Photodynamic Therapy for Urological Malignancies: Past to Current Approaches Jehonathan H. Pinthus, Arjen Bogaards, Robert Weersink, Brian C. Wilson and John Trachtenberg* From the Prostate Cancer Center, University Health Network and Department of Medical Biophysics, Ontario Cancer Institute (JHP, AB, RW, BCW), University of Toronto, Toronto, Ontario, Canada Purpose: Modern PDT for urological tumors is a potentially selective approach in which in situ photosensitization by a nontoxic drug, locally activated by light, generates cytotoxic reactive oxygen species, causing cell death. While urological clinical experience with PDT is largely limited to treatment for superficial bladder cancer, the advent of novel photosensi- tizers and technologies for treatment planning, light delivery and dosimetry, PDT for prostate and other urological cancers appears increasingly realistic. Materials and Methods: We reviewed the current literature on PDT for urological tumors, in addition to recent emerging data from our laboratory and elsewhere. Results: Remarkable progress has been made in the field of photochemistry and photobiology. Together with improved optical delivery and imaging systems PDT holds promise as an alternative, minimally invasive and potentially curative treatment for localized solid tumors as well as for palliative treatment for isolated, clinically problematic metastases. Conclusions: Current experience with photodynamic therapy using contemporary photosensitizing agents and light sources is mainly restricted to in vivo experimental models and early phase clinical trails. However, ongoing preclinical work and clinical trials indicate that safer and effective PDT treatments in uro-oncology are imminent. Key Words: photochemotherapy, bladder, prostate, kidney, testes C linical trials of PDT are showing promise for treating malignancies or premalignant lesions at multiple sites, including the esophagus, skin, brain, peritoneal cavity, bladder, head and neck, as well as nononcological disorders, such as age related macular degeneration and actinic keratosis. 1 However, in urology PDT is rarely prac- ticed currently due in part to perceptions that the technique is complex to apply, has limited selectivity and efficiency, may have significant side effects and in particular requires patient isolation to protect against skin phototoxicity. There is also general unfamiliarity with the treatment concept and the significant progress that has been made in other clinical specialties. Until recently clinical experience with PDT in urology has been limited to treatment for superficial bladder cancer. 2 The modest long-term response rates observed in these studies and adverse effects, including bladder contrac- tion using hematoporphyrin derivative, have limited the appeal of the technique compared to that of standard endo- scopic resection of bladder tumors. However, the emergence of more potent and safer photosensitizers, portable light sources, dependable light delivery devices, and more accu- rate dosimetry and treatment planning is renewing interest in PDT as a minimally invasive approach for solid genito- urinary tumors, such as prostate and renal cancer. The PDT mechanism relies on in situ generation of cyto- toxic agents by the activation of a light sensitive drug. Light delivery follows drug administration up to 48 hours after administration in the case of earlier generations of photo- sensitizers or within minutes in the case of some more recent drugs. Light is delivered locally and is wavelength matched to the absorption maximum of the drug. Light absorption by the photosensitizer initiates a photochemical reaction that generates short-lived ROS, in particular singlet oxygen, pro- ducing cell death and tissue damage. Individually the pho- tosensitizer and light have no effect but together they induce a local cytotoxic reaction. Hence, the treatment selectivity of PDT results from differential drug accumulation/retention between the tumor and normal tissue plus site specific illu- mination which, by the use of optic fibers coupled to appro- priate laser sources, can reach tumors not only by endoscopy in hollow organs, such as the esophagus, 3 bronchial tree 4 and bladder, 5–11 but also by the direct intraoperative surface or interstitial illumination of parenchymatous viscera, such as the liver 12 and brain. 13 Due to its extremely short half-life (less than 1 microsec- ond) 14 singlet oxygen can only cause damage in its immedi- ate vicinity, ie at cellular binding sites specific to the particular photosensitizer. In many cases the primary target is mitochondrial but plasma membrane and lysosomes may also be involved. 15 Targeting to the nucleus is not common and initial damage is usually the lipid peroxidation of cell Submitted for publication November 23, 2004. Preclinical and clinical research in the use of Tookad® PDT for PC at this institution is provided by Steba Biotech, France and National Institutes of Health Grant CA43892. * Correspondence: Department of Surgery, University of Toronto, Prostate Center University Health Network, Princess Margaret Hospital, Room 4-926, 620 University Ave., Toronto, Ontario, M5G 2M9 Canada (telephone: 416-946-2100; FAX: 416-598-9997; e-mail: john.trachtenberg@utoronto.ca). Review Articles 0022-5347/06/1754-1201/0 Vol. 175, 1201-1207, April 2006 THE JOURNAL OF UROLOGY ® Printed in U.S.A. Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/S0022-5347(05)00701-9 1201