Photodynamic therapy (PDT) involves light activation of a photosensitizer, resulting in oxygen-dependent, free radical-mediated cell death. Little is known about the efficacy of PDT in treating human sarcomas, despite an ongoing clinical trial treating i.p. sarcomatosis. The present study evaluates PDT treatment of a human sarcoma xenograft in nude mice and explores the mechanism of PDT-mediated antitumor effect. Athymic nude mice, 6-8 weeks of age, were s.c. injected with 5 x 10(6) cells of the A673 human sarcoma cell line. Tumors were allowed to grow to a diameter of about 10 mm. Photofrin (PF), 10 mg/kg, was injected by tail vein, and 24 h later, 630 nm light was delivered to the tumor with fluences of 50, 100, 150, or 300 J/cm2 at a fluence rate of 250 mW/cm2. To assess the efficacy of PDT in the treatment of sarcomas, photosensitizer uptake/retention studies and dose-response studies were performed. Studies carried out to determine the mechanism of tumor response included tumor temperature measurements before, during, and after treatment; tumor vascular perfusion studies with laser Doppler; electron microscopic analysis of tumor sections for vascular occlusion; and analysis of tumor cryosections for endothelial cell damage, apoptosis, and necrosis. At all time points of analysis, photosensitizer levels were greater in tumor than in muscle. Dose-response studies showed that at 100 J/cm2, five of six mice had a complete response to treatment, one of six had a partial response, and no deaths occurred. Temperature measurements indicated that thermal injury did not contribute to tumor response. Vascular perfusion studies demonstrated a significant reduction in blood flow as early as 6 h after PDT. Electron micrographs revealed erythrostasis in tumor microvessels starting as early as 2 h after treatment and complete occlusion of blood vessels by 12 h. Starting as early as 4 h after PDT, apoptosis first appeared in endothelial cells lining the occluded blood vessels and became more widespread at later time points. PDT is an effective treatment for this human sarcoma xenograft in nude mice. The mechanism of tumor destruction in this model appears to be vascular damage with initial apoptosis in tumor endothelial cells and delayed tumor cell apoptosis. This therapy may be valuable in the treatment of patients with sarcomatosis.