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Lasers in Surgery and Medicine Mar 2019Photodynamic therapy (PDT) has been widely used to treat malignant tumors. Our previous studies indicated that connexin (Cx) 32- and Cx26-composed gap junctional...
BACKGROUND AND OBJECTIVE
Photodynamic therapy (PDT) has been widely used to treat malignant tumors. Our previous studies indicated that connexin (Cx) 32- and Cx26-composed gap junctional intercellular communication (GJIC) could improve the phototoxicity of PDT. However, the role of heterotypic Cx32/Cx26-formed GJIC in PDT phototoxicity is still unknown. Thus, the present study was aimed to investigate the effect of Cx32/Cx26-formed GJIC on PDT efficacy.
METHODS
CCK8 assay was used to detect cell survival after PDT. Western blot assay was utilized to detect Cx32/Cx26 expression. "Parachute" dye-coupling assay was performed to measure the function of GJ channels. The intracellular Ca concentrations were determined using flow cytometer. ELISA assay was performed to detect the intracellular levels of PGE and cAMP.
RESULTS
The present study demonstrates there is a Cx32/Cx26-formed GJIC-dependent reduction of phototoxicity when cells were exposure to low concentration of Photofrin. Such a protective action is missing at low cell density due to the lack of GJ coupling. Under high-cell density condition, where there is opportunity for the cells to contact each other and form GJ, suppressing Cx32/Cx26-formed GJIC by either inhibiting the expression of Cx32/Cx26 or pretreating with GJ channel inhibitor augments PDT phototoxicity after cells were treated with at 2.5 µg/ml Photofrin. The above results suggest that at low Photofrin concentration, the presence of Cx32/Cx26-formed GJIC may decrease the phototoxicity of PDT, leading to the insensitivity of malignant cells to PDT treatment. The GJIC-mediated PDT insensitivity was associated with Ca and prostaglandin E (PGE ) signaling pathways.
CONCLUSION
The present study provides a cautionary note that for tumors expressing Cx32/Cx26, the presence of Cx32/Cx26-composed GJIC may cause the resistance of tumor cells to PDT. Oppositely, treatment strategies designed to downregulate the expression of Cx32/Cx26 or restrain the function of Cx32/Cx26-mediated GJIC may increase the sensitivity of malignant cell to PDT. Lasers Surg. Med. 51:301-308, 2019. © 2019 Wiley Periodicals, Inc.
Topics: Cell Communication; Cell Culture Techniques; Cell Survival; Connexin 26; Connexins; Dihematoporphyrin Ether; Gap Junctions; HeLa Cells; Humans; Photochemotherapy; Photosensitizing Agents; Gap Junction beta-1 Protein
PubMed: 30615224
DOI: 10.1002/lsm.23044 -
Photochemistry and Photobiology Jan 2019Malignant pleural mesothelioma remains difficult to treat, with high failure rates despite optimal therapy. We present a novel prospective trial combining proton therapy...
A Novel Prospective Study Assessing the Combination of Photodynamic Therapy and Proton Radiation Therapy: Safety and Outcomes When Treating Malignant Pleural Mesothelioma.
Malignant pleural mesothelioma remains difficult to treat, with high failure rates despite optimal therapy. We present a novel prospective trial combining proton therapy (PT) and photodynamic therapy (PDT) and the largest-ever mesothelioma PT experience (n = 10). PDT photosensitizers included porfimer sodium (2 mg·kg ; 24 h drug-light interval) or 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) (4 mg·m ;48 h) with wavelengths of 630 nm to 60J·cm and 665 nm to 15-45J·cm , respectively. With a median age of 69 years, patients were predominantly male (90%) with epithelioid histology (100%) and stage III-IV disease (100%). PT was delivered to a median of 55.0 CGE/1.8-2.0 CGE (range 50-75 CGE) adjuvantly (n = 8) or as salvage therapy (n = 2) following extended pleurectomy/decortication (ePD)/PDT. Two-year local control was 90%, with distant and regional failure rates of 50% and 30%, respectively. All patients received chemotherapy, and four received immunotherapy. Surgical complications included atrial fibrillation (n = 3), pneumonia (n = 2), and deep vein thrombosis (n = 2). Median survival from PT completion was 19.5 months (30.3 months from diagnosis), and 1- and 2-year survival rates were 58% and 29%. No patient experienced CTCAEv4 grade ≥2 acute or late toxicity. Our prolonged survival in very advanced-stage patients compares favorably to survival for PT without PDT and photon therapy with PDT, suggesting possible spatial or systemic cooperativity and immune effect.
Topics: Aged; Aged, 80 and over; Combined Modality Therapy; Female; Humans; Male; Mesothelioma; Middle Aged; Photochemotherapy; Photosensitizing Agents; Pleural Neoplasms; Prospective Studies; Proton Therapy; Treatment Outcome
PubMed: 30485442
DOI: 10.1111/php.13065 -
Photochemistry and Photobiology Jan 2019Inflammatory cells, most especially neutrophils, can be a necessary component of the antitumor activity occurring after administration of photodynamic therapy....
Inflammatory cells, most especially neutrophils, can be a necessary component of the antitumor activity occurring after administration of photodynamic therapy. Generation of neutrophil responses has been suggested to be particularly important in instances when the delivered photodynamic therapy (PDT) dose is insufficient. In these cases, the release of neutrophil granules and engagement of antitumor immunity may play an important role in eliminating residual disease. Herein, we utilize in vivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after PDT administration. Studies were performed in the AB12 murine model of mesothelioma, treated with Photofrin-PDT. Luminol-generated chemiluminescence increased transiently 1 h after PDT, followed by a subsequent decrease at 4 h after PDT. The production of luminol signal was not associated with the influx of Ly6G cells, but was related to oxidative burst, as an indicator of neutrophil function. Most importantly, greater levels of luminol chemiluminescence 1 h after PDT were prognostic of a complete response at 90 days after PDT. Taken together, this research supports an important role for early activity by Ly6G cells in the generation of long-term PDT responses in mesothelioma, and it points to luminol chemiluminescence as a potentially useful approach for preclinical monitoring of neutrophil activation by PDT.
Topics: Animals; Biomarkers; Dihematoporphyrin Ether; Luminescence; Luminol; Mesothelioma; Mice; Mice, Inbred BALB C; Neutrophil Activation; Neutrophils; Photochemotherapy; Photosensitizing Agents; Prognosis
PubMed: 30357853
DOI: 10.1111/php.13040 -
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 -
Biomaterials Research 2018Photodynamic therapy (PDT) is photo-treatment of malignant or benign diseases using photosensitizing agents, light, and oxygen which generates cytotoxic reactive oxygens... (Review)
Review
BACKGROUND
Photodynamic therapy (PDT) is photo-treatment of malignant or benign diseases using photosensitizing agents, light, and oxygen which generates cytotoxic reactive oxygens and induces tumour regressions. Several photodynamic treatments have been extensively studied and the photosensitizers (PS) are key to their biological efficacy, while laser and oxygen allow to appropriate and flexible delivery for treatment of diseases.
INTRODUCTION
In presence of oxygen and the specific light triggering, PS is activated from its ground state into an excited singlet state, generates reactive oxygen species (ROS) and induces apoptosis of cancer tissues. Those PS can be divided by its specific efficiency of ROS generation, absorption wavelength and chemical structure.
MAIN BODY
Up to dates, several PS were approved for clinical applications or under clinical trials. Photofrin® is the first clinically approved photosensitizer for the treatment of cancer. The second generation of PS, Porfimer sodium (Photofrin®), Temoporfin (Foscan®), Motexafin lutetium, Palladium bacteriopheophorbide, Purlytin®, Verteporfin (Visudyne®), Talaporfin (Laserphyrin®) are clinically approved or under-clinical trials. Now, third generation of PS, which can dramatically improve cancer-targeting efficiency by chemical modification, nano-delivery system or antibody conjugation, are extensively studied for clinical development.
CONCLUSION
Here, we discuss up-to-date information on FDA-approved photodynamic agents, the clinical benefits of these agents. However, PDT is still dearth for the treatment of diseases in specifically deep tissue cancer. Next generation PS will be addressed in the future for PDT. We also provide clinical unmet need for the design of new photosensitizers.
PubMed: 30275968
DOI: 10.1186/s40824-018-0140-z -
Gastrointestinal Endoscopy Feb 2019Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans....
BACKGROUND AND AIMS
Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans. We hypothesized that EUS-guided PDT for LAPC is safe, technically feasible, and produces a dose- and time-dependent increasing degree of image-defined tumor necrosis.
METHODS
In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naïve LAPC received intravenous porfimer sodium (Concordia Laboratories Inc, St Michael, Barbados) followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser (Pioneer Optics, Bloomfield, Conn) and illumination with a 630-nm light (Diomed Inc, Andover, Mass). A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel (125 mg/ m intravenously) and gemcitabine (1000 mg /m intravenously) were initiated 7 days after CT and given weekly for 3 of 4 weeks (1 cycle) until disease progression or unacceptable toxicity.
RESULTS
Twelve patients (mean age, 67 ± 6 years; 8 male) with tumors (mean diameter, 45.2 ± 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. The mean overall increases in volume and percentage necrosis were 10 ± 26 cm (P = .20) and 18% ± 22% (P = .016), respectively. After a median follow-up of 10.5 months (range, 1.0-37.4 months), median progression-free (PFS) and overall survival (OS) were 2.6 months (95% confidence interval, 0.7, not estimable) and 11.5 months (95% confidence interval, 1.1, 16.9), respectively. Surgical resection was attempted in 2 patients, and pathology showed a complete response (n = 1) and residual 2-mm tumor (n = 1). There were 8 serious adverse events and none related to EUS or EUS-PDT.
CONCLUSION
EUS-PDT for LAPC appears to be safe and produces measurable imaged-defined tumor necrosis. Phase 2 studies are warranted. (Clinical trial registration number: NCT01770132.).
Topics: Aged; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Dihematoporphyrin Ether; Endosonography; Female; Humans; Male; Middle Aged; Necrosis; Paclitaxel; Pancreas; Pancreatic Neoplasms; Photochemotherapy; Prospective Studies; Tomography, X-Ray Computed; Gemcitabine
PubMed: 30222972
DOI: 10.1016/j.gie.2018.09.007 -
ESMO Open 2018Endobiliary stenting is standard practice for palliation of obstructive jaundice due to biliary tract cancer (BTC). Photodynamic therapy (PDT) may also improve biliary...
BACKGROUND
Endobiliary stenting is standard practice for palliation of obstructive jaundice due to biliary tract cancer (BTC). Photodynamic therapy (PDT) may also improve biliary drainage and previous small studies suggested survival benefit.
AIMS
To assess the difference in outcome between patients with BTC undergoing palliative stenting plus PDT versus stenting alone.
METHODS
92 patients with confirmed locally advanced or metastatic BTC, ECOG performance status 0-3 and adequate biliary drainage were randomised (46 per group) to receive porfimer sodium PDT plus stenting or stenting alone. The primary end point was overall survival (OS). Toxicity and progression-free survival (PFS) were secondary end points. Treatment arms were well balanced for baseline factors and prior therapy.
RESULTS
No significant differences in grade 3-4 toxicities and no grade 3-4 adverse events due to PDT were observed. Thirteen (28%) PDT patients and 24 (52%) stent alone patients received subsequent palliative chemotherapy. After a median follow-up of 8.4 months, OS and PFS were worse in patients receiving PDT compared with stent alone group (OS median 6.2 vs 9.8 months (HR 1.56, 95% CI 1.00 to 2.43, p=0.048) and PFS median 3.4 vs 4.3 months (HR 1.43, 95% CI: 0.93 to 2.18, p=0.10), respectively).
CONCLUSION
In patients with locally advanced or metastatic BTC, PDT was associated with worse outcome than stenting alone, explained only in part by the differences in chemotherapy treatments. We conclude that optimal stenting remains the treatment of choice for malignant biliary obstruction and the use of PDT for this indication cannot be recommended outside of clinical trials.
TRIAL REGISTRATION NUMBER
ISRCTN 87712758; EudraCT 2005-001173-96; UKCRN ID: 1461.
PubMed: 30094069
DOI: 10.1136/esmoopen-2018-000379 -
Journal of Plastic, Reconstructive &... Oct 2018The prognosis of patients suffering from malignant cutaneous neoplasms can be improved by early diagnosis. Exact demarcation of tumor margins could contribute to optimum...
OBJECTIVES
The prognosis of patients suffering from malignant cutaneous neoplasms can be improved by early diagnosis. Exact demarcation of tumor margins could contribute to optimum results in surgical excision and reconstruction. The purpose of our study is to evaluate Photofrin with a new diagnostic procedure, photodynamic diagnosis (PDD), for the detection of Bowen's disease (squamous cell carcinoma (SCC) in situ), SCC, and basal cell carcinoma (BCC).
MATERIALS AND METHODS
Sixty patients with cutaneous neoplasms received 2.5 mg/mL Photofrin solution topically. After a period of 3 hours, the patients underwent fluorescence illumination (λex = 370-450 nm). Guided by their visible fluorescence, lesions were biopsied at four suspicious sites in each patient. All specimens were analyzed and measured by a pathologist. A quantitative analysis of the fluorescence contrast between the neoplasms and healthy tissue was performed using the Red, Blue, and Green (RGB) Mode and Gray Scale (GS). Statistical analysis was performed by the analysis of variance (ANOVA) test for multiple comparisons.
RESULTS
Of the 60 patients (20 Bowen's disease, 20 SCC, and 20 BCC), malignant neoplasms could be clearly distinguished from adjacent healthy tissue under fluorescence illumination (P < 0.0001). The sensitivity of the malignant neoplasms evaluated using the RGB and GS modes combined showed 92.74% in image results. The specificity of the malignant neoplasms evaluated using the RGB and GS modes combined showed 95.77%.
CONCLUSION
Light-induced fluorescence detection using topical Photofrin provides a sensitive, noninvasive technique for the early identification of malignant cutaneous neoplasms.
Topics: Adult; Aged; Aged, 80 and over; Bowen's Disease; Carcinoma, Basal Cell; Dihematoporphyrin Ether; Female; Humans; Male; Middle Aged; Optical Imaging; Photosensitizing Agents; Protoporphyrins; Sensitivity and Specificity; Skin Neoplasms
PubMed: 30017671
DOI: 10.1016/j.bjps.2018.05.051 -
Oncology Reports Jul 2018Concurrent low‑dose carboplatin/Photofrin® photodynamic therapy (ccPDT) has been shown to promote relapse‑free complete tumor regression in cervical or endometrial...
Concurrent low‑dose carboplatin/Photofrin® photodynamic therapy (ccPDT) has been shown to promote relapse‑free complete tumor regression in cervical or endometrial cancer patients as a fertility‑preservation therapy. This study aimed to investigate the molecular mechanism of the enhanced therapeutic efficacy of ccPDT by determining intracellular reactive oxygen species (ROS) and necrotic or apoptotic cell damage in HeLa cells loaded with fluorescent oxidant agents and Photofrin or/and carboplatin under light irradiation. The cytotoxic effects of ccPDT were compared when monitored with a light dose under carboplatin or Photofrin alone. Photofrin‑PDT alone did not enhance either hydroxyl radicals (OH•) or superoxide anions (O2•-), but a slight enhancement of hydrogen peroxide (H2O2) production was observed. A larger enhancement of ROS production was obtained in a dose‑dependent manner following ccPDT, especially OH• and H2O2, in conjunction with both necrotic and apoptotic cell death, compared with necrotic‑prone PDT alone. The carboplatin‑mediated Fenton reaction: 2[PtII]2 + H2O2 → [Pt2.25]4 + OH¯+ OH• was proposed to explain the dose‑dependent enhancement of OH•. In conclusion, the therapeutic enhancement of ccPDT in vitro was attributable to the carboplatin‑mediated synergetic production of OH▪ and apoptotic cellular damage, compared with Photofrin‑PDT alone.
Topics: Apoptosis; Carboplatin; Dihematoporphyrin Ether; Female; Fertility Preservation; HeLa Cells; Humans; Hydrogen Peroxide; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Superoxides; Uterine Cervical Neoplasms
PubMed: 29749554
DOI: 10.3892/or.2018.6415 -
Bioelectrochemistry (Amsterdam,... Oct 2018Electrochemotherapy became one of the therapeutic protocols successfully used in oncology. However, biological effects occurring in cells, especially those which are...
Electrochemotherapy became one of the therapeutic protocols successfully used in oncology. However, biological effects occurring in cells, especially those which are drug resistant, have not been studied thoroughly. This study presents response of wild and drug resistant breast cancer cells to classical photodynamic therapy with Photofrin or experimental photodynamic therapy with cyanine IR-775, combined with electroporation. Photodynamic reaction or electroporation alone had no cytotoxic effect, but their combination significantly disturbed cellular functions. Applying electroporation allowed the drugs to increase its accumulation, especially for a poorly permeant cyanine in drug resistant cells. FACS analysis showed that even at relatively mild electric field, ca. 90% of cells were permeabilized. High intracellular concentration of drugs triggered the cellular defense system through increased expression of glutathione S-transferase and multidrug resistance proteins (MDR1 and MRP7), particularly in drug resistant cells. Finally, expressively decreased cell metabolism and proliferation, as well as formation of apoptotic bodies and fragmentation of cells were observed after the combined treatment. The results show that electroporation can be used for effective delivery of photosensitizers, even to drug resistant breast cancer cells, which was not tested before. This shows that electro-photodynamic treatment could be a promising approach to overcome a problem of drug resistance in cancer cells.
Topics: Breast Neoplasms; Carbocyanines; Cell Line, Tumor; Cell Membrane Permeability; Cell Survival; Dihematoporphyrin Ether; Drug Resistance, Neoplasm; Electrochemotherapy; Female; Humans; MCF-7 Cells; Photosensitizing Agents
PubMed: 29715586
DOI: 10.1016/j.bioelechem.2018.04.008