Changes in perfusion of mouse tumours after photodynamic therapy

248

204

Summary It has been proposed that the generation of 102 during photodynamic therapy (PDT) may lead to photochemical depletion of ambient tumour oxygen, thus causing acute hypoxia and limiting treatment effectiveness. We have studied the effects of fluence rate on P02, in the murine RIF tumour during and after PDT using 5 mg kg-' Photofrin and fluence rates of 30, 75 or 150 mW cm-2. Median P02 before PDT ranged from 2.9 to 5.2 mmHg in three treatment groups. Within the first minute of illumination, median tumour P02 decreased with all fluence rates to values between 0.7 and 1.1 mmHg. These effects were rapidly and completely reversible if illumination was interrupted. During prolonged illumination (20-50 J cm-2) P02 recovered at the 30 mW cm-2 fluence rate to a median value of 7.4 mmHg, but remained low at the 150 mW cm-2 fluence rate (median P02 1.7 mmHg). Fluence rate effects were not found after PDT, and at both 30 and 150 mW cm-2 median tumour P02 fell from control levels to 1.0-1.8 mmHg within 1-3 h after treatment conclusion. PDT with 100 J cm-2 at 30 mW cm-2 caused significantly (P= 0.0004) longer median tumour regrowth times than PDT at 150 mW cm-2, indicating that lower fluence rate can improve PDT response. Vascular perfusion studies uncovered significant fluence rate-dependent differences in the responses of the normal and tumour vasculature. These data establish a direct relationship between tumour P02, the fluence rate applied during PDT and treatment outcome. The findings are of immediate clinical relevance.

Section: Discussionsupporting

confidence: 81%

Reduction of tumour oxygenation during and after photodynamic therapy in vivo: effects of fluence rate

Sitnik

Hampton²,

Henderson³

1998

248

204

“…Previously published Photofrin data (Baas et al, 1994) for regrowth time after PDT alone (--) or with MMC (-) are also indicated by the dashed lines. The data for m-THPC PDT were previously published (Van Geel et al, 1994 …”

Section: Resultsmentioning

confidence: 99%

“…This difference may be due to the higher light dose (400 J cm-') required for effective tumour treatment with Photofrin-mediated PDT. These light doses require 68 min for delivery, by which time vascular perfusion probably inhibits the access of MMC into the tumour (Van Geel et al, 1994 …”

Section: Resultsmentioning

confidence: 99%

Mechanisms for optimising photodynamic therapy: second-generation photosensitisers in combination with mitomycin C

Geel

Oppelaar²,

Oussoren³

et al. 1995

“…In addition to tumour cell-directed necrosis induced by PDT, HPD additionally accumulates in endothelial cells (Leunig et al, 1994), allowing destruction of the tumour vascular system (van Geel et al, 1994).…”

mentioning

confidence: 99%

Influence of a haematoporphyrin derivative on the protoporphyrin IX synthesis and photodynamic effect after 5-aminolaevulinic acid sensitization in human colon carcinoma cells

Messmann

Geisler²,

Groß³

et al. 1997

Summary Haematoporphyrin derivatives (HPDs) are potent sensitizers in photodynamic therapy (PDT), associated with prolonged skin photosensitivity. 5-Aminolaevulinic acid (5-ALA), a natural precusor of haem, is converted intracellularly into the photosensitive agent protoporphyrin IX (PPIX), causing direct cytotoxicity after laser light irradiation but limited skin photosensitivity over 1-2 days and higher tumour selectivity. Unfortunately, the use of 5-ALA in PDT has been shown to cause only superficial tissue necrosis. Therefore, a combination of HPD and 5-ALA could be of great clinical value in the treatment of tumours if a synergistic effect of both sensitizers on tumour cell necrosis with less skin photosensitivity could be demonstrated. Human colon adenocarcinoma cells (HT-29) were cultured with either HPD or 5-ALA alone, simultaneously for 24 h with 5-ALA and HPD or in succession with 5-ALA (18 h) followed by HPD (6 h at different concentrations. Intracellular PPIX concentrations were determined by high-performance thin-layer chromatography. Furthermore, PDT was performed with an incoherent light source (X = 580-740 nm) using a light dose of 30 J cm-2 and an output power of 40 mW cm-2. The intracellular PPIX concentration correlated well with 5-ALA drug dose and incubation time and was highest after single 5-ALA sensitization. In the presence of HPD, either simultaneously or sequentially, PPIX decreased significantly. The PDT effect after simultaneous incubation with both sensitizers for 24 h was not superior to incubation with HPD alone. If 5-ALA incubation (18 h) was followed by HPD (6 h) cytotoxicity after PDT was higher than with either single drug. 5-ALA (80 gg ml-') led to a decrease in tumour cell viability by 40%. A similar effect could be observed when 5-ALA and HPD were sequentially combined allowing for a reduction of the 5-ALA dose from 80 gg ml-1 in the absence of HPD to 60 9g ml-' and 5,g ml-' together with 0.5,g ml-' and 2,g ml-' HPD respectively. We speculate that the enhanced PDT effect after the combined administration of 5-ALA and HPD to cultures of colon carcinoma cells should be even more impressive in the tumour in vivo, since HPD primarily targets the tumour microvasculature and secondarily tumour cells.