CHAPTER 1
Introduction
James Cecil Kennedy
Table of Contents
1.1. Outline of the Theory and Technique of ALA-PDT 3 1.1.1. Tissue Specificity 4 1.1.2. Intracellular Targets 5 1.1.3. Fluorescence 5 1.1.4. ALA Administration and Approval 6 1.1.5. ALA/PpIX Clearance 7 1.2. Factors Affecting Photodynamic Therapy 8 1.2.1. Oxygen 8 1.2.2. Photosensitizer 9 1.2.3. Light 9 1.2.4. Light Dosimetry 10 1.3. Clinical Applications of ALA-PDT 11 1.4. Interaction between ALA-PDT and the Immune System 12 1.4.1. Squamous Cell Carcinoma of the Skin 12 1.4.2. Kaposi's Sarcoma 12 1.5. Conclusions 13
Abstract
This book is intended to be a very practical handbook for physicians who would like to add photodynamic therapy (PDT) to their clinical practice. It is concerned primarily with the specific type of PDT that involves administration of the porphyrin precursor 5-aminolevulinic acid (ALA), and which therefore is commonly referred to as ALA-PDT.
Chapter 1 provides brief descriptions of some basic physicochemical and biological mechanisms that are involved in ALA-PDT, and discusses some of their clinical implications. More detailed discussions are provided in Chapter 2, which is an in-depth coverage of the scientific principles involved in photosensitization. Subsequent chapters discuss the application of ALA-PDT to a variety of anatomical sites and clinical situations. Chapter 2 includes supplementary information of the physics of light delivery, and the Appendix a listing of suppliers of instrumentation used in ALA-PDT.
1.1. Outline of the Theory and Technique of ALA-PDT
Light is a form of energy. Molecules of certain chemical compounds (photosensitizers) have the ability to absorb a photon of visible light and then transfer most of their absorbed energy to a molecule of oxygen. This causes a transient increase in the chemical reactivity of the oxygen molecule, and converts it into a relatively strong oxidizing agent known as singlet oxygen (Figure 1). PDT makes use of light-induced singlet oxygen to kill cells by causing lethal oxidative damage to biologically important structures.
The excited states of both the photosensitizer and oxygen have very short half-lives. Consequently, in order to be effective, molecules of both must be in very close proximity to biologically important cellular structures. Moreover, the primary damage to cells occurs only while they are actually being exposed to the photoactivating light, although lethal cascades that were initiated during such an exposure may continue long after the treatment light has been turned off.
In order to become activated, the photosensitizer must absorb the light. The light therefore must be of wavelengths that lie within the absorption spectrum of the photosensitizer. However, since tissue contains pigments and particulate material that can absorb or scatter light in a wavelength-dependent manner, the particular photoactivating wavelengths that are selected should be ones that are neither absorbed nor scattered strongly by the tissue through which it passes. The choice of a wavelength for PDT usually is a compromise between strong absorption by the photosensitizer and good transmission by the tissue. For very superficial lesions, the major peak in the absorption spectrum works well, but for deeper lesions it is necessary to use light whose wavelength is more toward the red.
Ideally, the phototoxic damage will be restricted to the target tissue, although in practice we often accept a reasonable differential effect. The target tissue therefore must accumulate substantially more of the photosensitizer than does adjacent or underlying or overlying non-target tissue.
1.1.1. Tissue Specificity
The photosensitizer used in ALA-PDT is protoporphyrin (PpIX), which is synthesized in situ from exogenous ALA rather than given to the patient as a preformed molecule (Figure 2). The administration of exogenous ALA bypasses the rate-limiting step in the biosynthesis of heme, and thus forces each step in the pathway to produce its product at the maximum rate possible for that particular step. Since PpIX is the immediate precursor of heme, cells in which the rate of synthesis of PpIX is greater than the rate at which it can be converted into heme, excreted, or otherwise lost to the cell will accumulate PpIX.
The amount of PpIX that accumulates in malignant, premalignant, and certain other abnormal tissues usually is significantly greater than the amount that accumulates in normal tissues of similar origin. When exposed to exogenous ALA, malignant tissues show a strong tendency to become much more photosensitive than the normal tissues from which they were derived. This is the primary reason for the tissue specificity found with ALA-PDT. Secondary reasons for tissue specificity may involve differences in the capacity of the cells to repair oxidative damage, or differences in the concentration or location of some compound that can function as an anti-oxidant and thus render singlet oxygen harmless.
1.1.2. Intracellular Targets
Photosensitizers other than ALA are administered intravenously as preformed molecules. They enter the blood stream, and then enter cells though their plasma membranes. The selective distribution of such photosensitizers depends upon physicochemical differences between the different types of cells, and the phototoxicity that results is a function of the intracellular location and concentration of the photosensitizer. In contrast, PpIX is synthesized by the mitochondria, the primary source of energy for the cell. Oxidative damage to such structures interferes with energy metabolism and can lead to cell death. Once the extra PpIX is produced in the mitochondria, it cannot all be converted into heme. Thus a significant amount will diffuse into the cytoplasm and may eventually find its way into other organelles with the exception of the nucleus. The fact that PpIX was not introduced as a preformed molecule, but rather synthesized in situ, means that the final destination of excess ALA-induced PpIX may be quite different from the site of localization of preformed photosensitizers.
1.1.3. Fluorescence
As well as being a good photosensitizer, PpIX is strongly fluorescent. It is possible to use ALA-induced fluorescence to locate tiny patches of abnormal tissue. It is possible also to measure the effectiveness of a course of chemotherapy...
