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Immunology Feb 2011Two cationic porphyrins bearing an isothiocyanate group for conjugation to monocolonal antibodies have been synthesized. The two porphyrins conjugated efficiently to...
Two cationic porphyrins bearing an isothiocyanate group for conjugation to monocolonal antibodies have been synthesized. The two porphyrins conjugated efficiently to three monoclonal antibodies (anti-CD104, anti-CD146 and anti-CD326), which recognize antigens commonly over-expressed on a range of tumour cells. In vitro, all conjugates retained the phototoxicity of the porphyrin and the immunoreactivity of the antibody. Mechanistic studies showed that conjugates formed from the mono- and tri-cationic porphyrin and anti-CD104 antibody mediated apoptosis following irradiation with non-thermal red light of 630 ± 15 nm wavelength. In vivo antibody conjugates caused suppression of human LoVo tumour growth in immunodeficient NIH III mice, similar to the commercial photodynamic therapy (PDT) agent Photofrin, but at administered photosensitizer doses that were more than two orders of magnitude lower. Positron emission tomography (PET) following PDT showed a large, early increase in uptake of (18) fluorodeoxyglucose (FDG) by tumours treated with the anti-CD104 conjugates. This effect was not observed with Photofrin or with conjugates formed from the same photosensitizers conjugated to an irrelevant antibody.
Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Colonic Neoplasms; Dihematoporphyrin Ether; Humans; Immunoconjugates; Immunotherapy; Integrin beta4; Isothiocyanates; Light; Mice; Photochemotherapy; Photosensitizing Agents; Porphyrins; Treatment Outcome
PubMed: 21039468
DOI: 10.1111/j.1365-2567.2010.03359.x -
BMC Gastroenterology Sep 2010Recently, several new endoscopic treatments have been used to treat patients with Barrett's esophagus with high grade dysplasia. This systematic review aimed to... (Review)
Review
BACKGROUND
Recently, several new endoscopic treatments have been used to treat patients with Barrett's esophagus with high grade dysplasia. This systematic review aimed to determine the safety and effectiveness of these treatments compared with esophagectomy.
METHODS
A comprehensive literature search was undertaken to identify studies of endoscopic treatments for Barrett's esophagus or early stage esophageal cancer. Information from the selected studies was extracted by two independent reviewers. Study quality was assessed and information was tabulated to identify trends or patterns. Results were pooled across studies for each outcome. Safety (occurrence of adverse events) and effectiveness (complete eradication of dysplasia) were compared across different treatments.
RESULTS
The 101 studies that met the selection criteria included 8 endoscopic techniques and esophagectomy; only 12 were comparative studies. The quality of evidence was generally low. Methods and outcomes were inconsistently reported. Protocols, outcomes measured, follow-up times and numbers of treatment sessions varied, making it difficult to calculate pooled estimates.The surgical mortality rate was 1.2%, compared to 0.04% in 2831 patients treated endoscopically (1 death). Adverse events were more severe and frequent with esophagectomy, and included anastomotic leaks (9.4%), wound infections (4.1%) and pulmonary complications (4.1%). Four patients (0.1%) treated endoscopically experienced bleeding requiring transfusions. The stricture rate with esophagectomy (5.3%) was lower than with porfimer sodium photodynamic therapy (18.5%), but higher than aminolevulinic acid (ALA) 60 mg/kg PDT (1.4%). Dysphagia and odynophagia varied in frequency across modalities, with the highest rates reported for multipolar electrocoagulation (MPEC). Photosensitivity, an adverse event that occurs only with photodynamic therapy, was experienced by 26.4% of patients who received porfimer sodium.Some radiofrequency ablation (RFA) or argon plasma coagulation (APC) studies (used in multiple sessions) reported rates of almost 100% for complete eradication of dysplasia. But the study methods and findings were not adequately described. The other studies of endoscopic treatments reported similarly high rates of complete eradication.
CONCLUSIONS
Endoscopic treatments offer safe and effective alternatives to esophagectomy for patients with Barrett's esophagus and high grade dysplasia. Unfortunately, shortcomings in the published studies make it impossible to determine the comparative effectiveness of each of the endoscopic treatments.
Topics: Barrett Esophagus; Catheter Ablation; Esophagectomy; Esophagoscopy; Humans; Photochemotherapy; Treatment Outcome
PubMed: 20875123
DOI: 10.1186/1471-230X-10-111 -
British Journal of Cancer Jul 2010Photodynamic therapy (PDT) is a promising adjuvant therapy in cancer treatment. However, cancers resistant to PDT, mediated through the efflux of photosensitisers by...
BACKGROUND
Photodynamic therapy (PDT) is a promising adjuvant therapy in cancer treatment. However, cancers resistant to PDT, mediated through the efflux of photosensitisers by means of P-glycoprotein or ATP-binding cassette transporter proteins, have been reported. The DNA repair has also been suggested to be responsible for PDT resistance, but little is known about the repair pathways and mechanisms involved. Therefore, this study aimed to investigate the possible function of six major DNA repair mechanisms in glioma cells resistant to Photofrin-mediated PDT (Ph-PDT).
METHODS
The U87 glioma cells relatively resistant to Ph-PDT were obtained by recovering the viable cells 3 h after PDT treatment. The mRNA and protein expression levels of DNA repair genes were evaluated by quantitative real-time reverse transcription-polymerase chain reaction and western blotting, respectively. Small-interfering RNA and chromatin-immunoprecipitation assays were used to further examine the relationship between AlkB, an alkylation repair homologue 2 (Escherichia coli) (ALKBH2) and Ph-PDT responsiveness, and transcription factors involved in ALKBH2 transcription.
RESULTS
The ALKBH2 of DNA damage reversal was significantly increased at both mRNA and protein levels from 30 min to 48 h post-treatment with Ph-PDT. Conversely, down-regulating ALKBH2 expression enhances Ph-PDT efficiency. Furthermore, our data clearly show for the first time that tumour protein (TP53) is directly involved by binding to the promoter of ALKBH2 in mediating Ph-PDT resistance.
CONCLUSION
C The DNA damage reversal mechanisms may have important functions in Ph-PDT resistance through the activation of ALKBH2 by TP53.
Topics: AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Blotting, Western; Cell Line, Tumor; Cell Survival; Comet Assay; DNA Damage; DNA Repair Enzymes; Dihematoporphyrin Ether; Dioxygenases; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioma; Humans; Kinetics; Photochemotherapy; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Transfection; Tumor Suppressor Protein p53
PubMed: 20661249
DOI: 10.1038/sj.bjc.6605797 -
Alimentary Pharmacology & Therapeutics Sep 2010Porfimer is an intravenous (i.v.) injectable photosensitizing agent used in the photodynamic treatment of tumours and of high-grade dysplasia in Barrett's oesophagus.
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.
Topics: Adenocarcinoma; Aged; Barrett Esophagus; Dihematoporphyrin Ether; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Photochemotherapy; Photosensitizing Agents; Statistics as Topic; Time Factors; Treatment Outcome
PubMed: 20629974
DOI: 10.1111/j.1365-2036.2010.04400.x -
Future Oncology (London, England) Jun 2010Photodynamic therapy (PDT) is a tumor-ablative and function-sparing oncologic intervention. The relative simplicity of photosensitizer application followed by light... (Review)
Review
Photodynamic therapy (PDT) is a tumor-ablative and function-sparing oncologic intervention. The relative simplicity of photosensitizer application followed by light activation resulting in the cytotoxic and vasculartoxic photodynamic reaction has allowed PDT to reach a worldwide audience. With several commercially available photosensitizing agents now on the market, numerous well designed clinical trials have demonstrated the efficacy of PDT on various cutaneous and deep tissue tumors. However, current photosensitizers and light sources still have a number of limitations. Future PDT will build on those findings to allow development and refinement of more optimal therapeutic agents and illumination devices. This article reviews the current state of the art and limitations of PDT, and highlight the progress being made towards the future of oncologic PDT.
Topics: Aminolevulinic Acid; Dihematoporphyrin Ether; Forecasting; Humans; Mesoporphyrins; Nanoparticles; Neoplasms; Oxygen; Photochemotherapy; Photosensitizing Agents
PubMed: 20528231
DOI: 10.2217/fon.10.51 -
Photodiagnosis and Photodynamic Therapy Jun 2010Invasive anal cancers are generally successfully treated by combined chemotherapy with radiation therapy (XRT). For those patients who locally fail this intervention... (Review)
Review
Invasive anal cancers are generally successfully treated by combined chemotherapy with radiation therapy (XRT). For those patients who locally fail this intervention many are salvaged by surgery which generally results in permanent colostomy. We examined the treatment and outcome of Photofrin based photodynamic therapy (PDT) in a cohort of patients with anal cancer who failed locally despite chemo-radiation (N=6) and two patients with positive margins of resection after excision of small T(1) squamous cell anal cancers who refused further surgery or chemo-radiation. PDT consisted of outpatient infusion of Photofrin at 1.2mg/kg followed 48 h later by outpatient illumination. Red light (630 nm) illumination was delivered by a 5 cm diffusing fiber, treating transphincterally at 300 J/cm followed by microlens illumination at 200 J/cm(2) to the perianal tumor bed with 2 cm margin. All patients completed PDT without incident and all have maintained local control of disease in the anal region for the length of follow up (18-48 months). PDT may serve as a new means to salvage local failures and perhaps could be employed as a primary treatment modality in select patients with early stage of disease.
Topics: Antineoplastic Agents; Anus Neoplasms; Dihematoporphyrin Ether; Humans; Photochemotherapy
PubMed: 20510306
DOI: 10.1016/j.pdpdt.2010.04.002 -
The Tohoku Journal of Experimental... Apr 2010Photodynamic therapy (PDT) combines a drug or photosensitizer with a specific type of light to kill cancer cells. The cellular damage induced by PDT leads to activation...
Photodynamic therapy (PDT) combines a drug or photosensitizer with a specific type of light to kill cancer cells. The cellular damage induced by PDT leads to activation of the DNA damage repair, which is an important factor for modulating tumor sensitivity to this treatment. beta-Glucans are natural polysaccharides that bind complement receptor 3 on the effector cells, thereby activating them to kill tumor cells during PDT. The hypothesis of the present study was that adjuvant therapy with beta-glucans would increase the efficacy of PDT. C57BL/6 female mice were subcutaneously implanted with Lewis lung carcinoma cells. Ten days after implantation, the mice were administered intravenously sodium porfimer (10 mg/kg) 24 h prior to laser irradiation, with or without oral administration of beta-glucan (400 microg/d/mouse, 5 days) from either barley, baker's yeast, or marine brown algae that contains the storage glucan, laminarin. Tumor volume and necrotic area in excised tumors were measured. The expression of proliferating cell nuclear antigen (PCNA) was determined as an indicator of the activity of the DNA damage repair system. PDT in combination with each beta-glucan significantly reduced tumor growth (P < 0.05, n = 10) and expression of PCNA (P < 0.001, n = 9), and increased necrosis in tumor tissues (P < 0.001, n = 9). Furthermore, each structurally different
Topics: Animals; Combined Modality Therapy; Female; Lasers; Mice; Mice, Inbred C57BL; Neoplasms; Photochemotherapy; Xenograft Model Antitumor Assays; beta-Glucans
PubMed: 20410681
DOI: 10.1620/tjem.220.299 -
The Cochrane Database of Systematic... Jan 2010Treatments for Barrett's oesophagus, the precursor lesion of adenocarcinoma, are available but whether these therapies effectively prevent the development of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Treatments for Barrett's oesophagus, the precursor lesion of adenocarcinoma, are available but whether these therapies effectively prevent the development of adenocarcinoma, and in some cases eradicate the Barrett's oesophagus segment, remains unclear.
OBJECTIVES
To summarise, quantify and compare the efficacy of pharmacological, surgical and endoscopic treatments for the eradication of dysplastic and non-dysplastic Barrett's oesophagus and prevention of these states from progression to adenocarcinoma.
SEARCH STRATEGY
We searched CENTRAL (The Cochrane Library 2004, issue 4), MEDLINE (1966 to June 2008) and EMBASE (1980 to June 2008).
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing medical, endoscopic or non-resectional surgical treatments for Barrett's oesophagus. The primary outcome measures were complete eradication of Barrett's and dysplasia at 12 months, and reduction in the number of patients progressing to cancer at five years or latest time point.
DATA COLLECTION AND ANALYSIS
Three authors independently extracted data and assessed the quality of the trials included in the analysis.
MAIN RESULTS
Sixteen studies, including 1074 patients, were included. The mean number of participants in the studies was small (n = 49; range 8 to 208). Most studies did not report on the primary outcomes. Medical and surgical interventions to reduce symptoms and sequelae of gastro-oesophageal reflux disease (GORD) did not induce significant eradication of Barrett's oesophagus or dysplasia. Endoscopic therapies (photodynamic therapy (PDT with aminolevulinic acid or porfimer sodium), argon plasma coagulation (APC) and radiofrequency ablation (RFA)) all induced regression of Barrett's oesophagus and dysplasia. The data for photodynamic therapy were heterogeneous with a mean eradication rate of 51% for Barrett's oesophagus and between 56% and 100% for dysplasia, depending on the treatment regimens. The variation in photodynamic therapy eradication rates for dysplasia was dependent on the drug, source and dose of light. Radiofrequency ablation resulted in eradication rates of 82% and 94% for Barrett's oesophagus and dysplasia respectively, compared to a sham treatment. Endoscopic treatments were generally well tolerated, however all were associated with some buried glands, particularly following argon plasma coagulation and photodynamic therapy, as well as photosensitivity and strictures induced by porfimer sodium based photodynamic therapy in particular.
AUTHORS' CONCLUSIONS
Despite their failure to eradicate Barrett's oesophagus, the role of medical and surgical interventions to reduce the troubling symptoms and sequelae of GORD is not questioned. Whether therapies for GORD reduce the cancer risk is not yet known. Ablative therapies have an increasing role in the management of dysplasia within Barrett's and current data would favour the use of radiofrequency ablation compared with photodynamic therapy. Radiofrequency ablation has been shown to yield significantly fewer complications than photodynamic therapy and is very efficacious at eradicating both dysplasia and Barrett's itself. However, long-term follow-up data are still needed before radiofrequency ablation can be used in routine clinical care without the need for very careful post-treatment surveillance. More clinical trial data and in particular randomised controlled trials are required to assess whether or not the cancer risk is reduced in routine clinical practice.
Topics: Adenocarcinoma; Barrett Esophagus; Catheter Ablation; Esophageal Neoplasms; Gastroesophageal Reflux; Humans; Laser Coagulation; Photochemotherapy; Precancerous Conditions; Randomized Controlled Trials as Topic
PubMed: 20091557
DOI: 10.1002/14651858.CD004060.pub2 -
Photochemical & Photobiological... Dec 2009Photodynamic therapy (PDT) can lead to the creation of heterogeneous, response-limiting hypoxia during illumination, which may be controlled in part through illumination...
Photodynamic therapy (PDT) can lead to the creation of heterogeneous, response-limiting hypoxia during illumination, which may be controlled in part through illumination fluence rate. In the present report we consider (1) regional differences in hypoxia, vascular response, and cell kill as a function of tumor depth and (2) the role of fluence rate as a mediator of depth-dependent regional intratumor heterogeneity. Intradermal RIF murine tumors were treated with Photofrin PDT using surface illumination at an irradiance of 75 or 38 mW cm(-2). Regional heterogeneity in tumor response was examined through comparison of effects in the surface vs. base of tumors, i.e. along a plane parallel to the skin surface and perpendicular to the incident illumination. 75 mW cm(-2) PDT created significantly greater hypoxia in tumor bases relative to their surfaces. Increased hypoxia in the tumor base could not be attributed to regional differences in Photofrin concentration nor effects of fluence rate distribution on photochemical oxygen consumption, but significant depth-dependent heterogeneity in vascular responses and cytotoxic response were detected. At a lower fluence rate of 38 mW cm(-2), no detectable regional differences in hypoxia or cytotoxic responses were apparent, and heterogeneity in vascular response was significantly less than that during 75 mW cm(-2) PDT. This research suggests that the benefits of low-fluence-rate PDT are mediated in part by a reduction in intratumor heterogeneity in hypoxic, vascular and cytotoxic responses.
Topics: Animals; Cell Hypoxia; Dihematoporphyrin Ether; Fibrosarcoma; Light; Mice; Mice, Inbred C3H; Neoplasms, Radiation-Induced; Nitroimidazoles; Photochemotherapy; Photosensitizing Agents
PubMed: 20024165
DOI: 10.1039/b9pp00004f -
Ai Zheng = Aizheng = Chinese Journal of... Dec 2009The mechanism of tumor tissues selectively uptake the photosensitizer in photodynamic therapy (PDT) is still unclear. This study was to investigate the affinity of tumor...
BACKGROUND AND OBJECTIVE
The mechanism of tumor tissues selectively uptake the photosensitizer in photodynamic therapy (PDT) is still unclear. This study was to investigate the affinity of tumor cells to the photosensitizer photofrin-II.
METHODS
Ultraviolet spectrophotometer was applied to measure the absorption spectra of various cell culture media. The fluorescence spectrum of photofrin-II was determined by spectrofluorometer. The absorption and elimination condition of photofrin-II were detected in immortalized human esophageal epithelial cell line SHEE and its malignant transformation cell line SHEEC.
RESULTS
The maximum excitation wavelength of fluorescence for photofrin-II was (395.0+/-0.5) nm, and the maximum emission wavelength of that was (634.1+/-0.5) nm. The laser at the wavelength of 630 nm used in this experiment could permeate various types of cell culture media. There was no significant difference in the absorption and elimination of photofrin-II between SHEE and SHEEC at the same concentration and time. The absorption of photofrin-II in SHEE and SHEEC increased with the increase in photofrin-II concentration and duration, and reached the platform at the concentration of 30 microg/mL and a time point of 150 min, respectively. The photofrin-II contents of SHEE and SHEEC showed a slight change after 15-30 min, and diminished rapidly after 30 min.
CONCLUSION
High photosensitizer concentration in tumor tissues may be not correlated with the affinity of tumor cells.
Topics: Cell Line; Cell Line, Tumor; Dihematoporphyrin Ether; Epithelial Cells; Esophageal Neoplasms; Esophagus; Humans; Photosensitizing Agents; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet
PubMed: 19958617
DOI: 10.5732/cjc.008.10585