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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 -
British Journal of Cancer Jun 1992Bladders of anaesthetised mice were illuminated with laser light of 630 nm at 24 h after intraperitoneal administration of the photosensitiser Photofrin II (10 mg kg-1)....
Bladders of anaesthetised mice were illuminated with laser light of 630 nm at 24 h after intraperitoneal administration of the photosensitiser Photofrin II (10 mg kg-1). A range of light doses, at a power setting of 100 mW, was delivered intravesically by a fibre optic inserted into the centre of the bladder via the urethra. Functional bladder damage was assessed from increases in urination frequency and the presence of urethra. Functional bladder damage was assessed from increases in urination frequency and the presence of haematuria at 1 to 26 weeks after treatment. Whole bladder illumination with incident light doses exceeding 18.75 J cm-2 caused extensive oedema, haemorrhage and necrosis of the bladder wall and mice had to be sacrificed within 24 h. PDT with incident light doses of 3.75 to 15.0 J cm-2 caused haematuria and increased urination frequency during the first week in nearly all mice, but there was complete functional recovery by 6 to 10 weeks after doses of up to 7.5 J cm-2. Recovery was slower after higher doses and up to 50% of mice still had some increased urination frequency at 10 weeks after greater than or equal to 11.25 J cm-2, although haematuria was rare at this time. Histologically, early damage (one day after PDT) consisted of epithelial sloughing, submucosal oedema, fibrin imbibition, vascular ectasia and, rarely, thrombosis. Doses exceeding 7.5 J cm-2 were often associated with foci of necrosis. In some instances, necrosis was complicated by bacterial infection, resulting in an acute transmural inflammation with a tendency to suppuration. After doses of up to 11.25 J cm-2 there was a gradual recovery and only a mild degree of fibrosis of the bladder wall (with some increase in vascularity) remained at 6 months.
Topics: Animals; Body Weight; Dihematoporphyrin Ether; Dose-Response Relationship, Radiation; Female; Hematoporphyrin Photoradiation; Hematoporphyrins; Hematuria; Light; Mice; Mice, Inbred C3H; Survival Analysis; Urinary Bladder; Urinary Bladder Diseases; Urination
PubMed: 1535507
DOI: 10.1038/bjc.1992.185 -
Clinical Endoscopy Jan 2013This paper reviews the use of photodynamic therapy (PDT) in patients with Barrett's esophagus and esophageal carcinoma. We describe the history of PDT, mechanics,...
This paper reviews the use of photodynamic therapy (PDT) in patients with Barrett's esophagus and esophageal carcinoma. We describe the history of PDT, mechanics, photosensitizers for PDT in patients with esophageal disease. Finally, we discuss its utility and limitations in this setting.
PubMed: 23423151
DOI: 10.5946/ce.2013.46.1.30 -
Cancer Immunology, Immunotherapy : CII May 2007Cancer therapies, which deliver a rapidly induced massive tumor tissue injury, such as photodynamic therapy (PDT), provoke a strong host response raised for dealing with...
Cancer therapies, which deliver a rapidly induced massive tumor tissue injury, such as photodynamic therapy (PDT), provoke a strong host response raised for dealing with the inflicted local trauma. Activated complement system was identified as an important element of host response elicited by tumor PDT. The expression of genes encoding complement proteins C3, C5, and C9 was studied following tumor PDT mediated by photosensitizer Photofrin using mouse Lewis lung carcinoma (LLC) model. Treated tumors and the livers of host mice were collected at different times after PDT and the expression of the investigated genes was analyzed by RT-PCR. The results show a significant up-regulation of C3, C5, and C9 genes in PDT-treated tumors at 24 h after therapy, while no significant increase in the expression of these genes was found in the liver tissues. The expression of C3, C5, and C9 genes also became up-regulated in untreated tumor-associated macrophages (TAMs) co-incubated in vitro with PDT-treated LLC cells. This effect was abolished or drastically reduced in the presence of antibodies blocking heat shock protein 70 (HSP70), Toll-like receptor (TLR) 2 and TLR4, and specific peptide inhibitors of TIRAP adapter protein and transcription factor NF-kappaB. The presented study reveals that complement genes C3, C5, and C9 become up-regulated in tumors treated by PDT, but not in the host's liver. Tumor-localized up-regulation of these genes can be largely attributed to monocytes/macrophages invading the treated lesion after PDT. This effect appears to be induced by the recognition of danger signals from PDT-treated tumor cells such as HSP70 by TAMs that involve the TLR2- and TLR4-triggered signal transduction pathways leading to the activation of NF-kappaB.
Topics: Animals; Carcinoma, Lewis Lung; Complement C3; Complement C5; Complement C9; Dihematoporphyrin Ether; Gene Expression; Gene Expression Profiling; HSP70 Heat-Shock Proteins; Macrophages; Mice; Photochemotherapy; Photosensitizing Agents; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptor 2; Toll-Like Receptor 4
PubMed: 16947020
DOI: 10.1007/s00262-006-0221-z -
Cell Death & Disease Oct 2017Colorectal cancer (CRC) is a most common digestive system malignant tumor. p53 mutation has essential role in cancers and is frequently observed in CRC and presents a...
Colorectal cancer (CRC) is a most common digestive system malignant tumor. p53 mutation has essential role in cancers and is frequently observed in CRC and presents a huge challenge. p53 mutation has been reported to attenuate the inhibitory effect of photofrin-based photodynamic therapy (PDT). p53 mutation-induced gain of function brings up the dysfunction of carcinogenic factors, including miRNAs. Our research found that PDT suppressed CRC cell viability, reduced the tumor size and prolonged the survival time, all of which could be attenuated by p53 mutation or deletion. After p53 mutation or deletion, several miRNA expression levels were downregulated, among which miR-124 was the most strongly downregulated, whereas iASPP expression was upregulated. p53 binds to the promoter of miR-124 to promote its expression and then inhibited iASPP expression, so as to amplify the inhibitory effect of PDT on wild-type p53 cells. In p53-mutant or -deleted cells, this binding no longer worked to promote miR-124 expression, and iASPP expression increased, finally resulted in promoted CRC cell viability upon PDT. The interactive modulation among miR and iASPP in p53-mutant or -deleted cells may serve as a crucial pathway, which mediates therapy resistance when p53 is mutated or deleted, in the process of PDT treatment of CRC.
Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; DNA-Binding Proteins; Dihematoporphyrin Ether; HCT116 Cells; HT29 Cells; Humans; Mice; MicroRNAs; Neoplasm Transplantation; Photochemotherapy; Promoter Regions, Genetic; Transplantation, Heterologous; Tumor Suppressor Protein p53
PubMed: 29022915
DOI: 10.1038/cddis.2017.477 -
Lasers in Medical Science Sep 2009Photofrin photodynamic therapy (PDT) caused a dose-dependent decrease of enzymatic cell detachment by trypsin/ethylenediamine tetra-acetic acid (EDTA) in human glioma...
Photofrin photodynamic therapy (PDT) caused a dose-dependent decrease of enzymatic cell detachment by trypsin/ethylenediamine tetra-acetic acid (EDTA) in human glioma U251n and U87 cells. This happened coincidently with the increase of intracellular free calcium ([Ca(2+)](i)). Thapsigargin, which increased [Ca(2+)](i), induced further decrease in enzymatic cell detachment and increased cytotoxicity. Opposite effects were observed when 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid tetrakis, an intracellular Ca(2+) chelator, was used. PDT-induced changes in [Ca(2+)](i) and cell detachment were not blocked by calcium channel antagonists nickel (Ni(2+)) or nimodipine, nor were they altered when cells were irradiated in a buffer free from Ca(2+) and magnesium (Mg(2+)), suggesting that [Ca(2+)](i) is derived from the internal calcium stores. Decreased cell migration was observed after PDT, as assessed by chemotactic and wound-healing assays. Our findings indicated that internal calcium store-derived [Ca(2+)](i) plays an important role in PDT-induced enzymatic cell detachment decrease and cytotoxicity. Cell migration may be affected by these changes.
Topics: Calcium; Cell Adhesion; Cell Line, Tumor; Cell Movement; Dihematoporphyrin Ether; Egtazic Acid; Glioma; Humans; Photochemotherapy; Photosensitizing Agents; Thapsigargin
PubMed: 19198972
DOI: 10.1007/s10103-008-0640-5 -
British Journal of Cancer Apr 2000Photofrin-based photodynamic therapy (PDT) has recently been approved for palliative and curative purposes in cancer patients. It has been demonstrated that neutrophils...
Photofrin-based photodynamic therapy (PDT) has recently been approved for palliative and curative purposes in cancer patients. It has been demonstrated that neutrophils are indispensable for its anti-tumour effectiveness. We decided to evaluate the extent of the anti-tumour effectiveness of PDT combined with administration of granulocyte colony-stimulating factor (G-CSF) as well as the influence of Photofrin and G-CSF on the myelopoiesis and functional activity of neutrophils in mice. An intensive treatment with G-CSF significantly potentiated anti-tumour effectiveness of Photofrin-based PDT resulting in a reduction of tumour growth and prolongation of the survival time of mice bearing two different tumours: colon-26 and Lewis lung carcinoma. Moreover, 33% of C-26-bearing mice were completely cured of their tumours after combined therapy and developed a specific and long-lasting immunity. The tumours treated with both agents contained more infiltrating neutrophils and apoptotic cells then tumours treated with either G-CSF or PDT only. Importantly, simultaneous administration of Photofrin and G-CSF stimulated bone marrow and spleen myelopoiesis that resulted in an increased number of neutrophils demonstrating functional characteristics of activation. Potentiated anti-tumour effects of Photofrin-based PDT combined with G-CSF observed in two murine tumour models suggest that clinical trials using this tumour therapy protocol would be worth pursuing.
Topics: Adenocarcinoma; Animals; Bone Marrow Cells; Colonic Neoplasms; Colony-Forming Units Assay; Combined Modality Therapy; Dihematoporphyrin Ether; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Photochemotherapy; Recombinant Proteins; Spleen
PubMed: 10780531
DOI: 10.1054/bjoc.1999.1078 -
Scientific Reports May 2017In Photofrin-mediated photodynamic therapy (PDT), cell fate can be modulated by the subcellular location of Photofrin. PDT triggers oxidative damage to target cells,...
Oxidation of protein-bound methionine in Photofrin-photodynamic therapy-treated human tumor cells explored by methionine-containing peptide enrichment and quantitative proteomics approach.
In Photofrin-mediated photodynamic therapy (PDT), cell fate can be modulated by the subcellular location of Photofrin. PDT triggers oxidative damage to target cells, including the methionine (Met) oxidation of proteins. Here, we developed a new Met-containing peptide enrichment protocol combined with SILAC-based quantitative proteomics, and used this approach to explore the global Met oxidation changes of proteins in PDT-treated epidermoid carcinoma A431 cells preloaded with Photofrin at the plasma membrane, ER/Golgi, or ubiquitously. We identified 431 Met-peptides corresponding to 302 proteins that underwent severe oxidation upon PDT and observed overrepresentation of proteins related to the cell surface, plasma membrane, ER, Golgi, and endosome under all three conditions. The most frequently oxidized Met-peptide sequence was "QAMXXMM-E/G/M-S/G-A/G/F-XG". We also identified several hundred potential Photofrin-binding proteins using affinity purification coupled with LC-MS/MS, and confirmed the bindings of EGFR and cathepsin D with Photofrin. The enzyme activities of both proteins were significantly reduced by Photofrin-PDT. Our results shed light on the global and site-specific changes in Met-peptide oxidation among cells undergoing Photofrin-PDT-mediated oxidative stress originating from distinct subcellular sites, and suggest numerous potential Photofrin-binding proteins. These findings provide new insight into the molecular targets through which Photofrin-PDT has diverse effects on target cells.
Topics: Cell Line, Tumor; Cell Membrane; Dihematoporphyrin Ether; Endoplasmic Reticulum; Endosomes; Golgi Apparatus; Humans; Methionine; Oxidation-Reduction; Oxidative Stress; Peptides; Photochemotherapy; Proteomics
PubMed: 28465586
DOI: 10.1038/s41598-017-01409-9 -
Folia Biologica 2008Photofrin-mediated PDT was applied to malignant (A549 and MCF-7) and normal (HUV-EC-C) cells. The cells were incubated for different lengths of time after PDT. The cell...
Photofrin-mediated PDT was applied to malignant (A549 and MCF-7) and normal (HUV-EC-C) cells. The cells were incubated for different lengths of time after PDT. The cell responses to the therapy were examined by changes in SOD activity, phototoxicity, and mode of the cell death. PDT induced dynamic changes in SOD activity. Initially, an increase in SOD activity was observed, and after 6 hours of culture it decreased to the control level. Results obtained from MTT and the comet assay indicate that PDT caused immediate cell death via apoptosis in the A549, MCF-7, and HUV-EC-C cell lines. Our studies confirm that SOD is involved in the response of both cancer and normal cells to PDT.
Topics: Aged; Cell Line, Tumor; Comet Assay; Dihematoporphyrin Ether; Female; Formazans; Humans; Light; Male; Middle Aged; Neoplasms; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Superoxide Dismutase; Tetrazolium Salts
PubMed: 18226362
DOI: No ID Found -
Photochemistry and Photobiology Mar 2020The objective of the present study was to develop a predictive model for Photofrin -mediated interstitial photodynamic therapy (I-PDT) of locally advanced tumors. Our...
Irradiance, Photofrin Dose and Initial Tumor Volume are Key Predictors of Response to Interstitial Photodynamic Therapy of Locally Advanced Cancers in Translational Models.
The objective of the present study was to develop a predictive model for Photofrin -mediated interstitial photodynamic therapy (I-PDT) of locally advanced tumors. Our finite element method was used to simulate 630-nm intratumoral irradiance and fluence for C3H mice and New Zealand White rabbits bearing large squamous cell carcinomas. Animals were treated with light only or I-PDT using the same light settings. I-PDT was administered with Photofrin at 5.0 or 6.6 mg kg , 24 h drug-light interval. The simulated threshold fluence was fixed at 45 J cm while the simulated threshold irradiance varied, intratumorally. No cures were obtained in the mice treated with a threshold irradiance of 5.4 mW cm . However, 20-90% of the mice were cured when the threshold irradiances were ≥8.6 mW cm . In the rabbits treated with I-PDT, 13 of the 14 VX2 tumors showed either local control or were cured when threshold irradiances were ≥15.3 mW cm and fluence was 45 J cm . No tumor growth delay was observed in VX2 treated with light only (n = 3). In the mouse studies, there was a high probability (92.7%) of predicting cure when the initial tumor volume was below the median (493.9 mm ) and I-PDT was administered with a threshold intratumoral irradiance ≥8.6 mW cm .
Topics: Animals; Dihematoporphyrin Ether; Dose-Response Relationship, Radiation; Mice; Mice, Inbred C3H; Neoplasms; Photosensitizing Agents; Rabbits
PubMed: 31887227
DOI: 10.1111/php.13207