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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 -
Physics in Medicine and Biology Dec 2017Photosensitizer fluorescence excited by photodynamic therapy (PDT) treatment light can be used to monitor the in vivo concentration of the photosensitizer and its...
Photosensitizer fluorescence excited by photodynamic therapy (PDT) treatment light can be used to monitor the in vivo concentration of the photosensitizer and its photobleaching. The temporal integral of the product of in vivo photosensitizer concentration and light fluence is called PDT dose, which is an important dosimetry quantity for PDT. However, the detected photosensitizer fluorescence may be distorted by variations in the absorption and scattering of both excitation and fluorescence light in tissue. Therefore, correction of the measured fluorescence for distortion due to variable optical properties is required for absolute quantification of photosensitizer concentration. In this study, we have developed a four-channel PDT dose dosimetry system to simultaneously acquire light dosimetry and photosensitizer fluorescence data. We measured PDT dose at four sites in the pleural cavity during pleural PDT. We have determined an empirical optical property correction function using Monte Carlo simulations of fluorescence for a range of physiologically relevant tissue optical properties. Parameters of the optical property correction function for Photofrin fluorescence were determined experimentally using tissue-simulating phantoms. In vivo measurements of photosensitizer fluorescence showed negligible photobleaching of Photofrin during the PDT treatment, but large intra- and inter-patient heterogeneities of in vivo Photofrin concentration are observed. PDT doses delivered to 22 sites in the pleural cavity of 8 patients were different by 2.9 times intra-patient and 8.3 times inter-patient.
Topics: Clinical Trials, Phase II as Topic; Dihematoporphyrin Ether; Fluorescence; Humans; Mesothelioma; Monte Carlo Method; Phantoms, Imaging; Photochemotherapy; Photosensitizing Agents; Pleural Neoplasms; Radiometry; Randomized Controlled Trials as Topic; Spectrometry, Fluorescence
PubMed: 29106380
DOI: 10.1088/1361-6560/aa9874 -
Journal of Biomedical Optics Jan 2024Photodynamic therapy (PDT) is an established cancer treatment utilizing light-activated photosensitizers (PS). Effective treatment hinges on the PDT dose-dependent on PS...
SIGNIFICANCE
Photodynamic therapy (PDT) is an established cancer treatment utilizing light-activated photosensitizers (PS). Effective treatment hinges on the PDT dose-dependent on PS concentration and light fluence-delivered over time. We introduce an innovative eight-channel PDT dose dosimetry system capable of concurrently measuring light fluence and PS concentration during treatment.
AIM
We aim to develop and evaluate an eight-channel PDT dose dosimetry system for simultaneous measurement of light fluence and PS concentration. By addressing uncertainties due to tissue variations, the system enhances accurate PDT dosimetry for improved treatment outcomes.
APPROACH
The study positions eight isotropic detectors strategically within the pleural cavity before PDT. These detectors are linked to bifurcated fibers, distributing signals to both a photodiode and a spectrometer. Calibration techniques are applied to counter tissue-related variations and improve measurement accuracy. The fluorescence signal is normalized using the measured light fluence, compensating for variations in tissue properties. Measurements were taken in 78 sites in the pleural cavities of 20 patients.
RESULTS
Observations reveal minimal Photofrin concentration variation during PDT at each site, juxtaposed with significant intra- and inter-patient heterogeneities. Across 78 treated sites in 20 patients, the average Photofrin concentration for all 78 sites is , with a median concentration of . The average PDT dose for all 78 sites is , with a median dose of . A significant variation in PDT doses is observed, with a maximum difference of 3.1 times among all sites within one patient and a maximum difference of 9.8 times across all patients.
CONCLUSIONS
The introduced eight-channel PDT dose dosimetry system serves as a valuable real-time monitoring tool for light fluence and PS concentration during PDT. Its ability to mitigate uncertainties arising from tissue properties enhances dosimetry accuracy, thus optimizing treatment outcomes and bolstering the effectiveness of PDT in cancer therapy.
Topics: Humans; Dihematoporphyrin Ether; Photochemotherapy; Photosensitizing Agents; Radiometry
PubMed: 38223299
DOI: 10.1117/1.JBO.29.1.018001 -
Journal of Medicinal Chemistry Sep 2014Two Ru(II) polypyridyl complexes, Ru(DIP)2(bdt) (1) and [Ru(dqpCO2Me)(ptpy)](2+) (2) (DIP = 4,7-diphenyl-1,10-phenanthroline, bdt = 1,2-benzenedithiolate, dqpCO2Me =...
Two Ru(II) polypyridyl complexes, Ru(DIP)2(bdt) (1) and [Ru(dqpCO2Me)(ptpy)](2+) (2) (DIP = 4,7-diphenyl-1,10-phenanthroline, bdt = 1,2-benzenedithiolate, dqpCO2Me = 4-methylcarboxy-2,6-di(quinolin-8-yl)pyridine), ptpy = 4'-phenyl-2,2':6',2″-terpyridine) have been investigated as photosensitizers (PSs) for photodynamic therapy (PDT). In our experimental settings, the phototoxicity and phototoxic index (PI) of 2 (IC50(light): 25.3 μM, 420 nm, 6.95 J/cm(2); PI >4) and particularly of 1 (IC50(light): 0.62 μM, 420 nm, 6.95 J/cm(2); PI: 80) are considerably superior compared to the two clinically approved PSs porfimer sodium and 5-aminolevulinic acid. Cellular uptake and distribution of these complexes was investigated by confocal microscopy (1) and by inductively coupled plasma mass spectrometry (1 and 2). Their phototoxicity was also determined against the Gram-(+) Staphylococcus aureus and Gram-(-) Escherichia coli for potential antimicrobial PDT (aPDT) applications. Both complexes showed significant aPDT activity (420 nm, 8 J/cm(2)) against Gram-(+) (S. aureus; >6 log10 CFU reduction) and, for 2, also against Gram-(-) E. coli (>4 log10 CFU reduction).
Topics: Cell Line; Cell Survival; Coordination Complexes; Escherichia coli; HeLa Cells; Humans; Light; Microbial Viability; Microscopy, Confocal; Models, Chemical; Molecular Structure; Photochemotherapy; Photosensitizing Agents; Ruthenium; Staphylococcus aureus
PubMed: 25121347
DOI: 10.1021/jm500566f -
Japanese Journal of Cancer Research :... Nov 1993Photodynamic therapy utilizing Photofrin has proven to be an effective modality that can be used in the treatment of a wide variety of solid tumors and luminal cancers.... (Clinical Trial)
Clinical Trial
Photodynamic therapy utilizing Photofrin has proven to be an effective modality that can be used in the treatment of a wide variety of solid tumors and luminal cancers. An argon pumped dye laser or excimer dye laser was used to deliver 630 nm light via quartz fibers passed through the biopsy channel subsequent to i.v. injection of photosensitizer. In this study, 64 patients with superficial cancers were treated in this manner but only 58 patients, including 21 with roentgenographically occult lung cancer, 8 with stage I lung cancer, 5 with esophageal cancer, 12 with gastric cancer, 8 with cervical cancer and 4 with bladder cancer were evaluable. Complete remission was obtained in 48 out of 58 cases (82.8%). There was no serious complication except skin photosensitivity, which was seen in 13 patients. We conclude that photodynamic therapy is efficacious in the treatment of superficial cancers where complete remission may be achieved.
Topics: Adult; Aged; Dihematoporphyrin Ether; Female; Hematoporphyrin Derivative; Humans; Japan; Male; Middle Aged; Neoplasms; Photochemotherapy
PubMed: 8276725
DOI: 10.1111/j.1349-7006.1993.tb02823.x -
International Journal of Molecular... Feb 2015Photodynamic therapy (PDT) is an effective local treatment modality as a cancer-specific laser ablation in malignancy of some organs including digestive tracts or bile...
Photodynamic therapy (PDT) is an effective local treatment modality as a cancer-specific laser ablation in malignancy of some organs including digestive tracts or bile duct. In Japan, PDT has been applied at the early period after the first clinical induction in 1980's. Although the useful efficacy was clarified, PDT has not been fully applied because of the phototoxicity of the porfimer sodium. The next generated talaporfin-sodium was used for PDT, in which phototoxicity was reduced and, however, the clinical efficacy for digestive tract malignancy has not yet been clarified. By proceeding the experimental and clinical trials, it is necessary to clarify the evidence of efficacy as a local powerful treatment with the conventional surgery, brachiotherapy and chemotherapy in the future step.
Topics: Carcinoma; Dihematoporphyrin Ether; Endoscopy, Gastrointestinal; Gastrointestinal Neoplasms; Humans; Japan; Lasers; Photochemotherapy; Photosensitizing Agents; Porphyrins
PubMed: 25690028
DOI: 10.3390/ijms16023434 -
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 -
World Journal of Gastroenterology Nov 2013To compare effectiveness, safety, and cost of photodynamic therapy (PDT) and radiofrequency ablation (RFA) in treatment of Barrett's dysplasia (BD). (Comparative Study)
Comparative Study
AIM
To compare effectiveness, safety, and cost of photodynamic therapy (PDT) and radiofrequency ablation (RFA) in treatment of Barrett's dysplasia (BD).
METHODS
Consecutive case series of patients undergoing either PDT or RFA treatment at single center by a single investigator were compared. Thirty-three patients with high-grade dysplasia (HGD) had treatment with porfimer sodium photosensitzer and 630 nm laser (130 J/cm), with maximum of 3 treatment sessions. Fifty-three patients with BD (47 with low-grade dysplasia -LGD, 6 with HGD) had step-wise circumferential and focal ablation using the HALO system with maximum of 4 treatment sessions. Both groups received proton pump inhibitors twice daily. Endoscopic biopsies were acquired at 2 and 12 mo after enrollment, with 4-quadrant biopsies every 1 cm of the original BE extent. A complete histological resolution response of BD (CR-D) was defined as all biopsies at the last endoscopy session negative for BD. Fisher's exact test was used to assess differences between the two study groups for primary outcomes. For all outcomes, a two-sided P value of less than 0.05 was considered to indicate statistical significance.
RESULTS
Thirty (91%) PDT patients and 39 (74%) RFA were men (P = 0.05). The mean age was 70.7 ± 12.2 and 65.4 ± 12.7 (P = 0.10) year and mean length of BE was 5.4 ± 3.2 cm and 5.7 ± 3.2 cm (P = 0.53) for PDT and RFA patients, respectively. The CR-D was (18/33) 54.5% with PDT vs (47/53) 88.7% with RFA (P = 0.001). One patient with PDT had an esophageal perforation and was managed with non-surgical measures and no perforation was seen with RFA. PDT was five times more costly than RFA at our institution. The two groups were not randomized and had different BD grading are the limitations of the study.
CONCLUSION
In our experience, RFA had higher rate of CR-D without any serious adverse events and was less costly than PDT for endoscopic treatment of BD.
Topics: Aged; Aged, 80 and over; Barrett Esophagus; Biopsy; Catheter Ablation; Cost Savings; Cost-Benefit Analysis; Dihematoporphyrin Ether; Drug Administration Schedule; Drug Costs; Female; Health Care Costs; Humans; Male; Middle Aged; Photochemotherapy; Photosensitizing Agents; Proton Pump Inhibitors; Retrospective Studies; Texas; Time Factors; Treatment Outcome
PubMed: 24222954
DOI: 10.3748/wjg.v19.i41.7106 -
World Journal of Gastroenterology Oct 2012To evaluate the effect of photodynamic therapy (PDT) on metal stent patency in patients with unresectable hilar cholangiocarcinoma (CC).
AIM
To evaluate the effect of photodynamic therapy (PDT) on metal stent patency in patients with unresectable hilar cholangiocarcinoma (CC).
METHODS
This was a retrospective analysis of patients with hilar CC referred to our institution from December, 1999 to January, 2011. Out of 232 patients, thirty-three patients with unresectable hilar CC were treated. Eighteen patients in the PDT group were treated with uncovered metal stents after one session of PDT. Fifteen patients in the control group were treated with metal stents alone. Porfimer sodium (2 mg/kg) was administered intravenously to PDT patients. Forty-eight hours later, PDT was administered using a diffusing fiber that was advanced across the tumor by either endoscopic retrograde cholangiopancreatography or percutaneous cholangiography. After performance of PDT, uncovered metal stents were inserted to ensure adequate decompression and bile drainage. Patient survival rates and cumulative stent patency were calculated using Kaplan-Meier analysis with the log-rank test.
RESULTS
The PDT and control patients were comparable with respect to age, gender, health status, pre-treatment bilirubin, and hilar CC stage. When compared to control, the PDT group was associated with significantly prolonged stent patency (median 244 ± 66 and 177 ± 45 d, respectively, P = 0.002) and longer patient survival (median 356 ± 213 and 230 ± 73 d, respectively, P = 0.006). Early complication rates were similar between the groups (PDT group 17%, control group 13%) and all patients were treated conservatively. Stent malfunctions occurred in 14 PDT patients (78%) and 12 control patients (80%). Of these 26 patients, twenty-two were treated endoscopically and four were treated with external drainage.
CONCLUSION
Metal stenting after one session of PDT may be safe with acceptable complication rates. The PDT group was associated with a significantly longer stent patency than the control group in patients with unresectable hilar CC.
Topics: Adult; Aged; Aged, 80 and over; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Endoscopy; Female; Humans; Male; Middle Aged; Photochemotherapy; Republic of Korea; Retrospective Studies; Stents
PubMed: 23112552
DOI: 10.3748/wjg.v18.i39.5589 -
Photochemistry and Photobiology Mar 2020Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical...
Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical PDT. Tissue oxygen, however, is not routinely monitored intraoperatively even though it is one of the three major components of treatment. Quantitative information about in vivo tissue oxygenation during PDT is desirable, because it enables reactive oxygen species explicit dosimetry (ROSED) for prediction of treatment outcome based on PDT-induced changes in tumor oxygen level. Here, we demonstrate ROSED in a clinical setting, Photofrin-mediated pleural photodynamic therapy, by utilizing tumor blood flow information measured by diffuse correlation spectroscopy (DCS). A DCS contact probe was sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (blood flow index) during intraoperative PDT treatment. Isotropic detectors were used to measure treatment light fluence and photosensitizer concentration. Blood-flow-derived tumor oxygen concentration, estimated by applying a preclinically determined conversion factor of 1.5 × 10 μMs cm to the blood flow index, was used in the ROSED model to calculate the total reacted reactive oxygen species [ROS]rx. Seven patients and 12 different pleural sites were assessed and large inter- and intrapatient heterogeneities in [ROS]rx were observed although an identical light dose of 60 J cm was prescribed to all patients.
Topics: Animals; Dihematoporphyrin Ether; Humans; Mice; Photochemotherapy; Photosensitizing Agents; Pleural Neoplasms; Reactive Oxygen Species; Xenograft Model Antitumor Assays
PubMed: 31729774
DOI: 10.1111/php.13176