Publications by authors named "Barbara Henderson"

33 Publications

Irradiance, Photofrin Dose and Initial Tumor Volume are Key Predictors of Response to Interstitial Photodynamic Therapy of Locally Advanced Cancers in Translational Models.

Photochem Photobiol 2020 03 18;96(2):397-404. Epub 2020 Feb 18.

Photodynamic Therapy Center, Roswell Park Comprehensive Cancer Center (Roswell Park), Buffalo, NY.

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 , 24 h drug-light interval. The simulated threshold fluence was fixed at 45 J cm while the simulated threshold irradiance varied, intratumorally. No cures were obtained in the mice treated with a threshold irradiance of 5.4 mW cm . However, 20-90% of the mice were cured when the threshold irradiances were ≥8.6 mW cm . 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 and fluence was 45 J cm . 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 mm ) and I-PDT was administered with a threshold intratumoral irradiance ≥8.6 mW cm .
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http://dx.doi.org/10.1111/php.13207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138700PMC
March 2020

Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer.

Br J Cancer 2018 11 24;119(10):1191-1199. Epub 2018 Oct 24.

Photodynamic Therapy Center, Roswell Park Comprehensive Cancer Center (Roswell Park), Buffalo, NY, USA.

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.
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http://dx.doi.org/10.1038/s41416-018-0210-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251027PMC
November 2018

Intraoperative optical assessment of photodynamic therapy response of superficial oral squamous cell carcinoma.

J Biomed Opt 2016 Jan;21(1):18002

Roswell Park Cancer Institute, Department of Cell Stress Biology, Elm and Carlton Streets, Buffalo, New York 14263, United StatesbWright State University, Department of Biomedical, Industrial and Human Factors Engineering, 207 Russ Center, Dayton, Ohio 45.

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http://dx.doi.org/10.1117/1.JBO.21.1.018002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996863PMC
January 2016

A Phase I Study of Light Dose for Photodynamic Therapy Using 2-[1-Hexyloxyethyl]-2 Devinyl Pyropheophorbide-a for the Treatment of Non-Small Cell Carcinoma In Situ or Non-Small Cell Microinvasive Bronchogenic Carcinoma: A Dose Ranging Study.

J Thorac Oncol 2016 Feb 22;11(2):234-41. Epub 2015 Dec 22.

Department of Photodynamic Therapy, Roswell Park Cancer Institute, Buffalo, NY.

Introduction: We report a phase I trial of photodynamic therapy (PDT) of carcinoma in situ (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH). HPPH has the advantage of minimal general phototoxicity over the commonly used photosensitizer porfimer sodium (Photofrin; Pinnacle Biologics, Chicago, IL).

Methods: The objectives of this study were (1) to determine the maximally tolerated light dose at a fixed photosensitizer dose and (2) to gain initial insight into the effectiveness of this treatment approach. Seventeen patients with 21 CIS/MIC lesions were treated with HPPH with light dose escalation starting from 75 J/cm2 and increasing to 85, 95,125, and 150 J/cm2 respectively. Follow-up bronchoscopy for response assessment was performed at 1 and 6 months, respectively.

Results: The rate of pathological complete response (CR) was 82.4% (14 of 17 evaluable lesions; 14 patients) at 1 month and 72.7% (8/11 evaluable lesions; 8 patients) at 6 months. Only four patients developed mild skin erythema. One of the three patients in the 150 J/cm2 light dose group experienced a serious adverse event. This patient had respiratory distress caused by mucus plugging, which precipitated cardiac ischemia. Two additional patients treated subsequently at this light dose had no adverse events. The sixth patient in this dose group was not recruited and the study was terminated because of delays in HPPH supply. However, given the observed serious adverse event, it is recommended that the light dose does not exceed 125 J/cm2.

Conclusions: PDT with HPPH can be safely used for the treatment of CIS/MIC of the airways, with potential effectiveness comparable to that reported for porfimer sodium in earlier studies.
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http://dx.doi.org/10.1016/j.jtho.2015.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729686PMC
February 2016

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study.

Head Neck 2016 04 29;38 Suppl 1:E377-83. Epub 2015 Jun 29.

Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, New York.

Background: The purpose of this study was for us to report results regarding the safety of 3-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) mediated photodynamic therapy (PDT) in early laryngeal disease, and offer preliminary information on treatment responses.

Methods: A single-institution, phase Ib, open label, noncomparative study of HPPH-PDT in patients with high-risk dysplasia, carcinoma in situ, and T1 squamous cell carcinoma (SCC) of the larynx. The primary outcomes were safety and maximum tolerated dose (MTD), and the secondary outcome was response.

Results: Twenty-nine patients and 30 lesions were treated. The most common adverse event (AE) was transient hoarseness of voice. Severe edema, requiring tracheostomy, was the most serious AE, which occurred in 2 patients within several hours of therapy. The MTD was 100 J/cm(2) . Patients with T1 SCC seemed to have good complete response rate (82%) to HPPH-PDT at MTD.

Conclusion: HPPH-PDT can be safely used to treat early-stage laryngeal cancer, with potential efficacy. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E377-E383, 2016.
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http://dx.doi.org/10.1002/hed.24003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499022PMC
April 2016

A prospective study of pain control by a 2-step irradiance schedule during topical photodynamic therapy of nonmelanoma skin cancer.

Dermatol Surg 2014 Dec;40(12):1390-4

*Department of Dermatology, University of Arizona Cancer Center, Tucson, Arizona; Departments of †Cell Stress Biology/PDT Center, ‡Dermatology, and §Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York; ‖Department of Imaging Sciences, University of Rochester, Rochester, New York.

Background: Topical photodynamic therapy (PDT) for selected nonmelanoma skin cancer using 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) has yielded high long-term complete response rates with very good cosmesis. Pain during light activation of the photosensitizer can be a serious adverse event. A 2-step irradiance protocol has previously been shown to minimize ALA-PDT pain.

Objective: To determine the irradiance-dependent pain threshold for MAL-PDT, to adapt the 2-step protocol to a light-emitting diode (LED) light source, and assess clinical response.

Methods: In this prospective study, 25 superficial basal cell carcinoma (sBCC) received an initial irradiance by laser at 40 or 50 mW/cm², or LED at 35 mW/cm² followed by an irradiance at 70 mW/cm² for a total of 75 J/cm². Pain levels were recorded for both irradiance steps. Efficacy was assessed at 6, 12, or 24 months.

Results: Pain was mild in the 40/70 mW/cm² laser cohort. Three instances of irradiance-limiting pain occurred at 50/70 mW/cm². Pain was minimal in the 35/70 mW/cm² LED cohort. Clinical response rates were 80% in the 50/70 mW/cm² laser cohort and 90% in the 35/70 mW/cm² LED cohort.

Conclusion: Topical PDT can be effectively delivered to sBCC with minimal treatment-related pain by a 2-step irradiance protocol.
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http://dx.doi.org/10.1097/DSS.0000000000000183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323090PMC
December 2014

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide a for cancer of the oral cavity.

Clin Cancer Res 2013 Dec 2;19(23):6605-13. Epub 2013 Oct 2.

Authors' Affiliations: Photodynamic Therapy Center at the Department of Cell Stress Biology, Departments of Head and Neck Surgery, Molecular and Cellular Biology, Biostatistics and Bioinformatics, Dentistry, and Pathology, Roswell Park Cancer Institute (RPCI), Buffalo, New York.

Purpose: The primary objective was to evaluate safety of 3-(1'-hexyloxyethyl)pyropheophorbide-a (HPPH) photodynamic therapy (HPPH-PDT) for dysplasia and early squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives were the assessment of treatment response and reporters for an effective PDT reaction.

Experimental Design: Patients with histologically proven oral dysplasia, carcinoma in situ, or early-stage HNSCC were enrolled in two sequentially conducted dose escalation studies with an expanded cohort at the highest dose level. These studies used an HPPH dose of 4 mg/m(2) and light doses from 50 to 140 J/cm(2). Pathologic tumor responses were assessed at 3 months. Clinical follow up range was 5 to 40 months. PDT induced cross-linking of STAT3 were assessed as potential indicators of PDT effective reaction.

Results: Forty patients received HPPH-PDT. Common adverse events were pain and treatment site edema. Biopsy proven complete response rates were 46% for dysplasia and carcinoma in situ and 82% for squamous cell carcinomas (SCC) lesions at 140 J/cm(2). The responses in the carcinoma in situ/dysplasia cohort are not durable. The PDT-induced STAT3 cross-links is significantly higher (P = 0.0033) in SCC than in carcinoma in situ/dysplasia for all light doses.

Conclusion: HPPH-PDT is safe for the treatment of carcinoma in situ/dysplasia and early-stage cancer of the oral cavity. Early-stage oral HNSCC seems to respond better to HPPH-PDT in comparison with premalignant lesions. The degree of STAT3 cross-linking is a significant reporter to evaluate HPPH-PDT-mediated photoreaction.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911775PMC
December 2013

Adjuvant intraoperative photodynamic therapy in head and neck cancer.

JAMA Otolaryngol Head Neck Surg 2013 Jul;139(7):706-11

Department of Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, New York, USA.

Importance: There is an immediate need to develop local intraoperative adjuvant treatment strategies to improve outcomes in patients with cancer who undergo head and neck surgery.

Objectives: To determine the safety of photodynamic therapy with 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) in combination with surgery in patients with head and neck squamous cell carcinoma.

Design, Setting, And Participants: Nonrandomized, single-arm, single-site, phase 1 study at a comprehensive cancer center among 16 adult patients (median age, 65 years) with biopsy-proved primary or recurrent resectable head and neck squamous cell carcinoma.

Interventions: Intravenous injection of HPPH (4.0 mg/m2), followed by activation with 665-nm laser light in the surgical bed immediately after tumor resection.

Main Outcomes And Measures: Adverse events and highest laser light dose.

Results: Fifteen patients received the full course of treatment, and 1 patient received HPPH without intraoperative laser light because of an unrelated myocardial infarction. Disease sites included larynx (7 patients), oral cavity (6 patients), skin (1 patient), ear canal (1 patient), and oropharynx (1 patient, who received HPPH only). The most frequent adverse events related to photodynamic therapy were mild to moderate edema (9 patients) and pain (3 patients). One patient developed a grade 3 fistula after salvage laryngectomy, and another patient developed a grade 3 wound infection and mandibular fracture. Phototoxicity reactions included 1 moderate photophobia and 2 mild to moderate skin burns (2 due to operating room spotlights and 1 due to the pulse oximeter). The highest laser light dose was 75 J/cm2.

Conclusions And Relevance: The adjuvant use of HPPH-photodynamic therapy and surgery for head and neck squamous cell carcinoma seems safe and deserves further study.

Trial Registration: clinicaltrials.gov Identifier: NCT00470496.
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http://dx.doi.org/10.1001/jamaoto.2013.3387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302749PMC
July 2013

Quantification of PpIX concentration in basal cell carcinoma and squamous cell carcinoma models using spatial frequency domain imaging.

Biomed Opt Express 2013 Apr 6;4(4):531-7. Epub 2013 Mar 6.

Department of Cell Stress Biology & PDT Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

5-aminolaevulinic acid photodynamic therapy (ALA-PDT) is an attractive treatment option for nonmelanoma skin tumors, especially for multiple lesions and large areas. The efficacy of ALA-PDT is highly dependent on the photosensitizer (PS) concentration present in the tumor. Thus it is desirable to quantify PS concentration and distribution, preferably noninvasively to determine potential outcome. Here we quantified protoporphyrin IX (PpIX) distribution induced by topical and intra-tumoral (it) administration of the prodrug ALA in basal and squamous cell carcinoma murine models by using spatial frequency domain imaging (SFDI). The in vivo measurements were validated by analysis of the ex vivo extraction of PpIX. The study demonstrates the feasibility of non-invasive quantification of PpIX distributions in skin tumors.
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http://dx.doi.org/10.1364/BOE.4.000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617715PMC
April 2013

A retrospective review of pain control by a two-step irradiance schedule during topical ALA-photodynamic therapy of non-melanoma skin cancer.

Lasers Surg Med 2013 Feb 6;45(2):89-94. Epub 2013 Feb 6.

Department of Dermatology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Background And Objective: Photodynamic therapy (PDT) with topical δ-aminolevulinic acid (ALA) of non-melanoma skin cancers is often associated with treatment-limiting pain. A previous study on basal cell carcinomas (BCCs) at Roswell Park Cancer Institute evaluated a two-step irradiance scheme as a means of minimizing pain, preserving outcomes, and limiting treatment time. We used an initial low irradiance until 90% of the protoporphyrin IX was photobleached, followed by a high irradiance interval until the prescribed fluence was delivered. Success of this pilot investigation motivated integration of the protocol into routine practice. Here, we present a retrospective review of recent clinical experience in a broad patient population.

Study Design/materials And Methods: This was a retrospective review of an existing dermatology database. Fourteen caucasion patients-nine men and five women, ages 18-80, with a total of 51 superficial and 73 nodular BCCs, and three Bowen's disease lesions-were included. ALA was applied to each lesion for approximately 4 hours. Lesions received an initial irradiance of 30-50 mW/cm(2) for 20 J/cm(2) , followed by 150 mW/cm(2) for a total fluence of 200-300 J/cm(2) . Pain was assessed using a visual analog scale (VAS). Clinical outcome was determined at 6-12 months.

Results: Median VAS scores were 1.0 for both irradiances. Five of 127 lesions required pain control with 1% xylocaine. Pain was strongly influenced by lesion location but not by lesion type, number, or size. Complete responses were achieved in 84.1% of BCCs, which compares favorably with reported results for single ALA-PDT treatments. Two of three Bowen's disease lesions showed a complete response. Complete responses for nodular BCCs were 37%, which are also within the range of reported outcomes.

Conclusions: A two-step irradiance protocol in ALA-PDT effectively minimizes pain, maintains excellent clinical outcomes in superficial lesions, and adds minimal treatment time.
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http://dx.doi.org/10.1002/lsm.22118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685854PMC
February 2013

Interlesion differences in the local photodynamic therapy response of oral cavity lesions assessed by diffuse optical spectroscopies.

Biomed Opt Express 2012 Sep 16;3(9):2142-53. Epub 2012 Aug 16.

Department of Cell Stress Biology & PDT Center, Roswell Park Cancer Institute, Elm & Carlton St, Buffalo, NY 14263, USA.

Photodynamic therapy (PDT) efficacy depends on the local dose deposited in the lesion as well as oxygen availability in the lesion. We report significant interlesion differences between two patients with oral lesions treated with the same drug dose and similar light dose of 2-1[hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH)-mediated photodynamic therapy (PDT). Pre-PDT and PDT-induced changes in hemodynamic parameters and HPPH photosensitizer content, quantified by diffuse optical methods, demonstrated substantial differences between the two lesions. The differences in PDT action determined by the oxidative cross-linking of signal transducer and activator of transcription 3 (STAT3), a molecular measure of accumulated local PDT photoreaction, also showed >100-fold difference between the lesions, greatly exceeding what would be expected from the slight difference in light dose. Our results suggest diffuse optical spectroscopies can provide in vivo metrics that are indicative of local PDT dose in oral lesions.
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http://dx.doi.org/10.1364/BOE.3.002142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3447556PMC
September 2012

Antimicrobial susceptibilities of Aeromonas strains isolated from clinical and environmental sources to 26 antimicrobial agents.

Antimicrob Agents Chemother 2012 Feb 28;56(2):1110-2. Epub 2011 Nov 28.

Microbiology and Immunology, School of Biomedical, Biomolecular and Chemical Sciences, the University of Western Australia, Crawley, Western Australia.

We determined the susceptibilities of 144 clinical and 49 environmental Aeromonas strains representing 10 different species to 26 antimicrobial agents by the agar dilution method. No single species had a predominantly nonsusceptible phenotype. A multidrug nonsusceptible pattern was observed in three (2.1%) clinical strains and two (4.0%) strains recovered from diseased fish. Common clinical strains were more resistant than the corresponding environmental isolates, suggesting that resistance mechanisms may be acquired by environmental strains from clinical strains.
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http://dx.doi.org/10.1128/AAC.05387-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264277PMC
February 2012

Photodynamic therapy (PDT) using HPPH for the treatment of precancerous lesions associated with Barrett's esophagus.

Lasers Surg Med 2011 Sep;43(7):705-12

Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

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.
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http://dx.doi.org/10.1002/lsm.21112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218433PMC
September 2011

Cell-type selective phototoxicity achieved with chlorophyll-a derived photosensitizers in a co-culture system of primary human tumor and normal lung cells.

Photochem Photobiol 2011 Nov-Dec;87(6):1405-18. Epub 2011 Oct 3.

Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.

The ATP-dependent transporter ABCG2 exports certain photosensitizers (PS) from cells, implying that the enhanced expression of ABCG2 by cancer cells may confer resistance to photodynamic therapy (PDT) mediated by those PS. In 35 patient-derived primary cultures of lung epithelial and stromal cells, PS with different subcellular localization and affinity for ABCG2 displayed cell-type specific retention both independent and dependent on ABCG2. In the majority of cases, the ABCG2 substrate 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) was lost from fibroblastic cells more rapidly than from their epithelial counterparts, even in the absence of detectable ABCG2 expression, facilitating selective eradication by PDT of epithelial over fibroblastic cells in tumor/stroma co-cultures. Pairwise comparison of normal and transformed epithelial cells also identified tumor cells with elevated or reduced retention of HPPH, depending on ABCG2. Enhanced ABCG2 expression led to the selective PDT survival of tumor cells in tumor/stroma co-cultures. This survival pattern was reversible through HPPH derivatives that are not ABCG2 substrates or the ABCG2 inhibitor imatinib mesylate. PS retention, not differences in subcellular distribution or cell signaling responses, was determining cell type selective death by PDT. These data suggest that up-front knowledge of tumor characteristics, specifically ABCG2 status, could be helpful in individualized PDT treatment design.
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http://dx.doi.org/10.1111/j.1751-1097.2011.00992.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200467PMC
January 2012

Prevalence and genotypic characteristics of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae in Australia.

J Antimicrob Chemother 2011 May 23;66(5):1013-5. Epub 2011 Feb 23.

School of Human Life Sciences, University of Tasmania, Launceston, Tasmania, Australia.

Objectives: To determine the prevalence of β-lactamase-negative ampicillin-resistant (BLNAR) Haemophilus influenzae in Australia and characterize the associated amino acid substitutions in penicillin-binding protein 3.

Methods: Two hundred consecutive non-repeat clinical isolates of H. influenzae were collected and β-lactamase-negative isolates were screened for reduced ampicillin susceptibility using an ampicillin 2 μg disc (breakpoint <17 mm) and Etest (breakpoint ≥0.25 mg/L). All screen-positive isolates had their ampicillin MICs determined by reference broth microdilution and their ftsI genes were sequenced.

Results: No BLNAR strains (MIC ≥4 mg/L) were found, but 5 (2.5%) low BLNAR (L-BLNAR) strains (MIC ≥2 mg/L) and 36 (18%) genetic BLNAR (gBLNAR) strains (R517H or N526K) were found. Of the gBLNAR strains, four had the R517H substitution and the remainder had N526K, while no strains had combined N526K and M377I/S385T/L389F substitutions. A number of strains with neither R517H nor N526K substitutions that did not meet the gBLNAR definition had other BLNAR-associated substitutions.

Conclusions: BLNAR and L-BLNAR strains are uncommon in Australia, while gBLNAR strains are more common than previously recognized.
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http://dx.doi.org/10.1093/jac/dkr035DOI Listing
May 2011

Comparison of methods for AmpC β-lactamase detection in Enterobacteriaceae.

J Med Microbiol 2011 Jun 3;60(Pt 6):715-721. Epub 2011 Mar 3.

Department of Microbiology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia.

AmpC β-lactamases (Bla(AmpC)) are an emerging group of antimicrobial resistance determinants. The lack of an agreed Bla(AmpC) detection method hinders investigation of their epidemiology and understanding of their clinical significance. This study compared the sensitivity and specificity of phenotypic methods of Bla(AmpC) detection in a collection of 246 Enterobacteriaceae with a diverse range of β-lactam resistance profiles. The Bla(AmpC) screening methods evaluated were based on cephamycin, ceftazidime and cefepime susceptibility. These were compared with Bla(AmpC) screening using conventional ESBL detection methods. The confirmatory methods evaluated were biologically based assays, inhibitor-based assays, an AmpC Etest and a rapid chromogenic assay. A multiplex nucleic acid amplification test and the three-dimensional enzyme extraction assay were used as reference methods. Bla(AmpC) activity was present in 74 isolates. The majority of the enzymes were plasmid-encoded and belonged to the CMY, DHA and EBC families. The screening methods had sensitivities between 47 and 99 % and specificities of 45-95 %. The performance of confirmatory tests varied widely, ranging in sensitivity from 19 % to 97 % and in specificity from 88 % to 100 %. Only the Tris-EDTA and MAST ID D68C disc tests had a sensitivity and a specificity above 90 %. Further investigation is needed to establish the most suitable enzyme substrates, inhibitor types, inhibitor concentrations and interpretative cut-offs in order to refine the inhibitor-based methods. A simple disc-based protocol using cefoxitin non-susceptibility as a screening tool, followed by the Tris-EDTA method for confirmation, detects Bla(AmpC) activity with 95 % sensitivity and 98 % specificity.
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http://dx.doi.org/10.1099/jmm.0.029140-0DOI Listing
June 2011

Monitoring blood flow responses during topical ALA-PDT.

Biomed Opt Express 2010 Dec 15;2(1):123-30. Epub 2010 Dec 15.

Photodynamic therapy (PDT) using topical 5-aminolevulinic acid (ALA) is currently used as a clinical treatment for nonmelanoma skin cancers. In order to optimize PDT treatment, vascular disruption early in treatment must be identified and prevented. We present blood flow responses to topical ALA-PDT in a preclinical model and basal cell carcinoma patients assessed by diffuse correlation spectroscopy (DCS). Our results show that ALA-PDT induced early blood flow changes and these changes were irradiance dependent. It is clear that there exists considerable variation in the blood flow responses in patients from lesion to lesion. Monitoring blood flow parameter may be useful for assessing ALA-PDT response and planning.
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http://dx.doi.org/10.1364/BOE.2.000123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028487PMC
December 2010

Monitoring photobleaching and hemodynamic responses to HPPH-mediated photodynamic therapy of head and neck cancer: a case report.

Opt Express 2010 Jul;18(14):14969-78

Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.

We present initial results obtained during the course of a Phase I clinical trial of 2-1[hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH)-mediated photo-dynamic therapy (PDT) in a head and neck cancer patient. We quantified blood flow, oxygenation and HPPH drug photobleaching before and after therapeutic light treatment by utilizing fast, non-invasive diffuse optical methods. Our results showed that HPPH-PDT induced significant drug photobleaching, and reduction in blood flow and oxygenation suggesting significant vascular and cellular reaction. These changes were accompanied by cross-linking of the signal transducer and activator of transcription 3 (STAT3), a molecular measure for the oxidative photoreaction. These preliminary results suggest diffuse optical spectroscopies permit non-invasive monitoring of PDT in clinical settings of head and neck cancer patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964147PMC
http://dx.doi.org/10.1364/OE.18.014969DOI Listing
July 2010

Photodynamic therapy for head and neck dysplasia and cancer.

Arch Otolaryngol Head Neck Surg 2009 Aug;135(8):784-8

Department of Head and Neck Surgery/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Objective: To determine the response of dysplasia, carcinoma in situ (CIS), and T1 carcinoma of the oral cavity and larynx to photodynamic therapy with porfimer sodium.

Design: Prospective trial.

Setting: A National Cancer Institute-designated cancer institute.

Patients: Patients with primary or recurrent moderate to severe oral or laryngeal dysplasia, CIS, or T1N0 carcinoma.

Intervention: Porfimer sodium, 2 mg/kg of body weight, was injected intravenously 48 hours before treatment. Light at 630 nm for photosensitizer activation was delivered from an argon laser or diode laser using lens or cylindrical diffuser fibers. The light dose was 50 J/cm(2) for dysplasia and CIS and 75 J/cm(2) for carcinoma.

Main Outcome Measures: Response was evaluated at 1 week and at 1 month and then at 3-month intervals thereafter. Response options were complete (CR), partial (PR), and no (NR) response. Posttreatment biopsies were performed in all patients with persistent and recurrent visible lesions.

Results: Thirty patients were enrolled, and 26 were evaluable. Mean follow-up was 15 months (range, 7-52 months). Twenty-four patients had a CR, 1 had a PR, and 1 had NR. Three patients with oral dysplasia with an initial CR experienced recurrence in the treatment field. All the patients with NR, a PR, or recurrence after an initial CR underwent salvage treatment. Temporary morbidities included edema, pain, hoarseness, and skin phototoxicity.

Conclusion: Photodynamic therapy with porfimer sodium is an effective treatment alternative, with no permanent sequelae, for oral and laryngeal dysplasia and early carcinoma.

Trial Registration: clinicaltrials.gov Identifier: NCT00530088.
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http://dx.doi.org/10.1001/archoto.2009.98DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810853PMC
August 2009

Conjugation of 2-(1'-hexyloxyethyl)-2-devinylpyropheophorbide-a (HPPH) to carbohydrates changes its subcellular distribution and enhances photodynamic activity in vivo.

J Med Chem 2009 Jul;52(14):4306-18

PDT Center, Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

The carbohydrate moieties on conjugating with 3-(1'-hexyloxyethyl)-3-devinyl pyropeophorbide-a (HPPH) altered the uptake and intracellular localization from mitochondria to lysosomes. In vitro, HPPH-Gal 9 PDT showed increased PDT efficacy over HPPH-PDT as detectable by the oxidative cross-linking of nonphosphorylated STAT3 and cell killing in ABCG2-expressing RIF cells but not in ABCG2-negative Colon26 cells. This increased efficacy in RIF cells could at least partially be attributed to increased cellular accumulation of 9, suggesting a role of the ABCG2 transporter for which HPPH is a substrate. While such differences in the accumulation in HPPH derivatives by tumor tissue in vivo were not detectable, 9 still showed an elevated light dose-dependent activity compared to HPPH in mice bearing RIF as well as Colon26 tumors. Further optimization of the carbohydrate conjugates at variable treatment parameters in vivo is currently underway.
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http://dx.doi.org/10.1021/jm9001617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913405PMC
July 2009

Light delivery over extended time periods enhances the effectiveness of photodynamic therapy.

Clin Cancer Res 2008 May;14(9):2796-805

Department of Cell Stress Biology and Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Purpose: The rate of energy delivery is a principal factor determining the biological consequences of photodynamic therapy (PDT). In contrast to conventional high-irradiance treatments, recent preclinical and clinical studies have focused on low-irradiance schemes. The objective of this study was to investigate the relationship between irradiance, photosensitizer dose, and PDT dose with regard to treatment outcome and tumor oxygenation in a rat tumor model.

Experimental Design: Using the photosensitizer HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide), a wide range of PDT doses that included clinically relevant photosensitizer concentrations was evaluated. Magnetic resonance imaging and oxygen tension measurements were done along with the Evans blue exclusion assay to assess vascular response, oxygenation status, and tumor necrosis.

Results: In contrast to high-incident laser power (150 mW), low-power regimens (7 mW) yielded effective tumor destruction. This was largely independent of PDT dose (drug-light product), with up to 30-fold differences in photosensitizer dose and 15-fold differences in drug-light product. For all drug-light products, the duration of light treatment positively influenced tumor response. Regimens using treatment times of 120 to 240 min showed marked reduction in signal intensity in T2-weighted magnetic resonance images at both low (0.1 mg/kg) and high (3 mg/kg) drug doses compared with short-duration (6-11 min) regimens. Significantly greater reductions in pO(2) were observed with extended exposures, which persisted after completion of treatment.

Conclusions: These results confirm the benefit of prolonged light exposure, identify vascular response as a major contributor, and suggest that duration of light treatment (time) may be an important new treatment variable.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-4705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805854PMC
May 2008

Photodynamic therapy enhancement of antitumor immunity is regulated by neutrophils.

Cancer Res 2007 Nov;67(21):10501-10

Department of Cell Stress Biology and the Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Photodynamic therapy (PDT) is a Food and Drug Administration-approved local cancer treatment that can be curative of early disease and palliative in advanced disease. PDT of murine tumors results in regimen-dependent induction of an acute local inflammatory reaction, characterized in part by rapid neutrophil infiltration into the treated tumor bed. In this study, we show that a PDT regimen that induced a high level of neutrophilic infiltrate generated tumor-specific primary and memory CD8(+) T-cell responses. In contrast, immune cells isolated from mice treated with a PDT regimen that induced little or no neutrophilic infiltrate exhibited minimal antitumor immunity. Mice defective in neutrophil homing to peripheral tissues (CXCR2(-/-) mice) or mice depleted of neutrophils were unable to mount strong antitumor CD8(+) T-cell responses following PDT. Neutrophils seemed to be directly affecting T-cell proliferation and/or survival rather than dendritic cell maturation or T-cell migration. These novel findings indicate that by augmenting T-cell proliferation and/or survival, tumor-infiltrating neutrophils play an essential role in establishment of antitumor immunity following PDT. Furthermore, our results may suggest a mechanism by which neutrophils might affect antitumor immunity following other inflammation-inducing cancer therapies. Our findings lay the foundation for the rational design of PDT regimens that lead to optimal enhancement of antitumor immunity in a clinical setting. Immune-enhancing PDT regimens may then be combined with treatments that result in optimal ablation of primary tumors, thus inhibiting growth of primary tumor and controlling disseminated disease.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-1778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919236PMC
November 2007

Cross-linking of signal transducer and activator of transcription 3--a molecular marker for the photodynamic reaction in cells and tumors.

Clin Cancer Res 2007 Jun;13(11):3156-63

Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Purpose: Photodynamic therapy (PDT) depends on the delivery of a photosensitizer to the target tissue that, under light exposure, produces singlet oxygen and other reactive oxygen species, which in turn cause the death of the treated cell. This study establishes a quantitative marker for the photoreaction that will predict the outcome of PDT.

Experimental Design: Cells in tissue culture, murine s.c. tumors, and endobronchial carcinomas in patients were treated with PDT, and the noncleavable cross-linking of the latent signal transducer and activator of transcription 3 (STAT3) was determined.

Results: Murine and human cancer cell lines reacted to PDT by an immediate covalent cross-linking of STAT3 to homodimeric and other complexes. The magnitude of this effect was strictly a function of the PDT reaction that is determined by the photosensitizer concentration and light dose. The cross-link reaction of STAT3 was proportional to the subsequent cytotoxic outcome of PDT. An equivalent photoreaction as detected in vitro occurred in tumors treated in situ with PDT. The light dose-dependent STAT3 cross-linking indicated the relative effectiveness of PDT as a function of the distance of the tissue to the treating laser light source. Absence of cross-links correlated with treatment failure.

Conclusions: The data suggest that the relative amount of cross-linked STAT3 predicts the probability for beneficial outcome, whereas absence of cross-links predicts treatment failure. Determination of STAT3 cross-links after PDT might be clinically useful for early assessment of PDT response.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-2950DOI Listing
June 2007

Purpurinimide carbohydrate conjugates: effect of the position of the carbohydrate moiety in photosensitizing efficacy.

Mol Pharm 2007 May-Jun;4(3):448-64. Epub 2007 Mar 21.

Photodynamic Therapy Center, Department of Dermatology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

A lactose moiety was regioselectively introduced at various positions of N-hexyl-mesopurpurinimide (a class of chlorin containing a fused six-membered imide ring system, lambda(max): 700 nm) to investigate the effect of its presence and position on photosensitizing efficacy. The resulting novel structures produced a significant difference in in vitro and in vivo efficacy. Among the positional isomers in which the lactose moiety was introduced at positions 3, 8, and 12, the 3-lactose purpurin-18-N-hexylimide produced the best efficacy. Compared to these analogues, the lactose moiety joined with an amide bond at position 17(2), and with an N-benzyl group bearing a -C[triple bond]C- linkage at position 13(2) showed reduced in vitro/in vivo photosensitivity. A noticeable difference between lactose conjugates in cell uptake (RIF tumor cells) was observed at 3 and 24 h postincubation. Replacing the lactose (Galbeta1 --> 4Glc) with beta-galactose and glucose moieties at position 3 of purpurinimide produced an increase in both cell uptake and in in vitro efficacy, but with reduced in vivo efficacy. Sites of intracellular localization differed among photosensitizers with and without carbohydrate moieties. Molecular modeling shows favorable interactions of 3- and 12-lactose-purpurinimide analogues with both galectin-1 and galectin-3, but clear contributions were not found for the conjugate containing lactose moiety at position 8. In a comparative ELISA study of the lactose conjugates with free lactose, all carbohydrate-purpurinimides showed binding to both galectins with a significant variation between the batches of galectins.
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http://dx.doi.org/10.1021/mp060135xDOI Listing
August 2007

Endobronchial photodynamic therapy for lung cancer.

Lasers Surg Med 2006 Jun;38(5):364-70

Solid Tumor Division, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.

Background And Objective: Endobronchial photodynamic therapy (PDT) is a minimally invasive technique for the palliation of major airway obstruction from lung cancer, and for the treatment of endobronchial microinvasive lung cancer.

Study Design: Results of reported clinical trials were compared, and the author's preliminary results with second generation photosensitizers were also reviewed.

Results: A review of the clinical experience with endobronchial PDT is provided. Potential advantages of PDT include the duration of palliation achieved through the delayed cellular effects of PDT within tumor. Side-effects from FDA-approved photosensitizer (Photofrin, Porfimer sodium, Axcan Scandipharm, Montreal, Quebec) include skin photosensitivity. HPPH (2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide) is an example of a second-generation photosensitize that shows promise in the treatment of lung cancer, and appears to be free from significant skin photosensitivity.

Conclusion: PDT is an effective tool for the palliation of endobronchial lung cancers which obstruct the central airways and is also effective for the treatment of central microinvasive carcinoma and carcinoma in situ of the central airways.
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http://dx.doi.org/10.1002/lsm.20354DOI Listing
June 2006

Fluence rate as a modulator of PDT mechanisms.

Lasers Surg Med 2006 Jun;38(5):489-93

Department of Cell Stress Biology, The Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, New York, New York 14263, USA.

Background And Objectives: Molecular oxygen in the tissue to be treated by photodynamic therapy (PDT) is critical for photodynamic cell killing. The fluence rate of PDT light delivery has been identified as an important modulator of tissue oxygenation and treatment outcome. This article provides supporting evidence for the role of fluence rate in PDT and discusses the underlying mechanisms.

Study Design/materials And Methods: Intratumoral pO2 was measured polarographically in murine tumors before and during PDT light treatment using the Eppendorf pO2 Histograph. Tumor response as a function of fluence rate and fluence was also assessed in murine tumor models. Changes in vascular permeability as a function of fluence rate were determined in murine tumors by measuring tumor uptake of fluorescent beads (200 nm diameter).

Results: Severe oxygen depletion is shown to occur within seconds of illumination at a fluence rate of 75 mW/cm2 in radiation-induced fibrosarcoma (RIF) tumors photosensitized with AlPcS2. This effect was reversible and consistent with photochemical oxygen depletion, which has been shown by us and others to be fluence rate dependent. It is demonstrated that fluence rate affects the PDT tumor response in the Colon 26 tumor model, high fluence rate diminishing or even totally inhibiting tumor control, low fluence rate promoting tumor control. The influence of fluence rate is not restricted to cytocidal effects, but can also be seen in sublethal conditions such as vascular permeability.

Conclusions: Fluence rate of PDT light delivery exerts far-reaching control upon treatment outcome through its oxygenation modulating properties and possibly other mechanisms yet to be identified. This has been shown to be true in the preclinical and clinical setting. Further development of in situ dosimetry will be necessary to take full advantage of these discoveries.
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http://dx.doi.org/10.1002/lsm.20327DOI Listing
June 2006

A novel approach to a bifunctional photosensitizer for tumor imaging and phototherapy.

Bioconjug Chem 2005 Sep-Oct;16(5):1264-74

PDT Center, Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Optical imaging has attracted a great attention for studying molecular recognitions because minute fluorescent tracers can be detected in homogeneous and heterogeneous media with existing laboratory instruments. In our preliminary study, a clinically relevant photosensitizer (HPPH, a chlorophyll-a analog) was linked with a cyanine dye (with required photophysical characteristics but limited tumor selectivity), and the resulting conjugate was found to be an efficient tumor imaging (fluorescence imaging) and photosensitizing agent. Compared to HPPH, the presence of the cyanine dye moiety in the conjugate produced a significantly higher uptake in tumor than skin. At a therapeutic/imaging dose, the conjugate did not show any significant skin phototoxicity, a major drawback associated with most of the porphyrin-based photosensitizers. These results suggest that tumor-avid porphyrin-based compounds can be used as "vehicles" to deliver the desired fluorescent agent(s) to tumor. The development of tumor imaging or improved photodynamic therapy agent(s) by itself represents an important step, but a dual function agent (fluorescence imaging and photodynamic therapy) provides the potential for tumor detection and targeted photodynamic therapy, combining two modalities into a single cost-effective "see and treat" approach.
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http://dx.doi.org/10.1021/bc050177oDOI Listing
December 2005

Synthesis and photosensitizing efficacy of isomerically pure bacteriopurpurinimides.

J Med Chem 2004 Sep;47(20):4814-7

PDT Center, Department of Dermatology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

The isomerically pure 3-deacetyl-3-(1-heptyloxy)ethylbacteriopurpurin-N-hexylimides exhibiting long-wavelength absorption near 800 nm were obtained from 3-acetylbacteriopurpurin-N-hexylimide in high stereospecificity by following Corey's synthetic approach. Both heptyl ether derivatives (R- and S-isomers) showed similar in vitro photosensitizing efficacy and limited skin phototoxicity and were found to localize in mitochondria. However, in preliminary in vivo screening, compared to the S-isomer, the corresponding R-isomer produced enhanced in vivo photodynamic therapy efficacy.
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http://dx.doi.org/10.1021/jm049630sDOI Listing
September 2004

Choice of oxygen-conserving treatment regimen determines the inflammatory response and outcome of photodynamic therapy of tumors.

Cancer Res 2004 Mar;64(6):2120-6

Department of Cellular Stress Biology and the Photodynamic Therapy Center, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.

The rate of light delivery (fluence rate) plays a critical role in photodynamic therapy (PDT) through its control of tumor oxygenation. This study tests the hypothesis that fluence rate also influences the inflammatory responses associated with PDT. PDT regimens of two different fluences (48 and 128 J/cm(2)) were designed for the Colo 26 murine tumor that either conserved or depleted tissue oxygen during PDT using two fluence rates (14 and 112 mW/cm(2)). Tumor oxygenation, extent and regional distribution of tumor damage, and vascular damage were correlated with induction of inflammation as measured by interleukin 6, macrophage inflammatory protein 1 and 2 expression, presence of inflammatory cells, and treatment outcome. Oxygen-conserving low fluence rate PDT of 14 mW/cm(2) at a fluence of 128 J/cm(2) yielded approximately 70-80% tumor cures, whereas the same fluence at the oxygen-depleting fluence rate of 112 mW/cm(2) yielded approximately 10-15% tumor cures. Low fluence rate induced higher levels of apoptosis than high fluence rate PDT as indicated by caspase-3 activity and terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. The latter revealed PDT-protected tumor regions distant from vessels in the high fluence rate conditions, confirming regional tumor hypoxia shown by 2-(2-nitroimidazol-1[H]-yl)-N-(3,3,3-trifluoropropyl) acetamide staining. High fluence at a low fluence rate led to ablation of CD31-stained endothelium, whereas the same fluence at a high fluence rate maintained vessel endothelium. The highest levels of inflammatory cytokines and chemokines and neutrophilic infiltrates were measured with 48 J/cm(2) delivered at 14 mW/cm(2) ( approximately 10-20% cures). The optimally curative PDT regimen (128 J/cm(2) at 14 mW/cm(2)) produced minimal inflammation. Depletion of neutrophils did not significantly change the high cure rates of that regimen but abolished curability in the maximally inflammatory regimen. The data show that a strong inflammatory response can contribute substantially to local tumor control when the PDT regimen is suboptimal. Local inflammation is not a critical factor for tumor control under optimal PDT treatment conditions.
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http://dx.doi.org/10.1158/0008-5472.can-03-3513DOI Listing
March 2004