history of photodetection and photodynamic therapy, The

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

One of the major milestones in PDT development occurred in 1975 when Dougherty and coworkers (2) at the Roswell Park Cancer Institute in Buffalo reported the first successful complete tumor cure following administration of HpD and activation with red light in the treatment of experimental animal tumors. Mice carrying spontaneous or implanted mammary tumors were given 2.5-5.0 mg/kg HpD and rats with implanted Walker 256 carcinosarcomas or bearing 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors received 5-15 mg/kg HpD. Tumors were then exposed to red light from a xenon arc lamp for three 1 h periods over 5 days. Using a definition of cure as no palpable tumor at least 2 months after the last treatment, 48% of the transplanted mouse mammary tumors were cured. Similar results were observed with the rat DMBA-induced tumors using 15 mg/kg HpD with light exposure at 24 h. Lower doses of HpD or light failed to induce tumor regression, and neither drug nor light alone had any effect (2).

Spectrofluorimetric assay of minced tissue samples was also performed to determine the organ distribution of HpD. In normal tissues the greatest fluorescence was seen in the liver with a maximum tumor-normal ratio of 3.7:1 at 24 h following HpD administration. As a result of this finding tumors were treated at least 24 h after HpD administration. Toxicity studies in mice showed that exposure of the entire abdominal area to light 24 h after HpD administration produced a typical photosensitivity reaction with 50% mortality at 24 h. This mortality was greatly reduced when the drug to light interval was increased to 48 h, but at this time the tumor-liver ratio had decreased to 0.86 and the cure rate for the same tumor was reduced to 20%, less than half that seen at 24 h (2).

In the same year, Kelly, a urologist working at St. Mary's Hospital in London, UK, demonstrated that human bladder tumor cells transplanted into mice could be destroyed using PDT (45). Seven of 11 tumors implanted subcutaneously developed into tumor nodules and displayed typical red fluorescence following HpD administration. Subsequent light exposure produced ulceration and variable destruction of the tumor nodules with most (22 of 32) being totally or almost totally destroyed. There was also marked edema of the surrounding normal skin. However, when normal epithelium or smooth muscle was implanted little or no damage was seen following PDT.

EARLY HUMAN STUDIES

Another major event in the development of PDT occurred in 1976. Following the successful treatment of animal tumors using porphyrin-based PDT, Kelly and Snell proceeded to the first human study of the effects of PDT using HpD in five patients with bladder cancer. At cystoscopy, only limited tumor fluorescence was observed, but the resected specimens fluoresced brightly, indicating absorption of the short wavelength portion of the cystoscopic light source. Following total cystectomy, fluorescent microscopic studies of the specimens showed fluorescence restricted to malignant and premalignant lesions, including macroscopically normal areas, which were subsequently shown on histology to be dysplastic or malignant (46).