Proceedings Volume 2924

Photochemotherapy: Photodynamic Therapy and Other Modalities II

Stanley B. Brown, Benjamin Ehrenberg, Johan Moan
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Proceedings Volume 2924

Photochemotherapy: Photodynamic Therapy and Other Modalities II

Stanley B. Brown, Benjamin Ehrenberg, Johan Moan
View the digital version of this volume at SPIE Digital Libarary.

Volume Details

Date Published: 4 December 1996
Contents: 5 Sessions, 44 Papers, 0 Presentations
Conference: BiOS Europe '96 1996
Volume Number: 2924

Table of Contents

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Table of Contents

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  • Basic Studies
  • Preclinical Studies I
  • Preclinical Studies II
  • Clinical Studies
  • Basic Studies
  • Preclinical Studies II
  • Basic Studies
  • Clinical Studies
  • Preclinical Studies II
  • Basic Studies
  • Preclinical Studies II
  • Basic Studies
  • Preclinical Studies II
  • Basic Studies
  • Clinical Studies
  • Basic Studies
  • Clinical Studies
  • Preclinical Studies II
  • Plenary Paper
Basic Studies
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How many molecules of a photosensitizer are necessary to photosensitize a tumor cell?
Joerg G. Moser, Franz-Peter Montforts, Dirk Kusch, et al.
Diglycosylated porphyrinoids were shown to stack at the outer cell membrane of tumor cells in vitro. Similar phototoxicities are acquired as with the non-glycosylated drugs at amounts of only 1% of that normally taken up of the non-glycosylated drugs. This means that a strict positioning of sensitizers at sensitive compartments may reduce the amount of sensitizer necessary to sensitize a tumor cell to about 106 molecules per cell. Similar numbers were seen only in erythrocytes and with immunoconjugates in ovarian cancer. This low amount facilitates photosensitizer transport against intratumoral pressure gradients.
Measurement and modelling of protoporphyrin IX photo-oxidation during superficial PDT
Dominic J. Robinson, Mark R. Stringer, William R. Crum, et al.
The oxidation of photosensitizers during photodynamic therapy (PDT) has important implications for their therapeutic and diagnostic potential. The reduction in sensitizer concentration during illumination progressively reduces the effectiveness of therapy and, ultimately, limits the destruction of the host tissue. In the course of our studies of the effects of PDT upon superficial skin disorders, following topical application of 5- aminolaevulinic acid (ALA), we routinely record the surface fluorescence emission of protoporphyrin IX (PpIX) before, during, and after therapy, in order to monitor the sensitizer photo-oxidation. It is important, therefore, to establish that measurements made in this way are representative of the variation in sensitizer concentration throughout the illuminated volume. We have developed a time- dependent Monte-Carlo model to simulate PpIX photo-oxidation during either low intensity laser (488 nm) or white light irradiation of plaque psoriasis. We have assessed the effect of differences in the optical properties of tissue at sites on different patients prior to treatment, and the effect of these variations on the surface fluorescence signal detected during treatment, at sites within the same plaque. The results show that the PpIX fluorescence intensity recorded from plaque psoriasis is an accurate indicator of the relative concentration of the sensitizer and can be used as a direct comparison between different sites and different patients. Also, the reduction in fluorescence emission during PDT is an effective measure of the depletion in sensitizer concentration throughout the illuminated volume. These results illustrate that the light dose required to achieve significant PpIX photo-oxidation is significantly lower than that often adopted for the treatment of superficial skin conditions.
Energetics of chlorins as potent photosensitizers of PDT
Anatoly P. Losev, I. N. Nichiporovich, Ivan N. Zhuravkin, et al.
A number of derivatives of chlorin e6 (mono, di and trimethyl ethers), purpurin-18 (monomethyl ether) and tetracarboxyphenylporphyrin -- potential sensitizers of PDT have been prepared and spectral-kinetic properties of their lowest electronic excited singlet and triplet states have been studied. The extinction of Q-band of studied chlorins is much higher than conventional porphyrin photosensitizers and varies between 3 - 6 multiplied by 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 are lowest among 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 a number of sensitizers has been assigned to the channel of internal conversion. The internal conversion was eliminated by deuteration of NH group of macrocycle showing that high frequency NH vibrations are responsible for radiationless deactivation of electron energy of the S1 state of sensitizers. The comparison of photodynamic action chlorins and photofrin on cells level and tumors in vivo demonstrates that chlorins are more potent photosensitizers of PDT.
Control of photosensitizer in tissue during photodynamic therapy by means of absorption spectroscopy
Alexander A. Stratonnikov, N. E. Edinac, D. V. Klimov, et al.
The data about absorption spectra properties of the photosensitized tumor tissues in vivo are very important for the evaluation photosensitizer concentration and influence of the chemical environment on photosensitizer properties in tissue. This information will help one in the appropriate choosing of irradiation light dose and wavelength in the photodynamic therapy (PDT) treatment. The interaction of photosensitizer with tumor tissue may change its absorption spectrum. Moreover the light irradiation during PDT treatment can also affect the photosensitizer chemical structure and hence change its absorption spectrum. The simple technique based on the measurement of reflection spectra by means of fiber optic spectrometer has been developed. This method allows one to evaluate the contribution to the tissue absorption properties due to the presence of photosensitizer in it. The absorption spectra of photosensitized normal and tumor tissues presented in this paper has been obtained during PDT sessions of head and neck tumors. The photosensitizer -- sulphonated aluminum phthalocyanine (Photosence) (NIOPIC, Russia) -- has been injected intravenously in doses 0.5 - 2 mg per kg of body weight. It has been observed that absorption properties of this photosensitizer are not changed significantly in tissue as compared to that of in solution. The absorption spectra widening and red shift (4 nm) has been noticed. The qualitative pharmocokinetic of photosensitizer based on absorption spectra measurements is presented.
Preclinical Studies I
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Specific labeling of microtumors in the hen's egg test system by dimethoxyhematoporphyrin
Anja Vervoorts, Joerg G. Moser, Gelii V. Ponomarev, et al.
The accumulation of fluorescent dyes and anticancer drugs in tumors is a fundamental requirement for tumor-diagnosis and therapy. We tested various photosensitizers on vascularized microtumors in the hen's egg test system according to their distribution and accumulation by in-situ videofluorescence microscopy and their influence on tumor blood flow by laser- Doppler spectroscopy. Only 2,4-di((alpha) -methoxyethyl)- hematoporphyrin showed strict tumor localization while diglucosamidyl-heptyl-chlorin labeled cell membranes exclusively. Results from laser-Doppler spectroscopy did not show any influence on tumor blood flow. Intelligent combining of the properties of these sensitizers with accumulation strategies should show in principle strict tumor localization without targeting of non-tumor tissues.
Comparison of the photoactivation efficacy of two chlorin derivatives
Alberto Colasanti, Annamaria Kisslinger, Dirk Kusch, et al.
We investigated the in vitro photoactivation properties of two chlorin derivatives, 8-cis-heptylchlorin dicarboxylic acid and 3-trans-heptylchlorin bisamidoglucose derivative, that exhibit a very strong absorbance peak in the red region of the spectrum and a value of the extinction coefficient (at the wavelength of the maximum absorbance) higher by one order of magnitude than the corresponding value for the porphyrins. The experiments of photoactivation were performed on a normal epithelial cell line (FRTL-5), using as an irradiation source an array of diodes emitting red light (lambda equals 675 nm). We found that, in the concentration range of 1 to 3000 ng/ml, photoactivation of chlorins greatly enhanced mortality of drug exposed irradiated cells (density of energy equals 0.25 mJ/cm2) with respect to the ones exposed to the drug but kept in the dark. This response is immediate and it looks line an 'all or none' effect. The comparison between the extinction coefficient and the efficacy of photoactivation of the two chlorin derivatives seems to indicate that they have similar values of the photophysical and photochemical quantities characterizing the processes responsible of the generation of singlet oxygen, the reactive species to whom the photoinduced toxicity of chlorins was generally imputed.
Cyclic accumulation strategies for polyphasic photoimmunotherapy using the biotin-avidin system
Joerg G. Moser, Marina V. Demcheva, Alexander P. Savitzki, et al.
Polybiotinylated porphyrinoids and linear alkyl-dibiotins were used to describe accumulation behavior of avidin and POD-labelled avidin on tumor cells preincubated with biotinylated monoclonal antibodies. The accumulation behavior followed more a liner than a formerly postulated branched pattern. This allows for us to calculate necessary repeats of accumulation in order to acquire the necessary amount of sensitizer molecules per tumor cell at low concentration of tumor specific marker molecules at the cell surface.
In vitro phototoxicity of a new phthalocyanine-immunoconjugate for use in photodynamic therapy
Michael Martin, Sepp Kaul, Ute Drechsler, et al.
Non specific localization of photosensitizers after application in vivo limits progress in PDT. Relatively selective distribution of photosensitizers in malignant tissues is crucial for a successful treatment. The target specificity of photosensitizers may be improved by linking photosensitizers with monoclonal antibodies. In this approach, a high specific monoclonal antibody, BM-2 which is directed against epitopes of the mucine glycoprotein TAG-12 was used. This antibody shows reactivity with 96% of all primary breast carcinomas. BM-2 was conjugated with a second generation phthalocyanine photosensitizer which is only weakly phototoxic to human T-47D tumor cells without conjugation in vitro. With respect to future clinical application, illumination times from 25 to 100 minutes and a powerful diode laser with an emission of 690 nm was chosen, which provides deeper tissue penetration in vivo. We observed phototoxicity towards T-47D human breast carcinoma cells at concentrations ranging from 0.25 to 6 micromol/L and light doses from 6 to 24 J/cm2. The immunoconjugates discriminated mucine-positive and mucine-negative tumor cells and showed high photocytotoxic selectivity towards mucine-positive T-47D cells in vitro. The conjugate showed no dark toxicity. In vivo experiments will follow.
Fine structure of carcinosarcoma cells and peritoneal macrophages activated by photodynamic therapy during their interaction in vivo
Vasile F. Dima, Mircea D. Ionescu, Virgil V. Vasiliu, et al.
The interaction of the photodynamic therapy activated macrophages (PDT-AM0) of the host and rat Walker-256 carcinosarcoma target cells (ascitic form) was investigated. The periotoneal macrophages were sensitized with different concentrations of Photofrin II (0.1 to 12 (mu) g/2.5 multiplied by 106 cells) and irradiated with He-Ne laser (632.8 nm; 10 mW) at different dose fluences varying between 1.5 and 15 kJ/m2. The degree of macrophage activation by PDT was estimated by means of the following parameters: (1) in vitro assay of cytotoxic and cytostatic activities and (2) observation at the electron microscopy. The results obtained indicate the following: (1) the highest rate of cytotoxic activity against Walker-256 (39.7%) and K562 (21.6%) cells was found in Photofrin II sensitized with 0.8 mg and exposure to He-Ne laser irradiation (3.0 kJ/m2): (2) the cytostatic activity of PDT-AM0 was higher against murine Walker-256 (54.7%) and lower on human K562 (28.1%) cells, in comparison with normal macrophages (NM0); (3) during interaction of PDT-AM0 in peritoneal cavity, the tumor cells were accompanied by strong changes in nuclear and cytoplasmic fine structure. Summing up, in photobioactivated macrophages by PDT some functional activities (cytotoxic, cytostatic and phagocytosis) were enhanced and induced ultrastructural changes in Walker-256 ascites carcinosarcoma cells by their interaction 'in vivo.'
Preclinical Studies II
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In vivo uptake and biodistribution of lipophilic and hydrophilic photosensitizers
Karin Kunzi-Rapp, Nermin Akguen, Herbert Schneckenburger, et al.
Uptake and biodistribution of photosensitizers are crucial parameters for evaluating the efficacy of photodynamic therapy (PDT). We used the tumor baring chorioallantoic membrane (CAM) as an in vivo model system to study biodistribution of hydrophilic and lipophile compounds of natural porphyrins and pthalocyanines using confocal laser scanning microscopy (LSM) and time-gated microspectrometry. Simultaneously we observed tumor vessels and tumor cells after intravascular application at different incubation times. Differences in biodistribution of hydrophilic and lipophilic sensitizers could be observed. Hydrophilic compounds were characterized by selective accumulation in tumor cells. In contrast, more lipophilic sensitizers are accumulated in endothelial cells at short incubation times as well as in tumor cells. These facts are in correlation with our studies in tumor cells and endothelial cells in vitro, where hydrophilic sensitizers are characterized by low uptake and low phototoxicity towards endothelial cells. In contrast more lipophilic sensitizers were rapidly taken up and showed high phototoxicity.
In vivo photodynamic therapy with meso-tetra(m-hydroxyphenyl)chlorin (mTHPC): influence of light intensity and optimization of photodynamic efficiency
Hadjira Rezzoug, Ousama M. A'Amar, Muriel Barberi-Heyob, et al.
Photodynamic therapy (PDT) consists in administering a photosensitizer generating cytotoxic radical species when submitted to light irradiation. One of the difficulties encountered in PDT is to find a photosensitizer absorbing at a wavelength penetrating tissues deeply. Meso-tetra(m- hydroxyphenyl)chlorin(mTHPC) presents this characteristic since it is activated at 650 nm. The photodynamic efficiency of mTHPC (0.3 mg/kg) was evaluated 72 hrs after intraperitoneal injection in HT29 human tumor bearing mice. This interval has been determined by a biodistribution study using fluorescence spectroscopy and HPLC. Mice were irradiated at 650 nm, 10 J/cm2 using a dye laser. The photodynamic efficiency was evaluated by two methods: tumor growth after photodynamic treatment and macroscopic measurement of necrosis depth after tumoral resection using in vivo staining procedure with Evans blue dye. The normalization of the tumor volume (V equals 1/6 pi D3) to the initial volume showed no significant difference of control and treated mice, no regression was observed. Secondly the necrosis depth was determined 24 hrs after irradiation using Evans blue which circulates in vessels not damaged by the treatment. Only tumors from treated animals presented measurable necrosis area, mostly localized in surface around the irradiated site with a mean depth of 3.0 plus or minus 0.3 mm. No prolonged tumoral regression was observed. Unexpectedly, the photodynamic activity was higher when using a low irradiance (32 mW/cm2) than when using a higher one (160 mW/cm2). These results were not related to intratumoral mTHPC photodestruction. Tumor eradication may occur either in tumors measuring less than 3 mm, with a small light intensity, or through fractionated irradiation.
Flow cytometric studies of cellular uptake of PII, m-THPP and m-THPC: kinetics and cell density dependence
F. D. Hanisch, Harald B. Steen, Johan Moan
The uptake of the photosensitizers Photofrin II (PII), meso- tetra-hydroxyphenyl-porphyrin (m-THPP) and meso-tetra- hydroxyphenyl-chlorin (m-THPC) in REH-cells was studied by flow cytometry (FCM). The uptake kinetics were studied with and without metabolic inhibitors. The uptake of PII after 60 min incubation was roughly 50% lower in the presence of the metabolic inhibitors, suggesting a partly active uptake mechanism for PII in REH-cells. The accumulation of m-THPP and m-THPC was not reduced by the metabolic inhibitors. Incubating PII-loaded cells for 60 minutes in sensitizer- free medium reduced the fluorescence intensity by approximately 60%, but had only a minor impact on the fluorescence intensity of cells incubated with m-THPP or m- THPC, even when the washing medium contained 10% serum. The uptake per cell was 9.5, 16, and 11 times higher at 105 than at 107 cells ml-1 for PII, m-THPP and M- THPC in PBS, respectively. This was not solely due to depletion of dye from the medium, since the extracellular sensitizer-concentrations decreased less than 50%. Medium from suspensions of high cell density inhibited the uptake of the sensitizers in low cell density suspensions, indicating that the inhibition may be due to factors secreted by the cells.
Photodynamic treatment with zinc poly-substituted phthalocyanines causes the release of tissue factor in an endothelial cell line
Janet E. Cruse-Sawyer, B. Dixon, John Griffiths, et al.
Tissue factor (TF) is not expressed by endothelial cells unless they have ben perturbed. Identifying the extrinsic pathway of coagulation as the process involved in clot formation demonstrated that PDT induces release of TF by endothelial cells. EAhy 926 cells were incubated with 10 (mu) g ml-1 of photosensitizer for 24 h prior to illumination at 40 J cm-2. A clotting assay was then performed. PDT caused a significant reduction in clotting time. This was repeated using factor VII- or X-deficient serum. In factor VII-deficient serum there was no difference between treated and untreated cells. There was no clot formation with any cells in the presence of factor x- deficient serum. The data indicate that PDT-induced procoagulation activity is via the extrinsic pathway of coagulation and results from direct initiation of endothelial cells to release tissue factor.
Interaction of photosensitizers with membranes of liposomes and of erythrocytes
Gennady I. Klebanov, Eugeny Ph. Stranadko, Y. O. Teselkin, et al.
There was investigated the interaction of two Russian photosensitizers: Photohem (hematoporphyrin derivative, HPD) and Photosense (sulfonated aluminum phthalocyanine, AlPc) with membranes of the liposomes and of the erythrocytes; and effect of laser irradiation (LI) in the presence of HPD and AlPc on lipid peroxidation of liposomes and photosensitized hemolysis of human erythrocytes. There were studied the interaction of HPD and AlPc with membranes of the liposomes and of the erythrocytes by methods of ultra-centrifugation, ultra-filtration, gel-filtration. An increase of hemolysis of erythrocytes in vivo after PDT was found out. It was found out that, photosensitized lipid peroxidation of liposomes and photosensitized hemolysis of human erythrocytes in vivo and in vitro was inhibited by antioxidants (alpha-tocopherol, carotinoids, flavonoids).
Clinical Studies
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Development of photodynamic therapy for Barrett's esophagus
Tony Dix, Hugh Barr M.D.
High grade dysplasia in columnar lined (Barrett's) oesophagus is a premalignant condition. An oesophageal resection in these patients carries significant risks and is associated with considerable morbidity in often asymptomatic patients. Endoscopic destruction of these areas using photodynamic therapy (PDT) offers obvious benefits for patient care and treatment costs. An oesophageal dilator developed for patient endoscopic treatments is described. Experiments were performed to obtain information on the interaction of laser light with the oesophageal tissue. Fluorescence microscopy of tissue biopsies provided information on the distribution of aminolevulinic acid (ALA) induced protoporphyrin IX (PpIX) photosensitization. Six clinical treatments were performed, the results of which are reported.
Photodynamic therapy of recurrent cancer of oral cavity: an alternative to conventional treatment
Eugeny Ph. Stranadko, Oleg K. Skobelkin, Nikolai A. Markichev, et al.
Photodynamic therapy (PDT) with use of two Russian photosensitizers -- Photohem (hematoporphyrine derivative) in the dosage 1.5 - 5.0 mg/kg of body weight and Photosense (sulfonated aluminum phthalocyanine) in the dosage 0.5 - 1.5 mg/kg of body weight has been provided in 26 patients with spread recurrent tumors of oral cavity (tongue, oral mucose, uvula, lower lip). During PDT power density has been from 50 to 1000 mW/cm2, light irradiation doses ranging from 50 to 600 J/cm2. Therapeutic effect in term from 2 months to 3 years took place in 24 patients (92.4%). In 16 cases (61.5%) complete resorption of tumor was achieved, in 8 cases (30.9%) -- partial pesorption. No effect was found in 2 cases (7.6%). Our experience supposes that PD appears to be a reasonable alternative to the traditional therapy of recurrent tumors of oral cavity.
Four-year clinical experience in photodynamic therapy
Eugeny Ph. Stranadko, Oleg K. Skobelkin, Georgy N. Vorozhtsov, et al.
The analysis of the results of photodynamic therapy (PDT) for treating malignant neoplasms of skin, breasts, tongue, oral mucose, lower lip, larynx, stomach, bladder, rectum and other locations has been made. During 1992 - 1996 867 tumoral foci in 222 patients have been treated with PDT. All patients were previously treated with conventional techniques or they were not treated due to contraindications either because of severe accompanying diseases or because of old age. A part of the patients had PDT because of recurrences or intradermal metastases in 1 - 2 years after surgical, radial or combined treatment. Up to now we have follow-up control data within 2 months and 4 years. Positive effect of PDT was seen in 93.7% of patients including complete regression of tumors in 64.9% and partial in 28.8%. Currently this new perspective technique of treating malignant neoplasms is successfully being used in Russia; new photosensitizers and light sources for PDT and fluorescent tumor diagnostics are being developed as well.
Intraoperative photodynamic therapy in laryngeal part of pharynx cancers
Erwin V. Loukatch, Vasily Trojan, Vjacheslav Loukatch
In clinic intraoperative photodynamic therapy (IPT) was done in patients with primal squamous cells cancer of the laryngeal part of the pharynx. The He-Ne laser and methylene blue as a photosensibilizator were used. Cobalt therapy in the postoperative period was done in dose 45 Gr. Patients of control groups (1-th group) with only laser and (2-th group) only methylene blue were controlled during three years with the main group. The statistics show certain differences of recidives in the main group compared to the control groups. These facts are allowing us to recommend the use of IPT as an additional method in ENT-oncology diseases treatment.
Photodynamic therapy of head and neck tumors
Elena G. Vakoulovskaya M.D., Victor V. Shental M.D., N. A. Abdoullin, et al.
This paper deals with the results of stage 1 clinical trials for sulfated aluminum phthalocyanine (PHS) (Photosens, Russia) in 1994-1996. The results of photodynamic therapy (PDT) of head and neck tumors (HNT), side effects and ways of their correction and prevention, as well as changes in doses of injected photosensitizer (PS), regimes of light irradiation, choice of laser and type of irradiation (surface or interstitial) are discussed. PDT have been provided in 42 patients (93 tumor sites) with different head and neck tumors. Fluorescent diagnostics of tumor, accumulation of PS in tumor, adjacent tissue has been fulfilled. Total 78 PDT sessions have been done. As a source of light we used: quantoscope, solid laser, krypton laser, tunable dye laser, He-Ne-laser. In 38 tumor sites (21 patients) -- 40.8% -- we had clinical response, in 27 tumor sites (16 patients) -- 29.0% -- we had partial response, in 28 tumor sites (8 patients) -- 30.2% -- we had no response. Our experience shows pronounced efficacy of PDT for HNT, except of melanoma. Providing PDT twice with the interval 24 - 72 hours when retention of PS is sufficient for treatment, did additive effect to the tumor, but didn't increase adjacent tissue damage.
Basic Studies
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Experimental PDT: studies on new Si-phthalocyanines and Si-naphthalocyanines in Cremophor emulsions
Maria Shopova, Vanya Mantareva, Dieter Woehrle, et al.
In the present work the following silicon (IV) - phthalocyanines and -naphthalocyanines bearing methoxyethylene glycol or methoxypolyethylene glycol covalently bound at the silicon are investigated: SiPc[OCH2CH2OCH3]2 (SiPc1), SiNc[OCH2CH2OCH3]2 (SiNc), SiPc[(OCH2CH2)nOCH3] with n approximately 115 (SiPc2). The phototherapeutic effect was shown at Lewis lung carcinoma implanted in mice. SiPc2 is monomeric soluble in water whereas the other two compounds aggregated in this solvent. Therefore these compounds were dissolved monomer in in aqueous Cremophor solution before in vivo administration. Laser irradiation was applied 7 days after implantation and 24 h after drug administration at the following wavelength (eta) ext: 672 nm for SiPc1 and SiPc2, 782 nm for SiNc. In all cases a fluence rate of 370 mW/cm2 at fluence of 360 J/cm2 was used. The assessment criteria for the tumor response were the changes in the mean tumor diameter with time, regrowth delay and average survival time (AST). According to the first parameter the most promising result was obtained after treatment with SiPc1. For example the mean tumor diameter increases as follows: SiPc1 less than SiPc2 less than SiNc very much less than control group without photosensitizer. The regrowth delay showed the same trend. however, for AST another dependence was observed. AST was the longest for SiPc2 (26 days) and shortest for SiNc (22 days). Compared to the control group (without sensitizer and irradiation) the AST was 9 days longer after SiPc2 treatment. Comparing SiPc1 and SiPc2 the chain length of the substituents does not influence the phototherapeutic properties. The detected therapeutic results probably are connected with the long wavelength absorption of the photosensitizers. The relatively lower affectivity of SiNc may be due to a lower degree of tumor accumulation as it was observed in our preliminary pharmacokinetic studies. It is also possible that the shorter AST after treatment with SiNc is connected with a greater dark toxicity.
Preclinical Studies II
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Ozone-photodynamic effect in the experiment in vitro
L. E. Loginov, A. A. Budzinsky, Nadezgda L. Torshina, et al.
With the purpose of increased photodestruction oncocells we develop a method of ozone-photodynamic therapy. As a target cell for laser processing we are using photosensibilitable erythrocytes of integral blood patient, past seance of ozonetherapy.
Possibility of deep photodynamic action on tumor tissues using aluminium phtalocyanine
Gennadii A. Meerovich, Elena G. Vakoulovskaya M.D., Victor V. Shental M.D., et al.
We have determined the efficacy of PDT and depth of necrosis for advanced tumors. Clinical results of PDT have shown that it is possible to get the depth of tumors necrosis till 20 mm using lasers providing high power density of laser irradiation. One of the possible models can be enlightenment of sensitizer during laser irradiation.
Basic Studies
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Photodynamic activity of a number of photosensitizers in vitro
Raisa I. Yakubovskaya, Victor K. Oganezov, Larisa A. Shytova, et al.
The comparative study of the photosensitizers with different chemical, spectral-luminescent and photophysical properties (phthalocyanines -- photosense, di- and trisulphonated zinc (II) phthalocyanines; chlorines -- chlorine p6, desvinyl-3- formyl-chlorine p6 and 3-desvinyl-3-acetyl-chlorine p6; xanthenes --rhodamine 123, rhodamine 6G-chloride, rhodamine 6G-acetate, rhodamine 6G-iodide; arylamines -- oxazinne perchlorate, oxazine-1 zinc salt, 9-diethylamino-5- ethylaminobenzophe-nothiazonium acetate, methylene blue) was performed. The cyto- and the phototoxicity of these compounds were studied on the cells of two human tumor cell lines (Raji B-cell lymphoma and A-549 lung adenocarcinoma) by MTT-test. It was shown that phthalocyanines and chlorines were not cytotoxic, whereas xanthenes and arylamines possessed dark toxicity. On the basis of the IC50 (the substance concentration, which induced 50% inhibition of cell proliferation in the cell culture) the rows of phototoxicity of the compounds of various classes were set out: in phthalocyanines: ZnPcS2 greater than Photosence greater than ZnPcS3; in chlorines: 3dV-3F-Chl p6 greater than 3 dV-3Ac Chl p6 greater than Chl p6; in xanthenes: R6G- Ac greater than R6G-Cl greater than R6G-I greater than R 123; in arylamines: Meth B greater than or equal to 9-DE-B- Ac greater than Ox1-1/2ZnCl42- very much greater than Ox1-ClO4-. Phototoxicity of the studied compounds depended on the nature of the substitutes and of the counter ions in photosensitizers molecules as well as on the concentration of the photosensitizer, on the light doses and on the regimes of irradiation. The fractionation of the light doses increased the efficiency of the phototoxic effect of the dyes on the tumor cells significantly. It was shown by the luminescent microscopy that the dynamics and the intensity of the accumulation of the rhodamines derivatives in lung adenocarcinoma cells depended on the nature of the counter ion in the photosensitizer molecule and correlated with their cyto- and pho-toxicity. Thus, photosense, di- and trisulphonated zinc phthalocyanines, 3- desvinyl-3-formyl-chlorine p6, rhodamine 6G-acetate and methylene blue turned out to be promising for their further study as photodynamic agents and efficient modifiers of chemoradiotherapy and of PDT.
Photosensitizer for PDT based on phosphonate phthalocyanine derivative
Gennadii A. Meerovich, Eugeny A. Lukyanets, Olga A. Yuzhakova, et al.
It is very important to develop new sensitizer which could be efficiently excited at wavelengths exceeding 685 nm where own tissue absorption can be neglected. We have synthesize water soluble phthalocyanine derivative having phosphonate groups as substituents in macrocycle. New sensitizer efficiently absorbs in spectral range 685 - 710 nm. It exhibits intense fluorescence in range 690 -720 nm. The photodynamic activity of new sensitizer is higher than in the case of sulfonated aluminum phthalocyanine.
Spectroscopic studies of photosensitizer-human serum albumin complexes and their photostability
A. Jasaitis Jr., Giedre Streckyte, Ricardas Rotomskis
The interaction of haematoporphyrin (Hp), dimethoxyhematoporphyrin IX (DMHp), meso-tetraphenylporphine tetrasulphonate (TPPS4), photofrin II (PF), chlorin e6 (Cle6) and aluminum phthalocyanine tetrasulphonate (AlPcS4) with human serum albumin (HSA) in aqueous solution and the influence of complexation on the photostability of sensitizers have been investigated by means of steady state absorption spectroscopy. By using the binding isotherm method and graphical Scatchard plot the sequence of affinity of sensitizers to HSA was obtained: TPPS4 greater than DMHp, Cle6, Hp, AlPcS4 greater than PF. The influence of aggregation on the binding ability of sensitizers is discussed. It was observed that complexation with HSA decreases the photostability of sensitizers. The increased rates of sensitizer photobleaching in the presence of photo-oxidizable substrates can be explained by the changes of photophysical properties of sensitizers caused by the interaction with substrates or by the attack of the biomolecules photo- oxidized by the type I mechanism involving electron transfer from excited porphyrin molecule or by the type II mechanism via singlet oxygen on porphyrin microcycle. The sequence of photostability of sensitizers in the presence and in the absence of HSA was established.
Clinical Studies
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Multi-course PDT of malignant tumors: the influence on primary tumor, metastatic spreading and homeostasis of cancer patients
Victor V. Sokolov, Valery I. Chissov, Raisa I. Yakubovskaya, et al.
The first clinical trials of photodynamic therapy (PDT) of cancer with two photosensitizers, PHOTOHEME and PHOTOSENS, were started in P.A. Hertzen Research Oncological Institute (Moscow, Russia) in 1992 and 1994. Up to now, 208 patients with primary, recurrent and metastatic malignant tumors (469) of skin (34 patients/185 tumors), breast cancer (24/101), head and neck (30/31), trachea and bronchus (31/42), esophagus (35/35), stomach (31/32), rectum (4/4), vagina and uterine cervix (7/8) and bladder (12/31) have been treated by PDT. One-hundred-thirty patients were injected with PHOTOHEME, 64 patients were injected with PHOTOSENS, 14 patients were injected with PHOTOHEME and PHOTOSENS. Totally, 302 courses of treatment were performed: 155 patients had one course and 53 patients were subjected to two to nine PDT sources with intervals from 1 to 18 months. A therapeutic effect of a one-course and multi- course PDT of malignant tumors (respiratory, digestive and urogenital systems) was evaluated clinically, histologically, roentgenologically, sonographically and endoscopically. The biochemical, hematological and immunological investigations were performed for all the patients in dynamics. Results of our study showed that a multi-course PDT method seems to be perspective in treatment of malignant tumors of basic localizations.
Preclinical Studies II
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Pharmocokinetical study of Al- and Zn-sulphonated phthalocyanines
Natalia I. Kazachkina, Natalia N. Zharkova, Galina I. Fomina, et al.
The comparative pharmacokinetical study of Al- and Zn- sulphonated phthalocyanines (AlPcS and ZnPcS, respectively) is the aim of the present work. Mice bearing solid Ehrlich tumor were used in this study. AlPcS (sodium salt) and ZnPcS (ammonium and sodium salts were used as photosensitizers. The photosensitizers were injected i/v in various doses. The exogenous fluorescence of tissues (tumor, liver, spleen, kidneys, muscles, skin) was measured dynamically after sensitization. It was shown that all of the photosensitizers under study had similar distribution pattern in organisms of mice and were selectively accumulated in the Ehrlich tumor tissue. The exogenous fluorescence intensity of tissues and it tumor:normal muscle ratio (Cs) depended on the dosage of the preparation, on the time, which had passed after drug injection, and on the stage of tumor growth. It was also shown that the kinetics of the tissue uptake of the studied sensitizers varied to some extent. Thus, the obtained data may be interesting for deeper understanding of the interaction of the dye with malignant tissues.
Aggregation and hemolysis of human erythrocytes at photodynamic therapy
Alexander V. Priezzhev, Nikolai N. Firsov, Eugeny Ph. Stranadko, et al.
The goal of this work is to comparatively study the side effect PDT on blood with the use of two Russian photosensitizers -- photohem and photosense. These effects were studied at in vitro and in vivo conditions. The technique of backscattering nephelometry was used to measure the parameters of aggregation kinetics and the strength of aggregates of whole blood erythrocytes. The conventional method of absorption spectrophotometry was used to monitor the level of erythrocytes hemolysis. It was shown that sensitization of blood leads to the rise of the characteristic time of Rouleax formation, of the strength of aggregates, and of the level of hemolysis. The revealed tendency to increased strength of aggregates and level of hemolysis as a result of photodynamic action can be considered as a side effect of PDT.
Basic Studies
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Novel effective sensitizers for photodynamic cancer therapy on the base of chlorin p6 and its derivatives
Andrei F. Mironov, Ol'ga A. Efremova, Raisa I. Yakubovskaya, et al.
A series of chlorin p6 derivatives modified at the 3- position of the macrocycle were prepared on the base of purpurin 18. The chlorins obtained have intense absorption maxima in the range of 665 - 698 nm and posses good water- solubility. Studying photodynamic activity of these sensitizers in vitro showed that the most effective was 3- devinyl-3-formylchlorin p6. This sensitizer demonstrated also enhanced in vivo affinity to the tumor tissue in comparison to other chlorins, which correlated with the pH values of aqueous solutions of sensitizers studied.
Preclinical Studies II
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Combined treatment of photodynamic therapy and the topoisomerase I inhibitor camptothecin in growing V79 and NHIK 3025 cells
Jean-Michel Gaullier, Siv Kjersti Rodal, Johan Moan, et al.
The topoisomerase I (Topo I) inhibitor camptothecin (CPT) has been combined with photodynamic treatment (PDT) in V79 and NHIK 3025 cells. Meso-tetra (N-methyl-4-pyridyl) porphine (TMPyPH2) was used as a photosensitizer. The dye has been shown to localize in granules in the cytoplasm of both cell lines. Some of the granularly located TMPyPH2 is relocated to the cytosol after exposure to a light dose inactivation 70% of the cells. The human NHIK 3025 carcinoma from cervix were more resistant to PDT (D50 approximately equals 0.33 J/cm2) and CPT (D50 approximately equals 320 nM) than Chinese hamster V79 lung fibroblasts (PDT, D20 approximately equals 0.3 J/cm2 and CPT, D20 approximately equals 55 nM). When the cells were treated with CPT for 18 hours before PDT, the combination of treatments led to slight synergistic effects for low CPT concentrations (up to 100 nM in NHIK 3025 cells) and high PDT doses (above 0.15 J/cm2). For higher CPT concentrations and lower PDT doses, the combination of treatment became additive.
Enhancement of photosensitization efficiency by various combinations with radiosensitization in an experimental Ehrlich ascites tumor
Zivile Luksiene, G. Kaspariunaite, E. Aleknavicius, et al.
According to our previous results porphyrin can interact not only with visible light but with ionizing radiation also. This phenomenon gives us new possibility to combine photosensitization with radiosensitization. Data obtained on BALB/c mice with 7-day Ehrlich ascites tumors pretreated with 30 mg/kg HP dimethylether (not toxic and not mutagenic concentration) and irradiated with 60Co source (2 Gy) and visible light source (5 J/cm2) showed remarkable inhibition of tumor growth. Two Gy alone inhibited Ehrlich ascites tumor growth by 17%, whereas combination of 30 mg/kg HPde and 2 Gy (radiosensitization) -- by 38%. Photosensitization (30 mg/kg HPde plus 5 J/cm2) showed 37% tumor growth inhibition. Combination of photosensitization with radiosensitization inhibited tumor growth by 87%. It is important to note, that sequence of treatments (radiosensitization - 1 h - photosensitization or photosensitization - 1 h - radiosensitization) had no influence on tumor growth inhibition.
Quantitative analysis of anthracyclines kinetics in cells varying in drug responsiveness
Alberto Colasanti, Annamaria Kisslinger, Raffaele Liuzzi, et al.
A fluorimetric technique to measure transport parameters of fluorescent drugs through cellular membranes is described. This method eliminates procedures that would lead to errors in the measurement of drug accumulated by cells, and measures the fraction of free drug in cells. The use of a simple three-compartment model in conjunction with fluorescence measurements performed on the extracellular medium and on Triton-permeabilized cells at different times during daunorubicin incorporation allows determination of the kinetic parameters of the transport through cellular membranes. With this technique we found that LoVo cells have a greater daunorubicin uptake, a similar input rate constant and a lower output rate constant than the drug resistant LoVo/DX cells. Preliminary photoactivation measurements of these two cell lines with these compounds showed that phototoxic effects are related to the amount of drug bound to cellular sites.
Laser-induced fluorescence spectroscopy of AlPc4 and liposomal ZnPc in a rat bladder tumor model and correlation with PDT efficiency
N. J. Edinak, Angelika C. Rueck, Rudolf W. Steiner, et al.
The problem of opportune diagnostic and treatment modalities is very actual. In recent years special attention has been paid to the development of new methods for the diagnostic of tumor spreading. That allows a physician to determine the method of further therapy. The success of PDT is defined by available accumulation of the PS in tumor tissue, therefore the photosensitizer concentration control determines the efficacy of the therapy. The methods that allow accumulation of PS in the therapeutic dose allowed us to perform PDT with smaller administration dose and avoid the complications of photosensitivity. The preliminary results of using ZnPc and AlPc in the rats show that we can reduce the dose of the drug with the increasing of the efficacy of the treatment simultaneously, if we use the PS under the control of the accumulation for the best contrast between normal and tumor tissue and try to apply methods of treatment which allow us to receive more oxygenation and using the affect of more accumulation of the drug after preliminary laser stimulation.
Comparison of meso-tetrahydroxyphenyl-chlorin and meso-tetrahydroxyphenyl-bacteriochlorin with respect to photobleaching and PCT efficiency in vivo
Li Wei Ma, Johan Moan, Michael F. Grahn, et al.
Using BALB/c nude mice bearing WiDr human colon adenocarcinoma, we investigated photobleaching and photochemotherapeutic (PCT) effects of meso- tetrahydroxyphenyl-chlorin (mTHPC) and meso- tetrahydroxyphenyl-bacteroiochlorin (mTHPBC). For both studies, mice were injected i.p. 1 mg/kg mTHPC and mTHPBC, respectively, 24 hr before light irradiation. Photobleaching of the sensitizers in mouse skin was carried out using a dye laser (for mTHPC) and 1 KW xenon source equipped with a monochromator (for mTHPBC). Fluorescence measurements were made by means of a fiberoptic system, exciting and collecting the fluorescence from the mouse skin. The system was coupled to a PE L550 fluorimeter. For the PCT study, the mTHPC or mTHPBC-sensitized tumors were exposed to the laser at a fluence of 10 J/cm2. The responses of the treated tumors were evaluated by measuring the tumor growth. We found that both mTHPC and mTHPBC are photolabile. Approximately 80% of the fluorescence of the two dyes in the mouse skin is bleached by a fluence of 10 J/cm2. When mTHPBC in mouse skin was photobleached by light of 740 nm, the bacteriochlorin (peak at 740 nm) was significantly bleached while the chlorin (peak at 652 nm) was unaffected. The growth of the tumors was delayed by 13 days after PCT with 1 mg/kg mTHPC Irradiation at 652 nm) and 5 days delay after PCT with 1 mg/kg mTHPBC (irradiation at 515 nm). The present data indicate that (1) by proper choice of a low dose of mTHPC or MTHPBC, it is possible to photobleach the sensitizers in normal tissues without eliminating their PCT effect on tumor tissues; (2) in order to increase the efficiency of PCT with mTHPBC, fractionated irradiation with different wavelengths (740 nm and 652 nm) should be considered to be used.
Basic Studies
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Kinetic studies of porphyrin distribution in suspensions of tumor cells
Vladimir P. Zorin, Sergey B. Mel'nov, Valery P. Savitsky, et al.
Using a fluorescence activated cell sorting, we investigated the dynamics of porphyrins in suspensions of tumor cells. In addition to direct studies of the incorporation and output of several porphyrins (hematoporphyrin, hematoporphyrin dimethyl ester, chlorin e6 and its mono-, di-, trimethyl esters) from cells, their transfer between cells was investigated. It was shown that the rate of pigment accumulation by cells correlated with the rate of porphyrin penetration across the plasma membrane. As a result, apolar chlorins and HpDME displayed enhanced staining capacity which was independent on the integrity of plasma membrane of cells. To estimate the rate of pigment redistribution between cells, the suspension of tumor cells loaded with porphyrin had been mixed with unloaded cells and the distribution of all cells according to porphyrin fluorescence was determined in different intervals of time. It was obtained that the highest rate of the pigment transfer between cells was exhibited in the case of moderately apolar pigment. Porphyrins with dominantly hydrophobic and hydrophilic properties had a decreased capacity to intercellular migration. The results of this study indicate that, depending on the photosensitizer used, the processes of its distribution in the bulk of tumor tissue mediated by intercellular exchange may occur with a different rate.
Preclinical Studies II
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Bioelectric response of single neuron to photodynamic action of chlorin e6
Anatoly B. Uzdensky, Olga Y. Kutko, Natalya V. Pasikova, et al.
Photodynamic effect of chlorin e6 on bioelectric activity of single crayfish stretch receptor neuron was studied. The stable background firing of this cell provides precise evaluation of initial membrane activity shifts, dynamics of bioelectric changes, and terminal events leading to the cell death. Spikes of isolated neuron were amplified, and their frequency was continuously recorded. After 1 hour of stable control work neurons were incubated 30 min in saline with various chlorin e6 concentrations from 30 to 500 nM, and then irradiated by helium-neon laser (632.8 nm, 0.3 W/cm). Irradiation increased firing frequency and then induced abrupt irreversible cessation of spike generation. Rate of firing acceleration and neuron lifetime quadratically depended on the dye concentration, hence the excitation of two dye molecules is needed for neuron response. These data show that bioelectric activity of single nerve cell is very sensitive to chlorin e6 photodynamic injury and that plasma membrane is the main target of photodynamic effect.
Basic Studies
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Intravesical dosimetry applied to laser positioning in photodynamic therapy
Guillaume Beslon, Philippe Ambroise, Bernard Heit, et al.
Superficial bladder tumor is a challenging indication for photodynamic therapy. Due to lack of specificity of the sensitizers, the light has to be precisely monitored over the bladder surface, illuminated by an isotropic source, to restrict the cytotoxic effect to the tumor without affecting the normal epithelium. In order to assist the surgeon while processing the therapy, an urothelium illumination model is proposed. It is computed through a spline interpolation, on the basis of 12 intravesical sensors. This paper presents the overall system architecture and details the modelization and visualization processes. With this model, the surgeon is able to master the source displacement inside the bladder and to homogenize the tissue exposure.
Laser fluorescence investigation of chlorin e6 pharmacokinetics
Vladimir A. Hovanessian, Asatour Lalaian, Grigor Gyulkhandanyan
The pharmacokinetic behavior of chlorin e6 in different organs and tumor tissues of rats infected with Sarcoma-45 has been investigated with help of the fiber-optic spectrofluorometer at excitation by harmonics of YAG:Nd laser ((lambda) equals 355, 532 and 660 nm). The most intensive chlorine e6 fluorescence in tumor tissue was observed in 18 hours after pigment injection. The optimal time of fluorescence diagnosis has been determined (in 27 hours after pigment injection). The maximum of the tumor-to- normal tissue ratio of fluorescence was equal 10 at 666 nm. The rates of the accumulation and elimination of chlorin e6 in the skin, hypodermic tissues and tumors of rats were determined in vivo.
Clinical Studies
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Establishment of treatment parameters for ALA-PDT of plaque psoriasis
Mark R. Stringer, Dominic J. Robinson, P. Collins
We report an investigation into the use of photodynamic therapy (PDT), following topically applied 5-aminolaevulinic acid (ALA), as a treatment for plaque psoriasis. Treatment was performed 4 hours post-ALA, using white light doses of 2 - 16 J cm-2 delivered at 10 - 40 mW cm-2. The fluorescence emission of protoporphyrin IX was used as an indicator of the relative concentration of photosensitizer within each plaque before, during, and after therapy. Results show that the rate of sensitizer photo- oxidation is proportional to both pre-treatment fluorescence intensity and surface irradiance, consistent with a rate- equation analysis. A correlation of fluorescence measurements with clinical response of plaques indicates that the effectiveness of PDT is dominated by the level of PpIX at the onset of treatment, and is much less dependent upon light dose. Using these findings we have established a PDT treatment protocol that involves the delivery of 8 J cm-2 of white light, at a rate of 15 mW cm-2. The possibility of ALA-PDT being established as the therapy of choice is discussed.
Photodynamic therapy in patients with advanced breast cancer: preliminary results
Elena G. Vakoulovskaya M.D., V. V. Khailenko, Victor V. Shental M.D., et al.
Photodynamic therapy (PDT) using phtalocyanine Al, has been provided in 5 patients with advanced breast cancer (ABC). In 3 patients with ABC T4NO-2MO have been provided preoperative PDT, in 2 cases with T4N1Mx PDT have been done after previous combined treatment for subcutaneous metastases. Multiple lesions were treated in one patient. As a source of light we have used quantoscope (scanning electron beam semiconductive laser, and solid laser with doubled frequency. Combined surface and interstitial laser irradiation has been provided in cases of preoperative PDT. Preliminary results of our study show the pronounced efficacy of PDT for subcutaneous metastases of breast cancer and possibility of providing preoperative PDT for advanced breast cancer.
Basic Studies
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Kinetics of self-sensitized oxidation of dye for photodynamic therapy and of sensitized protein oxidation in aqueous solutions
Boris Ya. Kogan, Alexander V. Butenin, Oleg L. Kaliya, et al.
The kinetics of oxygen consumption in aqueous solutions of sulphonated hydroxyaluminum phthalocyanine and protein under irradiation with He-Ne laser was studied using the method of sensitizer fluorescence saturation. The constants of triplet state quenching were determined. The dye is oxidized with superoxide anion-radical, whereas the protein -- mainly by singlet oxygen.
Clinical Studies
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How to determine an appropriate dose when using various light sources in photodynamic therapy
Harry Moseley
Photodynamic therapy (PDT) using 5-aminolaevulinic acid (5- ALA) has emerged as a very effective treatment for superficial skin lesions. PDT has been traditionally performed using a laser. However, the availability of broad- band non-laser sources is challenging the role of the laser. Unfortunately, dosimetry of broad-band sources presents some practical difficulties. The effectiveness of a light source for PDT depends on the incident spectral irradiance of the light, tissue transmission to the desired depth, and sensitizer absorption which depends on the particular absorbing chromophore. These elements are combined mathematically to produce the 'total effective fluence rate' at a specified depth. On applying the model to several light sources, it would appear that green light is much more effective than red light for treating down to a depth of 2.0 m in dermis but red light appears to give better superficial skin sparing. The model may be easily applied to any light source provided the incident spectral irradiance is known. It is believed that this concept has considerable practical value.
Preclinical Studies II
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Nd: YAG laser destruction together with PDT in head and neck
Laima Bloznelyte-Plesniene M.D.
The visible light, which is used for the activation of photosensibilizator, penetrates the tissue approximately only 2 cm. If the tumor is large, PDT alone is only the palliative method of treatment. Nd:YAG laser evaporation of big size tumors together with PDT let us provide the radical treatment. Since 1989 to 1996 there were 119 patients with 172 tumors of head and neck treated with PDT. The size of the tumor varied from 0.2 cm2 to 6 cm2. The thickness of the tumor varied from 0.1 to 1.5 cm. There were 30 patients with 82 large head and neck tumors with the ones settled in the location difficult to reach too. Nd:YAG laser (30 - 40 W) was used in order to remove the tumors mass. After 2 - 4 days passed, the PDT treatment was provided for all these 30 patients. The immediate result of Nd:YAG laser evaporation of large tumors together with PDT was the same as in usual usage PDT, when PDT was provided for considerably smaller tumors.
Plenary Paper
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Colorful story of phototherapy for neonatal jaundice
Giovanni Agati, Franco Fusi, Riccardo Pratesi, et al.
Colors have always attracted our fantasy and imagination. Medicine, like many other human activities, did not escape their attraction, sometimes with fatal consequences. The scientific literature, magazines, etc. are full of reports on the beneficial, miraculous effects of colors. Even nowadays, where photobiology and photomedicine have been put on very firm bases, chromopaths are still at work. The evolution of light therapy from chromotherapy to photomedicine is presented in brief, with the aim of contributing to the action against the unscientific behavior of researchers and clinicians who support biological and/or clinical results without serious and well documented work. Colors have played an important role in the phototherapy of neonatal jaundice. It is an interesting example of how even a rigorous scientific search for the optimal color has progressed in part by change, due to the lack of an action spectrum, too hurried extrapolations of animal results to man, unsuspected dynamical behavior of bilirubin molecules, etc. The story of its evolution up to present knowledge is reported in this paper.