the treatment of human cancers. Studies have shown that the Bcl-2...
BACKGROUND/AIMS
Photodynamic therapy (PDT) is a promising noninvasive technique, which has been successfully applied to the treatment of human cancers. Studies have shown that the Bcl-2 family proteins play important roles in PDT-induced apoptosis. However, whether Bcl-2-interacting mediator of cell death (Bim) is involved in photodynamic treatment remains unknown. In this study, we attempt to determine the effect of Bim on Photofrin photodynamic treatment (PPT)-induced apoptosis in human lung adenocarcinoma ASTC-a-1 cells.
METHODS
The translocation of Bim/Bax of the cells were monitored by laser confocal scanning microscope. The levels of Bim protein and activated caspase-3 in cells were detected by western blot assay. Caspase-3 activities were measured by Caspase-3 Fluorogenic Substrate (Ac-DEVD-AFC) analysis. The induction of apoptosis was detected by Hoechst 33258 and PI staining as well as flow cytometry analysis. The effect of Bim on PPT-induced apoptosis was determined by RNAi.
RESULTS
BimL translocated to mitochondria in response to PPT, similar to the downstream pro-apoptotic protein Bax activation. PPT increased the level of Bim and activated caspase-3 in cells and that knockdown of Bim by RNAi significantly protected against caspase-3 activity. PPT-induced apoptosis were suppressed in cells transfected with shRNA-Bim.
CONCLUSION
We demonstrated the involvement of Bim in PPT-induced apoptosis in human ASTC-a-1 lung adenocarcinoma cells and suggested that enhancing Bim activity might be a potential strategy for treating human cancers.
Topics: Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Blotting, Western; Caspase 3; Cell Line, Tumor; Dihematoporphyrin Ether; Humans; Lasers; Membrane Proteins; Microscopy, Electron, Scanning; Mitochondria; Photochemotherapy; Photosensitizing Agents; Proto-Oncogene Proteins; RNA Interference; RNA, Small Interfering; bcl-2-Associated X Protein
PubMed: 25791936
DOI: 10.1159/000373968