Toxicity Of Photodynamic Therapy Research Articles

P209 Therapeutic effect and biohazard evaluation of photodynamic therapy for inoperable liver cancer

<h3>Background</h3> Photodynamic therapy (PDT) is a procedure that uses a non-toxic photosensitiser (PS) and visible light to generate reactive oxygen species (ROS) that kill tumour cells. The aim of this study was to investigate the efficiency of Photofrin as a PS for locally advanced hepatocellular carcinoma (HCC). The toxicity and pathological response on upper abdominal organs were investigated after PDT. <h3>Methods</h3> We created an orthotropic animal model with B6 mice using an HCC cell line (BNP), to assess the tumour response after PDT. Twenty-four tumour-bearing animals were divided into four groups and underwent PDT (PS: 5mg/kg, light source: 630-nm CW diode laser with a dose of 100J/cm²). Six animals did not receive PDT as control group, six animals received PS injection only (PS group), six animals revived laser exposure only (light group), and six animals received PDT. Tumour size was investigated 4days after treatment. Assessment of pathologic changes was performed using vital staining with Evans blue and morphologic investigation. The toxicity of PDT was evaluated histologically and by associated symptoms and mortality. <h3>Findings</h3> Partial to complete tumour responses were noted in 83% of mice in the PDT group, with no tumour reduction noted in the other groups. The percentage necrosis in HCC was significantly higher in animals who underwent PDT, at 92.1%, versus 8.7% in the PS group and 3.6% in the light group. No pathological effects were seen in the liver, pancreas, or intestines 4days after local PDT. Serum levels of creatinin, amylase, lipase, AST, and ALT did not differ significantly between the four groups. No mortality was noted. <h3>Interpretation</h3> Photofrin-mediated PDT may be a feasible and safe modality for inoperable HCC.

Toxicity of photodynamic therapy with LED associated to Photogem®: An in vivo study

The aims of this study were to evaluate the effects of Photogem®-mediated photosensitization on rat palatal mucosa and the biodistribution of the photosensitizer in this tissue. A solution of Photogem® (500 or 1000 mg/l) was applied to the palatal mucosa for 30 min and the exposure time to blue LED (460 nm) was 20 min (144 J/cm(2)). At 0, 1, 3, and 7 days, palatal mucosa was photographed for macroscopic analysis. After killing, the palate was removed for microscopic analysis. Thermal mapping evaluated temperature change in the tissue during irradiation. All experimental groups revealed intact mucosa in the macroscopic analysis. Tissue alterations were observed microscopically for only four out of 80 animals subjected to PDT. Fluorescence emitted by Photogem® was identified and was limited to the epithelial layer. A temperature increase from 35 to 41°C was recorded. Photogem®- mediated PDT was not toxic to the rat palatal mucosa.

Photodynamic treatment of neoplastic lesions of the gastrointestinal tract. Recent advances in techniques and results.

Photodynamic therapy (PDT) is a form of cancer treatment based on the selective accumulation of a photosensitizer (by exogenous or endogenous means) in neoplastic tissue. Subsequent activation of the photosensitizer by a specific wavelength of light results in tumor cell death. Activation of a photosensitizer to the appropriate energy state results in the production of singlet oxygen, a powerful oxidizing agent. PDT can kill cells by three mechanisms: direct cell death by photooxidation, apoptosis, or as a consequence of vascular shutdown. The toxicity of PDT is site specific and dependent on the organ being irradiated and the selectivity of the photosensitizer for target tissue over normal tissue. However, there are also reactions related to the sensitizer per se that are independent of those related to the treatment site. Such reactions include cutaneous photosensitization, nausea, vomiting, hypotension, and altered liver 'function' tests. Excitation of photosensitizer by an incident photon produces reemission of a fluorescent photon, which can be used to detect a tumor that is not ordinarily evident. The major limiting factor in using PDT is the depth of tumor kill. The majority of clinical experience involving PDT of the gastrointestinal tract involves patients who are considered to be poor operative risks, and reported follow-ups after treatment are not only limited but also variable.

Reduction of intracellular pH is not the mechanism for the synergistic interaction between photodynamic therapy and nigericin.

Previous studies showed that photodynamic therapy (PDT) sensitized by aluminum phthalocyanine can be dramatically potentiated by the K+/H+ ionophore nigericin. Nigericin equilibrates intracellular pH (pHi) and extracellular pH (pHe) and is most effective in potentiating PDT damage when cells are in an acidic environment (pH 6.5-6.7). We therefore hypothesized that the ability of nigericin to lower pHi is causally related to its ability to potentiate PDT. To test this, the pHi of A549 cells was reduced using pHe-adjusted growth medium, with or without addition of amiloride and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, inhibitors of the membrane-based exchangers responsible for regulating pHi. Using fluorescence ratio imaging, we found that pHi can be equilibrated to within +/- 0.05 pH unit, in the pH range of 6.0-6.8, for up to 1 h after pHe adjustment. Cells equilibrated to various pHi were subjected to PDT at various light fluences, then plated for clonogenic survival immediately after PDT treatment. There is no significant effect of lowering pHi, to values as low as 6.23, on the toxicity of PDT, regardless of whether pHi is lowered by adjustment of the medium alone or by addition of exchange inhibitors. However, cells equilibrated to pHi 6.0 are more sensitive to PDT, with survival reduced by 1 log at 20 kJ/m2 and 1.5 log at 30 kJ/m2, relative to cells treated at a pHi of 6.8 (controls). In contrast, 20 microM nigericin in medium at pHe 6.7 reduces pHi to 6.55, but reduces the surviving fraction at 20 kJ/m2 by nearly 3 logs relative to controls. These data conclusively demonstrate that the ability of nigericin to potentiate PDT is not directly related to its ability to lower pHi. Furthermore, they show that the expression of PDT damage is independent of pHi, except at the very low value of 6.0. Photodynamic therapy does not induce apoptosis in A549 cells, at surviving fractions of 0.1 to 0.01, under any of the treatment conditions used in this study.

Toxicity of photodynamic therapy with photofrin in the normal rat brain.

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. A Photofrin dose of 2 mg/kg of body weight produced a transient breakdown in the blood brain barrier around the site of the implanted optical fiber demonstrated by magnetic resonance imaging (MRI), extravasation of EB dye and pallor on hematoxylin and eosin-stained microscopic tissue sections. A much larger area of BBB disruption was seen at a dose of 4 mg/kg of Photofrin, and this drug dose resulted in significant permanent brain injury. In this model, a Photofrin dose of 4 mg/kg body weight is not tolerated by the normal brain.

中心型早期肺癌へのPDTの効用

A phase II was conducted between June 1989 and Feburary 1992 to evaluate the activity and toxicity of photodynamic therapy (PDT) with photofrin II in centrally located early-stage lung cancer and to determine the complete response (CR) rate as the primary end point.Patients and Methods: Patients had histologically proven lung cancer and endoscopically superficial thicking or small protrusions. All lesions were located in subsegmental or larger bronchi. All patients had a performance status (PS) of 0 to 2 and artial oxygen pressure tension (PaO2) ?60 torr. No lymph node or distant metastases were present. All patients received photofrin II (2 mg/kg) intravenously 48 hours before PDT. Tumor lesions were superficially photoradiated by argon dye laser or excimer dye laser. Results: Of 54 patients with 64 carcinomas, 51 with 61 carcinomas were eligible for toxicity evaluation and 49 with 59 carcinomas were assessable for response. Of the 59 assessable carcinomas, 50 (84.8%; 95% confidence interval, 73.0% to 92.8%) showed a CR after initial PDT. The median duration of CR was 14.0+ months (range, 2.0+ to 32.4+) The multiple regression model indicates that estimated length of longitudinal tumor extent was the only independent prognostic factor for CR (p=0.002). Ten carcinomas that had a CR had a local recurrece between 2 months to 19 months after initial PDT (median recurence time, 6 months). The 16 carcinomas that had a CR duration of 24 months, had no local recumence after initial PDT. Regression model shows that a longitudinal extent of tumor was important factor for local recurrence. Conclusion: PDT with photofrin II has an excellent effect on patients with centrally located early-stage lung cancer who have a longitudinal extent of 1 cm or less.