ALA-induced protoporphyrin IX (PpIX) is used for fluorescence diagnosis (ALA-FD) and for fluorescence-guided resection of both (pre)malignant and non-malignant diseases. ALA is also applied in photodynamic therapy (ALA-PDT) of superficial (pre)malignant lesions in dermatology, urology, neurosurgery, otorhinolaryngology, gynecology and gastroenterology. Today, ALA is approved as Levulan® for actinic keratoses, the ALA-methyl ester Metvix® for actinic keratoses and basal cell carcinoma, the ALA-hexyl ester Hexvix® for the diagnosis of bladder cancer and Gliolan® for malignant glioma. The use of ALA for PDT and FD was established around 25 years ago, with most of the fundamental knowledge gained at the “bench” and implemented at the “bedside” due to the diligence of a few researchers within the first 10 years of research. After 1993 ALA research was taken up by many groups. For patient treatment, several factors are relevant. Administered mainly in a topical or oral form, ALA penetrates tissue in a sub-optimal way, which is currently improved by special techniques and the use of ALA-esters. PpIX accumulation is elevated in many malignant tissues, several tissue abnormalities, and in mucosa. It is also found at elevated levels in macrophages, dendritic cells and activated lymphocytes. Following sufficient PpIX accumulation in the target cells, irradiation is carried out which may be accompanied by a burning sensation at the treatment site. Due to a saturation process of PpIX formation and rapid photobleaching during irradiation the risk of overtreatment is relatively low. Pharmacokinetical studies have demonstrated a low systemic photosensitivity and excretion of PpIXvia natural routes.

Macrophages (Mφ) play essential roles both in tumor defense and normal tissue homeostasis by removal of transformed as well as damaged and disintegrating cells. Whereas tissue necrosis is known to provoke inflammatory responses, removal of apoptotic cells has been assumed to be immunologically inert. We now show that while Mφ exposure to necrotized tumor cells causes pronounced stimulation of Mφ antitumor activity, exposure of Mφ to apoptotic tumor cells in contrast results in impairment of Mφ-mediated tumor defense and even support of tumor cell growth. Given the fact that apoptosis is a consequence of various cancer treatment modalities, this may lead to a suppression of local antitumor reactions and thus actually counteract endogenous immune-mediated tumor defense mechanisms.

As a treatment modality for malign and certain non-malignant diseases, photodynamic therapy (PDT) involves a two step protocol which consists of the (selective) uptake and accumulation of a photosensitizing agent in target cells and the subsequent irradiation with light in the visible range. Reactive oxygen species (ROS) produced during this process cause cellular damage and, depending on the treatment dose / severity of damage, lead to either cellular repair / survival, apoptotic cell death or necrosis. PDT-induced apoptosis has been focused on during the last years due to the intimate connection between ROS generation, mitochondria and apoptosis; by this PDT employs mechanisms different to those in the action of radio- and chemotherapeutics, giving rise to the chance of apoptosis induction by PDT even in cells resistant to conventional treatments. In this review, the (experimental) variables determining the cellular response after PDT and the known mechanistic details of PDT-triggered induction and execution of apoptosis are discussed. This is accompanied by a critical evaluation of wide-spread methods employed in apoptosis detection with special respect to in vitro / cellbased methodology.

During the last decades, Photodynamic Therapy (PDT) has been established as a powerful alternative approved by health agencies of several countries for treatment of various malignant and some non-malignant diseases. PDT makes use of the light-induced destruction of target cells by formation of cytotoxic products in the presence of a photosensitizing agent and oxygen. The light-dependent tumor destructive properties of Hypericin have drawn attention to its promising application as a photosensitizer in the frame of PDT. Hypericin is a naturally occurring secondary metabolite in plants of the Hypericum genus, with Hypericum perforatum (St. Johns wort) as it is a commonly known representative. This review focuses on the cellular mechanisms of Hypericin-based phototoxicity and provides an outlook for future application of Hypericin as a fluorescing and photosensitizing agent for diagnosis and treatment of cancerous diseases, respectively.