Porfimer Sodium Versus PS785 for Photodynamic Therapy (PDT) of Lung Cancer Xenografts in Mice.

BACKGROUND: Lung cancer is the greatest cause of cancer mortality in the United States, necessitating ongoing improvements in current treatment techniques. Photodynamic therapy (PDT) involves the interaction between a photosensitizer, light, and oxygen. The resulting release of reactive oxygen species causes tumor necrosis. It has been used as an endoscopic technique for the palliation of lung cancer. Porfimer sodium (Photofrin) is the only Food and Drug Administration-approved photosensitizer for PDT but has limited depth of penetration and produces prolonged skin phototoxicity. Multiple newer photosensitizers are in development, including PS785. The effectiveness of PS785 was compared with porfimer sodium in the treatment of human lung cancer xenografts in mice. METHODS: Human non-small cell lung cancer (NSCLC) xenografts were established in severe combined immunodeficient mice and grouped into small (3-5 mm) and large tumors (6-10 mm). PS785 or porfimer sodium was administered intravenously, and PDT was executed at 24, 48, or 72 h after injection. The primary endpoint was the delay of tumor regrowth after PDT. RESULTS: Porfimer sodium and PS785 produced statistically similar delays of tumor regrowth after PDT when small tumors were treated at 24 and 48 h. At 72 h, PS785 performed better in small tumors. However, for large tumors, PS785 produced no delay in tumor regrowth at any time point. CONCLUSIONS: PS785 and porfimer sodium were able to effectively treat NSCLC to a depth of ≤5 mm. However, porfimer sodium was more effective in treating NSCLC tumors to a depth of 6-10 mm. Further efforts are required to produce photosensitizers that will facilitate PDT of larger tumors.

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-1 , 24 h drug-light interval. The simulated threshold fluence was fixed at 45 J cm-2 while the simulated threshold irradiance varied, intratumorally. No cures were obtained in the mice treated with a threshold irradiance of 5.4 mW cm-2 . However, 20-90% of the mice were cured when the threshold irradiances were ≥8.6 mW cm-2 . 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-2 and fluence was 45 J cm-2 . 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 mm3 ) and I-PDT was administered with a threshold intratumoral irradiance ≥8.6 mW cm-2 .

Phase 1 study of EUS-guided photodynamic therapy for locally advanced pancreatic cancer.

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/ m2 intravenously) and gemcitabine (1000 mg /m2 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 cm3 (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.).

Biological effects in photodynamic treatment combined with electropermeabilization in wild and drug resistant breast cancer cells.

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.

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 mm3 . 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.

A novel photodynamic therapy-based drug delivery system layered on a stent for treating 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.

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.

Influence of iron oxide nanoparticles (Fe3O4) on erythrocyte photohemolysis via photofrin and Rose Bengal sensitization.

BACKGROUND: Iron oxide (Fe3O4) nanoparticles (IO-NP) were recently employed in medical applications as a diagnostic tool and drug carrier. Photofrin (PF) is a photosensitizer that clinically is used in Photodynamic therapy (PDT). STUDY DESIGN: The photosensitivity of PF and Rose Bengal (RB) mixed with (IO-NP) on red blood cells (RBCs) lysis was investigated. Second, Photohemolysis for post-irradiation (delayed) and during irradiation (continuous) with PF, RB and IO-NP combinations at different concentrations was investigated. Third, the photohemolysis rate, relative lysis steepness and power-concentration dependant parameter were evaluated by modeling and fitting the data using Gompertz function and power law. METHODS: RBCs were isolated from healthy male human volunteer. Washed cells (7.86×106 cells/mm3) were incubated with PF only or with IO-NP for 45min at 37°C then irradiated to a range of temperatures (4-41°C). CPH results were recorded and evaluated using Gompertz function. RESULTS: The relative steepness of the photohemolysis curves was approximately independent on light dose for delayed irradiation. The presence of IO-NP increases the rupturing time for 50% of the RBCs. Photohemolysis rate for delayed irradiation using the power law, led to 1.7 and 2.3 power dependence, respectively, for PF only and PF mixed with IO-NP. The power dependence of continuous irradiation measurements showed inverse proportionality for different concentrations of IO-NP combined with 2µg/ml PF concentration and 1.5µg/ml for RB concentration. CONCLUSION: Photosensitization of RBC with PF or RB mixed with IO-NP inhibited rupturing erythrocyte membrane and therefore a consideration should be taken against their combination in clinical applications.

A Comparison of Dose Metrics to Predict Local Tumor Control for Photofrin-mediated Photodynamic Therapy.

This preclinical study examines light fluence, photodynamic therapy (PDT) dose and "apparent reacted singlet oxygen," [1 O2 ]rx , 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-2 ) and in-air fluence rates (50-150 mW cm-2 ) at Photofrin dosages of 5 and 15 mg kg-1 and a drug-light interval of 24 h using a 630-nm, 1-cm-diameter collimated laser. A macroscopic model was used to calculate [1 O2 ]rx and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [1 O2 ]rx 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 [1 O2 ]rx ≥ 1.1 mm or PDT dose ≥1200 µm J cm-2 but cannot be predicted with fluence alone. LCR increases with increasing [1 O2 ]rx and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [1 O2 ]rx outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR.

Antimicrobial photodynamic therapy (aPDT) induction of biofilm matrix architectural and bioadhesive modifications.

BACKGROUND: Dental implants are commonly used today for the treatment of partially and fully edentulous patients. Despite the high success rate they are not resistant to complications and failure due to a variety of problems including peri-implantitis or peri-mucositis due to bacterial biofilm formation on the implant surface. The use of non-surgical and surgical treatment procedure to promote healing in cases with peri-implantitis have limited efficacy. Here we studied the ability of photodynamic therapy to destroy a known bacterial pathogen and the extracellular matrix architecture of biofilm attached to titanium plates and germanium prisms. METHODS: Titanium plates or germanium prisms were incubated for 24h with Fusobacterium nucleatum a fusiform, gram-negative bacterium was used to enable biofilm formation. Photodynamic therapy was carried out by incubating the biofilm samples on each substrata with porfimer sodium. Treatment was carried out using a diode laser at 630nm, 150mW/cm(2) for light doses ranging from 25-100J/cm(2). Evaluation of killing efficacy was done by counting colony forming units compared to controls. Multiple attenuated internal reflection-infrared spectroscopy (MAIR-IR) and SEM were used to analyze the samples pre and post PDT for validation. RESULTS: F. nucleatum was significantly reduced in a dose dependent manner by treatment with PDT. Changes in biofilm components and strength of bioadhesion were examined with MAIR-IR following jet impingement using calibrated water jets. SEM demonstrates significant morphological alterations in the bacteria, consistent with damage associated with exposure to reactive oxygen species. CONCLUSION: The results are indicative that aPDT is a method that can be used to eradicate micro-organisms associated with biofilm in peri-implantitis on relevant substrata. Data shows that the slime layer of the biofilm is removed and that further methods need to be employed to completely remove weakened or destroyed biofilm matrix components. Reactive oxygen species (ROS) mediated oxidative damage results in morphologic changes as a consequence of changes in cell membrane integrity.

Polymeric micelles for enhanced Photofrin II ® delivery, cytotoxicity and pro-apoptotic activity in human breast and ovarian cancer cells.

BACKGROUND: Searching for photodynamic therapy (PDT) - effective nanocarriers which enable a photosensitizer to be selectively delivered to tumor cells with enhanced bioavailability and diminished dark cytotoxicity is of current interest. The main objective of this study is to evaluate newly designed mixed polymeric micelles based on Pluronics P123 and F127 for the improved delivery of Photofrin II(®) (Ph II(®)) to circumvent unfavorable effects overcoming multidrug resistance (MDR) in tumor cells - in breast MCF-7/WT (caspase-3 deficient) and ovarian SKOV-3 (resistant to chemotherapy). METHODS: Ph II(®)-loaded micelles were obtained and analyzed for size and morphology, solubilization efficiency, physical stability and in vitro drug release. Intracellular uptake, reactive oxygen species (ROS) generation, mitochondrial oxidoreductive potential and proapoptotic activity (TUNEL assay) studies were evaluated in the examined cancer cells. The preliminary biocompatibility characteristics of all nanocarriers was determined by assessment of their hemolytic activity in human erythrocytes and dark toxicity in cancer cells. RESULTS: Dynamic light scattering (DLS) and atomic force microscopy (AFM) confirmed that almost monodisperse, sphere-shaped and nanosized (DH<20 nm) carriers were developed. Biological studies after photodynamic reaction (PDR) with encapsulated Ph II(®) revealed increased ROS level, malondialdehyde (MDA) concentration and protein damage in SKOV-3 and MCF-7/WT cells in comparison to treatment with free Ph II(®). Numerous apoptotic cells were detected after nano-therapy in both cell lines, with observed significant morphological disorders in ovarian cancer cells. In the case of encapsulated Ph II(®) only negligible disruption of human erythrocytes and cancer cells was observed. CONCLUSIONS: The obtained biocompatible long-lasting nanocarriers significantly enhance the Photofrin II(®) photodynamic effect and apoptosis in both SKOV-3 and MCF-7/WT cell lines.

[Photodynamic therapy of a cholangiocarcinoma in an 80-year-old man]. / Fotodynamisk behandling af kolangiokarcinom hos 80-årig.

70% of cholangiocarcinomas (CC) are perihilar lesions. At the time of diagnosis few are candidates for complete resection, and the standard palliative therapy has been biliary stenting. Studies have shown that photodynamic therapy (PDT) improves survival time. In this case report we describe an 80-year-old man with rheumatoid arthritis and perihilar CC classified as Bismuth-Corlette type II who successfully underwent PDT as the first patient in Denmark. The treatment was well tolerated with no phototoxic skin reaction, and a subsequent endoscopic retrograde cholangiopancreatography showed reduction of tumour.

Tumor delivery of Photofrin® by PLL-g-PEG for photodynamic therapy.

Photofrin® (porfimer sodium) is a photosensitive reagent used for photodynamic therapy (PDT) of tumors and dysplasias. Because only photo-irradiated sites are damaged, PDT is less invasive than systemic treatments. However, a photosensitive reaction is a major side effect of systemically delivered Photofrin. To enhance localization of Photofrin to tumors, we have formulated Photofrin with the tumor-localizing graft copolymer poly(ethylene glycol)-grafted poly(l-lysine), PLL-g-PEG. We demonstrate that Photofrin preferentially interacts with PLL-g-PEG through both ionic and hydrophobic interactions. The serum competitive study showed that the highly PEG-grafted PLL is better for preventing serum binding to the Photofrin/PLL-g-PEG complex. In tumor-bearing mice, formulation of Photofrin with PLL-g-PEG enhanced tumor localization of Photofrin as twice as Photofrin alone and concomitantly suppressed the photosensitivity reaction drastically.

Porfimer-sodium (Photofrin-II) in combination with ionizing radiation inhibits tumor-initiating cell proliferation and improves glioblastoma treatment efficacy.

Tumor relapse and tumor cell repopulation has been explained partially by the drug-free break period between successive conventional treatments. Strategies to overcome tumor relapse have been proposed, such as the use of chemotherapeutic drugs or radiation in small, frequent fractionated doses without an extended break period between treatment intervals. Yet, tumors usually acquire resistance and eventually escape the therapy. Several mechanisms have been proposed to explain the resistance of tumors to therapy, one of which involves the cancer stem cell or tumor-initiating cell (TIC) concept. TICs are believed to resist many conventional therapies, in part due to their slow proliferation and self-renewal capacities. Therefore, emerging efforts to eradicate TICs are being undertaken. Here we show that treatment with Photofrin II, among the most frequently used photosensitizers, sensitized a TIC-enriched U-87MG human glioblastoma cell to radiation, and improve treatment outcome when used in combination with radiotherapy. A U-87MG tumor cell population enriched with radiation-resistant TICs becomes radio-sensitive, and an inhibition of cell proliferation and an increase in apoptosis are found in the presence of Photofrin II. Furthermore, U-87MG tumors implanted in mice treated with Photofrin II and radiation exhibit a significant reduction in angiogenesis and vasculogenesis, and an increased percentage of apoptotic TICs when compared with tumors grown in mice treated with radiation alone. Collectively, our results offer a new possible explanation for the therapeutic effects of radiosensitizing agents, and suggest that combinatorial treatment modalities can effectively prolong treatment outcome of glioblastoma tumors by inhibiting tumor growth mediated by TICs.

Photodynamic therapy using intra-articular Photofrin for murine MRSA arthritis: biphasic light dose response for neutrophil-mediated antibacterial effect.

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.

Expression of complement and pentraxin proteins in acute phase response elicited by tumor photodynamic therapy: the engagement of adrenal hormones.

Treatment of solid tumors by photodynamic therapy (PDT) was recently shown to trigger a strong acute phase response. Using the mouse Lewis lung carcinoma (LLC) model, the present study examined complement and pentraxin proteins as PDT-induced acute phase reactants. The results show a distinct pattern of changes in the expression of genes encoding these proteins in the tumor, as well as host liver and spleen, following PDT mediated by photosensitizer Photofrin™. These changes were influenced by glucocorticoid hormones, as evidenced by transcriptional activation of glucocorticoid receptor and the upregulation of gene encoding this receptor. The expression of gene for glucocorticoid-induced zipper (GILZ) protein, whose activity is particularly susceptible to glucocorticoid regulation, was also changed in PDT-treated tumors. A direct demonstration that tumor PDT induces glucocorticoid hormone upregulation is provided by documenting elevated levels of serum corticosterone in mice bearing PDT-treated LLC tumors. Tumor response to PDT was negatively affected by blocking glucocorticoid receptor activity, which suggests that glucocorticoid hormones have a positive impact on the therapeutic outcome with this therapy.

Noninvasive extramammary Paget's disease treated with photodynamic therapy: case series from the Roswell Park Cancer Institute.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare low-grade cutaneous malignancy that affects apocrine gland-bearing areas and most commonly occurs on the perineal skin. Photodynamic therapy (PDT) may represent a useful treatment option for extensive, noninvasive EMPD, alone or as part of multimodal therapy. OBJECTIVE: To analyze the clinical outcomes of PDT for noninvasive EMPD with topical aminolevulinic acid (ALA) or intravenous porfimer sodium as photosensitizing agents and argon laser as the photoactivator. METHODS: Retrospective case series of patients with noninvasive EMPD treated at Roswell Park Cancer Institute with PDT from April 20, 1995, to December 4, 2008. Identified patients included five men and three women aged 50 to 80 (mean age 67) with a total of 24 distinct lesions of noninvasive EMPD without distant metastases. Four patients received topical ALA only as a photosensitizer, three received intravenous porfimer sodium only, and one received both. All patients were treated using a 632.8-nm argon-pumped dye laser, and some were also treated using a red lamp (590-729 nm). RESULTS: Seven of nine lesions (78%) treated with PDT using intravenous porfimer sodium showed a complete response (CR) and were disease free at 12 to 96 months. Eight of 16 lesions (50%) treated with PDT using topical ALA showed a CR, and 38% were disease free at 9 to 88 months. None of the treated patients developed any serious cosmetic or functional impairments, such as loss of sphincter control or dysesthesias. CONCLUSION: PDT with intravenous porfimer sodium or topical ALA and argon laser may represent a useful, surgery-sparing therapeutic option for management of noninvasive EMPD in selected patients. Prospective, randomized clinical trials are necessary to compare the effectiveness of PDT with that of surgery for noninvasive EMPD.

The pharmacokinetics and safety of porfimer after repeated administration 30-45 days apart to patients undergoing photodynamic therapy.

BACKGROUND: Porfimer is an intravenous (i.v.) injectable photosensitizing agent used in the photodynamic treatment of tumours and of high-grade dysplasia in Barrett's oesophagus. AIM: To assess the pharmacokinetics as well as the safety profiles of porfimer after a first and a second dose administered 30-45 days apart in patients undergoing photodynamic therapy. METHODS: Nineteen patients (16 with cholangiocarcinoma) were enrolled. Porfimer sodium was administered by i.v. injection over 3-5 min. Blood samples were collected prior to starting i.v. drug injection and postdose at different time points after the first and second administrations. RESULTS: Porfimer exposure values after the second administration were statistically higher than those observed after the first administration, suggesting a slight accumulation of porfimer following repeated administration. The apparent mean elimination half-life of porfimer increased from 410 h after the first administration to 725 h after the second administration. The safety profiles of porfimer after a first and a second administration were similar and did not raise additional concern. Eight patients experienced nine serious adverse events. Only photosensitivity was deemed study-drug related. CONCLUSION: Porfimer appears to display a safe and tolerable profile when used in patients requiring a second photodynamic therapy within 45 days.

Targeting the tumor microenvironment using photodynamic therapy combined with inhibitors of cyclooxygenase-2 or vascular endothelial growth factor.

Photodynamic therapy (PDT) involves the administration of a photosensitizer (PS) followed by localized exposure of a targeted tissue to PS adsorbing light. PDT induces cytotoxicity to exposed malignant cells and also effects non-malignant components of the tumor microenvironment. This indirect action of PDT leads to inflammatory and proangiogenic responses and modulates treatment effectiveness. Preclinical studies designed to determine how PDT modulates the tumor microenvironment use murine tumor models to investigate the expression and/or the activation of growth factors, proteinases, and inflammatory molecules following treatment. These studies demonstrate that improvements in treatment responsiveness following PDT are achieved using inhibitors targeting angiogenic and/or inflammatory pathways.