Thomas S. Mang

PHOTOBLEACHING OF PORPHYRINS USED IN PHOTODYNAMIC THERAPY AND IMPLICATIONS FOR THERAPY

Abstract— The development of an extraction procedure to quantitate dihematoporphyrin ether (DHE) concentration in tissues correlated to fluorescence measurements from instrumentation developed for in vivo fluorimetry was examined. In vivo fluorometric results from mouse mammary carcinoma (SMT‐F) were calibrated against results of the chemical extraction assay quantitated spectrophotometrically. Fluorescence and drug extractable levels increase in a linear fashion with injected dose. Loss of porphyrin fluorescence (photobleaching) and intra‐tumoral porphyrin level has been demonstrated both in vitro (NHIK cells) and in vivo (SMT‐F tumor) during illumination with light following exposure to Hpd or DHE. This process is essentially independent of porphyrin tumor level in vivo and could lead to tumor protection at very low porphyrin levels. On the other hand, this photobleaching process which occurs concurrent with cellular inactivation and tissue damage due to the photodynamic process can be exploited to protect normal tissue during photodynamic therapy (PDT) and thus greatly enhance the therapeutic ratio. This has been demonstrated in patients undergoing PDT.

The theory of photodynamic therapy dosimetry: consequences of photo-destruction of sensitizer

Abstract Photodynamic dose is defined as the area under the curve of sensitizer level plotted as a function of light dose. This is a photochemical definition of dose. We will show that this definition is useful in predicting photobiological response. The photodestruction of sensitizer during photodynamic therapy is shown to result in an upper limit on the photodynamic dose which can be delivered by an unlimited light dose. This limit results in the opportunity to make total photodynamic dose uniform to considerable depths (one to two centimeters). The existence of thresholds for permanent tissue damage allows protection of normal tissue from the large light doses required to achieve this limiting dose deep in the tissue. Higher sensitizer levels in the tumor permit tumor destruction while the normal tissues are protected. A clinical trial to determine the proper level of injected dose necessary for these results is required.

Lasers and light sources for PDT: past, present and future.

The more recent use of Photodynamic therapy in Oncology dates to the early 1970s, when Dr. Thomas J. Dougherty, began his investigations into the mechanisms and clinical uses hematoporphyrin derivative (HpD). Since then the therapy has found its way through the regulatory process in numerous countries throughout the world. In many of these locales as it was in the United States, this was the first drug device approval, for oncology, that had been undertaken and ultimately approved, by the regulatory agencies in the respective countries. Throughout this time changes occurred in the formulation of HpD as well as the development of other photosensitizers. The more difficult aspect, however, of this modality has been the availability of reliable, affordable and appropriate devices for the production and delivery of light to the targeted areas. In the last 10 years, however, there has been a slow yet improving landscape in the development of devices for PDT that ultimately will provide the impetus for greater acceptance of PDT in the medical community.

Photodynamic therapy in the treatment of Bowen's disease.

BACKGROUND The treatment of Bowens disease in anatomically difficult areas or especially large lesions can challenge accepted modalities of treatment. OBJECTIVE The purpose of this study was to illustrate the effectiveness of photodynamic therapy in the treatment of Bowens disease. In addition, photodynamic therapy may be used as adjuvant therapy for difficult lesions. METHODS Six patients with Bowens disease in various anatomic sites were treated with photodynamic therapy. Four were in a difficult anatomic site, or were especially large, or both. Photofrin, 1.0 mg/kg, was administered intravenously and laser treatment was given approximately 48 hours later with the argon dye laser. Light was administered at a wavelength of 630 nm and the light dose ranged from 185 to 250 joules/cm2. Treatment was given by surface radiation only. RESULTS Eight lesions were treated. All showed a complete response at 3 months (100%) and continue to show a complete response at 6 and 12 months. Morbidity was low; the most significant side effects were moderate pain and edema. Healing time varied depending on the size of the lesion. CONCLUSION Photodynamic therapy is an effective and useful alternative for Bowens disease, especially those lesions in anatomically difficult areas or those that are especially large.

An evaluation of photodynamic therapy in the management of cutaneous metastases of breast cancer

A series of 37 patients with cutaneous metastases of breast carcinoma were treated with photodynamic therapy (PDT) to the chest wall; decreasing doses of photofrin II and increasing light doses were used in order to test drug/light dose reciprocity and determine the lowest effective dose of photofrin II. 5 patients (13.5%) achieved a complete response, 13 (35.1%) demonstrated partial responses and 19 (51.4%) showed no benefit. The extent and type of recurrent disease were strong determinants of the likelihood of response. Minimal and nodular disease responded well to PDT (5/5 complete responses); partial responses were seen in 11/20 (55%) of patients with disease of moderate extent. No patient with extensive erythema derived any benefit (0/5), and only 2/12 (17%) patients with advanced nodularity showed a partial response. Reduction in photofrin dose to 0.75 mg/kg with reciprocal increases in light dose to 182 J/cm2 did not impair treatment efficacy.

TIME and SEQUENCE DEPENDENT INFLUENCE OF IN VITRO PHOTODYNAMIC THERAPY (PDT) SURVIVAL BY HYPERTHERMIA

Abstract— Experimental mouse mammary tumor cells (EMT‐6) were subjected to PDT (30 u‐g/mt DHE,620–640 nm at 3.94 mW/cnr) and hyperthermia (45.2°C, Haake FK2 waterbath) for varying lengths of time and sequences. The results show that the two modalities interact in a manner which is more cytotoxic than the sum of the individual treatments, and the sequence of administration is a determining factor in the degree of interaction. The greatest potentiation of PDT is seen when hyperthermia is administered immediately after PDT. Introducing a time interval at 37°C, between treatments, leads to a rapid loss of interaction. Analysis of dose‐response curves reveals a return of the shoulder and an increase in the D., after various incubation periods at 37°C. These data suggest that the cells accumulate and demonstrate recovery from sub‐lethal damage and also develop a tolerance to a second challenge. The appearance of stress proteins was also detected after PDT treatments, which may account for some of the phenomena observed.

Photodynamic therapy (PDT) for malignant brain tumors — Where do we stand?

INTRODUCTION 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. PURPOSE 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. METHOD 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. CURRENT RESULTS A measurable degree of necrosis is seen to a depth of about 5mm. Cavitary PDT with hematoporphyrin derivative (HpD) results are encouraging, but need an adequate Phase III trial. Talaporfin with cavitary light application appears promising, although only a small case series has been reported. Foscan for fluorescence guided resection (FGR) plus intraoperative cavitary PDT results were improved over controls, but are poor compared to other groups. 5-Aminolevulinic acid-FGR plus postop cavitary HpD PDT show improvement over controls, but the comparison to standard of care is still poor. 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 as an alternative treatment for disinfection of bacteria in oral biofilms

Biofilm‐related diseases such as caries and periodontal disease are prevalent chronic oral infections which pose significant oral and general health risks. Biofilms are sessile communities attached to surfaces. Photodynamic therapy (PDT) has been demonstrated to have a significant anti‐microbial effect and presents as an alternative to treating biofilm‐related disease. The aim of this study was to determine the ability of porfimer sodium induced PDT to treat localized infections of Streptococcus mutans in biofilm communities.

PHOTODYNAMIC THERAPY FOR THE TREATMENT OF NONMELANOMATOUS CUTANEOUS MALIGNANCIES

Photodynamic therapy (PDT) is a modality whose concept is not new to dermatologists. PDT has gained regulatory approval in the United States for the treatment of esophageal and lung malignancies. The field has grown over the last decade, and now phase II/III clinical trials using second generation drugs for the treatment of nonmelanoma skin cancers, palliation of metastases to the skin, and Kaposis sarcomas have been introduced. These new sensitizers tend to reduce the one side effect of PDT, namely persistent generalized cutaneous photosensitivity. PDT has shown efficacy in (1) patients who have failed conventional therapies, and for whom local treatment options are limited (2) patients in whom surgery would result in cosmetic disfigurement, and (3) patients prone to developing multiple lesions as in Gorlins syndrome. Dosimetry is based on well-understood treatment matrices that have optimized light delivery with known photosensitizer administrations. The advantages of PDT for cutaneous malignancies include the ability to treat numerous lesions in one setting, in a noninvasive manner without any apparent concern for the development of carcinogenicity.

PHOTODYNAMIC THERAPY IN THE TREATMENT OF PANCREATIC CARCINOMA: DIHEMATOPORPHYRIN ETHER UPTAKE and PHOTOBLEACHING KINETICS

Abstract Results of dihematoporphryin ether (DHE) uptake and fluorescence kinetics show that the concentration in the pancreas is on the order of 40‐60 μg DHE g−1 of tissue at an injected dose of 40 mg kg−1. Previously concentrations on this order have primarily been found in organs of the reticuloendothelial system. Two intra‐pancreatic carcinoma models, one of acinar origin (rat) and one of ductal origin (hamster), were studied. Both showed equal or higher concentrations of DHE as compared with normal pancreas when fluorescence measurements and chemical extraction procedures were performed. Photodynamic therapy (PDT) treatment of the normal pancreas and pancreatic tumors yielded atypical results. When the normal pancreas with DHE present is exposed to 630‐nm light from a dye laser (75 mW cm−2, 30 min), the normal photobleaching measurable by fluorescence decay does not occur. Yet the pancreatic tumor responds with a relatively normal fluorescence decay pattern, with hemorrhaging and a resultant loss of measurable DHE concentration.