Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1996-05-08
1998-11-24
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514181, 514258, 514261, 514263, 514275, 514309, 514334, 514415, 514474, 514646, A61K 3156, A61K 31505, A61K 3152, A61K 3147, A61K 3144, A61K 31405, A61K 3134, A61K 31135
Patent
active
058407197
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB94/01169, filed May 31, 1994.
This invention relates to the prevention or at least delay of death of cells, particularly non-dividing cells.
Controlling cell death is useful in the treatment of neurodegenerative diseases in general, including stroke, Alzheimer's disease, Parkinson's disease and motor-neuron disease in particular.
Neurons are examples of cells which have terminally differentiated and therefore are non-dividing. There are two general types of neuronal cell death: necrotic and apoptotic. The two differ in terms of initiating is factors, morphological changes, time course and mechanism. Necrotic cell death is often seen in situations in which there is excess calcium ion influx caused, or example, by application of the excitatory neurocransmitter glutamate. Apoptotic cell death is sometimes referred to as programmed cell death and is seen as a normal developmental event in the nervous system and in other tissues. Fully differentiated neurons are normally dependent on a trophic factor for their survival and apoptotic death can be triggered by trophic factor withdrawal.
The role of apoptotic death in neurodegenerative disease has not been fully established. However, there are a variety of diseases of the nervous system in which neurons destined to die can be rescued by application of appropriate growth factors while the cause of a cell's fate may vary from disease to disease, it seems likely that the final death pathway is apoptosis in each case.
The observation that the application of appropriate growth factors can rescue neurons destined to die has given rise to proposals for treatment for certain neurodegenerative diseases in the past. However, because the treatment is based on the use of peptide growth factors, which are unable to cross the blood-brain barrier, most current clinical trials for neurodegenerative disease are for diseases of the peripheral, rather than central, nervous system. Furthermore, such individual treatments as have been proposed are rather disease-specific; there has not hitherto existed the basis for developing a more generally applicable therapeutic or prophylactic regime for the management of neurodegenerative disease and other diseases involving the cell death of non-dividing cells.
it has now been discovered that cell death in a fully differentiated, non-dividing cell such as a neuron appears to be the result of an abortive attempt of the cell to re-enter or pass through the mitotic cycle. Therefore, agents which prevent entry into or passage through she mitotic cycle should be effective in preventing, or at least delaying, apoptotic cell death.
According to a first aspect of the present invention, there is provided a method of treating or preventing a disease involving apoptotic cell death, the method comprising administering to a subject, or to cells of a subject, an effective amount of an agent which prevents cell entry into or passage through the mitotic cycle; Provided that the agent is not bFGF, IGF-I, IGF-II, potassium ions or a cAMP-elevating agent.
The mitotic cell cycle has four distinct phases, G.sub.1, S, G.sub.3 and M. The beginning event in the cell cycle, called start, takes place in the G.sub.1 phase and has a unique function. The decision or commitment to undergo another cell cycle is made at start. Once a cell has passed through start, it passes through the remainder of the G.sub.1 phase, which is the pre-DNA synthesis phase. The second stage, the S phase, is when DNA synthesis takes place.
This is followed by the G.sub.2 phase, which is the period between DNA synthesis and mitosis. Mitosis itself occurs at the M phase. Fully differentiated cells such as neurons are generally regarded as not being in any of these four phases of the cycle; they are usually described as being in a G.sub.0 state, so as to indicate that they would not normally progress through the cycle.
Preferred agents useful in the invention may totally prevent entry into the cycle. Other agents may allow passage through the cycle to a certain ext
REFERENCES:
Finnegan, et al., Brain Research, vol. 591:160-164 (1992).
Rukenstein, et al., The Journal of Neuroscience, vol. 11(8): 252-2583 (1991).
Ferrari, et al., The Journal of Neuroscience, vol. 13(5): 1879-1887 (1993).
Batistatou, et al., J. Cell Biol., vol. 115(2):461-472 (1991).
Galli, et al., Experimental Cell Research, vol. 204:54-60 (1993).
Davidoff, et al., Experimental Hematology, vol. 21:456-460 (1993).
Thakkar, et al., Biochemical Pharmacology, vol 43, No. 3: 1683-1691 (1992).
Brooks, deceased Susan Frances
Rubin Lee Laurence
Eisai Company Ltd.
Jordan Kimberly
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