US 20070185.069A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0185069 A1 Plum et al. (43) Pub. Date: Aug. 9, 2007

(54) ANTI-ANGIOGENIC ACTIVITY OF Related U.S. Application Data 2-METHOXYESTRADIOL IN COMBINATION WITH ANT-CANCERAGENTS (60) Provisional application No. 60/736.220, filed on Nov. 14, 2005. Provisional application No. 60/788,354, (76) Inventors: Stacy M. Plum, Arlington, VA (US); filed on Mar. 31, 2006. Steven J. Strawn, Arlington, VA (US); Publication Classification Theresa M. LaVallee, Rockville, MD (US); Carolyn F. Sidor, Chapel Hill, (51) Int. Cl. NC (US); William E. Fogler, A6II 3/56 (2006.01) Rockville, MD (US); Anthony M. (52) U.S. Cl...... 514/182: 514/506 Treston, Rockville, MD (US) (57) ABSTRACT The present invention relates generally to methods and Correspondence Address: compositions of treating disease characterized by abnormal KING & SPALDING LLP cell proliferation and/or abnormal or undesirable angiogen 118O PEACHTREE STREET esis by administering antiangiogenic agents in combination ATLANTA, GA 30309-3521 (US) with chemotherapeutic agents. More specifically, the present invention relates to a methods and compositions of treating diseases characterized by abnormal cell proliferation and/or (21) Appl. No.: 11/599,997 abnormal or undesirable angiogenesis by administering 2-methoxyestradiol, in combination with chemotherapeutic (22) Filed: Nov. 14, 2006 agents.

4000 8 Vehicle -0-2ME2 (300mg/kg via DW) 6- Wel (1.5 mg/kg b.i.w.; i.p.) O Wel (1.0 mg/kg b.i.W.; i.p.) E 3000 -e-Weia v552ME; (1.0) + 2ME2 o TIC g 2000 0.80 0.66

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2SOO g 2000 Vehicle Control E O 2ME2400mg/kg qd G)E 1500 A Temodar 42mg/kg (qdx5) V Tenodar 42mg/kg+ 1000 2ME2400mg/kg O E H 500

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Vehicle 2ME2 Temodar 2ME2 and Control 400 mg/kg 42 mg/kg Temodar p.o. c.d. p.o. c.d. x 5 Tumor Volume (mean + sc) 1505 - 287 1204 210 993 + 151 193+41 TIC 1.OO 0.80 0.66 0.13

US 2007/0185.069 A1 Aug. 9, 2007

ANT-ANGOGENIC ACTIVITY OF “sprout' off the parent blood vessel where the endothelial 2-METHOXYESTRADOL IN COMBINATION cells undergo mitosis and proliferate. The endothelial WITH ANT-CANCERAGENTS sprouts merge with each other to form capillary loops, creating a new blood vessel. CROSS-REFERENCE TO RELATED APPLICATIONS 0006 Persistent, unregulated angiogenesis occurs in many disease states, tumor metastases, and abnormal growth 0001. The present application claims the benefit of U.S. by endothelial cells. The diverse pathological disease states Provisional Patent Application Ser. No. 60/736.220, filed in which unregulated angiogenesis is present have been Nov. 14, 2005, and U.S. Provisional Patent Application Ser. grouped together as angiogenic-dependent or angiogenic No. 60/788,354, filed Mar. 31, 2006, which are incorporated associated diseases. herein by reference in their entirety. 0007. The hypothesis that tumor growth is angiogenesis FIELD OF THE INVENTION dependent was first proposed in 1971. (Folkman, New Eng. J Med., 285:1182-86 (1971)). In its simplest terms, this 0002 The present invention relates generally to compo hypothesis states: “Once tumor take has occurred, every sitions comprising anti-angiogenic agents in combination increase in tumor cell population must be preceded by an with anti-cancer agents and methods of use. More specifi increase in new capillaries converging on the tumor. Tumor cally, the present invention relates to methods and compo take is currently understood to indicate a prevascular phase sitions of administering 2-methoxyestradiol with anti-cancer of tumor growth in which a population of tumor cells agents. More particularly, the present invention relates to occupying a few cubic millimeters Volume, and not exceed methods of treating diseases characterized by abnormal cell ing a few million cells, can Survive on existing host proliferation and/or abnormal or undesirable angiogenesis microVessels. Expansion of tumor Volume beyond this phase by administering 2-methoxyestradiol in combination with requires the induction of new capillary blood vessels. For anti-cancer agents. example, pulmonary micrometastases in the early prevascu lar phase in mice would be undetectable except by high BACKGROUND OF THE INVENTION power microscopy on histological sections. 0003. The direct targeting of tumor cells by cytotoxic 0008 Examples of the indirect evidence which support agents has been the main therapeutic strategy against this concept include: advanced human malignant tumors. This strategy has achieved limited Success in curing most cancer types, often 0009 (1) The growth rate of tumors implanted in subcu only achieving temporary remission at the expense of nega taneous transparent chambers in mice is slow and linear tive systemic side effects. Several solid epithelial tumors are before neovascularization, and rapid and nearly exponential not sensitive to chemotherapy and there is an increasing after neovascularization. (Algire, et al., J. Nat. Cancer Inst., problem in the development of drug resistance in tumors that 6:73-85 (1945)). are initially responsive to chemotherapy (Braverman, Am. 0010 (2) Tumors grown in isolated perfused organs Intern. Med. (1993); 118:630-32 and Gasparini et al. The Breast (1993); 2:27-32). In addition, there is a growing where blood vessels do not proliferate are limited to 1-2 appreciation for the role the stroma, or non-tumor cells, play mm but expand rapidly to >1000 times this volume when in determining the growth, proliferation and metastasis of a they are transplanted to mice and become neovascularized. tumor. Angiogenesis, in particular, has been shown to play (Folkman, et al., Annals of Surgery, 164:491-502 (1966)). an important role in this regard. 0011 (3) Tumor growth in the avascular cornea proceeds 0004 Angiogenesis is the generation of new blood ves slowly and at a linear rate, but Switches to exponential sels into a tissue or organ. Under normal physiological growth after neovascularization. (Gimbrone, Jr., et al., J. conditions, humans and animals undergo angiogenesis only Nat. Cancer Inst., 52:421-27 (1974)). in very specific, restricted situations. For example, angio 0012 (4) Tumors suspended in the aqueous fluid of the genesis is normally observed in wound healing, fetal and anterior chamber of a rabbit eye remain viable, avascular, embryonal development, and formation of the corpus and limited in size to <1 mm . Once they are implanted on luteum, endometrium and placenta. the iris vascular bed, they become neovascularized and grow 0005 Angiogenesis is controlled through a highly regu rapidly, reaching 16,000 times their original volume within lated system of angiogenic stimulators and inhibitors. The 2 weeks. (Gimbrone, Jr., et al., J. Exp. Med., 136:261-76). control of angiogenesis has been found to be altered in 0013 (5) When tumors are implanted on a chick embryo certain disease states and, in many cases, pathological chorioallantoic membrane, they grow slowly during an damage associated with the diseases is related to uncon avascular phase of >72 hours, but do not exceed a mean trolled angiogenesis. Both controlled and uncontrolled diameter of 0.93 +0.29 mm. Rapid tumor expansion occurs angiogenesis are thought to proceed in a similar manner. within 24 hours after the onset of neovascularization, and by Endothelial cells and pericytes, surrounded by a basement day 7 these vascularized tumors reach a mean diameter of membrane, form capillary blood vessels. Angiogenesis 8.0+2.5 mm. (Knighton, British J. Cancer, 35:347-56 begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. (1977)). Endothelial cells, lining the lumen of blood vessels, then 0014 (6) Vascular casts of metastases in a rabbit liver protrude through the basement membrane. Angiogenic reveal heterogeneity in size of the metastases, but show a stimulants induce the endothelial cells to migrate through relatively uniform cut-off point for the size at which vascu the eroded basement membrane. The migrating cells form a larization is present. Tumors are generally avascular up to 1 US 2007/0185.069 A1 Aug. 9, 2007

mm in diameter, but are neovascularized beyond that diam 0025 Thus, it is clear that angiogenesis plays a major role eter. (Lien, et al., Surgery, 68:334-40 (1970)). in the metastasis of cancer. If this angiogenic activity could be repressed or eliminated, then the tumor, although present, 00.15 (7) In transgenic mice that develop carcinomas in would not grow. In the disease State, prevention of angio the beta cells of the pancreatic islets, pre-vascular hyper genesis could avert the damage caused by the invasion of the plastic islets are limited in size to <1 mm. At 6-7 weeks of new microvascular system. Therapies directed at control of age, 4-10% of the islets become neovascularized, and from the angiogenic processes could lead to the abrogation or these islets arise large vascularized tumors of more than 1000 times the volume of the pre-vascular islets. (Folkman, mitigation of these diseases. et al., Nature, 339:58-61 (1989)). 0026 Angiogenesis has been associated with a number of different types of cancer, including Solid tumors and blood 0016 (8) A specific antibody against VEGF (vascular borne tumors. Solid tumors with which angiogenesis has endothelial growth factor) reduces microVessel density and been associated include, but are not limited to, rhabdomyo causes “significant or dramatic’ inhibition of growth of three sarcomas, retinoblastoma, Ewing's sarcoma, neuroblas human tumors which rely on VEGF as their sole mediator of toma, and osteosarcoma. Angiogenesis is also associated angiogenesis (in nude mice). The antibody does not inhibit with blood-borne tumors, such as leukemias, any of various growth of the tumor cells in vitro. (Kim, et al., Nature, acute or chronic neoplastic diseases of the bone marrow in 362:841-44 (1993)). which unrestrained proliferation of white blood cells occurs, 0017 (9) Anti-bFGF monoclonal antibody causes 70% usually accompanied by anemia, impaired blood clotting, inhibition of growth of a mouse tumor which is dependent and enlargement of the lymph nodes, liver and spleen. It is upon secretion of bFGF as its only mediator of angiogenesis. believed that angiogenesis plays a role in the abnormalities The antibody does not inhibit growth of the tumor cells in in the bone marrow that give rise to leukemia tumors and vitro. (Hori, et al., Cancer Res., 51.6180-84 (1991)). multiple myeloma diseases. 0018 (10) Intraperitoneal injection of bFGF enhances 0027. One of the most frequent angiogenic diseases of growth of a primary tumor and its metastases by stimulating childhood is the hemangioma. A hemangioma is a tumor growth of capillary endothelial cells in the tumor. The tumor composed of newly formed blood vessels. In most cases the cells themselves lack receptors for bFGF, and bFGF is not a tumors are benign and regress without intervention. In more mitogen for the tumor cells in vitro. (Gross, et al., Proc. Am. severe cases, the tumors progress to large cavernous and Assoc. Cancer Res., 31:79 (1990)). infiltrative forms and create clinical complications. Systemic forms of hemangiomas, hemangiomatoses, have a high 0.019 (11) A specific angiogenesis inhibitor (AGM-1470) mortality rate. Therapy-resistant hemangiomas exist that inhibits tumor growth and metastases in Vivo, but is much cannot be treated with therapeutics currently in use. less active in inhibiting tumor cell proliferation in vitro. It inhibits vascular endothelial cell proliferation half-maxi 0028 Angiogenesis is also responsible for damage found mally at 4 logs lower concentration than it inhibits tumor cell in heredity diseases such as Osler-Weber-Rendu disease, or proliferation. (Ingber, et al., Nature, 48:555-57 (1990)). heredity hemorrhagic telangiectasia. This is an inherited There is also indirect clinical evidence that tumor growth is disease characterized by multiple Small angiomas, tumors of angiogenesis dependent. blood or lymph vessels. The angiomas are found in the skin and mucous membranes, often accompanied by epitaxis 0020 (12) Human retinoblastomas that are metastatic to (nose bleeds) or gastrointestinal bleeding and sometimes the vitreous develop into avascular spheroids that are with pulmonary or hepatitic arteriovenous fistula. restricted to less than 1 mm despite the fact that they are viable and incorporate H-thymidine (when removed from 0029 Several compounds have been used to inhibit an enucleated eye and analyzed in vitro). angiogenesis. One such compound is 2-methoxyestradiol (2ME2). 2ME2 is a naturally occurring derivative of estra 0021 (13) Carcinoma of the ovary metastasizes to the diol and has been shown to be an orally active, well peritoneal membrane as tiny avascular white seeds (1-3 tolerated Small molecule that possess anti-tumor and anti mm). These implants rarely grow larger until one or more angiogenic activity (Pribluda et al. Cancer Metastasis Rev. of them become neovascularized. 19(1-2): 173-9 (2000)). 2ME2 has low affinity for estrogen 0022 (14) Intensity of neovascularization in breast can receptors, C. and B, and its antiproliferative activity is cer (Weidner, et al., New Eng. J. Med., 324:1-8 (1991); independent of the interaction with those receptors Weidner, et al., J. Nat. Cancer Inst., 84:1875-87 (1992)) and (LaVallee et al. Cancer Research 62(13):3691-7 (2002)). in prostate cancer (Weidner, et al., Am. J. Pathol., Several mechanisms have been proposed for 2ME2 activity, 143(2):401-09 (1993)) correlates highly with risk of future including those mediated by its ability to bind to the colchi metastasis. cines binding site of tubulin (Cushman et al., 1995; D'Amato et al., 1994), destabilization of microtubules and 0023 (15) Metastasis from human cutaneous melanoma inhibition of HIF-1C. nuclear accumulation (Mabeesh et al., is rare prior to neovascularization. The onset of neovascu 2003), induction of the extrinsic apoptotic pathway through larization leads to increased thickness of the lesion and an upregulation of Death Receptor 5 (LaVallee et al. Cancer increased risk of metastasis. (Srivastava, et al., Am. J. Research 63(2): 469-75 (2003)) and induction of the intrin Pathol., 133:419-23 (1988)). sic apoptotic pathway, potentially through the inhibition of Superoxide dismutase enzymatic activity (Huang et al. 0024 (16) In bladder cancer, the urinary level of an angiogenic protein, bFGF, is a more sensitive indicator of Trends Cell Biology 11 (8):343-8, (2001)). status and extent of disease than is cytology. (Nguyen, et al., 0030) 2ME2 has been shown to inhibit multiple mecha J. Nat. Cancer Inst., 85:241-42 (1993)). nisms of progression in myeloma cells in vitro and in vivo US 2007/0185.069 A1 Aug. 9, 2007

and the ability to evade resistance mechanisms implicated in clinical resistance to conventional therapies (Dingli et al. Clinical Cancer Research, 8:3984-3954 (2002)). Inhibition of diverse tumor types including osteosarcoma (Maran et al. Bone (2002); 30:393-398 and Golebiewska et al. Act Bio chim Pol (2002): 49:59-65), Ewing sarcoma (Djavaheri Mergny et al. Oncogene (2003); 22:2558-67), pancreatic adenoma (Qanungo et al. Oncogene (2002); 21:4149-57 and Ryschich et al Pancreas (2003); 26:166-172), colon HO (Carothers et al. Cancer Lett (2002); 187:77-86), medullo blastoma (Kumar et al. Carcinogenesis (2003); 24:209-216), and melanoma (Ghosh et al. Melanoma Research (2003); wherein R is selected from —OCH —OCHCH, —CH, 13:119-127) has also been demonstrated with 2ME2. —CHCH, CCCH, -CHCH-CH, or CH, CHCH 0.031) Anti-cancer therapy suffers from a number of limi simultaneously with one or more anti-cancer agents. tations including, development of drug resistance, unwanted systemic side effects and limited efficacy against metastases. 0034. In another embodiment, the present invention com The use of combination therapy in order to overcome drug prises a method of treating diseases or conditions associated resistance, limit the unwanted side effects of certain anti with or dependent on abnormal, undesirable and/or exces cancer agents, and improve their overall efficacy have been sive angiogenesis and/or undesirable cell proliferation in a explored using various anti-cancer agent combinations. human or animal comprising administering to the human or Finding safe and effective combination has not been easy. animal an amount of a compound selected from one or more Combining anti-cancer agents has often led to combined of the following: toxicities or formulations containing dosages of limited use or efficacy. Therefore, there is a need to find formulations and methods of administering anti-cancer agents that can be combined safely and effectively without having to resort to dose-reduction of either agent, or in the case where dose reduction is necessary or desired, the combination maintains efficacy by allowing for higher doses of the less toxic agent. 2-methoxyestradiol, with its multiple mechanisms of action, broad spectrum of inhibitory activity in a wide range of HO tumors, ability to overcome drug resistance in certain tumor types, and limited negative side effects make it a strong candidate for combination therapy. Previous studies have wherein R is selected from —OCH —OCHCH, —CH, not looked at the ability to combine 2-methoxyestradiol and —CHCH, or—CCCH, CHCH-CH, or CH, CHCH anti-cancer agents into a method of treating diseases char followed by administration of one or more anti-cancer acterized by abnormal cell proliferation and/or abnormal or agents. undesirable angiogenesis. What is needed therefore, are novel compositions and methods of treating diseases char 0035) In yet another embodiment, the present invention acterized by abnormal cell proliferation (i.e. abnormal mito comprises a pharmaceutical preparation comprising a com sis) and/or abnormal or undesirable angiogenesis compris ing combination therapy involving 2-methoxyestradiol pound selected from one or more of the following: together with one or more anti-cancer agents. 0032 Such compositions should be easy to administer and provide minimal or no side effects.

SUMMARY OF THE INVENTION 0033. The present invention comprises methods and compositions for treating disease characterized by abnormal cell proliferation and/or abnormal or undesirable angiogen HO esis comprising administering 2-methoxyestradiol in com bination with anti-cancer agents. 2-methoxyestradiol is a powerful antiangiogenic and also has the ability to enhance wherein R is selected from —OCH —OCHCH, —CH, the effects of other anti-cancer agents through its own —CHCH, CCCH, -CHCH-CH, or CH, CHCH anti-mitotic and pro-apoptotic capabilities. In one embodi in combination with one or more anti-cancer agents. The ment, the present invention comprises a method of treating pharmaceutical preparation can also comprise a pharmaceu diseases or conditions associated with or dependent on tically acceptable carrier, excipient or diluent. abnormal, undesirable and/or excessive angiogenesis and/or undesirable cell proliferation in a human or animal com 0036). Accordingly, it is an object of the present invention prising administering to the human or animal an amount of to provide a composition combining 2-methoxyestradiol in a compound selected from one or more of the following: combination with one or more anti-cancer agents. US 2007/0185.069 A1 Aug. 9, 2007

0037. A further object of the present invention is to provide a method for administering 2-methoxyestradiol in (I) combination with anti-cancer agents to mammals to more OH effectively inhibit angiogenesis and/or to more effectively treat diseases or conditions associated with undesirable and/or excessive angiogenesis and/or undesirable cell mito S1S. 0038. These and other objects, features and advantages of the present invention will become apparent after a review of HO the following detailed description of disclosed embodiments and the appended claims. wherein R is selected from —OCH, —OCHCH. —CH, - CHCH, CCCH, CHCH-CH, or CH, CHCH. BRIEF DESCRIPTION OF THE DRAWINGS In cases where stereoisomers are possible, both R and S Stereoisomers are envisioned as well as any mixture of 0039 FIG. 1 shows the dose dependent inhibition of U87 Stereoisomers. MG tumor cell and HUVEC proliferation by 2ME2. 0046) Also included in this invention are prodrugs of the 0040 FIG. 2 shows the activity of 2ME2 or Temodar R 2-methoxyestradiol and/or anti-cancer agents. Such pro (Schering Corp., Kenilworth, N.J.) against early stage U87 drugs are produced using chemical procedures and synthetic MG ectopic tumors. routes well known to those of ordinary skill in the art. Strategies for creating prodrugs are well known to those 0041 FIGS. 3A and 3B shows activity of 2ME2 in skilled in the art and include amides, esters, ethers, combination with Temodar R (Schering Corp. Kenilworth, thioesters, and thioethers of the agent. The chemical moi N.J.) against late stage U87 MG ectopic tumors. eties linked to the agent can include naturally occurring and non-naturally occurring amino acids, Sugars, peptides, low 0.042 FIG. 4 shows activity of 2ME2 in combination molecular weight organic moieties such as acetate and with Velcade(R) (Millennium, Cambridge, Mass.) in an carbamate and benzoate and benzoyl, proteins including RPMI-8226 xenograft model of myeloma antibodies, and polymers including, but not limited to, polyethyleneglycols (PEGs). These moieties can be cleaved DETAILED DESCRIPTION OF THE by enzymatic or non-enzymatic processes to generate the INVENTION active anti-angiogenic agent. The characteristics of the pro drug are chosen to be useful for the desired purposes and 0043. The present invention may be understood more routes of administration. For example, prodrugs containing readily by reference to the following detailed description of amino acids can be used to enhance water solubility, pro specific embodiments included herein. Although the present drugs containing peptides can be used to enhance bioavail invention has been described with reference to specific ability and/or to enhance target tissue binding, and prodrugs details of certain embodiments thereof, it is not intended that containing PEGs can be used to increase plasma half-life. Such details should be regarded as limitations upon the scope 0047 Those skilled in the art will appreciate that the of the invention. The entire text of the references mentioned invention extends to other anti-cancer agents within the herein are hereby incorporated in their entireties by refer definitions given and in the claims below, having the described characteristics. These characteristics can be deter CCC. mined for each test compound using assays known in the art. 0044) The present invention comprises methods and compositions for treating diseases or conditions associated Anti-Cancer Agents with or dependent on abnormal, undesirable and/or exces 0048 Anti-cancer agents that may be used with the sive angiogenesis and/or undesirable cell proliferation com following invention include, but are not limited to, chemo prising administering to a human or an animal 2-methox therapeutics, angiogenesis inhibitors, kinase inhibitors, his yestradiol in combination with one or more anti-cancer tone deacetylase inhibitors as well as other modifiers of agents. epigenetic pheomena and proteosome inhibitors. 2-methoxyestradiol Chemotherapeutic Agents 0049 Chemotherapeutic agents are those compounds that 0045 2-methoxyestradiol is an endogenous metabolite non-specifically target rapidly dividing cells. They include that is formed by the sequential hydroxylation of 17 B alkylating agents, antimetabolites, anti-tumor antibiotics, estradiol by cytochrome P450 followed by O-methylation by mitotic inhibitors and nitroSureas. Representative chemo catechol-O-methytransferase. 2-methoxyestradiol inhibits therapeutic agents that may be used in the instant invention growth and causes apoptosis in proliferating endothelial include, but are not limited to, the following: Aldeskeukin, cells and cancer cells in vitro and has antitumor and anti Alemtuzumab, alitretinoin, allopurinol, altretamine, amifos angiogenic effects in vivo against several tumor types tine, anastrozole, arsenic trioxide, asparaginase, BCG Live, (Mooberry. Current Opinion in Oncology (2003); 15:425 bexarotene capsules, beXarotene gel, bleomycin, buSulfan 430). In one embodiment, compounds are those of the intravenous, buSulfan oral, calusterone, capecitabine, carbo general Formulae I: platin, carmustine, carmustine with Polifeprosan 20 implant, US 2007/0185.069 A1 Aug. 9, 2007

celecoxib, chlorambucil, cisplatin, cladribine, cyclophos AG-490, WHI-P154, WHI-P131, Sirolimus, Everolimus, phamide, cytarabine, cytarabine liposomal, dacarbazine, AP23573, Fasudil hydrochloride, Flavopiridol, Seliciclib dactinomycin actinomycin D, Darbepoetin alfa, daunorubi (CYC202, roscovitine), SNS-032, Ruboxistaurin, Pk.c412, cin liposomal, daunorubicin, daunomycin, Denileukin difi Bryostatin, KAI-98.03, SF1126, VX-680, AZd 1152, Arry toX, dexraZOxane, docetaxel, doxorubicin, doxorubicin lipo 142886 (AZD-6244), SCIO-469, GW681323 (SB-681323), somal, Dromostanolone propionate, Elliot's B solution(R) CC-401, CEP-1347, Semaxanib (SU5416), Sunitinib (SU (Orphan Medical Inc. Minnetonka, Minn.), epirubicin, Epo 11248) and Sorafenib (BAY 43-9006). etin alfa, estramustine, etoposide phosphate, etoposide VP-16, exemestane, Filgrastim, floxuridine, fludarabine, Histone Deacetylase Inhibitors fluorouracil, fulvestrant, gemcitabine, bemtuzumab ozo 0052. Histone deacetylase inhibitors that may be used gamicin, goserelin acetate, hydroxyurea, Ibritumomab TiuX with the following invention include, but are not limited to, etan, idarubicin, ifosfamide, imatinib mesylate, Interferon AN-9 (butyric acid prodrug), sodium phenylbutrate, valp alfa-2a, Interferon alfa-2b, irinotecan, letrozole, leucovorin, roic acid, FK-228 (cyclic depsipeptide), MS-275 (benza levamisole, lomustine CCNU, meclorethamine (nitrogen mide), suberoylanilide hydroxamic acid and LAQ-824. mustard), megestrol acetate, melphalan (L-PAM), mercap topurine (6-MP), mesna, methotrexate, methoXSalen, mito Proteosome Inhibitors mycin C, mitotane, mitoxantrone, nadrolone phenpropi 0053 Proteasomes are enzymes with a complex structure onate, Nofetumomab, Oprelvekin, oxaliplatin, paclitaxel, and function. They are found abundantly in all cells, both pamidronate, pegademase, Pegaspargase, Pegfilgrastim, normal and cancerous, and are responsible for the degrada pnetostatin, pipobroman, plicamycin (mithramycin), por tion of all regulatory proteins. Proteosome inhibitors include fimer Sodium, procarbazine, quinacrine Rasburicase, Ritux those compounds capable of inhibiting the assembly and/or imab, Sargramotim, streptozocin, talc, tamoxifen, temoZo function of these complexes. An example of a proteosome lomide, teniposide (VM-26), testolactone, thioguanine inhibitor that may be used with the present invention (6-TG), thiotepa, topotecan, toremifene, Tositumomab, includes, but is not limited to, bortezomib. Trastuzumab, tretinoin (ATRA), Uracil Mustard, valrubicin, vinblastine, Vincristine, Vinorelbine and Zoledronate. Administration 0054. In accordance with the present invention, the com Angiogenesis Inhibitors pounds of Formulae I may be mixed with one or more 0050 Angiogenesis inhibitors are those compounds that anti-cancer agents into a single formulation. The compounds prevent the growth of new capillary blood vessels from of Formulae I and the anti-cancer agent may also be for preexisting vessels. Angiogenesis inhibitors that may be mulated and delivered separately. used with present invention include both small-molecule and 0055. The compositions described herein can be provided endogenous inhibitors of angiogenesis. Representative as physiologically acceptable formulations using known angiogenesis inhibitors that may be use with the present techniques, and the formulations can be administered by invention include, but are not limited to, the following; alpha standard routes. In general, 2-methoxyestadiol and the anti interferon, angiogenic steroids, Bevacizumab, Batimastat cancer agent can be administered by topical, oral, rectal or (BB-94), Carboxyaminoimidazole (CAI), CM101 (GBS parenteral (e.g., intravenous, Subcutaneous or intramuscular) toxin), CT-2548, hydrocortisone/beta-cyclodextran, inter route. In addition, the compositions can be incorporated into leukin-12, Linomide, Marimastat (BB-2516), Octreotide polymers allowing for Sustained release, the polymers being (Somatostatin analogue), Pentosan polysulfate, platelet fac implanted in the vicinity of where delivery is desired, for tor 4, Roquinimex (LS-2616, linomide), Suramin, SU101, example, at the site of a tumor or within or near the eye, or Tecogalan sodium (DS-4152), thalidomide and its deriva the polymers can be implanted, for example, Subcutaneously tives, TNP-470 (AGM-1470), angiostatin, endostatin, beta or intramuscularly or delivered intravenously or intraperi interferon, gamma interferon, cartilage-derived inhibitor toneally to result in systemic delivery of 2-methoxyestradiol (CDI), gamma interferon inducibile protein (IP-10), gro and/or anti-cancer agent. Other formulations for controlled, beta, heparinases, placental ribonuclease inhibitor, plasmin prolonged release of therapeutic agents useful in the present goenactivator inhibitor, proliferen-related protein, retinoids, invention are disclosed in U.S. Pat. No. 6,706,289, the thrombospondin, TIMP-2, and 16 kd prolactin. disclosure of which is incorporated herein by reference. Kinase Inhibitors 0056. The formulations in accordance with the present invention can be administered in the form of a tablet, a 0051 Kinase inhibitors that may be used with the present capsule, a lozenge, a cachet, a Solution, a Suspension, an invention include, but are not limited to, inhibitors of the following kinase families EGFR, HER2, VEGF receptor, emulsion, a powder, an aerosol, a Suppository, a spray, a FLT3, ABL, SRC, Janus (JAK), MTOR, Rho, cyclindepen pastille, an ointment, a cream, a paste, a foam, a gel, a dent kinases (CDK), protein kinase C(PKC), phosphatidyli tampon, a pessary, a granule, a bolus, a mouthwash, or a nositol-3-kinase (PI3K), Aurora, MAP/MEK, Jun N-termi transdermal patch. nal (JNK). Representative kinase inhibitors that may be used 0057 The formulations include those suitable for oral, with the following invention include, but are not limited to, rectal, nasal, inhalation, topical (including dermal, transder cetuximab, Erlotinib, gefitinib, PKI-166, Canertinib (CI mal, buccal and Sublingual), vaginal, parenteral (including 1033), SU-11464, Matuzumab (Emd7200), EKB-569, Subcutaneous, intramuscular, intravenous, intradermal, Zdé474, Trastuzumab, GW-572016 (lapatinib ditosylate), intraocular, intratracheal, and epidural) or inhalation admin PKC-412, Sutent, Vatalanib (Ptk787/ZK222584), CEP-701, istration. The formulations can conveniently be presented in SU5614, MLN518, XL999, VX-322, VEGF-trap, Imatinib unit dosage form and can be prepared by conventional mesylate, AZd0530, BMS-354825, SKI-606, CP-690, pharmaceutical techniques. Such techniques include the step US 2007/0185.069 A1 Aug. 9, 2007 of bringing into association the active ingredient and a 0066 Formulations suitable for parenteral administration pharmaceutical carrier(s) or excipient(s). In general, the include aqueous and non-aqueous sterile injection solutions formulations are prepared by uniformly and intimately which may contain anti-oxidants, buffers, bacteriostats and bringing into association the active ingredient with liquid solutes which render the formulation isotonic with the blood carriers or finely divided solid carriers or both, and then, if of the intended recipient; and aqueous and non-aqueous necessary, shaping the product. sterile Suspensions which may include Suspending agents and thickening agents. Formulations Suitable for parenteral 0.058 Formulations of the present invention suitable for administration include particulate preparations of the anti oral administration may be presented as discrete units such angiogenic agents, including, but not limited to, low-micron, as capsules, cachets or tablets each containing a predeter or nanometer (e.g. less than 2000 nanometers, preferably mined amount of the active ingredient; as a powder or less than 1000 nanometers, most preferably less than 500 granules; as a solution or a suspension in an aqueous liquid nanometers in average cross section) sized particles, which or a non-aqueous liquid; or as an oil-in-water liquid emul particles are comprised of 2-methoxyestradiol and/or anti sion or a water-in-oil emulsion, etc. cancer agent alone or in combination with accessory ingre 0059 A tablet may be made by compression or molding, dients ort in a polymer for sustained release. The formula optionally with one or more accessory ingredients. Com tions may be presented in unit-dose or multi-dose pressed tablets may be prepared by compressing, in a containers, for example, sealed ampules and vials, and may Suitable machine, the active ingredient in a free-flowing be stored in freeze-dried (lyophilized) conditions requiring form Such as a powder or granules, optionally mixed with a only the addition of a sterile liquid carrier, for example, binder, lubricant, inert diluent, preservative, surface-active water for injections, immediately prior to use. Extempora or dispersing agent. Molded tablets may be made by mold neous injection solutions and Suspensions may be prepared ing, in a Suitable machine, a mixture of the powdered from sterile powders, granules and tablets of the kinds compound moistened with an inert liquid diluent. The tablets previously described. may optionally be coated or scored and may be formulated 0067. In one embodiment, the compounds of Formulae I so as to provide a slow or controlled release of the active and the anti-cancer agent can be administered simulta ingredient therein. neously. In another embodiment, they can be administered 0060 Formulations suitable for topical administration in sequentially (i.e. 2ME2 dosage in the morning, anti-cancer the mouth include lozenges comprising the ingredients in a agent dosage in the evening). Mixtures of more than one flavored base, usually sucrose and acacia or tragacanth: anti-cancer agent can, of course, be administered. Indeed, it pastilles comprising the active ingredient in an inert base is often desirable to use mixtures or sequential administra Such as gelatin and glycerin, or Sucrose and acacia; and tions of different anti-cancer agents to treat tumors, espe mouthwashes comprising the ingredient to be administered cially anti-cancer agents from the different classes. in a Suitable liquid carrier. 0068 If the 2-methoxyestradiol formulation and the anti 0061 Formulations suitable for topical administration to cancer agent are to be administered sequentially, the amount the skin may be presented as ointments, creams, gels and of time between administration of the 2-methoxyestradiol pastes comprising the ingredient to be administered in a formulation and the anti-cancer agent will depend upon pharmaceutical acceptable carrier. In one embodiment the factors such as the amount of time it take the 2-methox topical delivery system is a transdermal patch containing the yestradiol formulation to be fully incorporated into the circulatory system of the host and the retention time of the ingredient to be administered. 2-methoxyestradiol formulation in the host’s body. In one 0062 Formulations for rectal administration may be pre embodiment, dosage formulations for 2-methoxyestradiol sented as a Suppository with a suitable base comprising, for are disclosed in U.S. patent application Ser. No. 11/288,989, example, cocoa butter or a salicylate. filed Nov. 29, 2005, which is incorporated herein by refer ence in its entirety. 0063 Formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder 0069. The anti-cancer agent is administered in a thera having a particle size, for example, in the range of 20 to 500 peutically effective amount. This amount will be determined microns which is administered in the manner in which Snuff on an individual basis and will be based, at least in part, on is taken; i.e., by rapid inhalation through the nasal passage consideration of the hosts size, the specific disease to be from a container of the powder held close up to the nose. treated, the severity of the symptoms to be treated, the Suitable formulations, wherein the carrier is a liquid, for results sought, and other Such considerations. An effective administration, as for example, a nasal spray or as nasal amount can be determined by one of ordinary skill in the art drops, include aqueous or oily solutions of the active ingre employing Such factors and using no more than routine dient. experimentation. 0064. Formulations suitable for vaginal administration 0070. It should be understood that, in addition to the may be presented as pessaries, tampons, creams, gels, ingredients particularly mentioned above, the formulations pastes, foams or spray formulations containing, in addition of the present invention may include other agents conven to the active ingredient, ingredients such as carriers as are tional in the art having regard to the type of formulation in question, for example, those Suitable for oral administration known in the art to be appropriate. may include flavoring agents, and nanoparticle formulations 0065 Formulation suitable for inhalation may be pre (e.g. less than 2000 nanometers, preferably less than 1000 sented as mists, dusts, powders or spray formulations con nanometers, most preferably less than 500 nanometers in taining, in addition to the active ingredient, ingredients such average cross section) may include one or more than one as carriers as are known in the art to be appropriate. excipient chosen to prevent particle agglomeration. US 2007/0185.069 A1 Aug. 9, 2007

Indications drugs of Formulae I, or prodrugs thereof, or other com 0071. The invention can be used to treat any disease pounds included by reference where the drug or prodrug is characterized by abnormal cell proliferation and/or abnor formulated in a biodegradable or non-biodegradable poly mal or undesirable angiogenesis. Such diseases include, but mer for sustained release. Non-biodegradable polymers are not limited to, abnormal stimulation of endothelial cells release the drug in a controlled fashion through physical or (e.g., atherosclerosis); Solid tumors; blood-borne tumors, mechanical processes without the polymer itself being Such as leukemias; tumor metastasis; benign tumors, for degraded. Biodegradable polymers are designed to gradually example, hemangiomas, acoustic neuromas, neurofibromas, be hydrolyzed or solubilized by natural processes in the trachomas, and pyogenic granulomas; vascular malfunc body, allowing gradual release of the admixed drug or tions; abnormal wound healing; inflammatory and immune prodrug. The drug or prodrug can be chemically linked to the disorders; Bechet's disease; gout or gouty arthritis; abnor polymer or can be incorporated into the polymer by admix mal angiogenesis accompanying: rheumatoid arthritis; skin ture. Both biodegradable and non-biodegradable polymers diseases, such as psoriasis; diabetic retinopathy, and other and the process by which drugs are incorporated into the ocular angiogenic diseases, such as retinopathy of prema polymers for controlled release are well known to those turity (retrolental fibroplasia), macular degeneration, corneal skilled in the art. Examples of such polymers can be found graft rejection, neovascular glaucoma; liver diseases and in many references, such as Brem et al., J. Neurosurg 74: pp. Oster Webber Syndrome (Osler-Weber Rendu disease), epi 441-446 (1991). These implants or devices can be implanted demic keratoconjunctivitis, Vitamin A deficiency, contact in the vicinity where delivery is desired, for example, at the lens overwear, atopic keratitis, Superior limbic keratitis, site of a tumor or a stenosis, or can be introduced so as to pterygium keratitis sicca, Sjögren's syndrome, acne rosacea, result in Systemic delivery of the agent. phylectenulosis, syphilis, Mycobacteria infections, lipid 0075 Because anything not formed in the body as a degeneration, chemical burns, bacterial ulcers, fungal ulcers, natural component may elicit extreme and unexpected Herpes simplex infections, Herpes zoster infections, proto responses, such as blood vessel closure due to thrombus Zoan infections, Kaposi's sarcoma, Mooren’s ulcer, Ter formation or spasm, and because damage to blood vessels by rien’s marginal degeneration, marginal keratolysis, trauma, the act of insertion of a vascular stent may be extreme and rheumatoid arthritis, systemic lupus, polyarteritis, Wegen unduly injurious to the blood vessel surface, it is prudent to er's sarcoidosis, Scleritis, Steven-Johnson disease, pem protect against Such events. Restenosis is a re-narrowing or phigoid, radial keratotomy, and corneal graph rejection. blockage of an artery at the same site where treatment, Such 0072 Other diseases associated with neovascularization as an angioplasty or Stent procedure, has already taken place. can be treated according to the present invention. Such If restenosis occurs within a stent that has been placed in an diseases include, but are not limited to, sickle cell anemia, artery, it is technically called “in-stent restenosis,” the end sarcoid, pseudoxanthoma elasticum, Paget’s disease, vein result being a narrowing in the artery caused by a build-up occlusion, artery occlusion, carotid obstructive disease, of substances that may eventually block the flow of blood. chronic uveitis/vitritis, Lyme’s disease, systemic lupus The compounds that are part of the present invention are erythematosis, Eales disease, infections causing a retinitis especially useful to coat vascular stents to prevent resteno or choroiditis, presumed ocular histoplasmosis, Best's dis sis. The coating should preferably be a biodegradable or ease, myopia, optic pits, Stargart's disease, pars planitis, non-biodegradable polymer that allows for a slow release of chronic retinal detachment, hyperviscosity syndromes, toXo a compound of the present invention thereby preventing the plasmosis, and post-laser complications. Other diseases restenosis event. include, but are not limited to, diseases associated with 0076. The present invention also relates to conjugated rubeosis (neovascularization of the iris and the angle) and prodrugs and uses thereof. More particularly, the invention diseases caused by the abnormal proliferation of fibrovas relates to conjugates of steroid compounds, Such as com cular or fibrous tissue including all forms of proliferative pounds of Formulae I, and the use of Such conjugates in the vitreoretinopathy, whether or not associated with diabetes. prophylaxis or treatment of conditions associated with 0073. The present invention may also be used to treat enhanced angiogenesis or accelerated cell division, Such as angiogenesis-dependent cancers including, but not limited cancer, and inflammatory conditions, such as asthma and to, any one or combination of rhabdomyosarcoma, retino rheumatoid arthritis and hyperproliferative skin disorders blastoma, Ewing's sarcoma, neuroblastoma, and osteosar including psoriasis. The invention also relates to composi coma. Other angiogenesis-dependent cancers treatable with tions including the prodrugs of the present invention and the present invention include, but are not limited to, breast methods of synthesizing the prodrugs. cancer, prostrate cancer, renal cell cancer, brain cancer, 0077. In one aspect, the present invention provides a ovarian cancer, colon cancer, bladder cancer, pancreatic conjugated prodrug of an estradiol compound, preferably cancer, Stomach cancer, esophageal cancer, cutaneous mela compounds of Formulae I, conjugated to a biological activ noma, liver cancer, Small cell and non-Small cell lung ity modifying agent. cancer, testicular cancer, kidney cancer, bladder cancer, cervical cancer, lymphoma, parathyroid cancer, penile can 0078. Alternatively, the conjugated prodrug according to cer, rectal cancer, Small intestine cancer, thyroid cancer, the present invention includes the compounds of Formulae uterine cancer, Hodgkin’s lymphoma, non-Hodgkin’s lym I, conjugated to a peptide moiety. phoma, lip cancer, oral cancer, skin cancer, leukemia or multiple myeloma. 0079 The incorporation of an estradiol compound, such as the compounds of Formulae I, into a disease-dependently Pharmaceutical Preparations activated pro-drug enables significant improvement of 0074 Also contemplated by the present invention are potency and selectivity of this anti-cancer and anti-inflam implants or other devices comprised of the compounds or matory agent. US 2007/0185.069 A1 Aug. 9, 2007

0080) A person skilled in the art will be able by reference EXAMPLES to standard texts, such as Remington’s Pharmaceutical Sci 0088. The data present in the Examples and the following ences 17th edition, to determine how the formulations are to table indicates that 2ME2 can be combined with a wide be made and how these may be administered. range of anti-cancer agents. The characteristics of 2ME2 and 0081. In a further aspect of the present invention there is compounds of Formulae I are such that they can be com provided use of compounds of Formulae I, or prodrugs bined with anti-cancer agents at the maximally tolerated or thereof, in combination with a anti-cancer agent according to maximally effective dose and schedule of the anti-cancer the present invention for the preparation of a medicament for agent. In some embodiments, combination with 2ME2 can the prophylaxis or treatment of conditions associated with be used to maintain the effectiveness while reducing the dose angiogenesis or accelerated cell division or inflammation. of the anti-cancer agent. Such reduction in dose can result in 0082 In a still further aspect of the present invention reduction of toxicity or reduction in any unacceptable effect there is provided a method of prophylaxis or treatment of a or side-effect or the anti-cancer agent. condition associated with angiogenesis or accelerated or increased amounts of cell division, hypertrophic growth or TABLE 1. inflammation, said method including administering to a Clinical Rationales from Tumor Models and Combinations patient in need of Such prophylaxis or treatment an effective amount of compounds of Formulae I, or prodrugs thereof, in Model Agent(s) Activity combination with an anti-cancer agent according to the U87MG Control %A = 416 present invention, as described herein. It should be under Temodar (R) 266 stood that prophylaxis or treatment of said condition 2ME2 333 includes amelioration of said condition. Combine -33 U87MG Control %A = 112O 0.083 Pharmaceutically acceptable salts of the com CPT-11 670 2ME2 890 pounds of the Formulae I, or the prodrugs thereof, can be Combine 460 prepared in any conventional manner, for example from the RPMI-8226 Velcade TC = 0.64 free base and acid. In vivo hydrolysable esters, amides and 2ME2 O.66 carbamates and other acceptable prodrugs of Formulae I can Combine O3S LLC met Paclitaxel TC = 0.38 be prepared in any conventional manner. 2ME2 0.37 Combine O.OS 0084 100% pure isomers are contemplated by this inven PC3 XRT T - C = 2 d" tion; however a stereochemical isomer (labeled as C. or B, or 2ME2 Od as R or S) may be a mixture of both in any ratio, where it Combine 23 d is chemically possible by one skilled in the art. Also con H2122 Paclitaxel MST = 24 d 2ME2 17 d templated by this invention are both classical and non Combine 35 d classical bioisosteric atom and Substituent replacements, LLC met Cisplatin TC = 0.19 such as are described by Patani and Lavoie (“Bio-isosterism: 2ME2 0.37 a rational approach in drug design Chem. Rev. (1996) p. Combine O.04 CT-26 5-FU TC = 0.38 3147-3176) and are well known to one skilled in the art. 2ME2 0.37 Such bioisosteric replacements include, for example, but are Combine O.OS not limited to, Substitution of =S or =NH for =O. *Percent change in tumor volume from start of treatment 0085. A particularly useful formulation in the present "Difference in tumor doubling time invention is a nanoparticulate liquid Suspension of 2-meth oxyestradiol disclosed in U.S. patent application Ser. No. 10/392.403, filed Mar. 20, 2003 (the disclosure of which is Example 1 incorporated herein by reference). This formulation is avail able from EntreMed, Inc., Rockville, Md., under the desig Activity of 2ME2 in Combination with nation Panzem(R) NCD. 5-Fluorouracil Against Syngenic Colon Carcinomas 0089 2-methoxyestradiol (2ME2) is an endogenous 0.086 Known compounds that are used in accordance metabolite of estradiol with antiproliferative, proapoptotic with the invention and precursors to novel compounds and antiangiogenic activity. PanzemR) capsules have been according to the invention can be purchased, e.g., from evaluated in several Phase 1 and Phase 2 oncology clinical Sigma Chemical Co., Steraloids or Research Plus. Other trials. A new formulation of 2ME2 with enhanced absorp compounds according to the invention can be synthesized tion, PanzemRNCD, is currently in clinical trials. In antici according to known methods from publicly available pre pation of Phase 2 clinical trials with Panzem R. NCD, tests CUSOS. were conducted to assess its anti-tumor activity as either 0087. The compositions and methods are further illus monotherapy or in combination with cytotoxic agents. In trated by the following non-limiting examples, which are not this preclinical study, the effectiveness of 2ME2 alone or to be construed in any way as imposing limitations upon the with the antimetabolite, 5-Fluorouracil (5-FU) in the CT-26 scope thereof. On the contrary, it is to be clearly understood syngeneic tumor model was evaluated. 5-FU is a well that resort may be had to various other embodiments, recognized and commonly used antineoplastic agent used modifications, and equivalents thereof which, after reading for treatment of colorectal cancer. Preliminary in vitro the description herein, may suggest themselves to those studies indicated that the IC50 for inhibition of proliferation skilled in the art without departing from the spirit of the with 2ME2 on CT-26 cells was 3.0 uM. Subsequent to these present invention. studies, male BALB/c mice were injected subcutaneously US 2007/0185.069 A1 Aug. 9, 2007 with 1x10 CT-26 cells. Starting 7 days after tumor cell Example 3 inoculation when mean tumor volume was approximately 100 mm, cohorts of mice (n=5/group) began treatment with Activity of 2ME2 or Temodar R. Against Early (a) vehicle alone; (b) 2ME(a 200mg/kg. p.o. d.d.; (c) 5-FU Stage U87 MG Ectopic Tumors 30mg/kg p.o. d.d.x5; (d) or a combination of 5-FU at 30 mg/kg p.o. d.d.x5 with 2ME2 at 50, 100, or 200 mg/kg p.o. 0093 Previous studies have shown that 2ME2 has anti q.d. This dose and regimen of 5-FU was determined to be the tumor activity in both ectopic and orthotopic glioma tumor MTD in this model. Cohorts of mice receiving the combi models. To assess whether 2ME2 or TemodargR (Schering nation of 5-FU and 2ME2 had oral administrations in the Corp. Kenilworth, N.J.) impact tumor growth of U87 MG, A.M. (5-FU) and the PM. (2ME2). On study date 29, mean we designed the following experiment. Male Balb/c SCID tumor volume in vehicle treated-control mice was mice were injected subcutaneously with 1x10 U87 MG 2494mm +/-487. Treatment with either 2ME2 alone gen tumor cells. 11 days following tumor cell inoculation when erated a T/C of 0.79 and 0.51. In comparison, 2ME2 at 50, mean tumor volume was approximately 100mm, cohorts of 100, or 200 mg/kg, in combination with a 5-day cycle of mice began treatment with either vehicle control, 2ME2400 30mg/kg 5-FU, resulted in T/C values of 0.19, 0.25, and 0.16 or 200 mg/kg p.o., q.d. or Temodar R (Schering Corp. respectively. Determination of mean changes in body weight Kenilworth, N.J.) 42 mg/kg p.o., q.d.X5. as a consequence of treatment indicated moderate to no change with either 5-FU or 2ME2 administration. In con TABLE II trast, mice treated with the combination demonstrated an unexpected decrease in body weight that was reversible with Study Design I continued low dose 2ME2 treatment. Group Dose Treatment No. of Mice 0090 This study demonstrated that a combination strat 1 Vehicle Control 0.2 ml p.o., q.d. 10 egy using 5-FU and 2ME2 can enhance the antitumor 2 2ME2 400 mg/kg p.o., q.d. 10 effectiveness of either agent alone in the treatment of a 3 2ME2 200 mg/kg p.o., q.d. 10 Syngeneic colon carcinoma. 4 Temodar (R) 42 mg/kg p.o., q.d. x 5 10 Example 2 Dose Dependent Inhibition of U87 MG Tumor 0094) Results: On study day 30, the mean tumor volume of the vehicle control animals was approximately 3000 Cells and HUVEC Proliferation by 2ME2 (FIG. 1) mm. As shown in FIG. 2, 2ME2 at both 400 and 200 mg/kg 0.091 U87 MG human glioblastoma cells were main inhibited tumor growth by approximately 40% (T/C =0.61). tained in vitro in DMEM supplemented with 5% FBS, 2 mM Using this dose and regimen in this model, Temodar R glutamine, 1 mM sodium pyruvate, MEM vitamins and blocked U87 MG tumor growth by 98% (T/C =0.02). A NEAA at 37° C. and 5% CO. HUVEC were maintained in separate tolerability study revealed this dose and regimen of M 200 media. For both HUVEC and U87 MG proliferation assays, cells were plated in a 96 well plate at 5x10 cells per Temodar R be the maximally tolerated dose. well and incubated at 37° C. overnight. At 24 hours, the 0.095 The study demonstrates that both 2ME2 and Temo media was aspirated and 2ME2 was administered to the cells dar R alone are effective against early stage glioblastomas at the following doses: 0.03, 0.1, 0.3, 1, 3, 10, 30 mM. and that Temodar R is more effective against early stage Proliferation was assessed 48 hours after application of drug glioblastomas than 2ME2. by WST-1(U87 MG) or BRDU (HUVEC). 0092 Results: 2ME2 blocked cellular proliferation of Example 4 both U87 MG cells and HUVEC in a dose dependent fashion. The IC50 value for inhibition of U87 MG prolif Activity of 2ME2 in Combination with Temodar R eration is 2.4 mM. The IC50 value for HUVEC proliferation Against Late Stage U87 MG Ectopic Tumors is 0.463 uM. The IC50 of Temodar R (Schering Corp. 0096. In a second preclinical study the effectiveness of Kenilworth N.J.) was not determined since the agent 2ME2 alone or in combination with Temodar R in the U87 requires in vivo activation to the active metabolite, 5-ami noimidazole-4 carboxamide. The IC50 value of 2ME2 MG glioblastoma xenograft tumor model was evaluated. against U87 MG in vitro helps determine an optimal dosage Given the effectiveness of Temodar R at the maximally range for use with in vitro U87 MG glioblastoma xenograft tolerated dose against 100 mm tumor burden, we altered the model. The study also demonstrates that the dosage at which treatment strategy such that treatment was initiated when 2ME2 demonstrates an anti-proliferative effect directly on mean tumor volume was approximately 300 mm. Cohorts glioblastoma cells is nearly five times the dosage at which of mice received treatment with either vehicle control, 2ME2 demonstrates an antiangiogenic effect on HUVEC. 2ME2400 mg/kg p.o., q.d., Temodar R. 42 mg/kg p.o., q.dx5. Therefore it is reasonable to assume that in vivo dosages or 2ME2400 mg/kg p.o., q.d.combined with Temodar R. 42 needed to inhibit growth of the primary tumor should also be mg/kg p.o., q.d.x5. Mice treated with the combination of more than Sufficient to inhibit angiogenesis in the Surround 2ME2 and Temodar R received oral administration in the PM ing stroma. and AM, respectively. US 2007/0185.069 A1 Aug. 9, 2007 10

phamide, cytarabine, cytarabine liposomal, dacarbazine, TABLE III dactinomycin actinomycin D, Darbepoetin alfa, daunorubi cin liposomal, daunorubicin, daunomycin, Denileukin difi Study Design II toX, dexraZoxane, docetaxel, doxorubicin, doxorubicin lipo Group Dose Treatment No. of Mice somal, Dromostanolone propionate, Elliot's B solution(R), epirubicin, Epoetin alfa, estramustine, etoposide phosphate, 1 Vehicle Control 0.2 ml p.o., q.d. 9 2 2ME2 400 mg/kg p.o., q.d. 5 etoposide VP-16, exemestane, Filgrastim, floxuridine, flu 3 Temodar (R) 42 mg/kg p.o., q.d. x 5 9 darabine, fluorouracil, fulvestrant, gemcitabine, bemtu 4 2ME2 -- 400 mg/kg p.o., q.d. + 42 9 Zumab ozogamicin, goserelin acetate, hydroxyurea, Ibritu Temodar (R) mg/kg p.o., q.d. x 5 momab TiuXetan, idarubicin, ifosfamide, imatinib mesylate, Interferon alfa-2a, Interferon alfa-2b, irinotecan, letrozole, leucovorin, levamisole, lomustine CCNU, meclorethamine 0097. Results: On study day 28, mean tumor volume in (nitrogen mustard), megestrol acetate, melphalan (L-PAM), the vehicle control animals was approximately 1500 mm. mercaptopurine (6-MP), mesna, methotrexate, methoXSalen, As shown in FIGS. 3a and 3b, under these experimental mitomycin C, mitotane, mitoxantrone, nadrolone phenpro conditions, treatment with either 2ME2 or Temodar R) alone, pionate, Nofetumomab, Oprelvekin, oxaliplatin, paclitaxel, generated a modest inhibition of tumor growth (20% and pamidronate, pegademase, Pegaspargase, Pegfilgrastim, 34% inhibition respectively). In contrast, 2ME2 at 400 pnetostatin, pipobroman, plicamycin (mithramycin), por mg/kg in combination with a 5-day cycle of an MTD dose fimer Sodium, procarbazine, quinacrine Rasburicase, Ritux (42 mg/kg) of Temodar R resulted in 87% inhibition of imab, Sargramotim, streptozocin, talc, tamoxifen, temoZo tumor development. lomide, teniposide (VM-26), testolactone, thioguanine 0098. This study demonstrates that the combination of (6-TG), thiotepa, topotecan, toremifene, Tositumomab, 2ME2 and Temodar R is more effective at inhibiting and Trastuzumab, tretinoin (ATRA), Uracil Mustard, valrubicin, reducing the tumor size of late stage glioblastoma tumors vinblastine, Vincristine, Vinorelbine and Zoledronate. than when either agent is administered alone. 5. The method of claim 1, wherein the anti-cancer agent We claim: is an angiogenesis inhibitor. 1. A method of treating diseases associated with undesir 6. The method of claim 5, wherein the angiogenesis able and/or excessive angiogenesis and/or undesirable cell inhibitor is selected from one or more of the following; alpha proliferation comprising administering simultaneously to an interferon, angiogenic steroids, Bevacizumab Batimastat animal or human; (BB-94), carboxyaminoimidazole (CAI), CM101 (GBS toxin), CT-2548, hydrocortisone/beta-cyclodextran, inter a) a first composition comprising a therapeutic agent leukin-12, Linomide, Marimastat (BB-2516), Octreotide selected from one or more of the following: (somatostatin analogue), Pentosan polysulfate, platelet fac tor 4, Roquinimex (LS-2616, linomide), Suramin, SU101, Tecogalan sodium (DS-4152), thalidomide and its deriva OH: tives, TNP-470 (AGM-1470), angiostatin, endostatin, beta interferon, gamma interferon, cartilage-derived inhibitor (CDI), gamma interferon inducibile protein (IP-10), gro beta, heparinases, placental ribonuclease inhibitor, plasmin goenactivator inhibitor, proliferen-related protein, retinoids, thrombospondin, TIMP-2, and 16 kd prolactin. HO 7. The method of claim 1, wherein the anti-cancer agent is a kinase inhibitor. 8. The method of claim 7, wherein the kinase inhibitor is wherein R is selected from —OCH —OCHCH selected from one or more of the following: cetuximab, —CH, —CHCH. —CCCH. —CHCH-CH, or Erlotinib, gefitinib, PKI-166, Canertinib (CI-1033), CH, CHCH, and a pharmaceutically acceptable car SU-11464, Matuzumab (Emd7200), EKB-569, Zdo474, rier, diluent, or excipient; and Trastuzumab GW-572016 (lapatinib ditosylate), PKC-412, b) and one or more anti-cancer agents. Sutent, Vatalanib (Ptk787/ZK222584), CEP-701, SU5614, 2. The method of claim 1, wherein the first composition MLN518, XL999, VX-322, VEGF-trap, Imatinib mesylate, and the one or more anti-cancer agents can be administered AZd0530, BMS-354825, SKI-606, CP-690, AG-490, WHI in a single formulation or in two or more separate formu P154, WHI-P131, Sirolimus, Everolimus, AP23573, Fasudil lations. hydrochloride, Flavopiridol, Seliciclib (CYC202, rosco 3. The method of claim 1, wherein the anti-cancer agent vitine), SNS-032, Ruboxistaurin, Pkc412, Bryostatin, KAI is a chemotherapeutic agent. 98.03, SF1126, VX-680, AZd 1152, Arry-142886 (AZD 4. The method of claim 3, wherein the chemotherapeutic 6244), SCIO-469, GW681323 (SB-681323), CC-401, CEP agent is selected from the following; Aldeskeukin, Alemtu 1347, Semaxanib (SU5416), Sunitinib (SU11248) and Zumab, alitretinoin, allopurinol, altretamine, amifostine, Sorafenib (BAY 43-9006). anastroZole, arsenic trioxide, Asparaginase, BCG Live, bex 9. The method of claim 1, wherein the anti-cancer agent arotene capsules, beXarotenegel, bleomycin, buSulfan intra is an histone deacetylase inhibitor. venous, buSulfan oral, calusterone, capecitabine, carbopl 10. The method of claim 9, wherein the histone deacety atin, carmustine, carmustine with Polifeprosan 20 implant, lase inhibitor is selected from on or more of the following: celecoxib, chlorambucil, cisplatin, cladribine, cyclophos AN-9 (butyric acid prodrug), sodium phenylbutrate, valp US 2007/0185.069 A1 Aug. 9, 2007 roic acid, FK-228 (cyclic depsipeptide), MS-275 (benza leukemia, psoriasis, atherosclerosis, pemphigoid, infections mide), suberoylanilide hydroxamic acid and LAQ-824. causing retinitis, infections causing choroiditis, presumed 11. The method of claim 1, wherein the anti-cancer agent ocular histoplasmosis, Best’s disease, proliferative vitreore is a proteosome inhibitor. tinopathy, Bartonellosis, acoustic neuromas, neurofibroma, 12. The method of claim 11, wherein the proteosome trachoma, pyogenic granulomas, vascular malfunctions, inhibitor is bortezomib. abnormal wound healing, gout or gouty arthritis, angiogen 13. The method of claim 2, wherein the administration of esis-dependent cancer, hereditary hemorrhagic telangiecta the single formulation is oral, parenteral, transdermal, topi sia, post-menopausal symptoms, osteoporosis, cardiovascu cal, intravenous, Subcutaneous, intramuscular, intradermal, lar disease, myocardial angiogenesis, plaque ophthalmic, epidural, intratracheal, Sublingual, buccal, rec neovascularization, hemophiliac joints, angiofibroma, tal, vaginal, nasal or inhalation. wound granulation, intestinal adhesions, Scleroderma, kel 14. The method of claim 2, wherein the administration of oids, endometriosis. the separate formulations is oral, parenteral, transdermal, 19. The method of claim 1, wherein the angiogenesis is topical, intravenous, Subcutaneous, intramuscular, intrader associated with angiogenesis-dependent cancers selected mal, ophthalmic, epidural, intratracheal, Sublingual, buccal, from breast cancer, prostrate cancer, renal cell cancer, brain rectal, vaginal, nasal or inhalation. cancer, ovarian cancer, colon cancer, bladder cancer, pan 15. The method of claim 1, wherein the first composition creatic cancer, stomach cancer, esophageal cancer, cutane further comprises an additive selected from an anti-oxidant, ous melanoma, liver cancer, lung cancer, testicular cancer, a buffer, a bacteriostat, a liquid carrier, a solute, a suspending kidney cancer, bladder cancer, cervical cancer, lymphoma, agent, a thickening agent, a flavoring agent, a gelatin, a parathyroid cancer, penile cancer, rectal cancer, Small intes glycerin, a binder, a lubricant, an inert diluent, a preserva tine cancer, thyroid cancer, uterine cancer, Hodgkin’s lym tive, a Surface active agent, a dispersing agent, a biodegrad phoma, lip and oral cancer, skin cancer, leukemia or multiple able polymer, or any combination thereof. myeloma. 16. The method of claim 2, wherein the single formulation 20. The method of claim 19, wherein the cancer is colon is administered in the form of a tablet, a capsule, a lozenge, CaCC. a cachet, a solution, a Suspension, an emulsion, a powder, an 21. The method of claim 19, wherein the cancer is ectopic aerosol, a Suppository, a spray, a pastille, an ointment, a or orthotopic glioma. cream, a paste, a foam, a gel, a tampon, a pessary, a granule, 22. The method of claim 19, wherein the cancer is a bolus, a mouthwash, or a transdermal patch. multiple myeloma. 17. The method of claim 2, wherein the separate formu 23. A method for treating diseases associated with unde lations are administered in the form of a tablet, a capsule, a sirable and/or excessive angiogenesis and/or undesirable lozenge, a cachet, a solution, a Suspension, an emulsion, a cell proliferation comprising administering sequentially to powder, an aerosol, a Suppository, a spray, a pastille, an an animal or human; ointment, a cream, a paste, a foam, a gel, a tampon, a a) a first composition comprising, a therapeutic agent pessary, a granule, a bolus, a mouthwash, or a transdermal selected from one or more of the following patch. 18. The method of claim 1, wherein the angiogenesis is associated with diabetic retinopathy, retinopathy of prema OH turity, corneal graft rejection, neovascular glaucoma, retro lental fibroplasias, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, Superior limbic keratitis, pterygium keratitis sicca, Sjögren's Syn drome, acne rosacea, phylectenulosis, syphilis, Mycobacte ria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes HO zoster infections, protozoan infections, Kaposi's sarcoma, Mooren’s ulcer, Terrien’s marginal degeneration, marginal wherein R is selected from —OCH —OCHCH keratolysis, trauma, arthritis, rheumatoid arthritis, pol —CH, —CHCH. —CCCH. —CHCH-CH, or yarteritis, Systemic lupus, Wegener's sarcoidosis, Scleritis, CH, CHCH, and a pharmaceutically acceptable car Stevens-Johnson disease, radial keratotomy, macular degen rier, diluent, or excipient; and eration, sickle cell anemia, sarcoid, pseudoxanthoma elas ticum, Paget’s disease, vein occlusion, artery occlusion, b) a second composition comprising one or more anti carotid obstructive disease, chronic uveitis, chronic vitritis, cancer agents. Lyme’s disease, Eales disease, Behcet’s disease, myopia, 24. The method of claim 23, wherein the anti-cancer agent optic pits, Stargardt’s disease, pars planitis, chronic retinal is a chemotherapeutic agent. detachment, hyperviscosity syndromes, toxoplasmosis, 25. The method of claim 24, wherein the chemotherapeu post-laser complications, abnormal proliferation offibrovas tic agent is selected from the following; Aldeskeukin, Ale cular or fibrous tissue, hemangiomas, Osler-Weber-Rendu mtuzumab, alitretinoin, allopurinol, altretamine, amifostine, disease, Solid tumors, blood-borne tumors, acquired immune anastroZole, arsenic trioxide, Asparaginase, BCG Live, bex deficiency syndrome, ocular neovascular disease, age-re arotene capsules, beXarotenegel, bleomycin, buSulfan intra lated macular degeneration, osteoarthritis, diseases caused venous, buSulfan oral, calusterone, capecitabine, carbopl by chronic inflammation, Crohn's disease, ulcerative colitis, atin, carmustine, carmustine with Polifeprosan 20 implant, tumors of rhabdomyosarcoma, tumors of retinoblastoma, celecoxib, chlorambucil, cisplatin, cladribine, cyclophos Ewing's sarcoma, neuroblastoma, tumors of osteosarcoma, phamide, cytarabine, cytarabine liposomal, dacarbazine, US 2007/0185.069 A1 Aug. 9, 2007

dactinomycin actinomycin D, Darbepoetin alfa, daunorubi 32. The method of claim 23, wherein the anti-cancer agent cin liposomal, daunorubicin, daunomycin, Denileukin difi is a proteosome inhibitor. toX, dexraZOxane, docetaxel, doxorubicin, doxorubicin lipo 33. The method of claim 32, wherein the proteosome somal, Dromostanolone propionate, Elliot's B solution(R), inhibitor is bortezomib. epirubicin, Epoetin alfa, estramustine, etoposide phosphate, 34. The method of claim 23, wherein the administration of etoposide VP-16, exemestane, Filgrastim, floxuridine, flu the first composition is oral, parenteral, transdermal, topical, darabine, fluorouracil, fulvestrant, gemcitabine, bemtu intravenous, Subcutaneous, intramuscular, intradermal, oph Zumab ozogamicin, goserelin acetate, hydroxyurea, Ibritu thalmic, epidural, intratracheal. Sublingual, buccal, rectal, momab TiuXetan, idarubicin, ifosfamide, imatinib mesylate, vaginal, nasal or inhalation. Interferon alfa-2a, Interferon alfa-2b, irinotecan, letrozole, 35. The method of claim 23, wherein the administration of leucovorin, levamisole, lomustine CCNU, meclorethamine the second composition is oral, parenteral, transdermal, (nitrogen mustard), megestrol acetate, melphalan (L-PAM), topical, intravenous, Subcutaneous, intramuscular, intrader mercaptopurine (6-MP), mesna, methotrexate, methoXSalen, mal, ophthalmic, epidural, intratracheal, Sublingual, buccal, mitomycin C, mitotane, mitoxantrone, nadrolone phenpro rectal, vaginal, nasal or inhalation. pionate, Nofetumomab, Oprelvekin, oxaliplatin, paclitaxel, 36. The method of claim 23, wherein the first composition pamidronate, pegademase, Pegaspargase, Pegfilgrastim, further comprises an additive selected from an anti-oxidant, pnetostatin, pipobroman, plicamycin (mithramycin), por a buffer, a bacteriostat, a liquid carrier, a solute, a Suspending fimer Sodium, procarbazine, quinacrine Rasburicase, Ritux agent, a thickening agent, a flavoring agent, a gelatin, a imab, Sargramotim, streptozocin, talc, tamoxifen, temoZo glycerin, a binder, a lubricant, an inert diluent, a preserva lomide, teniposide (VM-26), testolactone, thioguanine tive, a Surface active agent, a dispersing agent, a biodegrad (6-TG), thiotepa, topotecan, toremifene, Tositumomab, able polymer, or any combination thereof. Trastuzumab, tretinoin (ATRA), Uracil Mustard, valrubicin, 37. The method of claim 23, wherein the first composition vinblastine, Vincristine, Vinorelbine and Zoledronate. is administered in the form of a tablet, a capsule, a lozenge, 26. The method of claim 23, wherein the anti-cancer agent a cachet, a solution, a Suspension, an emulsion, a powder, an is an angiogenesis inhibitor. aerosol, a Suppository, a spray, a pastille, an ointment, a 27. The method of claim 26, wherein the angiogenesis cream, a paste, a foam, a gel, a tampon, a pessary, a granule, inhibitor is selected from one or more of the following: a bolus, a mouthwash, or a transdermal patch. Bevacizumab, alpha interferon, angiogenic steroids, Batim 38. The method of claim 23, wherein the administration of astat (BB-94), carboxyaminoimidazole (CAI), CM101 the second composition is oral, parenteral, transdermal, (GBS toxin), CT-2548, hydrocortisone/beta-cyclodextran, intravenous, Subcutaneous, intramuscular, intradernal, epi interleukin-12, Linomide, Marimastat (BB-2516), Oct dural, or intratracheal, Sublingual, buccual, rectal, vaginal, reotide (somatostatin analogue), Pentosan polysulfate, plate nasal or inhalation. let factor 4, Roquinimex (LS-2616, linomide), Suramin, 39. The method of claim 23, wherein the second compo SU101, Tecogalan sodium (DS-4152), thalidomide and its sition is administered in the form of a tablet, a capsule, a derivatives, TNP-470 (AGM-1470), angiostatin, endostatin, lozenge, a cachet, a solution, a suspension, an emulsion, a beta interferon, gamma interferon, cartilage-derived inhibi powder, an aerosol, a Suppository, a spray, a pastille, an tor (CDI), gamma interferon inducibile protein (IP-10), ointment, a cream, a paste, a foam, a gel, a tampon, a gro-beta, heparinases, placental ribonuclease inhibitor, plas pessary, a granule, a bolus, a mouthwash, or a transdermal mingoen activator inhibitor, proliferen-related protein, ret patch. inoids, thrombospondin, TIMP-2, and 16 kd prolactin. 40. The method of claim 23, wherein the angiogenesis is 28. The method of claim 23, wherein the anti-cancer agent associated with diabetic retinopathy, retinopathy of prema is a kinase inhibitor. turity, corneal graft rejection, neovascular glaucoma, retro 29. The method of claim 28, wherein the kinase inhibitor lental fibroplasias, epidemic keratoconjunctivitis, Vitamin A is selected from one or more of the following: cetuximab, deficiency, contact lens overwear, atopic keratitis, Superior Erlotinib, gefitinib, PKI-166, Canertinib (CI-1033), limbic keratitis, pterygium keratitis sicca, Sjögren's Syn SU-11464, Matuzumab (Emd7200), EKB-569, Zdo474, drome, acne rosacea, phylectenulosis, syphilis, Mycobacte Trastuzumab, GW-572016 (lapatinib ditosylate), PKC-412, ria infections, lipid degeneration, chemical burns, bacterial Sutent, Vatalanib (Ptk787/ZK222584), CEP-701, SU5614, ulcers, fungal ulcers, Herpes simplex infections, Herpes MLN518, XL999, VX-322, VEGF-trap, Imatinib mesylate, zoster infections, protozoan infections, Kaposi's sarcoma, AZd0530, BMS-354825, SKI-606, CP-690, AG-490, WHI Mooren’s ulcer, Terrien’s marginal degeneration, marginal P154, WHI-P131, Sirolimus, Everolimus, AP23573, Fasudil keratolysis, trauma, arthritis, rheumatoid arthritis, pol hydrochloride, Flavopiridol, Seliciclib (CYC202, rosco yarteritis, Systemic lupus, Wegener's sarcoidosis, Scleritis, vitine), SNS-032, Ruboxistaurin, Pkc412, Bryostatin, KAI Stevens-Johnson disease, radial keratotomy, macular degen 98.03, SF1126, VX-680, AZd 1152, Arry-142886 (AZD eration, sickle cell anemia, sarcoid, pseudoxanthoma elas 6244), SCIO-469, GW681323 (SB-681323), CC-401, CEP ticum, Paget’s disease, vein occlusion, artery occlusion, 1347, Semaxanib (SU5416), Sunitinib (SU11248) and carotid obstructive disease, chronic uveitis, chronic vitritis, Sorafenib (BAY 43-9006). Lyme’s disease, Eales disease, Behcet’s disease, myopia, 30. The method of claim 23, wherein the anti-cancer agent optic pits, Stargardt’s disease, pars planitis, chronic retinal is an histone deacetylase inhibitor. detachment, hyperviscosity syndromes, toxoplasmosis, 31. The method of claim 30, wherein the histone deacety post-laser complications, abnormal proliferation offibrovas lase inhibitor is selected from on or more of the following: cular or fibrous tissue, hemangiomas, Osler-Weber-Rendu AN-9 (butyric acid prodrug), sodium phenylbutrate, valp disease, Solid tumors, blood-borne tumors, acquired immune roic acid, FK-228 (cyclic depsipeptide), MS-275 (benza deficiency syndrome, ocular neovascular disease, age-re mide), suberoylanilide hydroxamic acid and LAQ-824. lated macular degeneration, osteoarthritis, diseases caused US 2007/0185.069 A1 Aug. 9, 2007

by chronic inflammation, Crohn's disease, ulcerative colitis, ine, carboplatin, carmustine, carmustine with Polifeprosan tumors of rhabdomyosarcoma, tumors of retinoblastoma, 20 implant, celecoxib, chlorambucil, cisplatin, cladribine, Ewing's sarcoma, neuroblastoma, tumors of osteosarcoma, cyclophosphamide, cytarabine, cytarabine liposomal, dacar leukemia, psoriasis, atherosclerosis, pemphigoid, infections bazine, dactinomycin actinomycin D. Darbepoetin alfa, causing retinitis, infections causing choroiditis, presumed daunorubicin liposomal, daunorubicin, daunomycin, ocular histoplasmosis, Best’s disease, proliferative vitreore Denileukin difitox, dexraZOxane, docetaxel, doxorubicin, tinopathy, Bartonellosis, acoustic neuromas, neurofibroma, doxorubicin liposomal, Dromostanolone propionate, Elliot's trachoma, pyogenic granulomas, vascular malfunctions, B Solution(R), epirubicin, Epoetin alfa, estramustine, etopo abnormal wound healing, gout or gouty arthritis, angiogen esis-dependent cancer, hereditary hemorrhagic telangiecta side phosphate, etoposide VP-16, exemestane, Filgrastim, sia, post-menopausal symptoms, osteoporosis, cardiovascu floxuridine, fludarabine, fluorouracil, fulvestrant, gemcitab lar disease, myocardial angiogenesis, plaque ine, bemtuzumab ozogamicin, goserelin acetate, hydrox neovascularization, hemophiliac joints, angiofibroma, yurea, Ibritumomab Tiuxetan, idarubicin, ifosfamide, ima wound granulation, intestinal adhesions, Scleroderma, kel tinib mesylate, Interferon alfa-2a, Interferon alfa-2b, oids, endometriosis. irinotecan, letrozole, leucovorin, levamisole, lomustine 41. The method of claim 23, wherein the angiogenesis is CCNU, meclorethamine (nitrogen mustard), megestrol associated with angiogenesis-dependent cancers selected acetate, melphalan (L-PAM), mercaptopurine (6-MP), from breast cancer, prostrate cancer, renal cell cancer, brain mesna, methotrexate, methoXSalen, mitomycin C, mitotane, cancer, ovarian cancer, colon cancer, bladder cancer, pan mitoxantrone, nadrolone phenpropionate, Nofetumomab, creatic cancer, stomach cancer, esophageal cancer, cutane Oprelvekin, oxaliplatin, paclitaxel, pamidronate, pegade ous melanoma, liver cancer, lung cancer, testicular cancer, mase, Pegaspargase, Pegfilgrastim, pnetostatin, pipobro kidney cancer, bladder cancer, cervical cancer, lymphoma, man, plicamycin (mithramycin), porfimer Sodium, procar parathyroid cancer, penile cancer, rectal cancer, Small intes bazine, quinacrine Rasburicase, Rituximab, Sargramotim, tine cancer, thyroid cancer, uterine cancer, Hodgkin’s lym streptozocin, talc, tamoxifen, temozolomide, teniposide phoma, lip and oral cancer, skin cancer, leukemia or multiple (VM-26), testolactone, thioguanine (6-TG), thiotepa, topo myeloma. tecan, toremifene, Tositumomab, Trastuzumab, tretinoin 42. The method of claim 41, wherein the cancer is colon (ATRA), Uracil Mustard, valrubicin, vinblastine, Vincris CaCC. tine, vinorelbine and Zoledronate. 43. The method of claim 41, wherein the cancer is ectopic 48. The composition of claim 45, wherein the anti-cancer or orthotopic glioma. agent is an angiogenesis inhibitor. 44. The method of claim 41, wherein the cancer is 49. The composition of claim 48, wherein the angiogen multiple myeloma. esis inhibitor is selected from one or more of the following: 45. A composition for treating diseases associated with Bevacizumab, alpha interferon, angiogenic steroids, Batim undesirable and/or excessive angiogenesis and/or undesir astat (BB-94), carboxyaminoimidazole (CAI), CM101 able cell proliferation comprising: (GBS toxin), CT-2548, hydrocortisone/beta-cyclodextran, interleukin-12, Linomide, Marimastat (BB-2516), Oct a) a compound selected from one or more of the follow reotide (somatostatin analogue), Pentosan polysulfate, plate ing: let factor 4, Roquinimex (LS-2616, linomide), Suramin, SU101, Tecogalan sodium (DS-4152), thalidomide and its derivatives, TNP-470 (AGM-1470), angiostatin, endostatin, OH: beta interferon, gamma interferon, cartilage-derived inhibi tor (CDI), gamma interferon inducibile protein (IP-10), gro-beta, heparinases, placental ribonuclease inhibitor, plas mingoen activator inhibitor, proliferen -related protein, ret inoids, thrombospondin, TIMP-2, and 16kd prolactin. 50. The composition of claim 45, wherein the anti-cancer HO agent is a kinase inhibitor. 51. The composition of claim 50, wherein the kinase inhibitor is selected from one or more of the following: wherein R is selected from —OCH —OCHCH cetuximab, Erlotinib, gefitinib, PKI-166, Canertinib (CI —CH, —CHCH. —CCCH, —CHCH-CH or 1033), SU-11464, Matuzumab (Emd7200), EKB-569, CH-CHCH: Zdé474, Trastuzumab(R), GW-572016 (lapatinib ditosylate), PKC-412, Sutent, Vatalanib (Ptk787/ZK222584), CEP-701, b) one or more anti-cancer agents; and SU5614, MLN518, XL999, VX-322, VEGF-trap, Imatinib c) a pharmaceutically acceptable carrier, diluent, or mesylate, AZd0530, BMS-354825, SKI-606, CP-690, excipient. AG-490, WHI-P154, WHI-P131, Sirolimus, Everolimus, 46. The composition of claim 45, wherein the anti-cancer AP23573, Fasudil hydrochloride, Flavopiridol, Seliciclib agent is a chemotherapeutic. (CYC202, roscovitine), SNS-032, Ruboxistaurin, Pk.c412, 47. The composition of claim 46, wherein the chemo Bryostatin, KAI-9803, SF1126, VX-680, AZd 1152, Arry therapeutic agent is selected from the following; Aldeskeu 142886 (AZD-6244), SCIO-469, GW681323 (SB-681323), kin, Alemtuzumab, alitretinoin, allopurinol, altretamine, CC-401, CEP-1347, Semaxanib (SU5416), Sunitinib amifostine, anastroZole, arsenic trioxide, Asparaginase, (SU11248) and Sorafenib (BAY 43-9006). BCG Live, beXaroteine capsules, beXarotenegel, bleomycin, 52. The composition of claim 45, wherein the anti-cancer buSulfan intravenous, buSulfan oral, calusterone, capecitab agent is an histone deacetylase inhibitor. US 2007/0185.069 A1 Aug. 9, 2007 14

53. The composition of claim 52, wherein the histone 54. The composition of claim 45, wherein the anti-cancer deacetylase inhibitor is selected from on or more of the agent is a proteosome inhibitor. following: AN-9 (butyric acid prodrug), sodium phenyl- 55. The composition of claim 54, wherein the proteosome butrate, valproic acid, FK-228 (cyclic depsipeptide), inhibitor is bortezomib. MS-275 (benzamide), suberoylanilide hydroxamic acid and LAQ-824. k . . . .