Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-04-06
2003-04-01
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S536000, C514S824000, C514S946000, C424S572000, C424S574000, C424S450000, C424S522000, C424S523000, C424S537000
Reexamination Certificate
active
06541519
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of 12-methyltetradecanoic acid which can kill tumor cells by inducing cell apoptosis related to inhibition of 5-lipoxygenase metabolites and 12-lipoxygenase metabolites or their related activities in various mammalian cancers. In particular, the present invention relates to the methods using 12-methyltetradecanoic acid (12-MTA) alone or in combination with other anti-cancer compounds that are targeted to inhibit cancer progression in a mammal by inducing tumor cell apoptosis.
DESCRIPTION OF RELATED ART
Normal tissue homeostasis is maintained by balanced cell proliferation and cell death, which occurs most frequently in the form of apoptosis or programmed cell death. Tumor cells differ significantly from their normal counterparts with respect to the control of cell growth and proliferation. Most tumor cells demonstrate a self-dominant growth pattern either due to their abnormal response to environmental stimuli (hormones, growth factors, cytokines, etc.) or due to an autonomous nature of growth (i.e., autocrine stimulation). Tumor cells also demonstrate abnormal apoptotic responses. Many factors have been shown to regulate apoptosis, including (i) growth factors and growth factor receptors such as retinoid acid, interleukin-3, stem cell factor, interferon-&ggr;, erythropoietin, NGF/NGF (nerve growth factor) receptor, TNF-&agr;/Fas (tumor necrosis factor-&agr;), steel factor/Kit receptor, TGF-&bgr;/TGF (transforming growth factor) receptor, insulin, EGF/EGFR (epidermal growth factor), IGF-1/IGF (insulin-like growth factor) receptor, and PDGF/PDGF (platelet-derived growth factor receptor); (ii) intracellular signal transducers such as protein kinase C, PI-3 (phosphoinositol-3) kinase, Ras and GTPase, PLC-&ggr; (phospholipase C-&ggr;), tyrosine kinases and protein phosphatases, lipid signaling molecules such as eicosanoids, sphingosine, ceramide, and Ca
2+
; (iii) cell cycle regulators exemplified by Cdc-2 and E2F-1; (iv) reactive oxygen species or other free radicals; (v) extracellular matrix regulators/cell adhesion molecules (extracellular matrix proteins such as fibronectin and transmembrane integrin receptors); and (vi) specific endonucleases such as Ca
2+
- and Mg
2+
-dependent DNase and cytoplasmic proteases typified by ICE (interleukin 1&bgr;-converting enzyme) family. Many of these regulators have been associated with various human malignancies and apoptosis. For example, studies on human tumors including neuroblastoma, glioma, lymphoma, breast carcinoma, colorectal adenocarcinoma, melanoma and gastrointestinal malignancies have demonstrated an overall positive correlation between increased expression of Bcl-2 (or Bcl-X
L
) or decreased expression of Bax and uncontrolled tumor cell growth, and, in some cases, with tumor progression and a poor prognosis of cancer patients. Another example is p53, a phosphoprotein known to modulate gene transcription, police cell cycle checkpoints, control DNA replication and repair, and maintain genomic stability. Wild type p53 also positively regulates apoptosis. p53 gene mutations have been linked to attenuated apoptosis in multiple cancers represented by Wilms' tumor, colon cancer, cervical carcinoma and breast cancer. Since apoptosis plays a critical role in multiple steps (transformation, progression and survival of metastases) of tumorigenesis as well as in tumor cells' response to chemotherapeutic drugs or radiation therapy, many chemoprevention and therapeutic regimens attempting to manipulate apoptotic process have been proposed to aid in the clinical treatment of cancer patients (Fesus, L., et al., J. Cell Biochem. 22:151-161 (1995); Lotan, R., J. Natl. Cancer Inst. 87:1655-1657 (1995); van Zandwijk, N., J. Cell Biochem. 22:24-32 (1995)).
Arachidonic acid (AA) is an essential component of the cell membrane phospholipids. AA released through the action of phospholipase A
2
is metabolized via three major biochemical pathways: (i) the cyclooxygenase (COX) pathway leading to the generation of prostaglandins, prostacyclin, and thromboxane; (ii) the lipoxygenase (LOX) pathway giving rise to various hydroperoxy (HPETEs) and hydroxy (HETEs) fatty acids as well as leukotrienes; and (iii) the P450-dependent epoxygenase pathway generating EETs. Mammalian LOX display varying degrees of substrate specificity for insertion of molecular oxygen into arachidonic acid at carbon positions 5, 12, and 15. The enzymes, based on the abundance of the majority products have thus been termed 5, 12, and 15 lipoxygenases, respectively. The 12-LOX catalyzes the transformation of AA into 12(S)-hydroperoxyeicosatetraenoic acid (12-HPETE) and its 12(S)-hydroxy derivatives, i.e., 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). Three types of mammalian 12-LOX enzymes have so far been reported. The first is human platelet-type 12-lipoxygenase expressed normally in platelets, HEL (human erythroleukemia) cells, and umbilical vein endothelial cells (Funk, C. D., et al., Proc. Natl. Acad. Sci. 87:5638-5642 (1990); Funk, C. D., et al., Proc. Natl. Acad. Sci. 89:3962-3966 (1992)). Platelet-type 12-LOX metabolizes only AA (but not C-18 fatty acids such as linoleic acid) to form exclusively 12(S)-HETE (Funk, C. D., et al., Proc. Natl. Acad. Sci. 87:5638-5642 (1990) Marnett, L. J., et al., Adv. Prostaglandin Thromboxane Leukotriene Res. 21:895-900 (1990)). The second is porcine leukocyte-type 12-LOX which metabolizes both AA and linoleic acid thus generating 12(S)-HETE as well as small amounts of 15(S)-HETE (Hada, T., et al., Biochim. Biophys. Acta 1083-1087 (1991)). The third type of 12-LOX (sometimes termed epithelial 12-lipoxygenase) has been isolated from bovine tracheal epithelial cells (De Marzo, N., et al., J. Physiol. 262:L198-L207 (1992)); rat brain (Watanabe, S., et al., Eur. J. Biochem. 212:605-612 (1993)), and murine macrophages (Freier-Moar, J., et al., Biochim. Biophys. Acta., 1254:112-116 (1995)), which shares more homology with 15-LOX and leukocyte-type 12-LOX than with platelet-type 12-LOX. This type of 12-LOX, like reticulocyte 15-LOX and leukocyte-type 12-LOX, catalyzes the formation of both 12(S)-HETE and 15(S)-HETE.
The role of AA metabolites in regulating cell proliferation has been recognized for more than two decades. Numerous studies have demonstrated a strong positive correlation between growth factor—(EGF, insulin, PDGF, etc.) promoted cell proliferation and generation of various COX products, primarily prostaglandins (Skouteris, G. G., et al., Biochem. Biophys. Res. Commun., 178:1240-1246 (1991); Nolan, R. D., et al., Mol. Pharmacol. 33:650-656 (1988); Smith, D. L., et al., Prostaglandins Leukotrienes Med., 16:1-10 (1984)). Similarly, it has been found that various eicosanoids derived from LOX pathways as well as epoxygenase pathways of AA metabolism play an essential role in mediating the growth factor-stimulated normal cell and tumor cell growth. Examples include 15-HETE as a mitogenic regulator of T-lymphocyte (Bailey, J. M., et al., Cell Immunol., 67:112-120 (1982)), 12-HETE and LTB.sub.4 as growth stimulators of epidermal cells (Chan, C., et al., J. Invest. Dermatol., 85:333-334 (1985)), 12-HETE stimulation of keratinocyte DNA synthesis (Kragballe, K., et al., Arch. Dermatol. Res., 278:449-453 (1986)), 15-/12-HETEs as mediators of insulin and EGF-stimulated mammary epithelial cell proliferation (Bandyopadhyay, G. K., et al., J. Biol. Chem., 263:7567-7573 (1988)) and as synergistic effectors of bFGF—(basic fibroblast growth factor) and PDGF-regulated growth of vascular endothelial cells and smooth muscle cells (Yamaja Setty, B. N., et al., J. Biol. Chem., 262:17613-17622 (1987); Dethlefsen, S. M., et al., Exp. Cell Res., 212:262-273 (1994)), 12(S)-HETE as a regulator of EGF- and insulin-stimulated DNA synthesis and protooncogene expression in lens epithelial cells (Lysz, T. W., et al., Cell Growth & Differ., 5:1069-1076 (1994)) and as the mediator of angiotensin II-induced aldosterone synthesis in adrenal glomerulosa cells (Nadler, R. D., et al., J. C
Collin Peter D.
Newman Robert
Yang Peiying
Coastside Bio Resources
Krass Frederick
Ostrup Clinton
Rothwell Figg Ernst & Manbeck
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