Enhancement of photodynamic therapy with 5-aminolaevulinic acid-induced porphyrin photosensitisation in normal rat colon by threshold and light fractionation studies

Abstract

5-Aminolaevulinic acid (ALA)-induced prophyrin photosensitisation is an attractive option for photodynamic therapy (PDT) since skin photosensitivity is limited to 1-2 days. However, early clinical results on colon tumours using the maximum tolerated oral dose of 60 mg kg-1 showed only superficial necrosis, presumably owing to insufficient intratumoral porphyrin levels, although inadequate light dosimetry may also be a factor. We undertook experiments using ALA, 25-400 mg kg-1 intravenously, to establish the threshold doses required for a PDT effect. Laser light at 630 nm (100 mW, 10-200 J) was delivered to a single site in the colon of photosensitised normal Wistar rats at laparotomy. The animals were killed 3 days later and the area of PDT-induced necrosis measured. No lesion was seen with 25 mg kg-1. The lesion size increased with larger ALA doses and with the light dose but little benefit was seen from increasing the ALA dose above 200 mg kg-1 or the light dose above 100 J. Thus there is a fairly narrow window for optimum doses of drug and light. Further experiments showed that the PDT effect can be markedly enhanced by fractionating the light dose. A series of animals was sensitized with 200 mg kg-1 ALA and then treated with 25 J. With continuous irradiation, the lesion area was 13 mm2, but with a single interruption of 150 s the area rose to 94 mm2 with the same total energy. Results were basically similar for different intervals between fractions (10-900 s) and different numbers of fractions (2-25). This suggests that a single short interruption in the light irradiation may dramatically reduce the net light dose required to achieve extensive necrosis.