Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2006-01-03
2006-01-03
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S450000, C424S009200, C424S138100
Reexamination Certificate
active
06982252
ABSTRACT:
The present invention relates to methods and compositions for inhibiting cell survival and/or promoting cell death following exposure to cytotoxic agents and stress such as radiation or chemotherapy exposure through inhibition of V-H+-ATPase. In particular, the formation and/or acidification of acidic vesicular organelles (AVOs) may be prevented or decreased by inhibiting the activity of vacuolar proton ATPase (“V-H+-ATPase”). The methods and compositions of the invention are based on the observation that (i) following irradiation surviving cancer cells accumulate AVOs and that their acidification is mediated by V-H+-ATPase; (ii) surviving colonies of cells contain higher levels of AVOs; and (iii) inhibition of V-H+-ATPase decreases the clonogenic survival of cells irradiated or exposed to chemotherapeutic agents. These observations led to the conclusion that V-H+-ATPase activity and AVO function serve to protect cells from radiation and chemotherapy damage. In addition, agents such as bFGF, TNF-α, PMA, rapamycin and tamoxifen were shown to be inducers of acidic organelle formation. Therefore signal transduction pathways mediated by these agents provide targets for drug screening assays designed to identify inhibitors of V-H+-ATPase activity and AVO formation/acidification. The present invention may be used to treat cancer subjects through sensitization of neoplastic cells to the toxic effects of radiation and chemotherapy.
REFERENCES:
patent: WO 90/11364 (1990-10-01), None
Okahashi et al., “Specific Inhibitors of Vacuolar H+ -ATPase Trigger Apoptotic Cell Death of Osteoclasts”, Journal of Bone and Mineral Research, vol. 12, No. 7, 1997.
Drose et al., “Review—Bafilomycins and Concanamycins as Inhibitors of V-ATPases and P-ATPases”, The Journal of Experimental Biology, 200, pp. 1-8, 1997.
Altan et al., “Defective Acidfication in Human Breast Tumor Cells and Implications for Chemotherapy”, J. Exp. Med., vol. 187:10, pp. 1583-1598 (1998).
Boyd et al., “Discovery of Novel Antitumor Benzolacetone Enamide Class That Selectively Inhibits Mammalian Vacuolor-Type (H+)-ATPases”, Journal of Pharmacology and Experimental Therapeutics, 297, pp. 114-120 (2001).
Altan et al., Defective Acidfication in Human Breast Tumor Cells and implications for Chemotherapy, J. Exp. Med., vol. 187:10, pp. 1583-1598 (1998) Bechimol et al., Functional Expression of Vacuolar-type H+-ATPase in the plasma membrane and intr.
Bechimol et al.,Functional Expression of a Vacuolar-type H+-ATPase in the plasma membrane and intracellular vacuoles of Trypanosoma cruzi, Biochem.J., V:332, p. 695-702 (1998).
Teicher et al. Signal Transduction Inhibitors As Modifiers Of Radiation Therapy In Human Prostate Carcinoma Xenografts, Radiation Oncology Investigations, 4/5, pp. 221-230 (1986).
Furuya et al., The Role Of Calcium, Ph, And Cell Proliferation in The Programmed (Apoptotic) Death Of Androgen-Independent Prostatic Cancer Cells Induced By Thapsigargin, Cancer Res., 54/23, pp. 6167-6175 (1994).
Boyd MR et al., 2001, “Discovery of a novel antitumor benzolactone enamide class that selectively inhibits mammalian vacuolar-type (H+)-atpases”J. Pharmacology and Experimental Therapeutics 297(1):114-120.
Gingras AC et al., 2001, “Regulation of translation initiation by FRAP/mTOR”Genes and Development 15:807-826.
Murakami T et al., 2001, “Elevated expression of vacuolar proton pump gene and cellular pH in cisplatin resistance”Int. J. Cancer 93:869-874.
Paglin S et al., 2001, “A novel response of cancer cells to radiation involves autophagy an formation of acidic vesicles”Cancer Res. 61:439-444.
Hollister TC et al., Nov. 4-8, 2001, “Vacuolar-proton-ATPase is involved in the response of cancer cells to ionizing radiation and is a new target for radiosensitization”,43rd Annual American Society for Therapeutic Radiology and Oncology(ASTRO).
Xu T et al., 2001, “Microtubules are involved in glucose-dependent dissociation of the yeast vacuolar [H+]-ATPase in vivo”,J Biol Chem. 276(27):24855-24861.
Gilles F et al., 2000, “A. MUCI dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphoma”Blood 95(9):2930-2936.
Kim J et al., 2000, “Autophagy, cytoplasm-to-vacuole targeting pathway, and pexophagy in yeast and mammalian cells”,Ann. Rev. Biochem. 69:303-342.
Petiot A et al., 2000, “Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells”J. Biol. Chem. 275(2):992-998.
Finkel E, 1999, “Does Cancer therapy trigger cell suicide?”Science 286(5448):2256-2258.
Reed J, 1999, “Dysregulation of apoptosis in cancer”J Clin Oncol. 17(9):2941-2953.
Forgac M, 1999, “Structure and properties of the vacuolar (H+) ATPases”J. Biol. Chem. 274(19):12951-12954.
Brown JM et al., 1999, “Apoptosis, p53, and tumor cell sensitivity to anticancer agents”Cancer Research 59:1391-1399.
Thangara M et al., 1999, “Interdependent regulation of intracellular acidification and SHP-1 in apoptosis”Cancer Research 59:1649-1654.
Gagliardi S et al., 1999, “Chemistry and structure activity relationships of bafilomycin Al, a potent and selective inhibitor of the vacuolar H+-ATPase”Current Medicinal Chemistry 6(12):1197-1212.
Mizushima N et al., 1998, “A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy”J Biol Chem. 273(51):33889-33892.
Mizushima N et al., 1998, “A protein conjugation system essential for autophagy”Nature 395(6700):395-398.
Altan N et al., 1998, “Defective acidification in human breast tumor cells and implications for chemotherapy”J Exp Med. 187(10):1583-1598.
Jänicke RU et al., 1998, “Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis”J. Biol. Chem. 273(16):9357-9360.
Noda T et al., 1998, “Tor, a Phosphatidylinositol Kinase Homologue, Controls Autophagy in Yeast”J. Biol. Chem. 273(7):3963-3966.
Hammond EM et al., 1998, “Homology between a human apoptosis specific protein and the product of APG5, a gene involved in autophagy”FEBS Lett. 425:391-395.
Ohta T et al., 1998, “Bafilomycin A1, induces apoptosis in the human pancreatic cancer cell line CAPAN-1”J. Pathology 185:324-340.
Blommaart EFC et al., 1997, “Autophagic proteolysis: control and specificity”Biochem. Journal 29:365-385.
Dröse S et al., 1997, “Bafilomycin and concanamycins as inhibitors of V-ATPases and P-ATPases”J. Exp. Biology 200:1-8.
Jia L et al., 1997, “Inhibition of autophagy abrogates tumour necrosis factor a induced apoptosis in human T-lymphoblastic leukaemic cells”British Journal of Haematology 98:673-685.
Keeling DJ et al., 1997, “Vacuolar (H+)-ATPases. Targets for drug discovery?”Ann. N.Y. Acad Sciences 834:600-608.
Paglin S et al., 1997, “Radiation-induced micronuclei formation in human breast cancer cells: Dependence on serum and cell cycle distribution”Biochem and Biophys Research Communications 237(RC977117):678-684.
Bristow RG et al., 1996, “The p53 gene as a modifier of intrinsic radiosensitivity: implications for radiotherapy”Radiotherapy and Oncology 40:197-223.
Bursch W et al, 1996, “Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy”Carcinogenesis 17:1595-1607.
Verheij M et al., 1996, “Requirement for ceramide initiated SAPK/JNK signaling in stress-induced apoptosis”Nature 380:75-79.
Bose R et al., 1995, “Cermide synthase mediates Daunorubicin-induced apoptosis: An alternative mechanism for generating death signals”Cell. 82:405-414.
Boyd MR et al.,
Delohery Thomas
Hollister Timothy
Paglin Shoshana
Yahalom Joachim
Edwards & Angell LLP
Leahy Amy M.
McIntosh III Traviss C.
Memorial Sloan-Kettering Cancer Center
Wilson James O.
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