history of photodetection and photodynamic therapy, The

Photochemistry and Photobiology, Nov 2001 by Ackroyd, Roger, Kelty, Clive, Brown, Nicola, Reed, Malcolm

The potential of using PDT in the treatment of esophageal cancer was soon realized. In 1984, McCaughan et al. (60) reported the use of PDT in the treatment of seven patients with obstructing carcinoma in which all lesions responded, regardless of histological type, with good palliation in all cases. Two patients obtained relief of dysphagia for up to 11 months following treatment. The following year Hayata et al. (61) reported the effects of PDT in superficial esophageal lesions and early gastric cancer in patients who refused or were unfit for surgery. In the esophagus complete responses were seen in four cases, although three of these also received radiotherapy. Of 16 patients with early gastric cancer four were treated with PDT alone and all had a complete response. Twelve patients in this series later underwent resection, and a complete response was seen in five patients previously treated with PDT. More recently, in 1995, Sibille et aL (62) published a large series of 123 patients with esophageal cancer treated with PDT. HpD was administered, followed 72 h later by laser irradiation using a 630 nm dye laser (62). The complete response rate at 6 months was 87% with an overall 5 year survival rate of 25 /- 6% and a disease specific 5 year survival rate of 74 /- 5%. This represents a significant survival benefit when compared with the outcome without treatment.

Over the last 20 years PDT has been successfully employed in the treatment of many other types of tumor. These include recurrent gynecological tumors (63), intra-ocular lesions (64,65), brain tumors (66,67), head and neck lesions (68,69) and rectal cancer (70).

MECHANISMS OF ACTION

Despite considerable investigation and debate (71,72) the mechanism of action of PDT is still not fully understood. PDT was initially shown to have effects at a cellular level (73) and subsequently on the tissue vasculature (74). The vascular response plays an integral role in tumor death with vessel shutdown and stasis starving the tumor of oxygen and nutrients and slowing of flow leading to thrombus formation (74,75). However, increasingly, the effects at a cellular level are being investigated and targeted.

The extent of photodamage and cytotoxicity is thought to be multifactorial, including the intracellular distribution and concentration of photosensitizer, light intensity and oxygen availability. Sites that have been localized include the plasma membrane, mitochondria, nuclei and lysosomes (76). It is easier to identify a specific target with newer sensitizers, as these tend to be a pure compound rather than a mixture. This is of importance as reactive singlet oxygen has a short lifetime and thus limited diffusion within the cell (77).

In 1991, it was shown that PDT causes an apoptotic response in cells (78) and this provided an explanation for the widespread efficacy of PDT. Apoptosis is an energy dependant process in nucleated cells and equates to programmed cell death. It has been suggested that this is primarily caused by mitochondrial damage (79). The initial photooxidative injury triggers a number of responses, including direct cytotoxicity within the tumor microenvironment (80). This, in combination with endothelial cell damage, results in microvascular collapse and hypoxic death (75,81).