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Lasers in Surgery and Medicine Sep 2011Photodynamic therapy (PDT) with porfimer sodium, FDA approved to treat premalignant lesions in Barrett's esophagus, causes photosensitivity for 6-8 weeks. HPPH... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Photodynamic therapy (PDT) with porfimer sodium, FDA approved to treat premalignant lesions in Barrett's esophagus, causes photosensitivity for 6-8 weeks. HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) shows minimal photosensitization of short duration and promising efficacy in preclinical studies. Here we explore toxicity and optimal drug and light dose with endoscopic HPPH-PDT. We also want to know the efficacy of one time treatment with HPPH-PDT.
STUDY DESIGN/MATERIALS AND METHODS
Two nonrandomized dose escalation studies were performed (18 patients each) with biopsy-proven high grade dysplasia or early intramucosal adenocarcinoma of esophagus. HPPH doses ranged from 3 to 6 mg/m2 . At 24 or 48 hours after HPPH administration the lesions received one endoscopic exposure to 150, 175, or 200 J/cm of 665 nm light.
RESULTS
Most patients experienced mild to moderate chest pain requiring symptomatic treatment only. Six patients experienced grade 3 and 4 adverse events (16.6%). Three esophageal strictures were treated with dilatation. No clear pattern of dose dependence of toxicities emerged. In the drug dose ranging study (light dose of 150 J/cm at 48 hours), 3 and 4 mg/m2 of HPPH emerged as most effective. In the light dose ranging study (3 or 4 mg/m2 HPPH, light at 24 hours), complete response rates (disappearance of high grade dysplasia and early carcinoma) of 72% were achieved at 1 year, with all patients treated with 3 mg/m2 HPPH plus 175 J/cm and 4 mg/m2 HPPH plus 150 J/cm showing complete responses at 1 year.
CONCLUSIONS
HPPH-PDT for precancerous lesions in Barrett's esophagus appears to be safe and showing promising efficacy. Further clinical studies are required to establish the use of HPPH-PDT.
Topics: Adenocarcinoma; Aged; Aged, 80 and over; Barrett Esophagus; Chlorophyll; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Administration Schedule; Esophageal Neoplasms; Esophagoscopy; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Photochemotherapy; Photosensitizing Agents; Precancerous Conditions; Treatment Outcome
PubMed: 22057498
DOI: 10.1002/lsm.21112 -
O determined from the measured PDT dose and O predicts long-term response to Photofrin-mediated PDT.Physics in Medicine and Biology Jan 2020Photodynamic therapy (PDT) that employs the photochemical interaction of light, photosensitizer and oxygen is an established modality for the treatment of cancer....
Photodynamic therapy (PDT) that employs the photochemical interaction of light, photosensitizer and oxygen is an established modality for the treatment of cancer. However, dosimetry for PDT is becoming increasingly complex due to the heterogeneous photosensitizer uptake by the tumor, and complicated relationship between the tissue oxygenation ([O]), interstitial light distribution, photosensitizer photobleaching and PDT effect. As a result, experts argue that the failure to realize PDT's true potential is, at least partly due to the complexity of the dosimetry problem. In this study, we examine the efficacy of singlet oxygen explicit dosimetry (SOED) based on the measurements of the interstitial light fluence rate distribution, changes of [O] and photosensitizer concentration during Photofrin-mediated PDT to predict long-term control rates of radiation-induced fibrosarcoma tumors. We further show how variation in tissue [O] between animals induces variation in the treatment response for the same PDT protocol. PDT was performed with 5 mg kg Photofrin (a drug-light interval of 24 h), in-air fluence rates (ϕ ) of 50 and 75 mW cm and in-air fluences from 225 to 540 J cm. The tumor regrowth was tracked for 90 d after the treatment and Kaplan-Meier analyses for local control rate were performed based on a tumor volume ⩽100 mm for the two dosimetry quantities of PDT dose and SOED. Based on the results, SOED allowed for reduced subject variation and improved treatment evaluation as compared to the PDT dose.
Topics: Animals; Dihematoporphyrin Ether; Female; Fibrosarcoma; Mice; Mice, Inbred C3H; Neoplasms, Radiation-Induced; Oxygen; Photobleaching; Photochemotherapy; Photosensitizing Agents; Radiometry; Singlet Oxygen
PubMed: 31751964
DOI: 10.1088/1361-6560/ab59f1 -
British Journal of Cancer Nov 2018Currently delivered light dose (J/cm) is the principal parameter guiding interstitial photodynamic therapy (I-PDT) of refractory locally advanced cancer. The aim of this...
BACKGROUND
Currently delivered light dose (J/cm) is the principal parameter guiding interstitial photodynamic therapy (I-PDT) of refractory locally advanced cancer. The aim of this study was to investigate the impact of light dose rate (irradiance, mW/cm) and associated heating on tumour response and cure.
METHODS
Finite-element modeling was used to compute intratumoural irradiance and dose to guide Photofrin I-PDT in locally advanced SCCVII in C3H mice and large VX2 neck tumours in New Zealand White rabbits. Light-induced tissue heating in mice was studied with real-time magnetic resonance thermometry.
RESULTS
In the mouse model, cure rates of 70-90% were obtained with I-PDT using 8.4-245 mW/cm and ≥45 J/cm in 100% of the SCCVII tumour. Increasing irradiance was associated with increase in tissue heating. I-PDT with Photofrin resulted in significantly (p < 0.05) higher cure rate compared to light delivery alone at same irradiance and light dose. Local control and/or cures of VX2 were obtained using I-PDT with 16.5-398 mW/cm and ≥45 J/cm in 100% of the tumour.
CONCLUSION
In Photofrin-mediated I-PDT, a selected range of irradiance prompts effective photoreaction with tissue heating in the treatment of locally advanced mouse tumour. These irradiances were translated for effective local control of large VX2 tumours.
Topics: Animals; Carcinoma, Squamous Cell; Dihematoporphyrin Ether; Female; Hot Temperature; Mice; Mice, Inbred C3H; Neoplasms, Experimental; Photochemotherapy; Photosensitizing Agents; Rabbits; Thermometry
PubMed: 30353043
DOI: 10.1038/s41416-018-0210-y -
Folia Biologica 2007Compared to current treatments including surgery, radiation therapy, and chemotherapy, PDT offers the advantage of an effective and selective method of destroying...
Compared to current treatments including surgery, radiation therapy, and chemotherapy, PDT offers the advantage of an effective and selective method of destroying diseased tissues without damaging surrounding healthy tissues. One of the aspects of antitumour effectiveness of PDT is related to the distribution of photosensitizing drugs. The localization of photosensitizers in cytoplasmic organelles during PDT plays a major role in the cell destruction; therefore, intracellular localization of Ph in malignant and normal cells was investigated. The cell lines used throughout the study were: human malignant A549, MCF-7, Me45 and normal endothelial cell line HUV-EC-C. After incubation with Ph cells were examined using fluorescence and confocal microscopy to visualize the photosensitizer accumulation. For cytoplasm and mitochondria identification, cells were stained with CellTracker Green and MitoTracker Green, respectively. Distribution of Ph was different in malignant and normal cells and dependent on the incubation time. The maximal concentration of Ph in two malignant cell lines (A549 and MCF-7) was observed after 4 hours of incubation, and the most intensive signal was observed around the nuclear envelope. Intracellular distribution of Ph in the Me45 cell line showed that the fluorescence emitted by Ph overlaid that from MitoTracker. This indicates preferential accumulation of the sensitizer in mitochondria. Our results based on the mitochondrial localization support the idea that PDT can contribute to elimination of malignant cells by inducing apoptosis, which is of physiological significance.
Topics: Adult; Aged; Biological Transport; Dihematoporphyrin Ether; Endothelial Cells; Female; Humans; Male; Microscopy, Confocal; Microscopy, Fluorescence; Middle Aged; Neoplasms; Tumor Cells, Cultured
PubMed: 17328837
DOI: No ID Found -
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 -
Immunology Feb 2011Two cationic porphyrins bearing an isothiocyanate group for conjugation to monocolonal antibodies have been synthesized. The two porphyrins conjugated efficiently to...
Two cationic porphyrins bearing an isothiocyanate group for conjugation to monocolonal antibodies have been synthesized. The two porphyrins conjugated efficiently to three monoclonal antibodies (anti-CD104, anti-CD146 and anti-CD326), which recognize antigens commonly over-expressed on a range of tumour cells. In vitro, all conjugates retained the phototoxicity of the porphyrin and the immunoreactivity of the antibody. Mechanistic studies showed that conjugates formed from the mono- and tri-cationic porphyrin and anti-CD104 antibody mediated apoptosis following irradiation with non-thermal red light of 630 ± 15 nm wavelength. In vivo antibody conjugates caused suppression of human LoVo tumour growth in immunodeficient NIH III mice, similar to the commercial photodynamic therapy (PDT) agent Photofrin, but at administered photosensitizer doses that were more than two orders of magnitude lower. Positron emission tomography (PET) following PDT showed a large, early increase in uptake of (18) fluorodeoxyglucose (FDG) by tumours treated with the anti-CD104 conjugates. This effect was not observed with Photofrin or with conjugates formed from the same photosensitizers conjugated to an irrelevant antibody.
Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Colonic Neoplasms; Dihematoporphyrin Ether; Humans; Immunoconjugates; Immunotherapy; Integrin beta4; Isothiocyanates; Light; Mice; Photochemotherapy; Photosensitizing Agents; Porphyrins; Treatment Outcome
PubMed: 21039468
DOI: 10.1111/j.1365-2567.2010.03359.x -
Glioma stem-like cells are less susceptible than glioma cells to sonodynamic therapy with photofrin.Technology in Cancer Research &... Dec 2012Despite remarkable progress in diagnosis and treatment, malignant glioma, a highly lethal cancer of the central nervous system, remains incurable. Although glioma...
Despite remarkable progress in diagnosis and treatment, malignant glioma, a highly lethal cancer of the central nervous system, remains incurable. Although glioma stem-like cells (GSCs) represent a relatively small fraction of the cells in malignant glioma, they can proliferate and self renew extensively, being crucial for tumor recurrence. Cancer treatment by sonodynamic therapy (SDT) chiefly depends on antitumor effects of reactive oxygen species (ROS) generated from a sonosensitizer activated by ultrasound. Although SDT effectively kills glioma cells, its efficiency against GSCs is not established. We attempted to compare the susceptibility of GSCs to SDT, using Photofrin, a porphyrin-derivative photosensitizer, with that of glioma cells. Cell viability and apoptosis assays showed that SDT damaged both GSCs and U251 glioma cells, but GSCs were significantly less susceptible to SDT (p < 0.01). To elucidate the mechanism of the antitumor effects of SDT, we evaluated intracellular ROS production and Photofrin uptake: ROS production and Photofrin content were significantly lower (p < 0.01) in GSCs than in U251 glioma cells. Thus, cellular differences in sonosensitizer uptake and ROS production influence the antitumor effects of SDT. Furthermore, the resistance of GSCs may be caused by decreased sonosensitizer uptake due to ABCG2 overexpression.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Dihematoporphyrin Ether; Glioma; Humans; Neoplasm Proteins; Neoplastic Stem Cells; Reactive Oxygen Species; Sound; Spheroids, Cellular; Tumor Cells, Cultured
PubMed: 22775340
DOI: 10.7785/tcrt.2012.500277 -
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 -
Lasers in Surgery and Medicine Mar 2011Bacterial arthritis does not respond well to antibiotics and moreover multidrug resistance is spreading. We previously tested photodynamic therapy (PDT) mediated by...
BACKGROUND AND OBJECTIVE
Bacterial arthritis does not respond well to antibiotics and moreover multidrug resistance is spreading. We previously tested photodynamic therapy (PDT) mediated by systemic Photofrin® in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) arthritis, but found that neutrophils were killed by PDT and therefore the infection was potentiated.
STUDY DESIGN/MATERIALS AND METHODS
The present study used an intra-articular injection of Photofrin® and optimized the light dosimetry in order to maximize bacterial killing and minimize killing of host neutrophils. MRSA (5 × 10(7) CFU) was injected into the mouse knee followed 3 days later by 1 µg of Photofrin® and 635-nm diode laser illumination with a range of fluences within 5 minutes. Synovial fluid was sampled 6 hours or 1-3, 5, and 7 days after PDT to determine MRSA colony-forming units (CFU), neutrophil numbers, and levels of cytokines.
RESULTS
A biphasic light dose response was observed with the greatest reduction of MRSA CFU seen with a fluence of 20 J cm(-2), whereas lower antibacterial efficacy was observed with fluences that were either lower or higher. Consistent with these results, a significantly higher concentration of macrophage inflammatory protein-2, a CXC chemokine, and greater accumulation of neutrophils were seen in the infected knee joint after PDT with a fluence of 20 J cm(-2) compared to fluences of 5 or 70 J cm(-2).
CONCLUSION
PDT for murine MRSA arthritis requires appropriate light dosimetry to simultaneously maximize bacterial killing and neutrophil accumulation into the infected site, while too little light does not kill sufficient bacteria and too much light kills neutrophils and damages host tissue as well as bacteria and allows bacteria to grow unimpeded by host defense.
Topics: Animals; Arthritis, Experimental; Arthritis, Infectious; Dihematoporphyrin Ether; Dose-Response Relationship, Radiation; Drug Administration Schedule; Hematoporphyrin Photoradiation; Injections, Intra-Articular; Knee Joint; Lasers, Semiconductor; Leukocytes; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Neutrophils; Photosensitizing Agents; Staphylococcal Infections; Synovial Fluid
PubMed: 21412806
DOI: 10.1002/lsm.21037 -
PloS One 2012Treatment failure at the primary site after chemoradiotherapy is a major problem in achieving a complete response. Photodynamic therapy (PDT) with porfimer sodium...
BACKGROUND
Treatment failure at the primary site after chemoradiotherapy is a major problem in achieving a complete response. Photodynamic therapy (PDT) with porfimer sodium (Photofrin®) has some problems such as the requirement for shielding from light for several weeks and a high incidence of skin phototoxicity. PDT with talaporfin sodium (Laserphyrin) is less toxic and is expected to have a better effect compared with Photofrin PDT. However, Laserphyrin PDT is not approved for use in the esophagus. In this preclinical study, we investigated tissue damage of the canine normal esophagus caused by photoactivation with Laserphyrin.
METHODOLOGY/PRINCIPAL FINDINGS
Diode laser irradiation was performed at 60 min after administration. An area 5 cm oral to the esophagogastric junction was irradiated at 25 J/cm(2), 50 J/cm(2), and 100 J/cm(2) using a three-step escalation. The irradiated areas were evaluated endoscopically on postirradiation days 1 and 7, and were subjected to histological examination after autopsy. The areas injured by photoactivation were 52 mm(2), 498 mm(2), and 831 mm(2) after irradiation at 25 J/cm(2), 50 J/cm(2), and 100 J/cm(2), respectively. Tissue injury was observed in the muscle layer or even deeper at any irradiation level and became more severe as the irradiation dose increased. At 100 J/cm(2) both inflammatory changes and necrosis were seen histologically in extra-adventitial tissue.
CONCLUSIONS/SIGNIFICANCE
To minimize injury of the normal esophagus by photoactivation with Laserphyrin, diode laser irradiation at 25 J/cm(2) appears to be safe. For human application, it would be desirable to investigate the optimal laser dose starting from this level.
Topics: Animals; Dogs; Drug Evaluation, Preclinical; Esophagus; Photochemotherapy; Photosensitizing Agents; Porphyrins
PubMed: 22719875
DOI: 10.1371/journal.pone.0038308