Photophysical and photobiological processes in the photodynamic therapy of tumours

Photodynamic therapy (PDT) is an innovative and attractive modality for the treatment of small and superficial tumours. PDT, as a multi-modality treatment procedure, requires both a selective photosensitizer and a powerful light source which matches the absorption spectrum of the photosensitizer. Quadra Logic's Photofrin ^®, a purified haematoporphyrin derivative, is so far the only sensitizer approved for phase III and IV clinical trials. The major drawbacks of this product are the lack of chemical homogeneity and stability, skin phototoxicity, unfavourable physicochemical properties and low selectivity with regard to uptake and retention by tumour vs. normal cells. Second-generation photosensitizers, including the phthalocyanines, show an increased photodynamic efficiency in the treatment of animal tumours and reduced phototoxic side effects. At the time of writing of this article, there were more than half a dozen new sensitizers in or about to start clinical trials. Most available data suggest a common mechanism of action. Following excitation of photosensitizers to long-lived excited singlet and/or triplet states, the tumour is destroyed either by reactive ringlet oxygen species (type II mechanism) and/or radical products (type I mechanism) generated in an energy transfer reaction. The major biological targets of the radicals produced and of singlet oxygen are well known today. Nucleic acids, enzymes and cellular membranes are rapidly attacked and cause the release of a wide variety of pathophysiologically highly reactive products, such as prostaglandins, thromboxanes and leukotrienes. Activation of the complement system and infiltration of immunologically active blood cells into the tumorous region enhance the damaging effect of these aggressive intermediates and ultimately initiate tumour necrosis. The purpose of this review article is to summarize the up-to-date knowledge on the mechanisms responsible for the induction of tumour necrotic reactions.