Method of treating tumorigenic disease

Details Method of treating tumorigenic disease Method of treating tumorigenic disease

1999-04-01

2002-01-22

Hauda, Karen M. (Department: 1632)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C435S320100, C435S325000, C435S375000, C435S173300

Reexamination Certificate

active

06340673

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to methods for blocking or delaying programmed cell death, for delivery of gene therapy to specific cells, and for treatment of cancer and other tumorgenic diseases, as well as treatment of viral infections, through the potentiation of programmed cell death in tumor or viral host cells. The present invention is also directed to assays for candidate substances which can either inhibit, or potentiate programmed cell death.
Description of the Related Art
a. Programmed Cell Death (Apoptosis)
In the last decade there has been increasing acceptance in the scientific community of the idea that cells may actually be internally programmed to die at a certain point in their life cycle. As an active cellular mechanism programmed cell death, is or apoptosis, has several important implications. First, it is clear that such an active process can provide additional means of regulating cell numbers as well as the biological activities of cells. Secondly, mutations or cellular events which potentiate apoptosis may result in premature cell death. Third, a form of cell death which is dependent on a specific active cellular mechanism can at least potentially be suppressed. Finally, an inhibition of preprogrammed cell death would be expected to lead to aberrant cell survival and could be expected to contribute to oncogenesis.
In general, apoptosis involves distinctive morphological changes including nuclear condensation and degradation of DNA to oligonucleosomal fragments. In certain circumstances it is evident that apoptosis is triggered by or is preceeded by changes in protein synthesis. Apoptosis appears to provide a very clean process for cellular destruction, in that the cells are disposed of by specific recognition and phagocytosis prior to bursting. In this manner cells can be removed from a tissue without causing damage to the surrounding cells. Thus, it can be seen that programmed cell death is crucial in a number of physiological processes, including morphological development, clonal selection in the immune system, and normal cell maturation and death in other tissue and organ systems.
It has also been demonstrated that cells can undergo apoptosis in response to environmental information. Examples include the appearance of a stimulus, such as glucocorticoid hormones for immature thymocytes, or the disappearance of a stimulus, such as interleukin-2 withdrawal from mature lymphocytes, or the removal of colony stimulating factors from hemopoietic precursors (for a review of literature see Williams,
Cell,
85; 1097-1098, Jun. 28, 1991). Furthermore, it has recently been demonstrated that the response of removal to nerve growth factor from established neuronal cell cultures mimics target removal, or axiotomy, or other methods of trophic factor removal, and it has been postulated that the cellular mechanism involved in this response is a triggering of a suicide program or programmed cell death following the nerve growth factor removal. (See Johnson et al.,
Neurobiol. of Aging,
10: 549-552, 1989). The authors propose a “death cascade” or “death program”, which envisions that trophic factor deprivation initiates the transcription of new mRNA and the subsequent translation of that mRNA into death associated proteins which act in sequence to ultimately produce “killer proteins”. Such an intracellular mechanism seems to fit well with the characteristics of apoptosis discussed above, eg., death of specific cells without the release of harmful materials and without the disruption of tissue integrity. Furthermore, the authors indicate that inhibitors of macromolecular synthesis prevented the death of neurons in the absence of nerve growth factor.
Studies have been conducted to explore the possibility that tumor cells could be eliminated by artificially triggering apoptosis. The APO-1 monoclonal antibody can induce apoptosis in several transformed human B and T cell lines. The antibody binds to a surface protein and could act either by mimicking a positive death-inducing signal or by blocking the activity of a factor required for survival. Also, anti-FAS antibodies have similar effects, and the recent cloning and sequencing of the gene for the FAS antigen has shown that it is a 63 kilodalton transmembrane receptor. Itoh et al.,
Cell
66: 233-243 (1991).
However, it is important to note that neither APO-1 nor FAS can function exclusively as triggers for cell death. Both are cell surface receptors that may activate quite different responses under other circumstances. Moreover, these antigens are not confined to tumor cells and their effect on normal cells is certainly an important consideration, as is the possible appearance of variants that no longer display the antigens.
It has also been demonstrated that the cell death induced by a range of cytotoxic drugs, including several used in cancer therapy, has also been found to be a form of apoptosis. In fact, the failure of apoptosis in tumor cells could be of fundamental importance in contributing not only to the evasion of physiological controls on cell numbers, but also to resistance both to natural defenses and to clinical therapy.
It has also been demonstrated that expression of the bcl-2 gene can inhibit death by apoptosis. The bcl-2 gene was isolated from the breakpoint of the translocation between chromosomes 14 and 18 found in a high proportion of the most common human lymphomas, that being follicular B cell lymphomas. The translocation brings together the bcl-2 gene and imunoglobulin heavy chain locus, resulting in an aberrantly increased bcl-2 expression in B cells. Subsequently, Henderson et al. (
Cell,
65: 1107-1115, 1991) demonstrated that expression of latent membranes protein 1 in cells infected by Epstein-Barr virus protected the infected B cells from programmed cell death by inducing expression of the bcl-2 gene. Sentman et al. (
Cell,
67: 879-88, Nov. 29, 1991) demonstrated that expression of the bcl-2 gene can inhibit multiple forms of apoptosis but not negative selection in thymocytes, and Strasser et al. (
Cell,
67: 889-899, Nov. 29, 1991) demonstrated that expression of a bcl-2 transgene inhibits T cell death and can perturb thymic self-censorship. Clem et al. (
Science,
245: 1388-1390, Nov. 29, 1991) identified a specific baculovirus gene product as being responsible for blocking apoptosis in insect cells.
b. Herpes Virus Infections and Neurovirulence
The family of herpes virus includes animal viruses of great clinical interest because they are the causative agents of many diseases. Epstein-Barr virus has been implicated in B cell lymphoma; cytomegalovirus presents the greatest infectious threat to AIDS patients; and. Varicella Zoster Virus, is of great concern in certain parts of the world where chicken pox and shingles are serious health problems. A worldwide increase in the incidence of sexually transmitted herpes simplex (HSV) infection has occurred in the past decade, accompanied by an increase in neonatal herpes. Contact with active ulcerative lesions or asymptomatically excreting patients can result in transmission of the infectious agent. Transmission is by exposure to virus at mucosal surfaces and abraded skin, which permit the entry of virus and the initiation of viral replication in cells of the epidermis and dermis. In addition to clinically apparent lesions, latent infections may persist, in particular in sensory nerve cells. Various stimuli may cause reactivation of the HSV infection. Consequently, this is a difficult infection to eradicate. This scourge has largely gone unchecked due to the inadequacies of treatment modalities.
The known herpes viruses appear to share four significant biological properties:
1. All herpes viruses specify a large array of enzymes involved in nucleic acid metabolism (e.g., thymidine kinase, thymidylate synthetase, dUTPase, ribonucleotide reductase, etc.), DNA synthesis (e.g., DNA polymerase helicase, primase), and, possibly, processing of proteins (e.g., protein kinase), although the exact array of enzymes may vary somewhat

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