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Leonard I. Grossweiner, Linda Ramball Jones, Irmgard K. Koehler M.D., Mehmet D. Bilgin M.D.
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237521
Skin reflection spectra were measured before and 24 hours after administration of Photofrin (Reg. TM) to basal cell nevus syndrome (BCNS) patients. The drug reduced the reflectivity of uninvolved BCNS skin and increased the reflectivity of basal cell cancers. Photofrin (Reg. TM) absorption in normal rat skin and uninvolved BCNS skin was resolved by the diffusion approximation. Optical constants calculated with a two-layer skin model indicate that the drug increased light scattering in tumor tissues. The possible use of reflection spectra for PDT light dosimetry is discussed.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237529
Seventy-nine patients with neoplastic diseases of the larynx, oral cavity, pharynx, and skin have been treated with photodynamic therapy (PDT) with follow-up to 65 months. Patients with carcinoma-in-situ (CIS) and T1 carcinomas obtained a complete response after one PDT treatment. All but two patients remain free of disease. Four patients with T2 and T3 superficial carcinomas were treated with PDT. One patient developed recurrence with 51- month follow-up. Eleven patients with deeply invasive T2, T3, and T4 carcinomas were treated with PDT. Of those eleven, eight obtained a complete response, but five have recurred locally. A response can be achieved with PDT, although not a consistent complete response because of the depth of invasion of the tumor. This is due to the inability to adequately deliver laser light to the depths of the tumor bed. Eight patients with massive neck recurrences of squamous cell carcinomas were treated with intraoperative adjuvant PDT following tumor resection. Only one patient developed recurrence with 30-month follow-up. PDT is highly effective for the curative treatment of early carcinomas (CIS, T1) of the head and neck. T2 and T3 superficial carcinomas, with invasion less than 0.5 cm, are also curatively treated with PDT with significantly reduced morbidity compared to conventional modes of treatment. Also, intraoperative adjuvant PDT may increase cure rates of large infiltrating carcinomas of the head and neck.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237536
Photodynamic therapy has been established as an alternative treatment for patients with Barrett's esophagus with dysplasia or early superficial cancer. Twenty-three patients have been treated and followed for 6 - 54 months. Twenty-one patients had high grade dysplasia and 2 had low grade dysplasia. Ten patients had early cancer (Tis-T1) and 1 had T2 cancer. All patients were maintained on omeprazole after treatment. Three separate PDT treatments were required in 2 patients, 2 in 5 patients and 1 in 16. Dysplasia and carcinoma were eliminated in all. Seventy-five to eighty percent of Barrette's mucosa was replaced by squamous epithelium. One patient developed a new carcinoma in an area of dysplasia treated 3 months earlier and was retreated successfully. Two patients developed new areas of dysplasia in untreated segments of the Barrett's esophagus, requiring a separate treatment. Twelve patients developed strictures, all responding well to dilatation.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237545
Photodynamic therapy was used to treat 111 lesions in 27 cases with squamous and basal cell carcinoma. There were 82 squamous cell carcinomas and 29 basal cell carcinomas. Photofrin was administered intravenously at either 1.0 mg/kg or 0.75 mg/kg. An argon/dye laser was used to deliver 630 nm light to the lesion superficially at either 215 J/cm2 or 240 J/cm2. In some cases the laser light was delivered both superficially and interstitially. The laser light was delivered two to four days after the Photofrin injection. There were 105 complete responses and 5 partial responses. One patient was lost to follow-up. Among partial responses were basal cell carcinoma on the tip of the nose and morphea basal cell carcinoma of the left cheek. Another partial response occurred in a basal cell carcinoma patient where insufficient margins were treated due to the proximity to the eye. When 0.75 mg/kg drug dose was used, the selectivity of tumor necrosis was improved. Decreased period of skin photosensitivity was documented in some cases.
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Stuart L. Marcus M.D., Russel S. Sobel, Allyn L. Golub, Ronald L. Carroll, Scott L. Lundahl, D. Geoffrey Shulman M.D.
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237548
Exogenous provision of ALA to many tissues results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX, (PpIX), to produce a photodynamic effect. Therefore, ALA may be considered the only current PDT agent in clinical development which is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous T-cell lymphoma, superficial basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses, and is also being examined for treatment of acne and hirsutism. PpIX induced by ALA application also may serve as a fluorescence detection marker for photodiagnosis (PD) of malignant and pre- malignant conditions of the urinary bladder and other organs. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and is beginning to be examined in human clinical studies. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. This brief paper reviews the current clinical and development status of ALA PDT.
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Nicholas J. Razum, Albert B. Snyder, Daniel R. Doiron
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237549
Tin Ethyl Etiopurpurin, SnET2, is a synthetic chlorin analog presently in Phase-II/III clinical trials for the treatment of cutaneous cancers. Trials to date include the treatment of basal cell carcinomas, squamous cell carcinomas, breast adenocarcinomas metastatic to the chest wall and cutaneous Kaposi's sarcomas in AIDS patients. Results to date have shown significant clinical responses for drug doses between 1.0 mg/kg and 1.6 mg/kg, with the threshold for Kaposi's sarcoma being slightly higher than in other indications. Light doses from 100 J/cm2 to 300 J/cm2 were delivered from 24 to 72 hours post SnET2 infusion. Induced transient skin photosensitivity at the lower therapeutic doses has been mild, lasting approximately a week. Results of the Phase I and II trials are presented.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237550
From 1983 to 1996 Phase II and III clinical studies at Henry Ford Hospital demonstrated complete or partial responses in 55 of 56 patients treated with hematoporphyrin-derivative or PHOTOFRIN-mediated photodynamic therapy (HPD-PDT) for a variety of benign and malignant upper aerodigestive tract disease: (1) superficial 'condemned mucosa' or 'field cancerization' of the oral cavity and larynx (7 cases); (2) Stage III/IV head and neck cancer (25 cases); (3) mucocutaneous AIDS-associated Kaposi's sarcoma of the upper aerodigestive tract and non AIDS-related Kaposi's sarcoma of the lower extremity (15 cases); (4) recurrent laryngotracheal papillomatosis (3 cases); (5) severe dysplasia/adenocarcinoma or squamous cell carcinoma in situ in Barrett's esophagus (4 cases); (6) partial or completely obstructing terminal esophageal cancer (9 cases). At the time of this report, HPD-PDT produced complete responses in 24 patients (follow up 6 months to 9 years) with 'field cancerization' (CIS, T1N0M0) of the oral cavity and larynx (6 cases), adenocarcinoma in situ in Barrett's esophagus (3 cases), mucocutaneous Kaposi's sarcoma (12 cases), obstructing esophageal carcinoma (1 case), and stage IV squamous cell carcinoma of the nasopharynx (1 case), and radiation therapy or solar-induced basal cell/squamous cell carcinomas (2 cases). PDT treatment protocols, results, complications, and application as adjunct or primary oncologic therapy for head and neck cancer are reviewed in this article.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237522
Hypericin has been studied as a novel natural photosensitizer for PDT. It has been extracted from plants (St.-John's-wort). Oral administration (10% alcohol solution in a dose 2 mg/kg b.w.) was applied for 15 patients with gastric cancers 18 - 48 h before surgery. Normal and cancerous tissue samples were resected and underwent fluorescence analysis 1 - 2 h after resection. Tissue fluorescence was excited by He-Cd (20 mW, 442 nm) and Ar laser beams (100 mW, 488 nm) and registered from 510 to 725 nm. In tissue hypericin has maximum fluorescence peak at 603 nm for both excitation wavelengths. Fluorescence intensity ratio I603/I503 chosen as a criterion for tissue classification was varied from 1.6 to 3.2 (mean 2.5) for adenocarcinoma under He-Cd excitation whereas Ar laser excitation gave from 2.5 up to 4.2 (mean 3.5). Normal tissue had this ratio from 0.48 to 0.65 (mean 0.55) and from 0.53 to 0.75 (mean 3.5) for He-Cd and Ar laser excitation, respectively. No side effects were observed in patients during 6 month follow-up.
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Christine J. Radasky, David H. Crean, Daniel R. Doiron
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237523
One of the key components of photodynamic therapy dosimetry studies is the actual light dose delivered to the tissue at a targeted, therapeutic depth. The light dose delivered to the tissue is dependent upon the incident irradiance at the initial point of light application as well as the tissue optical properties. Since the parameters defining the light and therapeutic dose may vary between subjects and treatment sites as well as during treatment, it is advantageous to monitor the dosimetry during photodynamic therapy. The objective of this work is to develop methodologies and systems to enable on-line dosimetry. This initial study examines the relationship between incident irradiance and space irradiance for cutaneous areas in various humans. Space irradiance levels (mW/cm2) were measured on the skin surface of 30 subjects using isotropic fiber optic probes (0.8 mm) and were compared to incident irradiance levels. Space irradiance values were obtained from various anatomical locations on each subject during surface illumination (664 plus or minus 7 nm) using an incident irradiance of 100 mW/cm2. The results demonstrate ratios of space irradiance: incident irradiance from 1.49 to 2.35 for all cutaneous areas. Abnormal skin features, such as scars, birthmarks, moles, freckles, etc., on the arm demonstrated ratios ranging from 1.58 to 1.84. Variances observed within and between subjects demonstrate the need for accurate dosimetry monitoring during therapy. A larger study is planned to fully characterize space irradiance variations in normal skin as well as cutaneous lesions in additional subjects.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237524
It is known that if the drug uptake by a tumor is below the required concentration the efficacy of PDT can be significantly reduced. There is, therefore, a need for a photodynamic drug detection (PD3) system to be used with PDT to monitor the drug concentration in tissue in real time and noninvasively. The system developed integrates laser, a fiber optic probe, and an optical detector to detect photodynamic drugs (Photofrin II, Protoporphyrin IX, and BPD). A series of drug concentrations was measured based on the detection of diffusely fluorescence photons. The fluorescence peak at 680 nm is suggested for intensity measurement. The effect of fluorescence reabsorption was observed when using high concentration Photofrin solutions. When PD3 is used in conjunction with monitoring through an endoscope, the system offers spectral information (displayed on a computer monitor) in addition to the conventional image (displayed on an endoscope monitor).
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237525
The effectiveness of a new excimer laser endoscopic imaging fluorescence analyzer system using the photosensitizer, mono-L-aspartyl chlorin e6 (NPe6) for the detection of tumors was evaluated. Autofluorescence (550 plus or minus 10 nm, green fluorescence) from normal sites, red fluorescence (664 nm) of NPe6 in areas of cancer and the red fluorescence/green fluorescence ratio (R/G ratio) as the color image can be detected respectively. The greatest NPe6 fluorescence from the lesion was obtained at 3 hours after injection and the fluorescence disappeared at 24 hours. The greatest difference in the fluorescence of NPe6 and the R/G ratio in areas of tumor and in normal areas were observed at 5 hours after administration. At this period, NPe6 fluorescence from normal sites was negligible. These data suggest that fluorescence photodiagnosis may be effective in the detection of cancers.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237526
We present a method to determine the back reflected radiance from an isotropically scattering halfspace with matched boundary. The bonus of this method lies in the fact that it is capable, in principle, to handle the case of narrow beams, something which, to our knowledge, no other analytic method can do. Essentially, the method derives from a mathematical criterion that effectively forbids the existence of solutions to the transport equation which grown exponentially as one moves away from the surface and deeper into the medium. Preliminary calculations for infinitely wide beams yield results which agree well with what is found in literature.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237527
Indocyanine green was used to enhance laser-induced photothermal destruction of murine mammary tumor cells. The 808-nm diode laser used in these experiments matches the absorption peak of the indocyanine green. The combination of the laser and in situ administration of aqueous ICG provided a highly selective photothermal destruction pattern of the tumor tissue. Histology showed that within the power range of 3 to 5 watts. The ICG- targeted tumor tissues were fatally injured, while the peripheral tissues such as skin and other interdicting tissue not containing ICG were spared. Higher powers (10 to 15 watts) could inflict severe surface damage but only resulted in limited tissue penetration. Post-treatment observation also revealed surviving tumor cells, the cause of which might be the non-uniform distribution of ICG as well as the random scattering of photons inside tissue. After laser-ICG treatment, the tumor continued to grow, but at a slower rate, and to metastasize, leading to the death of the rats. The findings of our experiments question the long-term efficacy of the photothermal effect of a single treatment using the ICG and diode laser. However, the controlled killing of tumor cells on a large scale may be proven crucial when the treatment is applied repeatedly and/or in an earlier stage so that tumor growth could be stopped and metastases prevented. This photothermal interaction may also be effective when used in conjunction with other modalities.
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Modestus Obochi, Jing-Song Tao, David W. C. Hunt, Julia G. Levy
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237528
The capacity of photosensitizers and light to ablate cancerous tissues and unwanted neovasculature constitutes the classical application of photodynamic therapy (PDT). Cell death results from either necrotic or apoptotic processes. The use of photosensitizers and light at doses which do not cause death has been found to affect changes in certain cell populations which profoundly effect their expression of cell surface molecules and secretion of cytokines, thereby altering the functional attributes of the treated cells. Cells of the immune system and the skin may be sensitive to modulation by 'sub-lethal PDT.' Ongoing studies have been conducted to assess, at the molecular level, changes in both lymphocytes and epidermal cells (EC) caused by treatment with low levels of benzoporphyrin derivative monoacid ring A (BPD) (a photosensitizer currently in clinical trials for cancer, psoriasis, endometriosis and age-related macular degeneration) and light. Treatment of skin with BPD and light, at levels which significantly enhanced the length of murine skin allograft acceptance, have been found to down-regulate the expression of Langerhans cell (LC) surface antigen molecules [major histocompatibility complex (MHC) class II and intracellular adhesion molecule (ICAM)-1] and the formation of some cytokines (tumor necrosis factor-alpha (TNF- (alpha) ).
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237530
Photodynamic therapy of neoplastic cell lines can lead to the rapid initiation of apoptosis, a mode of cell death that results in a characteristic pattern of cellular and DNA fragmentation. In this study, we examine the effects of protein tyrosine- and serine/threonine phosphatases and kinases on the fragmentation of DNA to 50 kb and photodynamic effects of lysosomal and mitochondrial photosensitizers on murine leukemia P388 cells. The data are consistent with the proposal that maintenance of phosphorylated tyrosine residues is essential for the PDT- induced processing of 50 kb DNA to nucleosomes, while maintenance of serine phosphorylation inhibits such processing. Factors involved in chromatin fragmentation to 50 kb particles have yet to be elucidated. Several agents which mediate membrane photodamage mimic the effect of protein serine/threonine phosphatase inhibitors, i.e., they inhibit further processing of the 50 kb DNA formed as a consequence of lysosomal or mitochondrial photodamage. These results indicate that even the rapid initiation of apoptosis by PDT is modulated by phosphatase and kinase activities.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237531
The photobleaching of the native fluorescence, as well as of the BPD-MA, an exogenous sensitizer, was measured in an in-vivo tumor bearing rat model. The photobleaching was evaluated in the time scale of seconds (approximately 0 sec - 30 sec) under continuous wave laser light irradiation at 441.6 nm. Three different sites were irradiated: the primary tumor, the mesenteric I lymph node, and the right medial iliac lymph node, at two excitation levels of 6.5 mW/mm2 (n equals 6), and approximately 35 mW/mm2 (n equals 6). Most of the fluorescence curves were adequately characterized by a biexponential decay. Increased levels of illumination were found to accelerate the photobleaching. No involvement of statistical significance of the irradiation site on the fluorescence decay was found.
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James A. Hampton, Patricia A. Mahama, Ronald L. Fournier, Jeffery P. Henning
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237532
We have developed a transient, one-dimensional mathematical model for the reaction and diffusion phenomena that occurs during photodynamic therapy (PDT). This model is referred to as the PDTmodem program. The model is solved by the Crank-Nicholson finite difference technique and can be used to predict the fates of important molecular species within the intercapillary tissue undergoing PDT. The following factors govern molecular oxygen consumption and singlet oxygen generation within a tumor: (1) photosensitizer concentration; (2) fluence rate; and (3) intercapillary spacing. In an effort to maximize direct tumor cell killing, the model allows educated decisions to be made to insure the uniform generation and exposure of singlet oxygen to tumor cells across the intercapillary space. Based on predictions made by the model, we have determined that the singlet oxygen concentration profile within the intercapillary space is controlled by the product of the drug concentration, and light fluence rate. The model predicts that at high levels of this product, within seconds singlet oxygen generation is limited to a small core of cells immediately surrounding the capillary. The remainder of the tumor tissue in the intercapillary space is anoxic and protected from the generation and toxic effects of singlet oxygen. However, at lower values of this product, the PDT-induced anoxic regions are not observed. An important finding is that an optimal value of this product can be defined that maintains the singlet oxygen concentration throughout the intercapillary space at a near constant level. Direct tumor cell killing is therefore postulated to depend on the singlet oxygen exposure, defined as the product of the uniform singlet oxygen concentration and the time of exposure, and not on the total light dose.
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Mladen Korbelik, Gorazd Krosl, Jana Krosl, Graeme J. Dougherty
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237533
Photodynamic treatment, consisting of intravenous injection of PhotofrinR (10 mg/kg) followed by exposure to 110 J/cm2 of 630 plus or minus 10 nm light 24 hours later, cured 100% of EMT6 tumors (murine mammary sarcoma) growing in syngeneic immunocompetent BALB/C mice. In contrast, the same treatment produced no cures of EMT6 tumors growing in either nude or SCID mice (immunodeficient strains). EMT6 tumors growing in BALB/C and SCID mice showed no difference in either the level of PhotofrinR accumulated per gram of tumor tissue, or the extent of tumor cell killing during the first 24 hours post photodynamic therapy (PDT). In an attempt to improve the sensitivity to PDT of EMT6 tumors growing in SCID mice, these hosts were given either splenic T lymphocytes or whole bone marrow from BALB/C mice. The adoptive transfer of lymphocytes 9 days before PDT was successful in delaying tumor recurrence but produced no cures. A better improvement in PDT response was obtained with tumors growing in SCID mice reconstituted with BALB/C bone marrow (tumor cure rate of 63%). The results of this study demonstrate that, at least with the EMT6 tumor model, antitumor immune activity mediated by lymphoid cell populations makes an important contribution to the curative effect of PDT.
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Jean Francois Bisson, Dominique Notter, P. Labrude, C. Vigneron, Francois H. Guillemin
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237534
Photochemotherapy using I.V. administered porphyrin photosensitizers has been used to treat superficial bladder cancers. In order to avoid cutaneous photosensitivity, lasting 6 - 8 weeks, we instilled the photosensitizer intravesically. After first studying the diffusion and localization of HpD in aqueous phase (5 mg/ml) in vitro through the bladder wall of pig by spectrofluorimetry ((lambda) ex equals 392 nm and (lambda) em equals 612.8 nm) and fluorescence microscopy, we determined the biodistribution of HpD in vivo in the rat bladder wall, 2 and 4 hours after bladder instillation of 0.4 ml of HpD: (1) the controls show only a weak autofluorescence restricted to the urothelium after 2 hours (24 micrometers plus or minus 5 micrometers, n equals 3) as well as after 4 hours (29.5 micrometers plus or minus 5 micrometers, n equals 3); (2) on the test preparation a higher fluorescence was observed: after 2 hours, HpD was localized in the urothelium and a very small part of the chorion (55 micrometers plus or minus 9 micrometers, n equals 9) whereas after 4 hours, it penetrated almost completely in the bladder wall (960 micrometers plus or minus 118 micrometers, n equals 9). In conclusion, a bladder instillation of 2 hours seems to be the optimal time of application in the rat since superficial bladder cancers, like carcinoma in situ, particularly occur in the urothelium (stage 0, pTa) or in the chorion (stage 1, pT1).
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237535
Lutetium texaphyrin (PCI-0123) is a pure, stabile, water-soluble photosensitizer with a broad absorption band centered at 732 nm. Lutetium texaphyrin has shown considerable promise in the treatment of murine mammary tumors. PDT requires the coexistence of a photosensitizer, oxygen and light. Light fluences, rates and delivery methods have a profound influence on oxygen depletion and re-equilibration and therefore tumor responsiveness. The effect of different photoirradiation and sensitizer dose in eradicating/retarding EMT6 tumors in BALB/c mice using lutetium texaphyrin was evaluated. An increase in light fluences increased efficacy. No difference was observed between a continuous versus a fractionated light protocol. A reduction in time between sensitizer injection and laser treatment enhanced tumor treatment.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237537
In order to evaluate structure-activity relationships in the benzochlorin ring system, a series of functionalized benzochlorins have been synthesized by modifying the sulfonic acid group of octaethylbenzochlorin sulfonic acid (OEBCS). Using very simple chemistry it has been possible to produce a large number of benzochlorins that differ only in the nature of functionality of a pendant side arm. The introduction of zinc or tin into the benzochlorin macrocycle produces the corresponding metallated benzochlorins that retain the original functionality. The synthesis and spectroscopic properties of the free base and metallobenzochlorins are discussed. Preliminary in vivo results show that different functionality causes significant differences in biological efficacy.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237538
Porphyrin derivatives substituted at a meso-position with a (2-cyanovinyl) group were synthesized from (2-formylvinyl) porphyrins. Demetallation and subsequent cyclization produced the corresponding cyanopurpurins. All cyanopurpurin derivatives show strong band I absorptions at 692 nm.
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Shwn-Ji H. Lee, Ricardo Orbegoso, Byron C. Robinson
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237539
A route to the synthesis of free base and metallo N-methylated chlorins based on trans- octaethylchlorin (t-OEC), octaethylbenzochlorin (OEBC) and ethyl etiopurpurin I (ET2) is presented. The 1H NMR spectra and electronic spectra of these compounds are discussed.
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Franz-Peter Montforts, Dirk Kusch, Frank Hoper, Stefan Braun, Benjamin Gerlach, Hans-Dieter Brauer, Guido Schermann, Joerg G. Moser
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237540
Chlorin type sensitizers have ideal photophysical properties for an application in PDT. The basic chlorin framework of these sensitizers has to be modified by attachment of lipophilic and hydrophilic residues to achieve a good cell uptake and tumor enrichment. In the present study we describe the selective synthesis of amphiphilic chlorins starting from the readily accessible red blood pigment heme. The photophysical properties of the well defined synthetic chlorins are characterized by photophysical investigations. The kinetic of cell uptake, the localization in the cell and the photodynamic behavior of the amphiphilic sensitizers are demonstrated by incubation of A 375 cancer cell lines with structurally different chlorins.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237541
The authors developed a new high-power red laser diode system (Matsushita Industrial Equipment Co., Ltd., Osaka) for photodynamic therapy (PDT) with mono-L-aspartyl chlorin e6 (NPe6, Meiji Seika Kaisha LTD.). The laser wavelength was adjusted to 664 nm and the power output could be varied in the range of 50-500 mW at the fiber tip in a continuous wave (cw) mode. The delivered energy could be adjusted from 50 - 1000 J. The system has a size of 49 by 20 by 40 cm, weighs 20 kg, and is readily portable. It runs on 100 V current. The laser power is easily controlled and the wavelength is stable (less than plus or minus 0.2 nm). The output beam is delivered via a quartz fiber. Furthermore, the full width at half-maximum power is less than 2 nm, which enables uniform, high-density photoirradiation. The power density distribution of the laser, analyzed by a CCD camera, was uniform throughout the photoirradiated field. In an animal study, tumor-bearing Balb/c mice were treated with the diode laser 5 hours after intravenous administration of NPe6 at a dose of 1.25 to 12.5 mg/kg i.v.. Total photoirradiation ranged from 3.13 to 250 J/cm2 which the energy density was adjusted to 100 mW/cm2. Percentages of cures were determined histopathologically from numbers of mice apparently disease-free 1 week after treatment. The results show that a laser energy of more than 12.5 J/cm2 was necessary to obtain 90% tumor cure rate at a maximum dose of NPe6 (12.5 mg/kg) and NPe6 dose of more than 2.5 mg/kg was necessary to obtain 90% cure rate at high laser energy of 200 J/cm2.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237542
Triarylmethanes represent a class of cationic dyes whose potential as photosensitizers for use in photodynamic therapy of neoplastic diseases has never been comprehensively evaluated. Here, the laser-induced photodecomposition of three triarylmethane dyes, crystal violet, ethyl violet, and malachite green, non-covalently bound to bovine serum albumin (a model biological target) was investigated. Upon laser excitation at 532 nm, the bleaching of the corresponding dye-protein molecular complexes follows spectroscopic patterns that suggest the formation of reduced forms of the dyes as major reaction photoproducts. That implies that an electron or hydrogen atom transfer from the protein to the dye's moiety within the guest-host complex is the first step of the photobleaching process. Since the availability of dissolved molecular oxygen was not identified as a limiting factor for the phototransformations to occur, these dyes can be seen as potential phototherapeutic agents for use in hypoxic areas of tumors. These triarylmethane dyes strongly absorb at relatively long wavelengths (absorption maximum around 600 nm; (epsilon) max approximately equals 105 M-1 cm-1), and only minor changes in their absorption characteristics are observed upon binding to the protein. However the binding event leads to a remarkable increase in their fluorescence quantum yield and photoreactivity.
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Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237543
Arthroscopic synovectomy, which is limited today to the large joints, is an important early treatment of rheumatoid arthritis (RA). Photodynamic therapy (PDT) is potentially to be a less invasive method of removing the synovial membrane. Therefore, in a rabbit model of RA, the accumulation of the photosensitizer Protoporphyrin IX (PPIX) after intra-articular and systemic application of ALA into arthritic rabbit knee joints was studied in skin, patella, synovial tissue, and meniscus by fluorescence microscopy. PPIX fluorescence was measured in biopsies taken at different times after application of neutral and acid ALA solutions. Significant PPIX fluorescence was observed in the synovial membrane and skin 2 and 4 hours after application. Using intra-articular application, ALA solutions prepared with pH 5.5 were at least as efficient as neutral solutions in sensitizing the synovial membrane. Skin also showed PPIX within 4 hours after application. After 24 hours, a marginal PPIX fluorescence was detected in these tissues. On the other hand, in cartilage and meniscus significant PPIX accumulation was still observed 24 hours after ALA injection. Systemic application of ALA also showed a good accumulation of PPIX. Further experiments are needed to show whether accumulation of the photosensitizer and tissue selectivity are sufficient for a successful treatment of rheumatoid synovitis.
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Anatoly P. Losev, I. N. Nichiporovich, Ivan N. Zhuravkin, Edvard A. Zhavrid M.D.
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237544
A number of derivatives of chlorin e6 (mono, di and trimethyl ethers) and purpurin-18 (monomethyl ether) potential sensitizers of PDT have been prepared and spectral-kinetic properties of their lowest electronic singlet and triplet states have been studied. The extinction of Q-band of the studied chlorins is much higher than convenient porphyrin photosensitizers and varies between 3 - 6 (DOT) 104 M-1 cm-1. The highest degree of polarization is 0.45 and related to S1-S0 transition. Quantum yields of fluorescence (rho) purpurin-18 in diethyl ether is lowest among the other studied chlorins and consists of 0.10 and decreases with increasing concentration as a result of the aggregation. The chlorin e6 derivatives have close values of quantum yields of fluorescence (0.16 - 0.18). Appreciable quantum yield of fluorescence is promising for application of chlorins for tumor detection due to photosensitizer retention in tumor tissues. The quantum yield of triplet formation (gamma) measured flash photolysis method was 0.70 - 0.76. The energy of the lowest triplet level estimated by maximum of phosphorescence band of chlorins is between 830 - 900 nm. The rate constant of oxygen quenching of triplets in solutions is one order less than diffusion rate constant. The luminescence of singlet oxygen has been observed as a result of energy transfer from triplet state of chlorins to molecular oxygen in organic solvents and deuterated water. Relative intensity of singlet oxygen luminescence 1272 nm photosensitized by different chlorins correlated with quantum yields of its triplets formation. The difference 0.05 - 0.20 between the unit and the sum of (rho) plus (gamma) for the number of chlorins has been assigned to the channel of internal conversion. The internal conversion was eliminated by deuteration of an NH group of chlorins showing that high frequency NH vibrations are responsible for radiationless deactivation of electron energy of the S1 state of chlorins. The comparison of photodynamic action chlorins and photofrin on cells level and tumors in vivo demonstrates that chlorins are more potent photosensitizers of PDT.
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Nadezgda L. Torshina, Anna M. Posypanova, Anna I. Volkova
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237546
At present, there are lots and lots of chemical compounds that are, to a certain extent, photodynamically active. Therefore, the task of carrying out the expressive screening of such compounds has been raised sharply enough. The primary screening in vitro of compounds, with the help of biological liquids, is notable for quickness and cheapness at the same time, it is possible to determine the comparative characteristics of compounds by their photodynamical activity. Decomposition of albumins of a mixture of photosensitizer and biological liquid when irradiating with light is the basis of this method. Efficiency of decomposition of components of biological liquids is determined using biochemical reactions (e.g., those for determining the total albumins or blood hemoglobin). Subsequently, with a sufficient efficiency of a photosensitizer, it will be possible to carry out a study in vivo, with the purpose of establishing accumulation of preparations in tumor.
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Laima Bloznelyte-Plesniene M.D., Vytautas Cepulis, Igor V. Ponomarev
Proceedings Volume Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy V, (1996) https://doi.org/10.1117/12.237547
One of the main problems which arise employing PDT is the patient's sensitization to the sunlight during a 4 - 6 week period after the i/v photosensitizers injection. Applying PDT for patients with head and neck cancer there often is the possibility to inject photosensitizer (the doses of photosensitizer used were many times smaller than in ordinary PDT) intra-arterially (i/a). This is followed by immediate tumor irradiation with laser light. The absorbed light's energy dose is the same as the dose usually used during the PDT. Since 1989 172 head and neck tumors were treated by us applying ordinary PDT and for 17 foci of oral cancer we provided intra-arterial photodynamic therapy. The result of i/a PDT was the same as in usual usage of PDT. But i/a PDT enables the usage of much smaller doses of photosensitizer. Patients need not be protected from the sunlight. I/a PDT enables us also to use effective but quickly splitting photosensitizers.
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