Detection of Early Stages of Carcinogenesis in Adenomas of Murine Lung by 5‐Aminolevulinic Acid‐Induced Protoporphyrin IX Fluorescence

Abstract

Administration of the heme precursor 5-aminolevulinic acid (ALA) leads to the selective accumulation of the photosensitizer protoporphyrin IX (PpIX) in certain types of normal and abnormal tissues. This phenomenon has been exploited clinically for detection and treatment of a variety of malignant and nonmalignant lesions. The present preclinical study examined the specificity of ALA-induced porphyrin fluorescence in chemically induced murine lung tumors in vivo. During the early stages of tumorigenesis, ALA-induced PpIX fluorescence developed in hyperplastic tissues in the lung and later in early lung tumor foci. In early tumor foci, maximum PpIX fluorescence occurred 2 h after the administration of ALA and returned to background levels after 4 h. There was approximately a 20-fold difference in PpIX fluorescence intensity between tumor foci and the adjacent normal tissue. The specificity of ALA-induced fluorescence for hyperplastic tissues and benign tumors in lung during tumorigenesis suggests a possible use for this fluorochrome in the detection of premalignant alterations in the lung by fluorescence endoscopy. Two non-small cell lung cancer cell lines developed ALA-induced PpIX fluorescence in vitro. These lines exhibited a light-dose-dependent phototoxic response to ALA photodynamic therapy (PDT) in vitro. Because PpIX is a clinically effective photosensitizer for a wide variety of malignancies, these results support the possible use of ALA-induced PpIX PDT for lung cancer.

Kinetics of 5-Aminolevulinic Acid-Induced Fluorescence in Organ Cultures of Bronchial Epithelium and Tumor

“…The patterns of PPIX kinetics in bronchial tissue after application of 5-ALA we found are similar to those in the gastric and colon mucosa [19]. Studies of PPIX fluorescence kinetics in murine lungs (not specifically bronchial tissue) and tumors have found maximal fluorescence intensities at 180 min in both of them [20]. …”

Photodynamic diagnosis of breast tumours after oral application of aminolevulinic acid

“…Clinical studies with PDD and PDT using ALA were performed for the treatment of neural tumours (Obwegeser et al, 1998), lesions of the oral cavity (Leuing et al, 1996), endoscopical detection of bronchial lesions (Campbell et al, 1996) and detection of carcinoma in situ of the bladder during cystoscopy (Kriegmair et al, 1994). The latter reached a sensitivity of 93%.…”

Protoporphyrin IX accumulation in cells treated with 5-aminolevulinic acid: Dependence on cell density, cell size and cell cycle

“…Several types of malignant tissues accumulate ALA-induced PpIX in higher concentrations than do most normal tissues (for a review, see Peng et al, 1997). This is the basis for ALA-PCT as well as for a promising method of tumor fluorescence diagnosis (Kennedy et al, 1990;Kennedy and Pottier, 1992;Warloe et al, 1992;Kriegmair et al, 1994;Campbell et al, 1996). Tumor selectivity may be related to several factors, such as increased permeability for ALA of the skin covering the tumor, low concentration of iron, low activity of the enzyme ferrochelatase and high activity of the enzyme porphobilinogen deaminase (PBGD) in tumors.…”