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

Abstract

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.

Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells

“…Photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA) as a prodrug that is converted to an intracellular photosensitiser, protoporphyrin IX (PpIX), represents an increasingly accepted treatment for superficial epithelial neoplasias (Kennedy et al, 1990;Marmur et al, 2004) and for diagnostic imaging of internal malignancies at locations where light can be delivered through an optical fibre (Kennedy et al, 1996;Eker et al, 1999;Landry et al, 2003;Schmidbauer et al, 2004). However, ALA-mediated PDT (ALA-PDT) remains suboptimal for the treatment of deeper tumours, such as nodular basal cell and squamous cell carcinoma of the skin, because recurrence rates after single treatments are unacceptably high as compared to the current standard of care, surgical excision (Marmur et al, 2004).…”

“…However, ALA-mediated PDT (ALA-PDT) remains suboptimal for the treatment of deeper tumours, such as nodular basal cell and squamous cell carcinoma of the skin, because recurrence rates after single treatments are unacceptably high as compared to the current standard of care, surgical excision (Marmur et al, 2004). For internal malignancies in organs such as the bladder, GU tract, and oesophagus, ALA-PDT has been used for palliative treatment of these cancers (Kennedy et al, 1996;Waidelich et al, 2001;Friesen et al, 2002). However, ALA-PDT in its current form seldom achieves a definitive cure of deep or refractory tumours in any location.…”

Photodynamic detection of diseased axillary sentinel lymph node after oral application of aminolevulinic acid in patients with breast cancer

“…Local intrauterine application of ALA has also been used for selective endometrial ablation in animal models and in human clinical studies (Steiner et al, 1995(Steiner et al, , 1996bWyss et al, 2001). By the use of blue light at 400 nm, PpIX induced by ALA has been applied as a fluorescence detection marker for photodiagnosis of cancer and dysplastic conditions of the urinary bladder and other organs (Kennedy et al, 1996). Application of ALA has been developed for detection of alterations in gynaecological tissues including the endometrium, the vulva and skin metastasis of breast cancer (Fehr et al, 1996Steiner et al, 1996a).…”

Hypoxia significantly reduces aminolaevulinic acid-induced protoporphyrin IX synthesis in EMT6 cells

“…For reasons that are not yet completely understood, PpIX is often produced in higher amounts by malignant cells, conferring selective photodynamic damage to the tumour area. Although most researchers have taken advantage of the selective PpIX accumulation in the tumour to treat the malignancy by means of photodynamic therapy, others have used PpIX fluorescence detection as a tool for the diagnosis of disease (Kriegmair et al, 1994;Kennedy et al, 1996).…”