Photodynamic therapy (PDT) is a rapidly advancing treatment for multiple diseases. PDT involves the administration of a nontoxic drug or dye known as a photosensitizer (PS), either systemically, locally, or topically, to a patient bearing a lesion (frequently but not always cancer), followed after some time by the illumination of the lesion with visible light; in the presence of oxygen, leads to the generation of cytotoxic species and consequently to cell death and tissue destruction. The light is absorbed by the PS molecule and the excited state PS transfers energy to ground state molecular oxygen, forming a reactive oxygen species that oxidize lipids, proteins, and nucleic acids. The resulting damage to essential biomolecules kills target cells by necrosis, apoptosis, or autophagy. When used as a cancer treatment PDT is known to cause direct tumor cell killing, severe damage to tumor blood vessels, and also produce an acute inflammatory reaction that can stimulate the immune system to recognize, track down, and even kill distant tumor cells that could cause metastases. This chapter focuses on studies of PDT that have employed a systems biology approach. These experiments have been frequently carried out using geneexpression micro-arrays. We will cover protective responses induced by PDT that include activation of transcription factors, heat shock proteins, antioxidant enzymes, and antiapoptotic pathways. Elucidation of these mechanisms might result in the design of more effective combination strategies to improve the antitumor efficacy of PDT. Specific pathways shown to be activated after PDT are heat shock proteins 90, 70, and 27, heme oxygenase, and cyclooxygenase-2.
Overview Of Photodynamic Therapy
PDT dates from the early days of the twentieth century when workers used dyes such as eosin together with light to treat skin cancer (Jesionek, 1903). Hematoporphyrin (HP) was also first used at this time (Hausman, 1911) and sporadic reports (Figge, 1948) of both selective localization of porphyrins in tumors and regression after exposure to visible light appeared until the 1960s. The modern explosion of interest in PDT dates from the discovery of hematoporphyrin derivative (HPD) by Lipson and Baldes in 1960 (Lipson, 1960), and was fueled by pioneering studies in both basic science and clinical application (Dougherty, 1974, Dougherty, 1978, Dougherty, 1979) by Dougherty et al. (notable among many groups). A semi-purified preparation of HPD known as Photofrin® (PF) was the first PS to gain regulatory approval for treatment of various cancers in many countries throughout the world, including the United States. After experience of treating tumors with HPD-PDT was accumulated, it was realized that this compound had significant disadvantages, including prolonged skin sensitivity necessitating avoidance of sunlight for many weeks (Baas, 1995), sub-optimal tumor selectivity (Orenstein, 1996), poor light penetration into the tumor due to the relatively short wavelength used (630 nm) (Spikes, 1990) and the fact that it was a complex mixture of uncertain structure (Kessel, 1987).
Key Terms in this Chapter
ROS: Reactive oxygen species general term for oxidizing species such as singlet oxygen, superoxide anion, hydrogen peroxide and hydroxyl radical.
HPD or PF: Hematoporphyrin or Photofrin, first clinically used PS derived from ox blood.
SOD: Superoxide oxide dismutase, an antioxidant enzyme that converts superoxide to hydrogen peroxide and oxygen.
BPD: Benzoporphyrin derivative, PS also known as Visudyne or Verteporfin clinically used by ophthalmologists.
PS: Photosensitizer, dye (frequently a tetrapyrrole) used in PDT.
3PS: Triplet state, a relatively long-lived excited state of PS.
Autophagy: Programmed cell death characterized by autodestruction using lysosomal machinery.
Apoptosis: Programmed cell death characterized by nuclear condensation and DNA fragmentation.
Bystander Effect: Phenomenon in which uninjured cells surrounding a dying cell also die.
PPIX: Protoporphyrin IX, naturally occuring PS whose production in cells is increased when 5-ALA is administered.
PC: Phthalocyanine, PS containing tetrapyrrole structure but made synthetically.
PDT: Photodynamic therapy, treatment combining dyes and light to destroy cells.
Photobleaching: Light dependent alteration of PS molecule.
RB: Rose Bengal, PS with xanthene structure and strong pink color.
5-ALA: 5-aminolevulinic acid, small amino-acid that is a natural precursor of PPIX.
Necrosis: Non-programmed cell death characterized by membrane bursting.
1O2: Singlet oxygen, excited state reactive form of oxygen.
m-THPC: m-tetrahydroxyphenylchlorin, PS also known as Foscan clinically used for cancer.