Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-15
2002-04-23
Nguyen, Dave T. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S370000, C548S250000, C435S025000, C435S026000
Reexamination Certificate
active
06376525
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of cellular organelle crystallizing agents to treat cancer cells, to pharmaceutical compositions containing cellular organelle crystallizing agent(s) adapted for such use, and to methods for the treatment of cancer cells by administering cellular organelle crystallizing agent(s).
BACKGROUND OF THE INVENTION
Surgery and non-surgical anti-cancer therapies such as radiotherapy, chemotherapy, photodynamic therapy, immunotherapy, electric/chemotherapy, hyperthermia therapy, hyperbaric oxygen therapy, ischemia/reperfusion therapy and gene therapy have been found to be effective in the treatment of cancer. However, all of these treatments have been limited by tumor recurrence. In recent years, fundamental advances have been made in the development of regimens for solving these problems. Cancers continue to be the most common cause of death in countries throughout the world. The need for new and effective methods for treating cancer and leukemia continues to fuel efforts to find new classes of anti-tumor compounds or methods, especially for the inoperable or metastatic solid tumors, such as the various forms of lung cancer and hepatic carcinoma.
The characteristics and functions of cells are determined and maintained by cellular organelles and cellular cytoskeleton. Cellular organelles include nucleus, mitochondria, peroxisomes, Golgi apparatus, endoplasmic reticulum, centrosome, and vacules. Cytoskeletal structures (cytoskeleton) refer to an extensive scaffolding of fibrillar elements, including the three filamentous systems: microfilaments (or actin filaments), microtubules, and intermediate filaments. It may also include linin filaments. The components of the cytoskeleton are involved in diverse cellular functions ranging from mitosis to cell motility to signal transduction. In essence, the intact structure of the cytoskeleton and organelles constitutes the foundation of cell life, especially in the development of a variety of resistances. Among these organelles and cytoskeletal structures, the centrosome, microtubules, mitochondrion, and nuclear envelope are most important.
The centrosome, a central body (or the major microtubule organizing center (MTOC) of the cell, is composed of two centrioles surrounded by the so-called pericentriolar material (PCM), which consists of a complex thin filament network and two sets of appendages (Paintrand, M. (1992)
J Struct Biol
108:107-128). The centrosome, a thixotropic blob, is believed to play a key role in the temporal and spatial distribution of the interphasic and mitotic microtubule network and is regarded as a major determinant of the overall organization of the cytoplasm and of the fidelity of cell division (Hsu, L. C. and White, R. L. (1998)
Proc Natl Acad Sci USA
27; 95(22): 12983-8). Cytoplasmic organization, cell polarity and the equal partition of chromosomes into daughter cells at the time of cell division, once and only once in each cell cycle, are all ensured through the actions of tightly regulated centrosomal function (Tanaka, T., et al., (1999)
Cancer Res
59(9): 2041-4). Centrosome association occurs throughout the mammalian cell cycle, including all stages of mitosis, and determines the number, polarity, and organization of interphase and mitotic microtubules (Tanaka, T., et al., (1999)
Cancer Res
59(9): 2041-4; Pihan, G. A., et al., (1998)
Cancer Res
58(17): 3974-85). The main function of the centrosome is the nucleation of microtubules and the formation of bipolar spindles (Tanaka, T., et al., (1999)
Cancer Res
58(17): 3974-85). Centrosomes and their associated microtubules direct events during mitosis and control the organization of animal cell structures and movement during interphase. The microtubule nucleating ability of centrosomes of tissue sections retain even after several years of storage as frozen tissue blocks (Salisbury, J. L., et al., (1999)
J Histochem Cytochem
47(10):1265-74).
Malignant tumors generally display abnormal centrosome profiles, characterized by an increase in size and number of centrosomes, by their irregular distribution, abnormal structure, aberrant protein phosphorylation, and by increased microtubule nucleating capacity in comparison to centrosomes of normal tissues (Lingle, W. L. et al., (1998)
Proc Natl Acad Sci USA
95(6): 2950-5; Sato. N., et al., (1999)
Clin Cancer Res
5(5):963-70; Pihan, G. A. et al., (1998)
Cancer Res
58(17):3974-85; Carroll, P. E., et al., (1999)
Oncogene
18(11): 1935-44; Xu, X., et al., (1999)
Mol Cell
3(3):389-95; Brinkley, B. R., et al., (1998)
Cell Motil Cytoskeleton
41(4):281-8; Doxsey, S. (1998)
Nat Genet
20(2):104-6; Kuo, K. K., et al., (2000)
Hepatology
31(1):59-64). Among the abnormalities, centrosome hyperamplification is found to be more frequent in a variety of tumor types (Carroll, P. E., et al., (1999)
Oncogene
18;18(11):1935-44; Hinchcliffe, E. H., et al., (1999)
Science
283(5403):851-4; Xu, X., et al., (1999)
Mol Cell
3(3):389-95; Weber, R. G., et al., (1998)
Cytogenet Cell Genet
83:266-269). Although the precise mechanisms by which the centrosomes are (up) regulated during cell cycle are largely unknown, the over-expression of centrosomal kinases or the lack of tumor suppressor genes are observed universally in malignant tumors (Carroll, P. E., et al., (1999)
Oncogene
18;18(11):1935-44; Mussman, J. G., et al., (2000)
Oncogene
23;19(13):1635-46; Zhou, H., et al., (1998)
Nat Genet
20(2): 189-93).
Except for the known key proteins, such as SKP1p, cyclin-dependent kinase 2-cyclin E (Cdk2-E) (Hinchcliffe, E. H., et al., (1999)
Science
283(5403): 851-4), kendrin (Flory, M. R., et al., (2000)
Proc Natl Acad Sci USA
23;97(11):5919-23), protein kinase C-theta (Passalacqua, M., et al., (1999)
Biochem J
337(Pt 1): 113-8), and EB1 protein, a variety of new cell cycle-regulated kinases or tumor suppressor genes are found to be located in or to be core components of the centrosome. They include Nek2 (Fry, A. M., et al., (1999)
J Biol Chem
274(23): 1304-10), protein kinase A type II isozymes (Keryer, G., et al., (1999)
Exp Cell Res
249(1):131-146), heat shock Cognate 70 (HSC70) (Bakkenist, C. J., et al., (1999)
Cancer Res
59(17):4219-21), PH33 (Nakadai, T., et al., (1999)
J Cell Sci
112 (Pt9):1353-64), AIKs (Kimura, M., et al., (1999)
J Biol Chem
274(11)7334-40), human SCF(SKP2) subunit p19(SKP1) (Gstaiger, M., et al., (1999)
Exp Cell Res
247(2)554-62), STK15/BTAK (Zhou, H., et al., (1998)
Nat Genet
20(2): 189-93), C-Nap1 (Fry, A. M., et al., (1998)
J Cell Biol
274(23): 1304-10), Tau-like proteins (Cross, D., et al., (1996)
Exp Cell Res
229(2):378-87), cyclin E (Carroll, P. E., et al., (1999; Mussman, J. G., et al., (2000)
Oncogene
23;19(13):1635-46), retinoblastoma protein pRB and BRCA1 (Hsu, L. C., et al., (1998)
Proc Natl Acad Sci USA
95(22):12983-8; Carroll, P. E., et al., (1999)
Oncogene
18;18(11):1935-44). These proteins are required in the initiation of DNA replication and mitotic progression (Gstaiger, M., et al., (1999)
Exp Cell Res
15;247(2):554-62).
As with most biological processes and particularly with the processes of cell cycle control and signal transduction, the story is more complicated than appears at first sight. It is likely that the proteins or kinases identified to be associated with centrosome dysfunction are only the couple of many in a complex pathway (or parallel pathway) that controls centrosome assembly and function. Support for this idea comes from other new molecules that were reported lately. For example, BTAK/AIK1 (Tanaka, T., et al., (1999)
Cancer Res
59(9): 2041-4), AIK3 (Kimura, M., et al., (1999)
J Biol Chem
274(11):7334-40), Mdm2 (Carroll, P. E. et al., (1999)
Oncongene
18;18(11):1935-44) and STK15/BTAK (Zhou, H., et al., (1998)
Nat Genet
20: 189-193) are reported to be associated with centrosome dysfunction. The changes such as the loss of p53 tumor suppressor protein and/or the overexpression of these centrosome kinases may cause abnormal centrosome function, abnormal spindle for
Nguyen Dave T.
Nguyen Quang
Sheridan & Ross P.C.
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