Biochemical basis of 5-aminolaevulinic acid-induced protoporphyrin IX accumulation: a study in patients with (pre)malignant lesions of the oesophagus

Hinnen, P.; Rooij, Felix W.M. de; Velthuysen, Marie‐Louise F. van; Edixhoven, Annie; Hillegersberg, Richard van; Tilanus, Hugo W.; Wilson, J. H. P.; Siersema, Peter D.

doi:10.1038/bjc.1998.559

Cited by 118 publications

(76 citation statements)

References 22 publications

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“…The grade of tumour differentiation and the grade of dysplasia in Barrett's mucosa were described according to Haggitt (Haggitt, 1994). In addition, adjacent biopsies were kept at -70°C until the activities of PBG-D and FC and porphyrin concentrations were determined (Hinnen et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

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Porphyrin biosynthesis in human Barrett's oesophagus and adenocarcinoma after ingestion of 5-aminolaevulinic acid

et al. 2000

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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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Section: Methodsmentioning

confidence: 99%

“…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.…”

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Porphyrin biosynthesis in human Barrett's oesophagus and adenocarcinoma after ingestion of 5-aminolaevulinic acid

et al. 2000

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“…The power of elevated activity of PBGD to produce PpIX was clinically demonstrated for malignant gliomas (Stummer et al, 1998b); oral cavity cancer (Leunig et al, 2000a); colonic and gastrointestinal dysplasia (Stepp et al, 1998); peritoneal endometriosis (Hillemanns et al, 2000); laryngeal neoplasms (Leunig et al, 2000b); malignant lesions of the oesophagus (Hinnen et al, 1998); lower urinary tract tumours (Kriegmair et al, 1999); bladder cancer (Kriegmair et al, 1996); malignant mucosa in head and neck cancer (Betz et al, 1999); Barrett's oesophagus and adenocarcinoma (Stepp et al, 1998); basal and squamous cell carcinoma (Orenstein et al, 1995(Orenstein et al, , 1996(Orenstein et al, , 1997Malik et al, 1998) and coetaneous lymphoma (Orenstein et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Nuclear distribution of porphobilinogen deaminase (PBGD) in glioma cells: a regulatory role in cancer transformation?

et al. 2002

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Recently, considerable interest has been directed to red-fluorescence photodiagnosis of brain and other tumours during surgery using the protoporphyrin IX natural precursor, 5-aminolaevulinic acid. In the present study we focused on the role of the rate-limiting enzyme porphobilinogen deaminase in glioma C6 cell activity, differentiation and sub-cellular distribution. Over-expression of the human housekeeping porphobilinogen deaminase in the glioma cells, using the housekeepingporphobilinogen deaminase plasmid, induced a G1 cell cycle attenuation accompanied by increases in enzyme activity and c6 differentiation toward astrocytes. Visualisation of subcellular localisation of the porphobilinogen deaminase using the independent techniques of fluorescence immuno-staining with specific anti-human porphobilinogen deaminase antibodies and cellular expression of porphobilinogen deaminase fused to green fluorescent protein, revealed (unexpectedly) a major fraction of porphobilinogen deaminase in the nucleus and only a minor fraction in the cytoplasm. Both C and N terminals of porphobilinogen deaminase fused to green fluorescent protein revealed a major fraction of the newly synthesized fused porphobilinogen deaminase in the nucleus. Furthermore, newborn rat brain cells grown in a primary culture showed the same localisation pattern of porphobilinogen deaminase in the nuclei. Stimulation of C6 glioma cell differentiation by butyrate induced a marked decrease in porphobilinogen deaminase both in the nucleus and in the cytoplasm as determined by Western blotting and fluorescence immuno-localisation. These findings suggest a possible dual role for housekeeping porphobilinogen deaminase in fast dividing glioma cells, one related to the porphyrin synthesis pathway and another coupled to nuclear function, which might be linked to tumorigenesis.

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“…Clinically, it was demonstrated that malignant gliomas (Stummer et al, 1998), colonic and gastrointestinal dysplasia , malignant lesions of the esophagus (Hinnen et al, 1998), bladder cancer (Kriegmair et al, 1996), basal and squamous carcinoma (Orenstein et al, 1995(Orenstein et al, , 1996Malik et al, 1998) and cutaneous lymphoma (Orenstein et al, 2000) produce excess PpIX following 5-ALA administration. One possible rationale for the specificity of PpIX accumulation through increased PBGD activity in rapidly dividing cancer cells is that their enhanced metabolism demands additional heme, which is mandatory for an increased aerobic ATP supply connected to the energy demands of the tumor.…”

Section: Introductionmentioning

confidence: 99%

A porphobilinogen deaminase (PBGD) Ran-binding protein interaction is implicated in nuclear trafficking of PBGD in differentiating glioma cells

Greenbaum

Katcoff

Dou³

et al. 2003

Oncogene

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Porphobilinogen deaminase (PBGD) is a rate-limiting enzyme of the heme biosynthesis pathway, whose level is elevated in various human tumors. PBGD was observed in both nuclear and cytoplasmic fractions of C6 glioma cells by immunostaining. During mitosis, chromatids were intensely stained for PBGD in comparison to the interphase chromatin. Using the yeast two-hybrid system, we identified RanBPM, the nuclear Ran-binding protein, as an interacting partner of PBGD. During butyrateinduced differentiation of C6, both nuclear and cytoplasmic PBGD levels declined as did Ran protein and its nucleotide exchange factor RCC1. N,N 0 -hexamethylene bis-acetamide-dependent differentiation resulted in an increase of the cytoplasmic PBGD, whereas nuclear PBGD, Ran protein and RCC1 remained unchanged. mRNA levels of PBGD remained unchanged during stimulation with both butyrate and N,N 0 -hexamethylene bis-acetamide. The enzymatic activity of PBGD and protoporphyrin IX synthesis in C6 cells were dependent on the differentiation induction agent. We conclude that PBGD possibly has a nuclear role in addition to its cytosolic enzymatic activity required for heme synthesis, which is related to cell transformation and differentiation.

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Biochemical basis of 5-aminolaevulinic acid-induced protoporphyrin IX accumulation: a study in patients with (pre)malignant lesions of the oesophagus

Cited by 118 publications

References 22 publications

Porphyrin biosynthesis in human Barrett's oesophagus and adenocarcinoma after ingestion of 5-aminolaevulinic acid

Porphyrin biosynthesis in human Barrett's oesophagus and adenocarcinoma after ingestion of 5-aminolaevulinic acid

Nuclear distribution of porphobilinogen deaminase (PBGD) in glioma cells: a regulatory role in cancer transformation?

A porphobilinogen deaminase (PBGD) Ran-binding protein interaction is implicated in nuclear trafficking of PBGD in differentiating glioma cells

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