Methylene blue in photodynamic therapy: From basic mechanisms to clinical applications.

Worldwide, photochemotherapy ( P a ) * is being evaluated as a new modality of cancer treatment. It is based on injection of photosensitizing and tumor localizing dyes followed by exposure of the tumor region to high fluence rates of light, usually from a laser. A variety of different types of tumors respond to PCT. However, PCT is efficient only in cases where the entire tumor can be reached by light. Thus, tumors thicker than 5-7 mm are rarely eradicated by PCT, unless the light is applied interstitially through fibers. Extracorporal PCT, with 8methoxypsoralen as sensitizer, of T-cells of patients suffering from the erythrodermic form of cutaneous T-cell lymphoma has been reported to give good clinical results. Extracorporal PCT for elimination of residual tumor cells from autologous bone marrow grafts is also being evaluated. The biological effects of surgical lasers, like the C0,-laser and the Nd:YAG-laser, are based on the heating that occurs when the laser radiation is absorbed by tissues. Unlike this, PCT is based on photochemical reactions and not on tissue heating. A combination of injection of a tumor localizing and photosensitizing dye and local exposure of the tumor region to light constitutes the basis for PCT. The fact that certain porphyrins administered to tumor-bearing animals tend to accumulate in tumor tissue has been known for more than 50 years (Policard, 1924). Since most porphyrins exhibit a characteristic red fluorescence, their tumor localizing properties can be used for tumor detection (Lipson, 1976; Pope et al . , 1991). The photosensitizing properties of porphyrins, together with their tumor-localizing properties, were first exploited for therapeutic purposes by Auler and Banzer in 1943 (Auler and Banzer, 1943). The first cancer patients were treated with PCT in 1976 (Kelly and Snell, 1976). Since that time a number of clinical trials have been performed (Dougherty, 1987). Also a large number of experimental investigations have been carried out (Moan, 1986a; Henderson and Dougherty; 1992). In the following some of the most recent knowledge gained through experimental and clinical research on PCT will be reviewed.

Photochemotherapy of cancer: experimental research.

The light-induced reactions of methylene blue and related phenothiazinium dyes with biological substrates are described. The properties of the excited states of the dyes, their reactions with nucleic acids and their photosensitised chemical modifications of nucleic acid bases are examined. Reports on phenothiazinium dye-induced damage to proteins, lipids, biological membranes, organelles, viruses, bacteria, mammalian cells and carcinomas are reviewed.

Photochemical interactions of methylene blue and analogues with DNA and other biological substrates.

The literature in the field of porphyrin photosensitization has been growing with an increasing rate since the last yearly review on the topic was published in this journal (Kessel, 1984). The reason for this growth is mainly to be found in the development of photodynamic cancer therapy (PDT), and this field will receive significant attention in the present review, which mainly covers the period July 1984December 1985. During this period several reviews have appeared on the same or closely related topics (Jori and Spikes, 1984; Dougherty, 1984; Spikes, 1984; Spikes, 1985; Spikes and Straight, 1985) and I will try not to overlap these reviews too much. A more complete list of recent, as well as older literature, can be found elsewhere (Kessel, 1985).

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-1097.1986.tb05647.x

Porphyrin photosensitization and phototherapy

Most of the photosensitizers used in experimental and clinical photochemotherapy (PCT)? of cancer (i.e. photodynamic therapy [PDT]) localize extranuclearly in cells: in the plasma membrane, in mitochondria, in endoplasmic reticulum, in Golgi apparatus and in lysosomes. The intracellular localization is dependent upon the chemical properties of the sensitizer, i.e. its hydrophobicity, charge and amphiphilic character (1). The intracellular localization seems also to be to some extent cell line dependent. The identity of the intracellular targets responsible for photochemically induced cell death depends on the parameters mentioned above. The special cases of lysosomes and microtubules (MT) as targets for photochemical treatment of cells in culture will be discussed.

Lysosomes and microtubules as targets for photochemotherapy of cancer.

— The photodynamically-induced liberation of lysosomal enzymes using s-galactosidase as marker for the lysosomal enzymes has been studied by microspectrofluorometry on mouse L cells. Similar studies have been carried out using N-acetyl-s-D-glucosaminidase as marker for the lysosomal enzymes of human fibroblasts. The high sensitivity of the fluorescence detection makes it possible to use 4-methylumbelliferyl substrates for the enzymes contained in a single cell. Methylene blue and hematoporphyrin readily incorporate into both cells and upon excitation, sensitize lysosomal membrane damages, leading to enzyme release accompanying strong morphological changes.

Permeation of lysosomal membranes in the course of photosensitization with methylene blue and hematoporphyrin: Study by cellular microspectrofluorometry.

P. M. Tocci

Papers

Permeation of lysosomal membranes in the course of photosensitization with methylene blue and hematoporphyrin: Study by cellular microspectrofluorometry.