Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
1996-11-20
2001-01-30
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
Reexamination Certificate
active
06180402
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to the field of medicine and pharmacotherapeutics, particularly with the proteolytic events leading to the rapid onset of apoptotic cell death. More specifically, the invention is a composition and method for inhibiting or decreasing the extent or rate of apoptosis in a subject, particularly in association with standard photodynamic therapy protocols, which involve administering a photosensitive agent and subsequently irradiating the subject with light of a wavelength that is absorbed by the photosensitive agent.
BACKGROUND ART
Photodynamic therapy (“PDT”) is an approved cancer treatment that can be used for many purposes, such as the treatment of solid tumors; the impairment of blood-borne targets such as leukemic cells, immunoreactive cells, and unwanted microorganisms; the prevention of restenosis; the treatment of ocular neovascular disorders such as macular degeneration; and the removal of atherosclerotic plaque. PDT involves the topical or systemic application of a light-absorbing photosensitive agent, usually a porphyrin derivative, which accumulates selectively in target tissues. A particularly potent photosensitizer is benzoporphyrin derivative mono-acid ring A (“BPD-MA” or “verteporfin”), which is a second generation chlorin-type photosensitizer exhibiting distinct advances over its hematoporphyrin forerunners in terms of effectiveness at lower concentrations and ability to absorb longer, more penetrating wavelengths of light.
Upon irradiation with visible light of an activating wavelength, reactive oxygen species are produced in cells containing the photosensitizer, which promotes cell death. Evidence has been developed indicating that PDT using a photosensitizer may cause cells to die via an apoptotic pathway. Kessel et al., “Rapid Initiation of Apoptosis by Photodynamic Therapy”,
Photochem. Photobiol.,
63:528-34 (1996); Oleinik et al., “Photodynamic Therapy Induces Rapid Cell Death of Apoptosis in L5178 Mouse Lymphoma Cells”,
Cancer Res.,
51:5993-96 (1991).
Apoptosis is the term used to describe a type of cellular death that occurs in many tissues as a normal physiological process. Apoptosis is a morphologically distinct form of cell death that plays an important role during normal development, differentiation, and homeostasis or turnover of tissues. Also called “programmed cell death,” this form of cellular demise involves the activation in cells of a built-in genetic program for cell suicide by which cells essentially autodigest.
The goal of apoptosis is to attain an orderly disintegration of cells into structures suitable for phagocytosis. Morphologically, apoptosis is begun by loss of contact with neighboring cells and smoothening of the cell surface (vesicle formation on the cell surface and membrane “blebbing”). It is further characterized by the concentration of the cytoplasm, endonuclease activity-associated chromatin condensation and pyknosis, and segmentation of the nucleus. The orderly disintegration of cells also includes the degradation of genomic DNA into nucleosomal fragments and cellular fission to form apoptotic bodies. The nucleosome units of the resulting DNA fragments are about 180-200 bases in size. The final fragments of apoptotic body cells are phagocytosed by neighboring cells. The remnants of these dead cells are then cleared almost without a trace by neighboring phagocytic cells, without resulting in inflammation or scarring.
Apoptosis thus stands in marked contrast to necrotic cell death caused, for example by oxygen-deprivation in myocardial infarction or stroke, where cells lose their energy supplies, rupture and spill their contents into the extracellular milieu. Morphologically, necrosis is characterized by marked swelling of mitochondria, swelling of cytoplasm and nuclear alteration, followed by cell destruction and autolysis. It occurs passively or incidentally. Tissue necrosis is generally caused by physical trauma to cells or a chemical poison.
The concept that apoptosis is a finely regulated process is now well established. Kerr et al., “Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics”,
Br. J. Cancer,
26:239-45 (1972). However, the precise molecular mechanism remains as yet uncharacterized.
Apoptosis is thus known to be involved in developmental and tissue specific processes that require the removal of cell populations. In addition to the normal physiological process where cells are turned over within the body, apoptosis can be induced to occur by cellular, hormonal or other stimuli to remove unwanted cells from the body. For example, apoptosis is also known to be involved in the immunological process of cell selection. Specifically, the killing of tumor cells and virus-infected cells by the immune system's cytolytic T-cells occurs via apoptosis following target recognition. Further, apoptosis accounts for cell death in a wide variety of clinically important areas. For example, essentially all chemotherapeutic drugs currently used in the treatment of cancer, as well as x-irradiation in may cases, ultimately kill malignant cells by activating intracellular pathways leading to apoptosis.
Dysregulation of apoptosis, however, may be involved in the pathogenesis of a number of disease states and pathological conditions, such as cancer, acquired immunodeficiency syndrome (AIDS), and neurodegenerative disorders. Specifically, during spontaneous tumor regression, tumor cell death has been shown to follow an apoptotic pathway. During HIV infection, virally induced T-cell death has been shown to follow an apoptotic pathway. And the death of neurons that occurs in diseases such as Alzheimer's dementia and Parkinson's disease shows many hallmarks of apoptosis.
Control of apoptosis has been shown to be useful with respect to specific cells having crucial relevance to developmental biology. Additionally, it would be useful to control apoptosis with respect to treatments involving viral and bacterial pathogens. Cancer chemotherapy could also be enhanced by controlling apoptotic pathways. Efforts have been made using conventional chemotherapy to treat many of the disease states that result in inappropriate apoptotic cell death, but have so far yielded only minor progress toward effective treatment.
The chemical induction of apoptosis is target cell dependent. Glucocorticoids, such as dexamethasone, have been shown to induce apoptosis in thymocytes. Cycloheximide, a known inhibitor of protein synthesis, and actinomycin D, a known inhibitor of mRNA transcription, have also been shown to be powerful inducers of apoptosis in many cell lines. Other inducers of apoptosis include UV irradiation, captothecin, aphidocholin, cisplatin, vincristine, and phorbol myristate acetate plus ionomycin, glucocorticoids, atrophy of hormone-dependent tissues, NK cell, killer cells, tumor necrosis factor (TNF), lymphotoxin (LT), and other cytokines.
The inhibition of apoptosis is also target cell dependent. In addition to being classified as apoptosis inducers, actinomycin D and cycloheximide have also been classified as powerful inhibitors of apoptosis in many cell lines. Other known apoptosis inhibitors include various endonuclease inhibitors, e.g., Zn
2+
and aurintricarboxylic acid.
Inhibition of apoptotic deletion of autoreactive T-cell clones may be achieved by treatment with immunosuppressant cyclosporin A. Other special inhibitors of apoptosis include various steroids and interleukins. The latter stage of apoptosis, i.e., the induction of fission events leading to the formation of apoptosis bodies, may be inhibited by the use of microfilament-disrupting agents, such as cytochalasin B and staurosporin. Agents that inhibit the expression of the oncogene cMyc or that cause the over-expression of the proto-oncogene bcl-2 can inhibit the induction of apoptosis. Calcium ion (Ca
+2
) chelating agents; hematopoietic system cytokines, such as IL-3, granulocyte macrophage colony stimulating factor and granulocyte colony stimulating factor; IL-2; a
Granville David J.
Hunt David W. C.
Levy Julia G.
Morrison & Foerster / LLP
QLT Inc.
Saucier Sandra E.
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