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Photodiagnosis and Photodynamic Therapy Jun 2018Photodynamic therapy (PDT) is an office-based treatment for precancerous and early cancerous skin changes. PDT induces cell death through the production of reactive...
Photodynamic therapy (PDT) is an office-based treatment for precancerous and early cancerous skin changes. PDT induces cell death through the production of reactive oxygen species (ROS). Cyclobutane pyrimidine dimers (CPDs) are the most important DNA changes responsible for ultraviolet (UV) carcinogenesis. Recently ROS induced by UVA were shown to generate CPDs via activating melanin. This raised the possibility that PDT induced ROS may also induce CPDs and mutagenesis in melanin containing cells. Previously the effect of PDT on CPDs in melanin containing cells has not been assessed. Our current work aimed to compare the generation of CPDs in melanin containing cells subjected to UVA treatment and porfimer sodium red light PDT. We used ELISA to detect CPDs. After UVA we found a dose dependent increase in CPDs in melanoma cells (B16-F10, MNT-1) with CPD levels peaking hours after discontinuation of UVA treatment. This indicated the generation of UVA induced dark-CPDs in the model. Nevertheless, PDT in biologically relevant doses was unable to induce CPDs. Our work provides evidence for the lack of CPD generation by PDT in melanin containing cells.
Topics: DNA Damage; Dihematoporphyrin Ether; Enzyme-Linked Immunosorbent Assay; Humans; Melanins; Melanocytes; Melanoma; Photochemotherapy; Photosensitizing Agents; Pyrimidine Dimers; Ultraviolet Rays
PubMed: 29702258
DOI: 10.1016/j.pdpdt.2018.04.018 -
BMC Cancer Feb 2018Accumulating evidence suggest that autophagy plays a pivotal role in various anticancer therapies, including photodynamic therapy (PDT), acting as a pro-death or...
BACKGROUND
Accumulating evidence suggest that autophagy plays a pivotal role in various anticancer therapies, including photodynamic therapy (PDT), acting as a pro-death or pro-survival mechanism in a context-dependent manner. Therefore, we aimed to determine the role of autophagy in Photofrin-based PDT.
METHODS
In vitro cytotoxic/cytostatic effects of PDT were evaluated with crystal violet cell viability assay. Autophagy induction was analyzed by immunoblotting and immunofluorescence using anti-LC3 antibody. Autophagy was inhibited by shRNA-mediated ATG5 knockdown or CRISPR/Cas9-mediated ATG5 knockout. Apoptosis was assessed by flow cytometry analysis of propidium iodide and anexin V-positive cells as well as by detection of cleaved PARP and caspase 3 proteins using immunoblotting. Protein carbonylation was evaluated by the 2,4-dinitrophenylhydrazine (DNPH) method.
RESULTS
Photofrin-PDT leads to robust autophagy induction in two cancer cell lines, Hela and MCF-7. shRNA-mediated knockdown of ATG5 only partially blocks autophagic response and only marginally affects the sensitivity of Hela and MCF-7 cells to PDT. ATG5 knockout in HeLa cell line utilizing CRISPR/Cas9 genome editing results in increased PDT-mediated cytotoxicity, which is accompanied by an enhanced apoptotic response and increased accumulation of carbonylated proteins.
CONCLUSIONS
Altogether, these observations imply that autophagy contributes to Photofrin-PDT resistance by enabling clearance of carbonylated and other damaged proteins. Therefore, autophagy inhibition may serve as a strategy to improve PDT efficacy.
Topics: Antineoplastic Agents; Autophagy; Autophagy-Related Protein 5; Cell Line, Tumor; Cell Survival; Dihematoporphyrin Ether; Gene Expression; Gene Knockdown Techniques; Gene Targeting; Humans; Light; Photochemotherapy; Photosensitizing Agents; RNA Interference; RNA, Small Interfering
PubMed: 29463237
DOI: 10.1186/s12885-018-4126-y -
Lasers in Surgery and Medicine Jul 2018Photodynamic therapy (PDT) is a minimally invasive treatment for malignant tumors. The aim of this study was to determine the efficacy of PDT in patients with head and...
BACKGROUND
Photodynamic therapy (PDT) is a minimally invasive treatment for malignant tumors. The aim of this study was to determine the efficacy of PDT in patients with head and neck squamous cell carcinoma (HNSCC).
METHODS
Thirty-three patients with HNSCC were treated with porfimer sodium-mediated PDT followed by intraoperative light activation at 630 nm via fiber optic microlens delivered after 48 hours of injection.
RESULTS
The complete response (CR) rate was 72.7%, while the efficacy (CR + partial response) rate was 97.0%. The rate of good local control (i.e., CR without recurrence after PDT) achieved after the initial PDT (82.6%) was significantly higher than that achieved after the second or third PDT (10%); this rate remained at 62.1% without functional disturbance and disfigurement even after excluding four previously untreated patients. The final local control rate following PDT plus additional therapies was 73.8%.
CONCLUSIONS
PDT is an effective therapy to treat HNSCC, and leads to an improved quality of life in patients with residual or recurrent disease. Lasers Surg. Med. 50:420-426, 2018. © 2018 Wiley Periodicals, Inc.
Topics: Adult; Aged; Aged, 80 and over; Dihematoporphyrin Ether; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm, Residual; Photochemotherapy; Photosensitizing Agents; Retrospective Studies; Squamous Cell Carcinoma of Head and Neck; Survival Rate; Treatment Outcome
PubMed: 29399863
DOI: 10.1002/lsm.22802 -
Lasers in Surgery and Medicine Jul 2018In the setting of lung cancer, photodynamic therapy (PDT) is typically used to treat centrally located endobronchial tumors. The development of navigational bronchoscopy...
OBJECTIVE
In the setting of lung cancer, photodynamic therapy (PDT) is typically used to treat centrally located endobronchial tumors. The development of navigational bronchoscopy has opened the potential for using PDT to treat peripheral lung tumors. However, there is limited information about the feasibility of this approach for treating peripheral lung cancers, and about its effects on surrounding healthy lung tissue. We studied the use of PDT delivered by electromagnetic navigational bronchoscopy to treat peripheral lung cancer in dogs.
MATERIALS AND METHODS
Three dogs with peripheral lung adenocarcinomas were given intravenous porfimer sodium (Photofrin® [Pinnacle Biologics, Inc., Chicago, IL]) to photosensitize the tumors, then navigational bronchoscopy was used to deliver photoradiation. One week after PDT, the tumors and involved lung lobe were surgically excised and evaluated histologically.
RESULTS
PDT was successful in all three dogs and was associated with tolerable and manageable adverse effects. Tissue sections from within PDT-treated tumors showed regions of coagulative central necrosis admixed with small numbers of inflammatory cells, and arterial thrombosis. Viable adenocarcinoma was seen in the surrounding areas.
CONCLUSION
These results suggest that PDT can be successfully deployed to treat peripheral lung cancers using navigational bronchoscopy. Furthermore, damage to surrounding noncancerous tissues can be minimized with accurate placement of the optical fiber. Studies of this modality to treat peripheral lung cancers in humans may be warranted. Lasers Surg. Med. 50:483-490, 2018. © 2018 Wiley Periodicals, Inc.
Topics: Adenocarcinoma; Animals; Bronchoscopy; Dihematoporphyrin Ether; Disease Models, Animal; Dogs; Lung Neoplasms; Photochemotherapy; Photosensitizing Agents; Pneumonectomy
PubMed: 29399826
DOI: 10.1002/lsm.22781 -
Journal of Photochemistry and... Feb 2018Sulforaphene (SFE), a natural isothiocyanate from cruciferous vegetables has shown a potential anticancer effect against cervical and lung cancer. Palliative treatments...
Sulforaphene (SFE), a natural isothiocyanate from cruciferous vegetables has shown a potential anticancer effect against cervical and lung cancer. Palliative treatments like photodynamic therapy (PDT) are being implemented for a long time however, the results are still not promising in case of aggressive cancers like anaplastic thyroid cancer. The objective of this work is to establish an alternative method with the combination of photofrin-PDT and sulforaphene, a natural isothiocyanate from cruciferous vegetables, against human anaplastic thyroid cancer to enhance the efficacy of PDT. In this study, cell viability of FRO cells due to combination treatment was analyzed by MTT assay, Cell cycle arrest, MMP depolarization and ROS generation, analyzed by flow cytometry. Western blot analysis of various proliferative proteins was performed to assess the activity of combination treatment against FRO cells. From the results, sulforaphene alone showed no cytotoxicity against normal cells, however, combination of sulforaphene and photofrin mediated PDT showed a noticeable decrease in cell proliferation against FRO cells. Combination treatment synergistically caused cell cycle arrest via ROS generation and MMP depolarization. The expressions of Ras, MEK, ERK, B-Raf proteins significantly modulated due to combination treatment. PDT and SFE can induce apoptosis in anaplastic thyroid cancer cells individually but while treated in combination, it enhanced the apoptotic and anti-proliferative effect, much higher than the individual doses. In summary, our work designates sulforaphene as a unique natural enhancer of efficacy with PDT against anaplastic thyroid cancer.
Topics: Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Dihematoporphyrin Ether; Extracellular Signal-Regulated MAP Kinases; Humans; Isothiocyanates; Membrane Potential, Mitochondrial; Mitogen-Activated Protein Kinase Kinases; Photochemotherapy; Photosensitizing Agents; Protein Kinase Inhibitors; Reactive Oxygen Species; Signal Transduction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; raf Kinases; ras Proteins
PubMed: 29331658
DOI: 10.1016/j.jphotobiol.2017.12.013 -
Journal of Photochemistry and... Jan 2018The inhibitor of DNA binding and cell differentiation (Id) proteins are dominant negative regulators of the helix-loop-helix transcription factor family and play a key...
The inhibitor of DNA binding and cell differentiation (Id) proteins are dominant negative regulators of the helix-loop-helix transcription factor family and play a key role during development as well as in vascular disorders and cancer. In fact, impairing the Id-protein activity in cancer cells reduces cell growth and even chemoresistance. Recently, we have shown that a synthetic Id-protein ligand (1Y) consisting of a cyclic nonapeptide can reduce the viability of the two breast cancer cell lines MCF-7 and T47D and of the bladder cancer cells T24 to about 50% at concentrations ≥100μM. Moreover, the cyclopeptide displays both proapoptotic and antiproliferative effects on MCF-7 cells. Herein, we show that the cyclopeptide does not induce cell death at the dose of 5μΜ, but it still inhibits MCF-7 and T24 cell proliferation, which correlates with an increased protein level of the cell-cycle regulator p27. Furthermore, 1Y-pretreated MCF-7, T47D, and T24 cells are more susceptible than untreated cells to the phototoxic effects of the three photosensitizers meta-tetra(hydroxyphenyl)chlorin, porfimer sodium, and hypericin, which are applied in photodynamic therapy (PDT). The combination of the Id-protein ligand with each of the light-activated photosensitizers shows synergistic effects on the reduction of cell viability. In conclusion, an Id-protein ligand with moderate cancer cell killing activity at concentrations ≥100μM can be applied at a 20-fold lower and barely toxic dose to raise the sensitivity of cancer cells towards phototoxicity associated with photodynamic treatment. This suggests the potential benefit of targeting the Id proteins in combined drug approaches for cancer therapy.
Topics: Anthracenes; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p27; Dihematoporphyrin Ether; Drug Synergism; Humans; Inhibitor of Differentiation Protein 1; Light; MCF-7 Cells; Nanostructures; Peptides, Cyclic; Perylene; Photosensitizing Agents; Porphyrins
PubMed: 29245122
DOI: 10.1016/j.jphotobiol.2017.11.038 -
Lasers in Surgery and Medicine Jul 2018The goal of this study was to compare tumor response to Photofrin photodynamic therapy using intravenous and intratumoral injection of photosensitizer. Systemic skin...
Photofrin photodynamic therapy with intratumor photosensitizer injection provides similar tumor response while reducing systemic skin photosensitivity: Pilot murine study.
OBJECTIVES
The goal of this study was to compare tumor response to Photofrin photodynamic therapy using intravenous and intratumoral injection of photosensitizer. Systemic skin photosensitivity and photosensitizer distribution were also compared between the two delivery methods.
METHODS
SCCVII tumors were initiated in the hind legs of female C3H mice and grown to a volume of ∼1,000 mm . Photofrin was delivered intravenously via the tail vein at a concentration of 2 mg/kg or intratumorally at concentrations ranging from 0.5-2 mg/kg. A 630 nm laser illumination was delivered via interstitial diffuser placement at a fluence rate of 400 mW/cm and fluence of 100 J/cm. Mice were maintained under normal room lighting for 24 hours after treatment, at which point photographs were captured for assessment of skin photosensitivity. Animals were then sacrificed, and their tumors were excised, sectioned, imaged, and stained with hematoxylin and eosin (H&E). H&E slides were imaged to assess necrosis post-PDT, and skin photographs were evaluated by two blinded reviewers for quantification of skin photosensitivity. Whole-body fluorescence imaging was performed before and after photodynamic therapy.
RESULTS
Tumor necrosis was not significantly different based on treatment group (P = 0.33), while skin photosensitivity was significantly reduced in animals that received Photofrin intratumorally (P = 0.0005). Fluorescence imaging revealed similar photosensitizer fluorescence in excised tumors for intratumor and intravenous injection of Photofrin (P = 0.48), although fluorescence decreased significantly with decreasing intratumor injection concentration (P= 0.01).
CONCLUSIONS
This pilot study shows that intratumoral administration of Photofrin has the potential to produce similar tumor outcomes, while reducing systemic skin photosensitivity. Further studies are warranted to characterize and optimize intratumor delivery. Lasers Surg. 50:476-482, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Dihematoporphyrin Ether; Disease Models, Animal; Female; Injections, Intralesional; Injections, Intravenous; Mice; Mice, Inbred C3H; Photochemotherapy; Photosensitizing Agents; Skin
PubMed: 29214668
DOI: 10.1002/lsm.22774 -
Photodiagnosis and Photodynamic Therapy Mar 2018To assess the effect of photodynamic therapy (PDT) with talaporfin sodium, a second-generation photosensitizer, on oral squamous cell carcinoma (SCC).
OBJECTIVE
To assess the effect of photodynamic therapy (PDT) with talaporfin sodium, a second-generation photosensitizer, on oral squamous cell carcinoma (SCC).
METHODS
Eight patients who were diagnosed with oral SCC without any metastasis and underwent talaporfin sodium-mediated PDT (t-PDT) were included in this study. Biopsies were performed 4-6 weeks after t-PDT. The clinical response was evaluated using Response Evaluation Criteria in Solid Tumors.
RESULTS
Complete response (CR) was achieved in six of eight cases, and two cases showed partial response (PR) as a clinical outcome of t-PDT. Recurrence occurred in one of the CR cases 9 months after irradiation. The patient underwent tumor resection and no recurrence was found after surgery. The two cases with PR died from the cancer despite additional PDT.
CONCLUSION
t-PDT is an effective treatment strategy for oral SCC. Talaporfin sodium has an advantage with regard to early elimination from the body compared with porfimer sodium.
Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Female; Humans; Lasers, Semiconductor; Male; Middle Aged; Mouth Neoplasms; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Porphyrins
PubMed: 29198764
DOI: 10.1016/j.pdpdt.2017.11.016 -
Biomedical Microdevices Nov 2017This study aimed to investigate the drug delivery efficacy and bio-effectiveness of a novel photodynamic therapy (PDT)-matrix drug delivery system for cholangiocarcinoma...
This study aimed to investigate the drug delivery efficacy and bio-effectiveness of a novel photodynamic therapy (PDT)-matrix drug delivery system for cholangiocarcinoma (CCA). Metallic stents were coated with polyurethane (PU) as the first layer. A 2-hydroxyethyl methacrylate (2-HEMA)/ethylene glycol dimethacrylate (EGDMA)/benzoyl peroxide (BPO) layer and a poly(ethylene-co-vinyl acetate) (PEVA)/poly(n-butyl methacrylate) (PBMA)/polyvinylpyrrolidone K30 (K30) layer containing various concentrations of Photofrin were then incorporated onto the stent as the second and third layers. After incubating the layered membranes with cultured CCA cell line, the release of Photofrin, cell viability, the intracellular uptake of Photofrin, reactive oxygen species (ROS) generation, and apoptosis were determined. Using a single-layer diffusion model, the maximum release of Photofrin from the 5 to 10% K30 formulas was 80 and 100%, respectively, after 24 h. When using the multiple-layer diffusion model, the released Photofrin showed an initial burst of the loading dose from the PEVA/PBMA/K30 layer. In the immobilized model, less than 5% of the Photofrin from the 2-HEMA/EGDMA/BPO layer was released over the 24-h period. Cell viability decreased linearly with increasing Photofrin concentrations, and ROS generation and apoptosis were shown to increase significantly with increasing Photofrin concentrations, until the concentration of Photofrin reached a saturation point of 1.5 μg/ml. This new, multiple-layered, PDT-based stent with dual-release mechanisms is a promising treatment for CCA and cancer-related ductal stenosis.
Topics: Antineoplastic Agents; Apoptosis; Bile Duct Neoplasms; Cell Line, Tumor; Cholangiocarcinoma; Dihematoporphyrin Ether; Drug Delivery Systems; Drug Liberation; Drug-Eluting Stents; Humans; Methacrylates; Photochemotherapy; Polymethacrylic Acids; Polyvinyls; Reactive Oxygen Species
PubMed: 29164403
DOI: 10.1007/s10544-017-0249-1 -
Scandinavian Journal of Gastroenterology May 2018Photodynamic therapy (PDT) was used as therapy for early neoplasia associated with Barrett's oesophagus (BE). This is 5-year follow-up of patients enrolled into... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Photodynamic therapy (PDT) was used as therapy for early neoplasia associated with Barrett's oesophagus (BE). This is 5-year follow-up of patients enrolled into randomised controlled trial of 5-aminolaevulinic acid (ALA) vs. Photofrin PDT.
METHODS
Biopsies were taken from original Barrett's segment during endoscopic follow up using Seattle protocol. Endoscopic mucosal resection (EMR) ± radiofrequency ablation (RFA) was preferred therapy in patients who failed PDT and/or had recurrent neoplasia.
RESULTS
Fifty eight of 64 patients enrolled in the original trial were followed up including 31 patients treated with ALA PDT (17 patients with ≤6 cm, 14 patients with >6 cm segment of BE) and 27 treated with Photofrin PDT (14 patients with ≤6 cm, 13 patients with >6 cm BE). Initial success was achieved in 65% (20/31) ALA and 48% (13/27) Photofrin patients (p = .289). Thirty five percent patients (7/20) relapsed in ALA group and 54% (7/13) relapsed in Photofrin group (p = .472). At a median follow-up of 67 months, no significant difference was found in long-term complete reversal of intestinal metaplasia (CR-IM) and complete reversal of dysplasia (CR-D) between ALA and Photofrin groups (78% vs. 63%; p = .18; 90% vs. 76%; p = .26). Original length of BE did not alter long-term outcome. Four patients from each group progressed to invasive oesophageal adenocarcinoma. Initial success of ALA PDT was associated with significantly better likelihood of long-term remission (p = .03).
CONCLUSIONS
Initial response to PDT plays key role in long term outcome. RFA ± EMR have, however, become preferred minimally invasive ablative therapy for BE-related neoplasia due to poor efficacy of PDT.
Topics: Adenocarcinoma; Adult; Aged; Aminolevulinic Acid; Barrett Esophagus; Catheter Ablation; Dihematoporphyrin Ether; Disease Progression; Endoscopic Mucosal Resection; Esophageal Neoplasms; Female; Humans; Hyperplasia; Kaplan-Meier Estimate; Male; Metaplasia; Middle Aged; Neoplasm Recurrence, Local; Photochemotherapy; Remission Induction; Treatment Outcome
PubMed: 29161901
DOI: 10.1080/00365521.2017.1403646