Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-10-08
2001-08-14
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S045000, C514S049000
Reexamination Certificate
active
06274576
ABSTRACT:
GOVERNMENT INTEREST
The invention described herein may be manufactured, licensed, and used for United States of America governmental purposes without the payment of any royalties to the inventors, or assignee.
FIELD OF THE INVENTION
This invention relates to a method of potentiating cell damage by administering an agent that retards the rate of movement of a target cell through some portion of the cell-division cycle and administering a cytotoxic agent that acts within a portion of the cell-division cycle through which movement has been slowed. The method of the invention can be used in chemotherapy as well as in other medical and non-medical applications. In a specific embodiment, deoxythymidine (dThd) is the agent retarding the rate of movement of a target cell through a portion of the cell-division cycle and staurosporine is the cytotoxic agent. The invention also relates to a method of using a microculture indicator system (MIS) and auxiliary data analysis procedures to determine the degree of interaction between agents. In a specific embodiment, data are collected reflecting the effect on cell growth of two or more agents arrayed in serial bivariate dilutions, and a database is caused to process the data in a spreadsheet according to predetermined relationships with reference measurements of cell growth and to present, in graphical or tabular form, the spectrum of interaction of the agents with respect to reference measurements.
BACKGROUND OF THE INVENTION
The use of drugs or other agents for destroying or inflicting permanent damage on living cells serves a number of valuable and legitimate objectives. A major clinical use is for the ablation of malignant tumors or other abnormal tissue growths. V T DeVita, Jr., IN: Cancer, Principles and Practice of Oncology, 4th ed., pp. 276-292, JB Lippincott Co. Philadelphia (1994).
Other valuable clinical uses have included (1) medical control of abnormal immunologic reactions, K Wilson et al., Rheumatol. 21:1674-7 (1994); C M Neuwelt et al., Am. J. Med. 98:32-41; (1995); (2) exfoliative dermatological disease, G D Weinstein et al., J. Am. Acad. Dermatol. 28:454-9 (1993), R J Van Dooren-Greebe et al., Br. J. Dermatol. 130:204-10 (1994); (3) killing of cells infected by viruses, viral replicative elements, or prions, P Calabresi et al., Section XII—Chemotherapy of neoplastic diseases IN: Goodman and Gilman's The; Pharmacologic Basis of Therapeutics, 8th ed., 1202-1263 (Pergammon Press, New York 1990):, S Chou et al., Antiviral chemotherapy, Chapter 17 IN: Virology, pp. 323-348, ed. B N Field; et al., Raven Press, New York (1985); (4) therapies for systemic or topical elimination of infective agents including bacteria, mycobacteria, mycoplasma, rickettsia, fungi, yeast, or parasitic organisms, H P Willett, The action of chemotherapeutic agents, Chapter 10, IN: Zinsser Microbiology, 17th ed., pp. 234-277, ed. Joklik et al., Appleton-Century-Crofts, NY (1980); Lorian, Antibiotics in Laboratory Medicine, 3d ed., Williams and Wilkins, Baltimore (1991); S Sternberg, Science 266:1632-1634 (1994), (5) and fertility control. Nonclinical uses cf agents capable of inflicting permanent damage on living cells occur in agriculture, horticulture, or public health, e.g., application of specific pesticides or herbicides.
A vast array of physical, chemical, or biological agents are hazardous to living cells and can inflict damage upon biological systems such as tissues or organs. In many cases, however, the damage is not specifically targeted to events related to the cell-division cycle.
In other cases, cell damage may be initiated in direct relation to the hierarchy of the cell-division cycle. A cytotoxic agent that acts during some portion of the cell-division cycle, causing biologically significant or irreversible damage to a proliferating cell, may serve as a “targeted cytotoxic insult” or “TCI”, as defined herein. The portion of the cell-division cycle during which a given TCI initiates a relevant action is its “target interval.”
Known agents that can act as TCIs are diverse and include natural substances, products of microbial or other cellular origins, synthetic or semi-synthetic organic or inorganic chemical compounds, or simple inorganic reagents. Other factors that can act as a TCI are also known and may include deprivation of nutrients essential to cell growth or sustenance as well as changes in the physicochemical environment. Examples of the latter include temperature changes and exposure of the cells to radiant or particulate energies, vibrational waves, or various other physical forces.
Cytotoxic effects of a TCI may not be immediate, so that cell damage initiated in one phase of the cell-division cycle may not become manifest until a later phase or a subsequent cell cycle. As just one example, in cisplatin treatment, permanently injured progeny cells may be sterile or exhibit a reduced capacity to proliferate or survive. M Sorenson, J Natl. Cancer Inst. 82:749-55 (1990). Thus, an understanding of the cell-division cycle hierarchy becomes useful to further understanding of agents that can act as TCIs.
I. The Cell-Division Cycle
All growing cells must duplicate their genomic DNA and pass identical copies of this genetic information to their progeny. In order to accomplish this task, proliferating somatic (non-reproductive) and germ (reproductive) cells of all living organisms undergo repetitive cell-division cycles (hereinafter “cell cycle” or “CC”). Each completed cell-division cycle results in the duplication of the cell's genetic information and the division of the parent cell into two daughter cells, with an equal division of the parental cell DNA.
The biochemical and biomolecular processes that comprise the cell cycle include, among other things, enzyme-dependent DNA replication, enzyme-dependent phosphorylation, signal cascades, association and dissociation of transcriptional activating molecular complexes, and formation and dissociation of macromolecular assemblies of cytostructural elements including cytomembranes and the cytoskeleton.
A. Cell Cycle Hierarchy
The processes characterizing the cell cycle form a regulated hierarchy and advance in a strict order dependence under the control of a cell cycle “engine” or “control system.” The control system functions as a biomolecular “clock” or “oscillator” and includes critical controls at “checkpoints.” L N Edmunds, Jr., Ann. N.Y. Acad. Sci. 719:77-96 (1994); I A Carre et al., J Cell Sci. 104:1163-73 (1993); B G Gabrielli et al., J. Biol Chem 267:1969-75 (1992); A Goldbeter, Proc. Natl. Acad. Sci. (USA) 88:9107-11 (1991); Murray A W and Kirschner M W, Science 246:614-621 (1989).
In the normal cell cycle hierarchy, DNA replication is followed by mitosis and cytokinesis. See generally A W Murray, Nature 359:599-604 (1992); B Alberts et al., The cell-division cycle, IN:
Molecular Biology of the Cell
, 3d edition, Garland Publishing Inc., New York (1994); B A Edgar et al., Genes Dev 8:440-52 (1994). A series of molecular processes, each process functioning in an appropriate order during the cell cycle, moves the cell in the direction of cell division with a downstream momentum. In this context, the term “downstream” refers to events that occupy a “subordinate position” in the cell cycle hierarchy as defined by Alberts, supra. Order dependence in the cell cycle hierarchy ensures that DNA replication proceeds with maximal fidelity. See L H Hartwell et al., Science 246:629-634 (1989); P M O'Connor et al., Semin. Cancer Biol. 3:409-416 (1992).
The hierarchy of the eukaryotic cell cycle relates to four conserved functional landmarks (FIG.
1
): S phase, in which nucleotides are synthesized and DNA is semi-conservatively replicated in double-stranded helixes of polynucleotides; G
2
phase, which follows completion of DNA synthesis and during which DNA associates with nucleoproteins; M phase, in which nuclear filaments condense as chromosomes and chromosomes segregate for mitosis; and G
1
. phase, during which cells prepare for renewed division by replacement of depleted produc
Grimley Philip M.
Mehta Sunil
Chang Ceila
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
The Henry Jackson Foundation for the Advancement of Military Med
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