Analysis of acute vascular damage after photodynamic therapy using benzoporphyrin derivative (BPD)
VH Fingar1, PK Kik1, PS Haydon1, PB Cerrito2, M Tseng3, E Abang3 and TJ Wieman1
1Department of Surgery, Division of Surgical Oncology, 2Department of Mathematics, 3Department ofAnatomy and Neurobiology, University of Louisville, Louisville, KY 40292, USA
Summary Benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) is currently under investigation as a photosensitizer for photodynamic therapy (PDT). Since BPD exhibits rapid pharmacokinetics in plasma and tissues, we assessed damage to tumour and muscle microvasculature when light treatment for PDT was given atshort times after injection of photosensitizer. Groups of rats with chondrosarcoma were given 2 mg kg-1 of BPD intravenously 5 min to 180 min before light treatment of 150 J cm-2 690 nm. Vascular response was monitored using intravital microscopy and tumour cure was monitored by following regrowth over 42 days. For treatment at 5 or 30 min after BPD injection, blood flow stasis was limited totumour microvasculature with lesser response in the surrounding normal microvasculature, indicating selective targeting for damage. No acute changes were observed in vessels when light was given 180 min after BPD injection. Tumour regression after light treatment occurred in all animals given PDT with BPD. Long-term tumour regression was greater in animals treated 5 min after BPD injection and least inanimals given treatment 180 min after drug injection. The correlation between the timing for vascular damage and cure implies that blood flow stasis plays a significant role in PDT-induced tumour destruction. Keywords: photodynamic therapy; BPD; vascular effects, chondrosarcoma
Photodynamic therapy (PDT) is a rapidly evolving treatment modality with uses ranging from oncology, cardiovasculardisease to hyperproliferative disorders. PDT relies on the ability of certain photosensitizing agents, usually porphyrins, to absorb light and convert this energy into cytotoxic molecules including singlet oxygen. The therapeutic value of this treatment is defined by the location of photosensitizer during light treatment. The initial photosensitizer to enter clinical trials, Photofrin, has beenrecently approved for use in the USA, Canada, and abroad for treatment of solid tumours and new drugs are in various stages of pre-clinical and clinical development. Benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) is a second generation photosensitizer that has several favourable characteristics for use in PDT over Photofrin (Levy, 1994). This agent is chemically pure and is activatedwith light at long wavelengths (690 nm) which allows theoretically for deeper penetration of light into the treatment area. Benzoporphyrin derivative has rapid plasma and tissue pharmacokinetics and is thus quickly cleared from tissues, resulting in a diminished period of skin photosensitivity compared to other drugs including Photofrin (Richter et al, 1990; Levy et al, 1993). A wide range ofdiseases are under investigation for treatment with PDT using BPD including solid tumours (Richter et al, 1993), choroidal neovascularization (Lin et al, 1994), arthritis (Chowdary, 1994), HIV therapy (North et al, 1996) and uterine endometrial ablation (Wyss et al, 1994). Although the targets for BPD based PDT-induced destruction of tissue remain largely unresolved, studies by Schmidt-Erfurth et al(1995) have demonstrated vascular damage leading to blood flow
Received 19 June 1998 Revised 1 September 1998 Accepted 2 September 1998 Correspondence to: VH Fingar
stasis. The predominance of vascular damage in treated tissues correlates well with the high serum levels of photosensitizer that are present at short times after drug injection. Light treatment is generally given within 3 h of...