Oral Administration Of ALA Research Articles

Photodynamic diagnosis of pleural malignant lesions with a combination of 5-aminolevulinic acid and intrinsic fluorescence observation systems.

BackgroundWe have developed a new diagnostic method using the photosensitizer 5-aminolevulinic acid (5ALA) for diagnosing intrathoracic malignant lesions. When ingested exogenously, 5ALA is metabolized to a heme precursor, protoporphyrin IX, which stays in malignant cells and emits red to pink luminescence of about 630 nm.MethodsWe enrolled 40 patients who underwent respiratory surgery and consented to participate in this study. Twenty-eight patients had primary lung cancer, 8 metastatic lung tumors, 2 malignant pleural tumors, and 2 benign tumors. Localization of malignant lesions was attempted by observing such lesions with an autofluorescence imaging system and by comparing the color tone of the autofluorescence between malignant lesions and normal tissues after oral administration of 5ALA. Malignant lesions on the pleural surface emitted pink autofluorescence in contrast to the green autofluorescence of the surrounding normal tissues.ResultsWhen 28 patients with primary lung cancer were examined according to the degree of pleural infiltration (pl), red fluorescence was confirmed in 10 of 10 patients (100%) with p11-p13 and 5 of 18 patients (27.7%) with p10. The latter 5 patients had been diagnosed with PL1 preoperatively or intraoperatively.ConclusionThis system achieved accurate localization of malignant lesions, suggesting that it may also be applicable to photodynamic therapy.

Selection of Patients by Membrane Transporter Expressions for Aminolevulinic Acid (ALA)-Guided Photodynamic Detection of Peritoneal Metastases

Background. Photodynamic diagnosis (PDD) with 5-aminolevulinic acid (ALA) was used to detect peritoneal metastasis (PM). This study was done to verify the roles of the expressions of the peptide transporter PEPT1 and ATP-binding cassette transporter ABCG2 genes on the selection of patients in ALA PDD. Methods. The study group comprised 138 patients with PM. After oral administration of 5-ALA, PM was evaluated by PDD. Tissue protoporphyrin IX (PpIX) levels, and PEPT1/ABCG2 mRNA expressions were determined. Results. The tumor detection rate on PDD was 45.6% (63/138). PDD is a safe technique for the detection of PM from ovarian cancer, mesothelioma, and colorectal cancer. PpIX levels of ALA-PDD-positive PM were significantly higher than those of ALA-PDD-negative PM. The PpIX levels in PM that simultaneously expressed PEPT1 and ABCG2 mRNA were significantly higher than those in PM that expressed either PEPT1 or ABCG2 mRNA, as well as PM that expressed neither PEPT1 nor ABCG2 mRNA. PM with PEPT1 mRNA up-regulation showed simultaneous up-regulation of ABCG2 mRNA. PpIX accumulates in PM with PEPT1 up-regulation. At the same time, PpIX may be excreted into stromal tissue through ABCG2 transporter, resulting in the accumulation of excess PpIX in the stromal tissue near cancer cells. Conclusions. Preoperative evaluations of the expressions of the PEPT1 and ABCG2 genes by RT-PCR methods might facilitate the selection of patients most likely to benefit from ALA-PDD.

Effect of alpha lipoic acid on the blood cell count and iron kinetics in hypertensive patients.

The -lipoic acid (ALA) has been used as a treatment to reduce oxidative damage in Systemic Arterial Hypertension (SAH), but there are no in vivo studies reporting the effect of its mechanism of action on iron metabolism. To evaluate the antioxidant effect of -lipoic acid on Blood cell count (CBC) and iron metabolism in hypertensive subjects with or without anemia. Double-blind, randomized, placebo-controlled clinical trial. The sample consisted of 60 hypertensive patients that were randomly divided into treatment group (n = 32), receiving 600 mg / day of ALA for twelve weeks and control group (n = 28), receiving placebo for the same period. Blood cell count, serum iron, ferritin, Latent Iron-Binding Capacity (LIBC), Total Iron-Binding Capacity (TIBC), Transferrin Saturation Index (TSI) and transferrin were assessed before and after intervention. To assess changes between groups, the Student t-test and ANOVA were used, adopting a significance level of 5%. After intervention, ALA supplementation showed a statistically significant (p < 0.05) association with the reduction of total leukocytes, increase in the number of neutrophils and reductions in the serum levels of iron and TSI. Oral administration of ALA as a therapeutic adjuvant changes the hematologic response of white blood cells and reduces the absorption of iron. It is observed that the mechanism of metals chelation by lipoic acid may be responsible for these changes and, consequently, could trigger a condition of iron deficiency anemia in hypertensive individuals.

Malignant glioma: MR imaging by using 5-aminolevulinic acid in an animal model.

To evaluate the use of 5-aminolevulinic acid (5-ALA) for the noninvasive detection of malignant gliomas by using in vivo magnetic resonance (MR) imaging in a mouse brain tumor model. The experiments were animal care committee approved. U-87 glioblastoma cells were exposed to 5-ALA (500 µmol/L) for 6 hours, cells were harvested, and intracellular concentrations of iron, heme, protoporphyrin IX, and ferrochelatase were measured (six in each group). BALB/c nude mice (n = 10) were inoculated with U-87 glioma cells to produce orthotopic brain tumors. T2-weighted imaging was performed 3 weeks after inoculation, and T2* maps were created with a 7-T MR imager before and 24 hours after oral administration of 5-ALA (0.1 mg/g of body weight; n = 6) or normal saline (n = 4). Intratumoral iron concentrations were measured with laser ablation inductively coupled plasma mass spectrometry. For in vitro experiments, differences in the measured data were assessed by using the Mann-Whitney U test with Bonferroni correction. For the in vivo studies, differences in T2* values and iron concentrations of the tumors in the 5-ALA and control groups were assessed by using the Mann-Whitney U test. The intracellular concentration of heme and iron was increased at both 24 and 48 hours after 5-ALA exposure (P = .004). 5-ALA promoted expression of ferrochelatase in glioblastoma cells at both 24 and 48 hours after 5-ALA exposure compared with that at 1 hour (P = .004). In vivo MR imaging revealed a lower median T2* value in glioblastomas treated with 5-ALA compared with those in control mice (14.0 msec [interquartile range, 13.0-14.5 msec] vs 21.9 msec [interquartile range, 19.6-23.2 msec]; P = .011), and laser ablation inductively coupled plasma mass spectrometry revealed that iron concentrations were increased in glioblastomas from the 5-ALA group. Administration of 5-ALA increased the intracellular iron concentration of glioblastomas by promoting the synthesis of heme, which is the metabolite of 5-ALA. Because intracellular iron can be detected at MR imaging, 5-ALA may aid in the identification of high-grade foci in gliomas.

Fluorescence-guided surgery with 5-aminolevulinic acid for resection of brain tumors in children—a technical report

5-aminolevulinic acid (5-ALA) can be used as an adjunct for the surgery of adult malignant glioma and improves the rate of gross total resection and patient survival. So far, only three casuistic reports of fluorescence-guided surgery used in children have been published. We report our pilot series of 16 pediatric brain tumors treated with 5-ALA. Sixteen patients (mean age 9 years, range 1-16 years) received a standardized 5-ALA dose according to the published protocol after informed parental consent. The fluorescence status (positive versus negative) in correlation with histology as well as blood samples and adverse clinical symptoms were recorded. Histology revealed pilocytic astrocytoma (n = 7), classical medulloblastoma (n = 4), anaplastic astrocytoma (n = 1), glioblastoma (n = 3) and anaplastic ependymoma (n = 1). Positive fluorescence was observed in cases of anaplastic astrocytoma, glioblastoma, and medulloblastoma, respectively. Significant increases were registered for alanine aminotransferase (14.92 ± 1.106 U/l vs. 37.70 ± 3.795 U/l, P = 0.0020) and gamma glutamyl transpeptidase (12.69 ± 1.638 U/l vs. 39.29 ± 6.342 U/l, P = 0.0156), correlated with young age. No further adverse reactions were evident. Positive fluorescence was observed in two high-grade gliomas and one medulloblastoma after oral administration of 5-ALA. Thus, 5-ALA appears capable of inducing fluorescence in pediatric high-grade tumors. Adverse reactions observed in children were similar to those reported for adults, although very young children might be at increased risk. Further studies are required to elucidate pharmacokinetic and pharmacodynamic properties of 5-ALA in children and to assess its prognostic role in the resection of pediatric brain tumors.

Safety Evaluation of Artocarpus altilis as Pharmaceutical Agent in Wistar Rats.

This study was designed to elucidate the acute toxicity of Artocarpus altilis leaf and bark extracts. In acute toxicity study, no mortality or any toxic reaction was recorded in any group after 14 days of administering the extracts (2000 mg Kg−1 BW). The extracts (ALA, ABA, ALM, and ABM) did not cause any behavioural or physical changes in experimental rats. There was no significant (P ≤ 0.05) difference in the biochemical parameters analysed between the groups. Slight elevation in activities of AST and ALT in extract treated groups was observed, but this did not exert any deleterious effect on the normal metabolism which was supported by the histopathology of liver. Histopathological studies showed no remarkable changes after 14 days of oral administration of ALA, ABA, ALM, and ABM extracts. The study contributes to establishing the nontoxic quality parameters of Artocarpus altilis leaf and bark parts and the results suggest the safety of the extracts in therapeutic uses.

α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase

Sirtuin 1 (SIRT1) is a longevity-associated protein, which regulates energy metabolism and lifespan in response to nutrient deprivation. It has been proposed to be a therapeutic target for obesity and metabolic syndrome. We investigated whether α-lipoic acid (ALA) exerts a lipid-lowering effect through regulation of SIRT1 activation and production in C(2)C(12) myotubes. ALA-stimulated AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), adipose triacylglycerol lipase (ATGL) and fatty acid synthase (FAS) production, as well as intracellular triacylglycerol accumulation and fatty acid β-oxidation were analysed in the absence or presence of a SIRT1 inhibitor (nicotinamide), SIRT1 small interfering (si) RNA and an AMPK inhibitor (compound C) in C(2)C(12) myotubes. Mice with streptozotocin/nicotinamide-induced diabetes and db/db mice fed on a high-fat diet were used to study the ALA-mediated lipid-lowering effects in vivo. ALA increased the NAD(+)/NADH ratio to enhance SIRT1 activity and production in C(2)C(12) myotubes. ALA subsequently increased AMPK and ACC phosphorylation, leading to increased palmitate β-oxidation and decreased intracellular triacylglycerol accumulation in C(2)C(12) myotubes. In cells treated with nicotinamide or transfected with SIRT1 siRNA, ALA-mediated AMPK/ACC phosphorylation, intracellular triacylglycerol accumulation and palmitate β-oxidation were reduced, suggesting that SIRT1 is an upstream regulator of AMPK. ALA increased ATGL and suppressed FAS protein production in C(2)C(12) myotubes. Oral administration of ALA in diabetic mice fed on a high-fat diet and db/db mice dramatically reduced the body weight and visceral fat content. ALA activates both SIRT1 and AMPK, which leads to lipid-lowering effects in vitro and in vivo. These findings suggest that ALA may have beneficial effects in the treatment of dyslipidaemia and obesity.

Adenosine monophosphate kinase activator α-lipoic acid: A promising therapeutic agent for metabolic syndrome?

Adenosine monophosphate kinase activator α-lipoic acid: A promising therapeutic agent for metabolic syndrome?

Abstract 4144: Identification of molecules involved in PpIX accumulation in brain tumor induced by oral administration of 5-ALA

Abstract [Background and Purpose] 5-aminolevulinic acid (5-ALA) is one of leading compounds widely used in photodynamic diagnosis and therapy of solid tumors: 5-ALA is metabolically converted to protoporphyrin IX (PpIX), a fluorescent molecule in response to excitation with a laser beam of 405 nm wavelength, that accumulates specifically in tumor lesions. This is found to be very effective for intra-operative detection of malignant brain tumors such as glioblastoma multiforme (GBM). On the other hand, we occasionally encountered cancerous lesions that are apparently malignant under a white light, while showing no fluorescence of the PpIX during cyto-reductive operation of the GBM. In order to overcome this problem, we hereby searched for factors associated with either presence or absence of the PpIX fluorescence by means of comprehensive gene expression analysis. [Materials and Methods] Thirty-one patients of brain tumor (21 GBM, 3 pilocytic astrocytoma and 7 oligodendroglial tumors), orally-administrated with 5-ALA followed by operation under a fluorescence-guide, were enrolled in this study. Tumor specimens with or without the 5-ALA induced-fluorescence were collected from these patients and snap-frozen in liquid nitrogen. Total RNAs were extracted from the frozen tissues and were subjected to a comprehensive gene expression analysis using Whole Human Genome 4×44K Oligo Microarray (Agilent). We then compared gene expression levels between specimens with or without the fluorescence among individuals and selected candidate genes of which gene expression levels significantly differ between these. For validation, quantitative gene expression analyses were conducted for the candidates with real-time RT-PCR using gene specific-primers and probes. Knockdown experiments using specific siRNAs were also performed in cell lines derived from GBM to test their biological significance. [Results and Discussion] A total of 14 genes were initially selected as candidates that were associated with PpIX accumulation in GBM in the microarray analysis. Among these, CDH13 (cadherin 13) gene was expressed significantly higher in the fluorescence-positive GBMs than in negative ones. Knockdown of CDH13 gene expression in GBM cells treated with 5-ALA, attenuated the fluorescence intensity, indicating its possible role in PpIX accumulation. Further experiments are underway to elucidate molecular mechanisms of CDH13 in 5-ALA-induced PpIX fluorescence in brain tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4144. doi:10.1158/1538-7445.AM2011-4144

The effect of 5-aminolevulinic acid on cytochrome c oxidase activity in mouse liver

Background5-Aminolevulinic acid (ALA) is a precursor of heme that is fundamentally important in aerobic energy metabolism. Among the enzymes involved in aerobic energy metabolism, cytochrome c oxidase (COX) is crucial. In this study, the effect of ALA on cytochrome c oxidase activity was measured.Findingsc57BL/6N species of mice were administered ALA orally for 15 weeks. After ALA administration, mice were sacrificed and livers were obtained. COX activity in mitochondria from ALA-administered mouse livers was 1.5-fold higher than that in mitochondria from PBS-administered mouse livers (P < 0.05). Furthermore, ATP levels in ALA-administered mouse livers were much higher than those in PBS-administered mouse livers. These data suggest that oral administration of ALA promotes aerobic energy metabolism, especially COX activity.ConclusionsThis is the first report of a drug that functions in aerobic energy metabolism directly. Since COX activity is decreased in various diseases and aging, the pharmacological effects of ALA will be expanding.

δ‐Aminolevulinic acid is a substrate for the amino acid transporter SLC36A1 (hPAT1)

delta-Aminolevulinic acid (ALA) is used in cancer patients for photodynamic diagnosis or therapy. Oral administration of ALA has been used in patients with prostate and bladder cancer. The present aim was to investigate the mechanism of intestinal absorption of ALA and its transport via the amino acid transporter SLC36A1. In vitro investigations of ALA affinity for and uptake via SLC36A1 and SLC15A1 were performed in Caco-2 cell monolayers. Interaction of ALA with SLC15A1 was investigated in MDCK/SLC15A1 cells, whereas interactions with SLC36A1 were investigated in COS-7 cells transiently expressing SLC36A1. ALA inhibited SLC36A1-mediated L-[(3)H]Pro and SLC15A1-mediated [(14)C]Gly-Sar uptake in Caco-2 cell monolayers with IC(50) values of 11.3 and 2.1 mM respectively. In SLC36A1-expressing COS-7 cells, the uptake of [(14)C]ALA was saturable with a K(m) value of 6.8 +/- 3.0 mM and a V(max) of 96 +/- 13 pmol x cm(-2) x min(-1). Uptake of [(14)C]ALA was pH and concentration dependent, and could be inhibited by glycine, proline and GABA. In a membrane potential assay, translocation of ALA via SLC36A1 was concentration dependent, with a K(m) value of 3.8 +/- 1.0 mM. ALA is thus a substrate for SLC36A1. In Caco-2 cells, apical [(14)C]ALA uptake was pH dependent, but Na(+) independent, and completely inhibited by 5-hydroxy-L-tryptophan and L-4,4'-biphenylalanyl-l-proline. CONCLUSIONS AND IMPLICATIONS. ALA was a substrate for SLC36A1, and the apical absorption in Caco-2 cell was only mediated by SLC36A1 and SLC15A1. This advances our understanding of intestinal absorption mechanisms of ALA, as well as its potential for drug interactions.

Long-term results of photodynamic therapy with 5-aminolevulinic acid for superficial Barrett's cancer and high-grade intraepithelial neoplasia

Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) has proven to be safe and effective in patients with early neoplasia in Barrett's esophagus. However, long-term results in patients with high-grade intraepithelial neoplasia (HGIN) or with early cancer are still lacking. The aim of the study was to evaluate the efficacy of ALA-PDT and the survival of patients with early Barrett's neoplasia. ALA-PDT was carried out in 66 patients. Protoporphyrin IX induced by oral administration of ALA (60 mg/kg body weight orally applied 4-6 hours before PDT) was used as the photosensitizer. Acid suppression was maintained in all patients. Between September 1996 and September 2002, 667 patients with early neoplasia in Barrett's esophagus were referred for local endoscopic therapy. A total of 558 patients fulfilled the criteria for local endoscopic therapy, and 66 patients (mean [standard deviation] age 61.4 [10.2] years) with HGIN (group A; n = 35) and early adenocarcinoma (group B; n = 31) were treated by PDT. A total of 82 ALA-PDT were performed. A total of 34 of the 35 patients in group A (97%) and all patients in group B (100%) achieved a complete response during a median follow-up period of 37 months (interquartile range 23-55) (not significant). One local recurrence was observed in group A and 10 in group B (p < 0.005). Seven patients died during follow-up; but, all deaths were not tumor related. No major complications were observed. Disease-free survival in patients with HGIN was 89%, and, in patients with mucosal cancer, it was 68%. The calculated 5-year survival was 97% in group A and 80% in group B, but there occurred no death related to Barrett's neoplasia. The excellent long-term results of PDT with ALA in patients with HGIN or mucosal cancer might offer PDT with ALA as an alternative to surgical esophagectomy and endoscopic resection, especially in cases with multifocal Barrett's neoplasia.

Fractionated illumination for oesophageal ALA-PDT: effect on blood flow and PpIX formation.

The effect of fractionating the 633 nm illumination of 5-aminolaevulinic (ALA)-based photodynamic therapy (PDT) of the normal rat oesophagus was studied. Fractionation of the illumination could enhance the PDT effect in two ways: (a) delay of the vascular shutdown or relaxation of the vasoconstriction induced by ALA-PDT and (b) use of newly formed protoporphyrin IX (PpIX), produced during the dark interval. Forty rats were randomly allocated to two groups of 20 animals each. To study vascular effects, in group 1 illumination with 633 nm (100 mW/cm) was performed at 3 h after oral ALA administration (200 mg/kg) either continuously with 20 J/cm diffuser length (n = 5) or fractionated 2 x 10 J/cm with a 150 s interval (n = 5), five animals served as controls. Blood flow was measured with a laser Doppler flowmeter. To study the effect of renewed PpIX forming, animals in group 2 were illuminated continuously at 3 h after ALA with 20 J/cm (n = 5) or 40 J/cm (n = 5) or fractionated 2 x 20 J/cm with a 3 h interval (n = 5), five animals served as controls. In all animals the in vivo fluence rate and PpIX fluorescence were measured during illuminations and animals were killed at 48 h after PDT. ALA-PDT did not cause any significant vasoconstriction. Fluorescence measurements and dosimetric results in group 1 did not differ between animals illuminated continuously or fractionated with a 150 s interval. In group 2, during a 3 h dark interval, PpIX fluorescence increased and was bleached during the second illumination. The tissue optical properties changed during the 3 h dark interval, resulting in a lower in vivo fluence rate (p < or = 0.001). Fractionation did not result in more oesophageal damage. It was concluded that a 150 s interval during illumination in ALA-PDT does not increase oesophageal blood flow. During an interval of 3 h new PpIX is formed. In the present study, fractionated illumination using short or long time intervals did not result in more damage. Thus, this study shows no evidence for improved PDT effect with fractionated light delivery.

5‐Aminolevulinic Acid Photosensitization of Dysplastic Barrett's Esophagus: A Pharmacokinetic Study

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) may have a role in the treatment of dysplastic Barrett's esophagus. Before ALA-induced PDT can be used clinically, optimum treatment parameters must be established. In this study of 35 patients, the issues of drug dosage, time interval between drug and light delivery and side effects of oral ALA administration are addressed. Spectrofluorometric analysis of tissue samples demonstrates that oral ALA administration induces porphyrin accumulation in esophageal tissues, with maximum levels at 4-6 h. High-performance liquid chromatography confirms the identity of this porphyrin as PpIX, and fluorescence microscopy analysis demonstrates that it preferentially accumulates in the esophageal mucosa, rather than in the underlying stroma. Side effects of ALA administration included malaise, headache, photosensitivity, alopecia, transient derangement of liver function, nausea and vomiting. Fewer side effects and less hepatic toxicity was seen with 30 mg/kg than 50 mg/kg ALA. In conclusion, oral ALA administration induces preferential PpIX accumulation in the esophageal mucosa, with peak PpIX fluorescence noted at 4 h and minimal systemic toxicity at a dose of 30 mg/kg.

Fluorescence diagnostics and kinetic studies in the head and neck region utilizing low-dose δ-aminolevulinic acid sensitization

Diagnostic measurements and pharmacokinetic studies were performed in 17 patients with various kinds of malignant, premalignant and benign lesions in the head and neck region by means of point monitoring laser-induced fluorescence. For marking different types of tissue, δ-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) was used. The ALA-induced PpIX synthesis was monitored at different time intervals after oral administration of ALA in low doses, 5 and 15 mg/kg b.w. Besides the porphyrin-related signal the tissue endogenous fluorescence was also recorded. The fluorescence spectra were evaluated at two different wavelengths corresponding to the specific drug-related fluorescence peak and the endogenous tissue fluorescence emission at 635 and 490 nm, respectively. The evaluated fluorescence data were correlated to the histopathological tissue investigation. A fall-off in the overall fluorescence intensity at 490 nm was obtained for all the malignant and premalignant areas, as well as an increased red fluorescence. A ratio between the red and the blue/green fluorescence intensity was formed for each time interval after the ALA administration. The lower drug dose seems to be sufficient to obtain a useful demarcation ratio between normal and diseased tissue with a very low PpIX fluorescence intensity in the normal tissue. A PpIX fluorescence maximum seems to occur between 3 and 4 h in normal tissues, whereas malignant tumour tissue shows a higher level for a longer period of time.

5-aminolevulinic acid (ALA)-induced protoporphyrin IX fluorescence and photodynamic effects in the rat bladder: An in vivo study comparing oral and intravesical ALA administration

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) for sensitization is a promising treatment for carcinoma in situ and diffuse premalignant changes of the bladder. We studied the biodistribution of PpIX in a range of tissues with oral and intravesical routes of administration of ALA and compared the photodynamic effects on bladder and skin. Normal Wistar rats were given oral or intravesical ALA and PpIX levels in the liver, kidney, skin, and bladder measured by fluorescence microscopy on tissue sections. At the time of maximum PpIX levels, the bladder and skin on the back were illuminated with light at 630 nm and the PDT effects compared. PpIX fluorescence in the urothelium after 200 mg/kg given intravesically was comparable to that found after 100 mg/kg orally. The ratio of PpIX levels between the urothelium and the underlying muscle was the same for both routes of administration, although there appeared to be more selectivity of urothelial PDT necrosis after intravesical administration. Skin photosensitization was greater after oral ALA, the epidermal PpIX level being three times higher than after intravesical administration for comparable urothelial levels and the PDT effect being more marked. Intravesical instillation is preferable to oral administration of ALA for PDT ablation of the urothelium of the rat bladder without damage to the underlying tissue layers and for minimizing skin photosensitivity. The technique is now ready for clinical trials.

Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): mechanisms and clinical results.

5-Aminolevulinic acid (ALA), when added to many tissues, results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway, to produce a photodynamic effect when exposed to activating light. Therefore, ALA is the only photodynamic therapy (PDT) agent in current clinical development that is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous superficial and nodular basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and in human clinical studies has shown selective formation of PpIX within the endometrium. PpIX induced by ALA application has also been used as a fluorescence detection marker for photodiagnosis (PD) of cancer and dysplastic conditions of the urinary bladder and other organs. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. The current state of knowledge of the mechanisms of endogenous topical and systemic photosensitization using ALA, the results of published clinical trials, and possible methods of increasing the efficacy of endogenous photosensitization for ALA PDT are reviewed in this paper.

Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): current clinical and development status.

Exogenous provision of 5-aminolevulinic acid (ALA) to many tissues results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway, to produce a photodynamic effect when exposed to activating light. Therefore, ALA may be considered the only current photodynamic therapy (PDT) agent in clinical development that is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous superficial and nodular basal cell carcinoma, Bowen's disease, actinic (solar) keratoses, and T cell lymphoma. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and, in human clinical studies, it has shown selective formation of PpIX within the endometrium. PpIX induced by ALA application has also been used as a fluorescence detection marker for photodiagnosis (PD) of cancer and dysplastic conditions of the urinary bladder and other organs. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. This paper reviews the current clinical and development status of ALA PDT and PD.