Damage Threshold of Normal Rat Brain in Photodynamic Therapy (original) (raw)
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Toxicity of photodynamic therapy with photofrin in the normal rat brain
Lasers in Surgery and Medicine, 1994
The widespread acceptance of photodynamic therapy (PDT), a potential adjuvant brain tumor therapy under clinical evaluation since 1980, has been partially restrained by its potential toxicity toward normal brain tissue. This study examined PDT-produced injury of normal rat brain as a function of photosensitizer dose. Brain injury was characterized by correlating measurements of the area of cerebral edema using T2-weighted magnetic resonance images, measurement of brain water content at the lesion site, microscopic examination of histological sections through the PDT lesion, and by evaluation of the area of blood brain barrier (BBB) disruption using computerized morphometric analysis of the region of Evans blue (EB) dye-labelled albumin extravasation. Monochromatic red light (630 nm) was delivered intracerebrally using a 5-mm-long cylindrical, diffusion-tip optical fiber at a constant energy dose of 15 joules.
Photochemistry and Photobiology, 1989
The response of photodynamic therapy on normal brain was investigated in 140 Fisher rats. The rats were injected i.p. with Photofrin II (12.5 mg/kg) and 48 h later the dural area over the frontal cortex was photoactivated with red light (630 +/- 1 nm) from an argon dye laser. Treatment was performed with optical energy densities of 140 and 70 J/cm2. Histopathology, vascular permeability and specific gravity measurements were conducted on different populations of rats at 4 h, 24 h, 72 h and 1 week after photodynamic therapy (PDT). Histopathology revealed similar gross and microscopic pathology associated with light energies of 70 and 140 J/cm2 after all time points. A large cerebral infarct approximately the size of the brain surface area treated, evolved 24 h following treatment. Evans blue extravasation indicated a small area of vascular permeability evident as early as 4 h following PDT treatment at both energy levels, with increasing permeability evident at later time points. Specific gravity measurements taken on a representative area of the lesion indicated a significant (P less than 0.01) amount of edema present at 24 h post treatment with a gradual reduction approaching control values over the time period of 1 week. The data indicate a significant amount of damage to normal brain from low PDT treatment doses.
Experimental research photodynamic effects in perifocal, oedematous brain tissue
Acta neurochirurgica, 2002
Photodynamic therapy (PDT) has been under discussion as additional treatment option for malignant gliomas. However, damage not only to tumour tissue but also to normal brain has been demonstrated. The mechanisms of this unwanted side effect have not yet been clearly identified. Spreading of photosensitiser with oedema after disruption of the blood-brain-barrier and potential sensitisation of normal tissue has been found previously. The present study investigates the time- and dose-dependency of normal tissue damage to photodynamic therapy using Photofrin II after disruption of the blood-brain-barrier. Male wistar rats anaesthetised with chloral hydrate were subjected to focal, cerebral cold lesions. Simultaneously, Photofrin II (PFII) was injected (2,5 or 5 mg/kg b.w.). Laser irradiation (630 nm) was performed after 4 h, 12 h and 24 h with varying light doses. Control groups were subjected to focal cold lesion alone, cold lesion with laser irradiation, PFII followed by laser irradia...
Apoptosis induced in vivo by photodynamic therapy in normal brain and intracranial tumour tissue
British Journal of Cancer, 2000
The apoptotic response of normal brain and intracranial VX2 tumour following photodynamic therapy (PDT) mediated by 5 different photosensitizers (Photofrin, 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX), chloroaluminium phthalocyanine (AlCIPc), Tin Ethyl Etiopurpurin (SnET 2), and meta-tetra(hydroxyphenyl)chlorin (mTHPC)) was evaluated following a previous analysis which investigated the necrotic tissue response to PDT at 24 h post treatment. Free DNA ends, produced by internucleosomal DNA cleavage in apoptotic cells, were stained using a TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling) assay. Confocal laser scanning microscopy (CLSM) was used to quantify the local incidence of apoptosis and determine its spatial distribution throughout the brain. The incidence of apoptosis was confirmed by histopathology, which demonstrated cell shrinkage, pyknosis and karyorrhexis. At 24 h post PDT, AlClPc did not cause any detectable apoptosis, while the other photosensitizers produced varying numbers of apoptotic cells near the region of coagulative necrosis. The apoptotic response did not appear to be related to photosensitizer dose. These results suggest that at this time point, a minimal and fairly localized apoptotic effect is produced in brain tissues, the extent of which depends largely on the particular photosensitizer.
Modulation of light delivery in photodynamic therapy of brain tumours
Journal of Clinical Neuroscience, 1999
This study was performed to determine whether modulation of light delivery could improve tumour kill in photodynamic therapy (PDT) of brain tumours, as optimal dosimetry has not been fully established. One hundred and sixty-five adult Wistar rats were treated, of which 70 had an implanted C6 ce-rebral glioma. Haematoporphyrin derivative (HpD) was injected at doses between 0 and 20 mg/kg, 24 h prior to irradiation with 630 nm laser light. The total energy dose was varied from 0 to 1200 J/cm 2, with fluence rates of 625, 3125 or 9375 mW/cmL In some studies, the light delivered at 3125 mW/cm 2 was divided into 10 fractions of approximately 13 s, with refractory intervals of 60 s. The most striking finding was that HpD was much more potent than previously reported. All doses greater than 1.0 mg/kg resulted in normal brain damage with light doses above 50 J/cmL However, at 1.0 mg/kg, significant normal injury was not apparent until 1200J/cmL Failure of drug-light dose reciprocity indicated that photobleaching occurred, protecting normal tissue. Selective tumour kill was observed to 2.2 mm depth (SE _+ 0.44 mm). Using lower power or fractionated light did not improve tumour kill and normal tissue injury occured with fluence rates of 9375 mW/cmL In conclusion, the doses of HpD currently used in clinical brain tumour trials may be too high to achieve selective tumour kill. Higher light fluence rates allowed shorter intraoperative irradiation times with no loss of efficacy. Photodynamic therapy continues to demonstrate potential as an effective treatment for local control of cerebral lesions.
Photodynamic therapy (PDT) for malignant brain tumors – Where do we stand?
Photodiagnosis and Photodynamic Therapy, 2015
What is the current status of Photodynamic therapy (PDT) with regard to treating malignant brain tumors? Despite several decades of effort, PDT has yet to achieve standard of care. The questions we wish to answer are: where are we clinically with PDT, why is it not standard of care, and what is being done in clinical trials to get us there. Rather than a meta-analysis or comprehensive review, our review focuses on who the major research groups are, what their approaches to the problem are, and how their results compare to standard of care. Secondary questions include what the effective depth of light penetration is, and how deep can we expect to kill tumor cells. CONCLUSION: Continued research in PDT will determine whether the advances shown will mitigate morbidity and mortality, but certainly the potential for this modality to revolutionize the treatment of brain tumors remains. The various uses for PDT in clinical practice should be pursued.
Photodynamic therapy of cerebral glioma – A review Part II – Clinical studies
Journal of Clinical Neuroscience, 2006
Photodynamic therapy (PDT) is a binary treatment modality that has been used to treat malignant brain tumours for 25 years. The treatment involves the selective uptake of a photosensitizer (PS) by the tumour cells followed by irradiation of the tumour with light of the appropriate wavelength to excite and activate the PS resulting in selective tumour destruction and is a potentially valuable adjunct to surgical excision and other conventional therapies. PDT has undergone extensive laboratory studies and clinical trials with a variety of PS and tumour models. These are discussed with reference mainly to clinical studies involving the PDT of brain tumours.
Experimental determination of threshold dose in photodynamic therapy in normal rat liver
Laser Physics Letters, 2007
Using normal rat liver we investigated the depth of necrosis induced by photodynamic therapy when different light doses and photosensitizer (Photogem R ) concentrations. All experiments were done with a fluence rate of 250 mW/cm 2 . Photosensitizer concentration was varied from 1.0, 1.5, 2.0, and 5.0 mg/kg of body weight and it was administered through the left tail vein. For each photosensitizer concentration the light dose was varied from 10, 50, 100, 150, and 200 J/cm 2 . Each experimental point was done using five animals. The depth of necrosis analysis allows us to determine the threshold dose and compare its value with the existent results in the literature. Our result suggested a value about 3 times higher than the conventionally adopted value. It indicates the dependence of such value with the employed concentration photosensitizer. The use of simple models to understand basic features of the PDT (Photodynamic Therapy) may contribute to the solid establishment of dosimetry in PDT enhancing its use in the clinical management of cancers and others lesions.
Journal of Neurosurgery, 1993
v, Photodynamic therapy was studied in dogs with and without posterior fossa glioblastomas. This mode of therapy consisted of intravenous administration of Photofrin-II at doses ranging from 0.75 to 4 mg/kg 24 hours prior to laser light irradiation in the posterior fossa. Tissue levels of Photofrin-lI were four times greater in the tumor than in the surrounding normal brain. Irradiation was performed using 1 hour of 500 mW laser light at a wavelength of 630 nm delivered through a fiberoptic catheter directly into the tumor bed via a burr hole. All animals receiving a high dose (4 or 2 mg/kg) of Photofrin-II developed serious brain-stem neurotoxicity resulting in death or significant residual neurological deficits. A lower dose (0.75 mg/kg) of Photofrin-II produced tumor kill without significant permanent brain-stem toxicity in either the control animals or the animals with cerebellar brain tumors receiving photodynamic therapy.
Photoradiation therapy and its potential in the management of neurological tumors
Journal of neurosurgery, 1988
v~ Photoradiation therapy is a form of local treatment that depends on the selective retention of a photosensitizer, such as hematoporphyrin derivative (HpD), by the tumor followed by treatment with light of an appropriate wavelength to activate the sensitizer in the tumor. The selective uptake of HpD by cerebral tumors has been demonstrated both in laboratory animal model studies and in clinical studies, and selective destruction of intracerebral tumors has been demonstrated in animal glioma models. The biological basis for photoradiation therapy and, in particular, the mechanisms for the selective uptake of the sensitizer into the tumor and the destruction of tumor with photoradiation therapy are discussed. Current evidence suggests that singlet oxygen is the major intermediary leading to cell damage, although other radicals such as hydrogen peroxide and hydroxyl radicals may be involved. Other studies suggest that the initial damage is to the blood vessels, and the tumor subsequently undergoes ischemic changes. Sixty-four patients treated with photoradiation therapy have been reported in the literature. The initial clinical studies were disappointing in their therapeutic effect but these studies often included treatment of recurrent gliomas and low doses of light were used. Technical advances, particularly in laser technology, have enabled more effective photoradiation therapy and the clinical trials are reviewed. KEY WORDS 9 brain neoplasm 9 hematoporphyrin derivative 9 glioma 9 laser 9 photoradiation therapy