Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-15
2003-11-04
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S184000, C514S188000, C514S492000, C514S863000, C514S883000, C514S908000, C424S646000
Reexamination Certificate
active
06642221
ABSTRACT:
BACKGROUND OF THE INVENTION
All proliferating eucaryotic cells must undergo a process termed mitosis before separating into two new cells. Mitosis is a process in which the parent or replicating cell undergoes a series of molecular events that results in the formation of two nuclei in the place of one. Traditionally, mitosis has been described as a series of six dynamic stages: prophase, prometaphase, metaphase, anaphase, telophase and cytokinesis. Briefly, mitosis begins in prophase with the formation of the mitotic spindle having two centrosomes and associated microtubules. During prometaphase and metaphase the centrosomes migrate to opposite ends of the cell to form two spindle poles, followed by the previously duplicated chromosomes aligning at the metaphase plate in-between the two poles. One of each duplicated chromosomes is separated to each pole, nuclei are re-form containing the complement of chromosomes, and the cytoplasm cleaved in half to form two separate daughter cells.
Critical to the separation of the replicated chromosomes and formation of the two nuclei in the mitotic process is the bipolar mitotic spindle. Cells must properly form a bipolar mitotic spindle with bivalent chromosomes properly attached to each pole of the spindle (Gorbsky et al,
Bioessays
, 19: 193-197, 1997; Hardwick, K. G.,
Trends Genet
., 14: 1-4, 1998). Cells which do not form a correct mitotic spindle arrest at metaphase of mitosis indefinitely or progress into apoptosis. Several proteins from yeast and mammals have been implicated in this process; MAD1 (mitotic arrest deficient), MAD2, and MAD3 (Li et al,
Cell
, 66: 519-531, 1991 (published erratum appears in
Cell
, 79(2), following p388)), BUB1 (budding uninhibited by benzimidazole), BUB2 and BUB3 (Hoyt et al,
Cell
, 66: 507-517, 1991). Mammalian counterparts for these proteins include HsMAD2 (Li et al, Supra) and hBUB1 (Cahill et al,
Nature
, 392: 300-303, 1998).
One of the most crucial and tightly regulated events during mitosis is centrosome duplication (Schatten, G.,
Dev. Biol
., 165: 299-335, 1994; Balczon, R.,
International Review of Cytology
, 169: 25-82, 1996). The centrosome is an organelle consisting of a pair of centrioles surrounded by an amorphous electron dense material and represents the mammalian equivalent of the yeast spindle pole body. This organelle serves as a site of microtubule organization in the cell. During cell cycle progression the centrosome duplicates, separates and functions as the poles for the mitotic spindle. It is crucial for proper chromosome segregation and fidelity that centrosome replication be tightly regulated, doubling just once during each cell cycle. Centrosome regulation is tightly linked to the S-phase checkpoint (Khan et al.,
Cancer Res
., 58: 396-401, 1998; Lanni et al.,
Mol. Cell Biol
., 18: 1055-1064, 1998). For example blocking cells at the beginning of S-phase leads to the formation of multiple centrosomes (Baczon et al.,
J. Cell Biol
., 130: 105-115, 1995).
Considerable efforts are underway to develop new anti-proliferative agents for use as therapies in the treatment of cancer, as well as non-cancer proliferative disorders such as epithelial hyperplasia, polycytemia, erythrocytemia, thrombocytemia, EBV transformed lymphoproliferative syndrome, dysplastic nevus syndrome, restenosis after angioplasty for coronary heart disease, mastocytosis, histiocytosis, psoriasis, polyps, and the like. One target for anti-proliferative agents is the mitotic pathway. Accordingly, there is a need for the development of novel, effective anti-proliferative agents that target the mitotic pathway.
Vanadocene dichloride (VDC) has been shown to arrest tumor cell growth (Kopf-Maier, et al,
J. Cancer Res. Clin. Onccol
., 106: 44-52. 1983), and the oxovanadium compound, [VO(Phen)(H
2
O)
2
](SO
4
), has been shown to be an active agent against pharyngonasal cancer as determined by a single assay (Sakurai, et. al,
BBRC
, 206; 133, 1995). Vanadium compounds have also been shown to induce apoptosis in certain cancer cells (Uckun et al., WO 00/35930).
Against this backdrop the present invention has been developed.
SUMMARY OF THE INVENTION
It has now been found that vanadium compounds of the invention, and particularly vanadium compounds and oxovanadium compounds described herein, are effective anti-proliferation agents. These compounds act to disrupt mitotic and meiotic spindle formation and thus are useful to prevent cell mitosis (proliferation) and meiosis.
The invention provides a method for disrupting mitosis or meiosis comprising administering to a subject a effective mitosis or meiosis disrupting amount of a vanadium compound, preferably a vanadium cyclopentadienyl compound (vanadocene), or an oxovanadium compound. Exemplary compounds useful in the method of the invention are described, for example, in published PCT applications W099/36063; WO 00/27389; and WO 00/35930. VDC and VDacac are specific compounds useful in the method invention, as well as other compounds of the invention described below.
The invention are useful applications where disruption of meiosis or mitosis is advantageous, for example, the treatment and prevention of cancer and non-cancer proliferative disorders including those described above, as well as in any other applications where the inhibition of mitosis and/or meiosis in cells is desired or useful.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention is drawn to the use of vanadium compounds, preferably vanadium cyclopentadienyl compounds (vanadocenes) and oxovanadium compounds, including, but not limited to those described in published PCT applications WO99/36063; WO 00/27389; and WO 00/35930. Vanadium compounds useful in the method invention include vanadocene compounds such as vanadocene dichloride (VDC), vandocene acetylacetonate (VDacac), and those vanadium compounds shown below. Specifically, the present invention relates to the finding that these compounds effect disruption of normal mitotic and meiotic spindle formation, and are inhibitors of mitosis and meiosis. The anti-mitotic and anti-meiotic activity makes these compounds particularly attractive anti-proliferative agents, particularly for the treatment of non-cancer proliferative disorders.
Vanadium is a physiologically essential element that can be found in both anionic and cationic forms with oxidation states ranging from −3 to +5 (I—V). This versatility provides unique properties to vanadium complexes. In particular, the catonic form of vanadium complexes having an oxidation state of +4 (IV) has been shown to function as a modulator of cellular redox potential, to regulate enzymatic phosphorylation, and to exert pleiotropic effects in multiple biological systems by catalyzing the generation of reactive oxygen species (ROS). Besides the ability of vanadium metal to assume various oxidation states, its coordination chemistry also plays a key role in its interactions with various biomolecules. In particular, it is demonstrated herein that vanadium compounds, such as vanadium cyclopentadienyl compounds, or derivatives thereof, exhibit anti-mitotic and anti-meiotic properties. The effects of vandocene are primarily via disruption of mitotic and meiotic spindle formation.
Definitions
The following terms and phrases as used herein have the noted definitions, unless otherwise described:
“Halo” is fluoro, chloro, bromo, or iodo.
“Alkyl”, “alkoxy”, etc. denote both straight and branched hydrocarbon groups; but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” is specifically referenced.
“Organometallic compound” is an organic compound comprised of a metal attached directly to carbon (R—M).
“Coordination compound” is a compound formed by the union of a central metal atom or ion with ions or molecules called ligands or complexing agents.
“Ligand” or a “complexing agent” is a molecule, ion or atom that is attached to the central metal atom or ion of a coordination compound.
“Monodentate
Navara Christopher S
Uckun Faith M
Pak John
Parker Hughes Institute
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