OXYGEN AND LIGHT DEPENDENCY OF PHOTODYNAMIC THERAPY

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It has been the long-term goal of this project to elucidate the role of oxygen in photodynamic therapy (PDT), with the hope of improving the treatment of solid tumors. This competing renewal application continues on this path. We have established that with the photosensitizer Photofrin, PDT can be self-limiting due to oxygen depletion caused by vascular damage. Recently the photochemical depletion of oxygen in tissue through generation of cytotoxic oxygen species has been suggested as an additional limitation. This proposal deals with this aspect of PDT. We will examine the suggestion that by lowering the rate of light delivery this oxygen depletion can be diminished, leading to increased efficiency of treatment. We hypothesize that for certain disease conditions, fluence rate reductions will increase PDT efficiency sufficiently to allow reductions in total fluence, thus not unduly prolonging treatment time. This may eventually allow light delivery with less powerful and technically simplified light sources. We suggest that it may be possible to increase PT efficacy in cases where the complete response rate is unsatisfactory and to enhance the therapeutic ratio. We further hypothesize that this approach will not be beneficial for all conditions, and may be detrimental for some. Finally, we hypothesize that such light delivery modifications will affect both vascular and direct tumor cell responses. This project will try to confirm these hypotheses both preclinically and/or clinically. We will concentrate on photosensitizing compounds which are in current clinical use, i.e., Photofrin, delta- aminolevulinic acid (ALA), tin etiopurpurin (SnET2) and a pyropheophorbide (HPPH). AIM 1 will determine whether employing low fluence rate regimes can safely increase PDT efficiency to such an extent as to achieve tumor effects at least equal to high fluence-rate treatments, at equal or shorter treatment times. Fluence rates will be chosen based on a mathematical model which provides time dependent concentrations of 3/O/2 and 1/O/2 in the tissue. AIM 2 will try to validate the model predictions of PDT oxygen depletion by direct measurements of tissue pO/2 before, during and after light treatment, examine the effects of fluence rate on drug photobleaching and define the effects upon tumor cells and/or the vasculature. AIM 3 will determine clinically photosensitizer tissue concentrations and light attenuation in patients with thin, intermediate and thick lesions of basal cell carcinoma, Kaposis's sarcoma, cutaneous T cell lymphoma and recurrent/metastatic breast cancer. These data will be used in the mathematical model to predict fluence rate modifications which will result in varying tumor pO/2 levels. Predictions will be validated by direct pO/2 measurements, and treatment protocols will be designed to test our stated hypotheses, i.e., that we can achieve greater, or at least comparable efficacy and selectivity to current high fluence rate therapies, but with lower total fluence and without a substantial increase in treatment time.