Photodynamic Therapy (PDT) and Photodiagnosis (PD) Using Endogenous Photosensitization Induced by 5-Aminolevulinic Acid (ALA): Current Clinical and Development Status

Abstract

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.

Clinical Pharmacokinetics of 5-Aminolevulinic Acid in Healthy Volunteers and Patients at High Risk for Recurrent Bladder Cancer

“…Exogenously administered ALA bypasses this control point and induces intracellular accumulation of PpIX (Kennedy and Pottier, 1992). Selectivity of PpIX accumulation in malignant and premalignant tissue has been demonstrated in a number of animal models and in human clinical studies, and may be useful for enhancing visual detection of tumors, including bladder malignancies (Marcus et al, 1996). ALA may also have a role in the treatment of esophageal cancer and squamous cell carcinoma (Ackroyd et al, 2000;Hinnen et al, 2000).…”

Photodynamic diagnosis of breast tumours after oral application of aminolevulinic acid

“…In some tumours, deaminase-isomerase, the rate-limiting enzyme that converts porphobilinogen into uroporphyrinogen in the haem synthesis pathway is increased and ferrochelatase is reduced, so that PPIX accumulates preferentially in tumour cells (Hua et al, 1995;Heyerdahl et al, 1997;Peng et al, 1997). Photosensitization by ALA-induced PPIX is tissue specific and is primarily enhanced in tissues that cover body surfaces, or line body cavities and exocrine glands such as mammary glands (Kennedy and Pottier, 1994;Marcus et al, 1996;Riesenberg et al, 1996).…”

Detection and treatment of dysplasia in Barrett’s esophagus: a pivotal challenge in translating biophotonics from bench to bedside

“…This is a rate-limiting precursor in heme biosynthesis such that, when given in excess, it leads to increased levels of the fluorescent photosensitizer protoporphyrin IX ͑PpIX͒. 35 Many studies in different organs, such as the bladder, cervix, and lung, have shown that ALA-PpIX can give high fluorescence contrast in early malignancy, 21,35 most likely due to increased metabolic rate and/or to reduced ferrochelatase, the enzyme responsible for converting PpIX to heme. ALA-PpIX has been studied extensively for photodynamic therapy for numerous early stage lesions, including dysplasia in BE, as discussed later.…”