Summary Administration of 5-aminolaevulinic acid (ALA) leads to porphyrin accumulation in malignant and premalignant tissues, and ALA is used as a prodrug in photodynamic therapy (PDT). To understand the mechanism of porphyrin accumulation after the administration of ALA and to investigate whether ALA-induced protoporphyrin IX Correspondence to: FWM de Rooij lead to the development of adenocarcinoma through a multistep process of progression from metaplasia to lo%--agrade dysplasia.high-grade dysplasia and ultimately to invasixe cancer (Hamilton and Smith. 1987: Hameeteman et al. 1989). High-grade dysplasia in Barrett's oesophagus presents a difficult management problem.Options include endoscopic sun eillance and/or oesophagectomr (Lexine et al. 1993: Clark et al. 1996: Cameron. 1997. A new nonsurgical management option involhes eradicating the dysplastic epithelium and columnar mucosa by PDT. In contrast to other photosensitizers. mans of which localize in the microxvasculature of all tissue layers of hollow organs. ALA induces much higher levels of PPIX in the mucosa than submucosa or muscularis mucosae (Loh et al. 1993). ALA-PDT has been used to treat high-grade dy splasia in Barrett's oesophagus. resulting in necrosis of dysplastic mucosa with regeneration of normal squamous mucosa (Gossner et al. 1995: Reaula et al. 1995: Barr et al. 1996.To optimize ALA-PDT for Barrett's oesophagus and early carcinoma. knowledae of the mechanism of porphyrin accumulation in these tissues is required. We determined the activities of PBG-D and FC in normal tissue as well as in malignant and premalignant tissue of the human oesophagrus. These tw o enzymes play an important role after the administration of ALA: PBG-D is in many cells the rate-limiting enzyme w-hen exogenous ALA is administered and FC is the enzN-me directly responsible for the conx ersion of PPIX to haem. We propose the use of a PDT power index for the intertissue variation in the abilitv to accumulate PPIX. in order to create a parameter that might indicate the susceptibilitv of tissues to ALA-PDT. 679

Barrett's oesophagus (BE) is a pre-malignant condition in which progression from metaplasia to low-grade dysplasia and highgrade dysplasia could lead to invasive adenocarcinoma of the oesophagus (AC) (Hameeteman et al, 1989;van der Burgh et al, 1996;Drewitz et al, 1997). High-grade dysplasia is often regarded as an indication for oesophagectomy (Clark et al, 1996;Edwards et al, 1996;Cameron and Carpenter, 1997). A possible alternative, which is less mutilating and also applicable in patients with a high surgical risk, is 5-aminolaevulinic acid-induced photodynamic therapy (ALA-PDT).Two relevant clinical studies have been performed, in which patients with high-grade dysplasia or early cancer in BE received an oral dose of ALA (60 mg kg -1 ), followed by photoactivation 4-6 h later (Barr et al, 1996;Gossner et al, 1998). Both high-grade dysplasia and early cancer were eradicated allowing regeneration of squamous epithelium without scarring or stricture formation. However, the presence of islands of columnar cells remaining beneath regenerating squamous epithelium created the concern that superficial healing could mask underlying dysplasia. These results suggest that ALA-PDT needs to be improved.Haem biosynthesis, an essential process in every cell, is the basis of ALA-PDT ( Figure 1). ALA is the first intermediate, and two molecules of ALA are converted to porphobilinogen (PBG) which is metabolized to porphyrinogen intermediates by porphobilinogen deaminase (PBG-D). The last step of haem biosynthesis is the insertion of iron into PPIX by ferrochelatase (FC). Normally, haem synthesis is regulated by feedback inhibition of the enzyme ALA synthase. Exogenous ALA bypasses this feedback inhibition and the activities of PBG-D and FC and the intracellular iron pool become rate-limiting factors. As a result porphyrins, predominantly PPIX, will accumulate (Bishop and Desnick, 1982;Kennedy and Pottier, 1992). Previously, we observed an imbalance between the activities of PBG-D and FC in BE and AC (Hinnen et al, 1998). The ratio between PBG-D and FC activities, normalized for squamous epithelium, was found to be significantly higher in BE and AC. In that study, we suggested that this ratio, which we have called the PDT power index, might be a useful parameter for predicting the accumulation of PPIX in tissues after the administration of ALA.In this study, we examined the relation between the PDT power index and the intracellular concentration of PPIX in tissues of patients with BE and AC at approximately 6 h after ALA ingestion (60 mg kg -1 ) as this is the clinically most frequently used time interval. We determined the intracellular concentrations of ALA and other haem intermediates by biochemical extraction methods rather than fluorescence microscopy as used by others (Regula et al, 1995;Barr et al, 1996). In addition, plasma pharmacokinetics of ALA and porphyrins were studied and side-effects were monitored. MATERIALS AND METHODS PatientsIn total 10 patients (two women and eight men; age 44-81 years; mean 65 years) gave ...

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