Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-06
2004-01-13
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06677370
ABSTRACT:
BACKGROUND OF THE INVENTION
Of great importance to man is the control of pathological cellular proliferation. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling cellular proliferation, new methods and compositions are needed.
In searching for new biologically active compounds, it has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activity of great diversity. For example, the diterpene commonly known as taxol, isolated from several species of yew trees, is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin (Fuchs, D. A., R. K. Johnson (1978)
Cancer Treat. Rep.
62:1219-1222; Schiff, P. B., J. Fant, S. B. Horwitz (1979)
Nature
(London) 22:665-667). Taxol is also known to have antitumor activity and has undergone a number of clinical trials which have shown it to be effective in the treatment of a wide range of cancers (Rowinski, E. K., R. C. Donehower (1995)
N. Engl. J. Med.
332:1004-1014). See also, e.g., U.S. Pat. Nos. 5,157,049; 4,960,790; and 4,206,221.
Marine sponges have also proven to be a source of biologically active chemical molecules. A number of publications disclose organic compounds derived from marine sponges including Scheuer, P. J. (ed.)
Marine Natural Products, Chemical and Biological Perspectives
, Academic Press, New York, 1978-1983, Vol. I-V; Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata (1985)
J. Am. Chem. Soc.
107:4796-4798; Minale, L. et al. (1976)
Fortschr. Chem. org. Naturst.
33:1-72; Faulkner, D. J. (1998)
Natural Products Reports
15:113-158; Gunasekera, S. P., M. Gunasekera, R. E. Longley and G. K. Schulte (1990)
J. Org. Chem.,
55:4912-4915.
A prime target for the discovery and design of novel therapeutic agents against cancer is the mitotic apparatus of the cell and more specifically, microtubule assembly and its function (Wilson, L. (1975) “Microtubules as drug receptors: pharmacological properties of microtubule protein”
Ann. N.Y. Acad. Sci.
253:213-231). Ancillary functions of microtubules, including intracellular transport, signal transduction and the maintenance of cellular shape and motility are important factors which contribute to the overall growth of tumor cells and resulting metastases (Dustin, P. (1980)
Sci. Am.
243:66-76). Taxol is a microtubule interactive agent whose mechanism of action includes the premature polymerization of tubulin, resulting in hyperstable microtubule formation, blockage of cellular proliferation in the G
2
/M phase of the cell cycle, mitotic spindle disorganization and cell death. Additional compounds, which are chemically unrelated to Taxol, are rapidly coming onto the scene which share a similar mechanism of action with Taxol and are the subject of intense research into their potential as novel antitumor agents. These include the epothilones A and B, macrolides isolated from a myxobacterium,
Sorangium cellulosum
(Bollag, D. M., P. A. McQueney, J. Zhu et al. (1995)
Cancer Res.
55:2325-2333); eleutherobin, obtained from a marine soft coral (Lindel, T., P. R. Jensen, W. Fenical et al. (1997)
J Am. Chem. Soc.
119:8744-8745); laulimalide, isolated from a marine sponge (Mooberry, S. L., G. Tien, A. H. Hernandez et al. (1999)
Cancer Res.
59:653-660); and discodermolide isolated from a marine sponge (Gunasekera, S. P., M. Gunasekera, R. E. Longley (1990)
J. Org. Chem.
55:4912-4915 and Ter Haar E., R. J. Kowalski, E.Hamel, et. al. (1996)
Biochemistry
3:243-250). All of these compounds induce microtubule hyperstabilizing activity and are cytotoxic in vitro to tumor cells in the nanomolar range.
The success of chemotherapy for the treatment of various cancers can be substantially negated though cellular mechanisms which have evolved to enable neoplastic cells to subvert the cytotoxic effects of the drug. Some cells have developed mechanisms, which confer resistance to a number of structurally unrelated drugs. This multi-drug resistance (or MDR) phenomenon may arise through a number of different mechanisms. One of these involves the ability of a cell to reduce intracellular concentrations of a given drug through efflux from cytoplasm through and out the cell membrane by a series of unique ATP-dependent transporter proteins called-P-glycoproteins (Pgp) (Casazza, A. M. and C. R. Fairchild (1996)
Cancer Treat Res.
87:149-171). The surface membrane, 170 kDa Pgp, is encoded by the mdr-1 gene and appears to require substrate binding before transport begins. A wide range of compounds including a number of structurally unrelated chemotherapeutic agents (adriamycin, vinblastine, colchicine, etoposide and Taxol), are capable of being transported by Pgp and render the cell resistant to the cytotoxic effects of these compounds. While many normal cell types possess Pgp, in general, tumor cell lines, which possess high levels of mRNA specific for Pgp, also exhibit overexpression of membrane Pgp and demonstrate resistance to various drugs. This intrinsic resistance can be increased multifold by incubation of cells with stepwise increasing doses of a particular drug over a period of several months. This can be further facilitated by the addition of the MDR reversal agent, verapamil (Casazza, A. M. and C. R. Fairchild (1996) supra) in combination with the particular drug. Drug resistant cell lines produced in this fashion exhibit resistance to drug cytotoxicity from 20 to 500 fold, compared to parental cell lines.
An additional target for cancer drug discovery is a high molecular weight membrane protein associated with multi-drug resistance properties of certain tumor cells known as the multidrug resistance-associated protein (MRP). MRP is a 190 kD membrane-bound glycoprotein (Bellamy, W. T. (1996),
Annu. Rev. Pharmacol. Toxicol.,
36: 161-183) which belongs to the same family of proteins as the p-glycoprotein pump P-gp (Broxterman, H. J., Giaccone, G., and Lankelma, J. (1995),
Current Opinion in Oncology,
7:532-540) but shares less than 15% homology of amino acids with P-gp (Komorov, P. G., Shtil, A. A., Holian, O., Tee, L., Buckingham, L., Mechetner, E. B., Roninson, I. B., and Coon, J. S. (1998),
Oncology Research,
10: 185-192). MRP has been found to occur naturally in a number of normal tissues, including liver, adrenal, testis, and peripheral blood mononuclear cells (Krishan, A., Fitz, C. M., and Andritsch, I. (1997),
Cytometry
29: 279-285). MRP has also been identified in tissues of the lung, kidney, colon, thyroid, urinary bladder, stomach, spleen (Sugawara, I. (1998)
The Cancer Journal
8(2)) and skeletal muscle (Kruh, G. D., Gaughan, K. T., Godwin, A., and Chan, A. (1995)
Journal of the National Cancer Institute
87(16): 1256-1258). High levels of MRP have been implicated in multidrug resistance (MDR) in cancers of the lung and pancreas (Miller, D. W., Fontain, M., Kolar, C., and Lawson, T. (1996)
Cancer Letters
107: 301-306), and in neuroblastomas, leukemias and cancer of the thyroid (Kruh, G. D., Gaughan, K. T., Godwin, A., and Chan, A. (1995)
Journal of the National Cancer Institute
87(16): 1256-1258), as well as bladder, ovarian and breast cancers (Barrand, M., Bagrij, T., and Neo, S. (1997)
General Pharmacology
28(5): 639-645). MRP-mediated MDR involves some of the same classes of compounds as those which are mediated by P-gp, including vinca alkaloids, epipodophyllotoxins, anthracyclins and actinomycin D (Barrand, M., Bagrij, T., and Neo, S. (1997)
General Pharmacology
28(5): 639-645). However, the substrate specificity has been demonstrated to differ from that of P-gp (Komorov, P. G., Shtil, A. A., Holian, O., Tee, L., Buckingham, L., Mechetner, E. B., Roninson, I. B., and Coon, J. S. (1998)
Oncology Research
10: 185-192). Drugs which would inhibit or which are not substrates for the MDR pump would, therefore, be useful as chemotherapeutic agents.
Some cancer cell lines, which have been induced to develop resistance to one type of microtubul
Cummins Jennifer L.
Isbrucker Richard A.
Longley Ross E.
Pomponi Shirley A.
Wright Amy E.
Goldberg Jerome D.
Harbor Branch Oceanographic Institution Inc.
Saliwanchik Lloyd & Saliwanchik
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