The Mechanism of PDT

There are two main ways in which light can react with a sensitiser and ground state triplet oxygen and so cause damage in living tissue. 

Type I involves the excited triplet state of the photosensitiser reacting with a substrate, by electron transfer or hydrogen abstraction, giving a radical. This radical reacts with triplet oxygen producing hydroperoxides, which initiate free radical autoxidation. 

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The mechanisms of PDT are based on photooxidative reactions and the primary target depends on the pathology, the absorbency and chemistry of the sensitiser and the incubation time [9,13,14]. 

As mentioned earlier, the mechanism of PDT action (via singlet oxygen production) is similar to the way bilirubin photosensitises its own destruction... 

The mechanism of PUVA and PDT both involve the formation of singlet oxygen, which is cytotoxic, and the former also probably also includes some direct action on DNA. 

The goal of this chapter is to briefly introduce PDT, to summarize the salient features of mechanistic studies, and to discuss some strategies to further improve the selectivity of PDT. Different aspects, such as the photochemical and molecular/cellular processes, will be reviewed, as well as the mechanisms by which PDT is thought to achieve tumor cure in vivo. A separate section is dedicated to ALA-based PDT and its use in diagnosis and therapy. No attempt has been made to make this an exhaustive review of any of these aspects and this is essentially a subjective summary and analysis. Excellent reviews on PDT exist and are referred to for further reading [1-4],... 

In summary, these studies into the working mechanisms of PDT at a cellular level have shown that (a) PDT with mitochondria-based photosensitizers can induce extremely rapid apoptosis, (b) it can bypass some of the normal control mechanisms, such as bcl-2 and (c) although PDT induced apoptosis is dependent on p53 status, overall cell killing is not, which is of importance since many human tumors have non-functional p53. The majority of these studies have been performed in vitro and further studies should indicate whether the same responses occur in vivo. In addition, the role of apoptosis in the overall tumor response is not clear and recent data, using cell lines deficient in apoptotic machinery, indicate that these cells are still sensitive to PDT, probably by using a necrotic pathway [134]. This sensitivity could possibly be used in the treatment of tumors which are chemoresistant, and indeed several studies have already shown the effective use of PDT in this area [84,85,88,156]. 

As with cancer treatments, PDT does not uniformly lead to a total eradication of tumors in all patients. It is, therefore, important to examine the mechanisms associated with tumor recurrence following PDT and to evaluate methods to improve the efficacy of PDT. 

Our recent experiments indicate that PDT can elicit the up-regulation of a variety of pro-angiogenic genes. This could have significant clinical implications. It is important to characterize both the mechanism of activation (oxidative stress and/or hypoxia related) as well as the PDT parameters producing activation and the biological relevance of this activation. 

PUVA is a treatment for eczema, psoriasis and vitiligo, which uses psoralen (furocoumarin molecule) as a photosensitiser, excited with UVA irradiation. The mechanism of PUVA action is similar to that of PDT, with photodynamic action utilising either a Type I or Type II mechanism. Psoralens are typically found in plants. They were known as early as ancient Egypt, but were only synthesised in a pure form in the 1970s. For PUVA therapy, psoralen can be taken orally or can be applied directly to the skin. PUVA therapy is highly effective at clearing skin problems such as psoriasis. 

Thus, PDT started and continues as a treatment for solid tumors. However, there are also munerous other applications in use clinically or under pre-clinical or clinical investigations [5], as listed in Table 1. These applications exploit the different biological mechanisms that can be selectively activated, depending on the PDT treatment parameters. The invention of the laser and optical fibers in the 1960 s was also important for the development of PDT although non-laser sources can be used, the ability to deliver high intensity laser light to almost any site in flie body is critical for many applications. 

The effect of PDT on the host immune system is dichotomous, resulting in immune suppression or immune activation. Although the mechanism leading to immune activation or suppression is unclear, recent studies indicated that the nature and extent of the tissue treated and the dose play a major role. >" Cutaneous PDT suppresses allograft rejection and contact hypersensitivity (CHS) reactions. - " PDT suppression of CHS in murine models was demonstrated with a number of different photosensitizers " and is antigen specific. The kinetics of CHS suppression is photosensitizer dependent. TPPS4 and HpD-PDT induce immediate CHS suppression, while m-THPC and Photofrin-PDT suppression require 72 h to develop. Kinetic differences were linked to photosensitizer... 

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