Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• This invention relates generally to the use of selenate or its pharmaceutically acceptable salts, especially in supranutritional amounts, in methods and compositions for inhibiting the growth or proliferation of benign tumor cells.
• the present invention also relates to the use of selenate or a pharmaceutically acceptable salt thereof in combination with at least one other therapy for treating or preventing benign tumors or for inhibiting the growth, or proliferation of benign tumor cells.
• the methods of the invention are useful for treating or preventing benign tumors, especially benign tumors in which the Akt signaling pathway is activated or benign tumors in which Bcl-2 levels are elevated.
• the present invention relates to the use of selenate or a pharmaceutically acceptable salt thereof for preventing malignant conversion of benign tumor cells or benign tumors to malignant tumor cells or malignant tumors.
• benign tumors Although many benign tumors are asymptomatic and harmless, some benign tumors occur in positions that cause symptoms such as pain and in the brain or spine symptoms such as loss of mobility, loss of sight etc. Some benign tumors may cause clinical symptoms that are bothersome to a patient, for example, lower urinary tract symptoms (LUTS) resulting from benign prostatic hyperplasia. Some benign tumors may grow to a size that causes damage to tissues, organs or nerves in its vicinity, whilst others may cause serious illness or death if they occur near vital organs or press against vital organs. Some 13,000 deaths per year in the US are attributed to benign tumors and many more benign tumors require treatment. Furthermore, some benign tumors are known to have a high propensity to undergo malignant conversion to produce malignant or cancerous tumors.
• LUTS lower urinary tract symptoms
• Selenium compounds used in chemoprevention studies can broadly be classified into inorganic and organic selenium forms.
• the typical form of inorganic selenium, sodium selenite, (Na 2 SeO 3 ) is relatively toxic, causing single- and double-strand break DNA damage, whilst the typical organic selenium entity, selenomethionine (SeMet) is relatively non-toxic and non-DNA-damaging (Lu et al. 1995, Biochem. Pharmacol. 50(2):213-9; Sinha et al. 1996, Cancer Lett. 107(2):277-84; Stewart et al. 1999, Free Radic. Biol. Med. 26(l-2):42-8).
• Akt is a serine/threonine kinase that is activated in response to membrane receptor stimulated PI3K phosphorylation.
• Akt regulates the activity of several proteins involved in the control of apoptosis, including the Forkhead (FKHR) transcription factors, Bad, Caspase 9, GSK-3 ⁇ and mTOR (Vivanco, I. and Sawyers, CL. 2002, Nat. Rev. Cancer 2:289-501).
• FKHR Forkhead transcription factors
• Bad Caspase 9
• GSK-3 ⁇ mTOR
• Akt overactivity may occur in benign tumors resulting in lack of apoptosis.
• higher than normal levels of Bcl-2 proteins may occur in benign tumors, including those that may be susceptible to malignant conversion.
• Radiotherapy resistance in tumor cells has also been linked with upregulation of the PI3K/Akt pathway (Soderlund et al. 2005, Int. J. Oncol., 26:25-32; Zhan et al. 2004, Histol. Histopathol., 19:915-923; Tanno et al. 2004, Cancer Res., 64:3486-3490; Li et al. 2004, Oncogene, 23:4594-4602; McKenna et al., 2003, Genes Chromosomes Cancer, 28:330-338; Liang et al. 2003, MoI Cancer Ther. 2:353-360).
• the present invention is predicated in part on the discovery that a specific type of inorganic selenium compound, namely selenate, significantly inhibits benign tumor cell proliferation, especially when used at high or supranutritional amounts, as compared to other selenium compounds. It has also been found that selenate and its pharmaceutically acceptable salts have an inhibitory effect on benign tumor cells, especially those in which the Akt signaling pathway is activated or those in which Bcl-2 activity is elevated, and have a strong synergistic inhibitory effect on benign tumor cell growth when used in combination with at least one of a cytostatic agent, a cytotoxic agent and a radiotherapy that is optionally administered with a radiosensitizing agent. Further, it has been found that selenate and its pharmaceutically acceptable salts have an inhibitory effect on malignant conversion of benign tumor cells to malignant tumor cells.
• the present invention provides methods for inhibiting the growth or proliferation of benign tumor cells. These methods generally comprise exposing the benign tumor cells to an effective amount of selenate or a pharmaceutically acceptable salt thereof.
• the benign tumor cells are tumor cells in which the Akt-signaling pathway is activated.
• the activation of the Akt signaling pathway involves activation of at least one member selected from Akt, mTOR, GSK-3 ⁇ and FKHR.
• the activation of the Akt signaling pathway involves phosphorylation of Akt (e.g., phosphorylation of the Thr 308 and Ser 473 residues of Akt).
• the activation of the Akt signaling pathway involves inactivation of PTEN. In some embodiments, the Akt signaling pathway is over-activated. In some embodiments, the benign tumor cells have an abnormally increased Bcl-2 activity. In some embodiments, the amount of selenate or its pharmaceutically acceptable salt, to which the tumor cells are exposed, is a nutritional amount. In other embodiments, the amount is a supranutritional amount.
• the tumor cells are selected from benign adenoma tumor cells, angiofibroma tumor cells, hemangioma tumor cells, leiomyoma tumor cells (fibroid), benign chorangioma tumor cells, cystadenoma tumor cells, dermoid tumor cells, desmoid tumor cells, fibroadenoma tumor cells, fibroma tumor cells, benign ganglioneuroma tumor cells, lipoma tumor cells, meningioma tumor cells, myxoma tumor cells, neurofibroma tumor cells, nevus tumor cells, osteochondroma tumor cells, pheochromocytoma tumor cells, polyposis tumor cells, schwannoma tumor cells, benign teratoma tumor cells, benign thymoma tumor cells and Brenner tumor cells.
• the tumor cells are prostatic intraepithelial neoplasia (PIN) tumor cells, benign prostatic hyperplastic (hypertrophic) tumor cells, ductal carcinoma in situ (DCIS) tumor cells, meningioma tumor cells or benign colonic tumor cells (colon polyps).
• PIN prostatic intraepithelial neoplasia
• DCIS ductal carcinoma in situ
• colon polyps benign colonic tumor cells
• the present invention provides methods for preventing malignant conversion of a benign tumor cell to a malignant tumor cell. These methods generally comprise administering to the subject a therapeutically effective amount of selenate or a pharmaceutically acceptable salt thereof.
• the therapeutically effective amount is a nutritional amount.
• the therapeutically effective amount is a supranutritional amount.
• the benign tumor cell is a benign colonic or rectal tumor cell, a high grade prostatic intraepithelial neoplasia tumor cell, an atypical small acinar proliferative tumor cell or a ductal carcinoma in situ (DCIS) tumor cell.
• DCIS ductal carcinoma in situ
• the present invention provides a use of selenate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a benign tumor.
• the present invention provides a use of selenate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing malignant conversion of benign tumors to malignant tumors.
• the selenate or its pharmaceutically acceptable salt is administered in combination with at least one of a cytostatic agent, a cytotoxic agent or a radiotherapy that is optionally administered with a radiosensitizing agent.
• the selenate is formulated in a composition with at least one cytostatic agent or cytotoxic agent.
• the selenate is formulated in a composition with a radiosensitizing agent for use in combination with radiotherapy.
• Figure 1 graphically represents the growth inhibitory (cytostatic) effect of sodium selenate at 25 ⁇ M, 50 ⁇ M and 100 ⁇ M on prostate stromal cells with time.
• Figure 2 graphically represents the growth inhibitory effect of sodium selenate at 25 ⁇ M, 50 ⁇ M and 100 ⁇ M on the proliferation of prostate stromal cells at 4 days (A), 11 days (B) and 18 days (C).
• the term "Akt signaling pathway activation-inhibiting amount” in the context of treating or preventing a benign tumor or inhibiting the growth of benign tumor cells is meant the administration of an amount or series of doses of selenate, which is effective in antagonizing the Akt signaling pathway, including preventing or reducing activation of Akt by preventing or reducing the expression of Akt or an upstream member of the pathway, or by reducing the level or functional activity of an expression product of the Akt gene or of an upstream gene member of the pathway, or by preventing or reducing phosphorylation of Akt.
• an Akt signaling pathway activation-inhibiting amount is a nutritional or supranutritional amount of selenate.
• Bcl-2 activity-reducing amount in the context of treating or preventing a benign tumor or inhibiting the growth of benign tumor cells is meant the administration of an amount or series of doses of selenate, which is effective in reducing the levels of Bcl-2 activity in benign tumor cells or benign tumors, including downregulating Bcl-2 transcription and modulation of activity of Bcl-2.
• the amount will vary depending on the health and physical condition of the individual to be treated, the taxonomic group of the individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall within a relatively broad range that can be determined by routine trials.
• a Bcl-2 activity-reducing amount is a nutritional or supranutritional amount of selenate.
• benign tumor in which Bcl-2 activity is elevated is meant a benign tumor which has levels of Bcl-2 protein that are above levels found in normal cells. Normal levels of Bcl-2 protein found in normal cells are very low and generally not detectable. Benign tumors in which Bcl-2 activity is elevated may undergo malignant conversion to malignant tumors in which Bcl-2 activity is elevated. Examples of such benign tumors include colonic polyps and DCIS which may convert to colon cancer or breast cancer respectively.
• Benign tumor refers to abnormal growth or proliferation cells in a localised manner. Benign tumors do not invade surrounding tissue or metastasize to other organs. Benign tumors may be asymptomatic, and discovered, for example, by screening, or they may be symptomatic and require treatment. Benign tumors although causing no immediate threat to the subject, may grow and press on other tissues or organs resulting in symptoms of the tumor, for example a meningioma in the brain may grow to a size where it damages the brain or causes malfunction in the brain. In some cases, a benign tumor may undergo malignant conversion to give a malignant tumor or cancer.
• benign tumors include, but are not limited to benign adenomas, angiofibromas, hemangiomas, leiomyomas, benign chorangiomas, cys.tadenomas, dermoid tumors, desmoid tumors, fibroadenomas, fibromas, benign ganglioneuromas, lipomas, meningiomas, myxomas,. neurofibromas, nevus tumors, osteochondromas, pheochromocytomas, polyps such as colonic polyps, schwannomas, benign teratomas, benign thyomas and Brenner tumors.
• Other types of benign tumors include prostatic intraepithelial neoplasia, benign prostatic hyperplastic (hypertrophic) tumors and ductal carcinoma in situ.
• cytostatic agent refers to a substance that can inhibit cell proliferation or cell division without necessarily killing the cell.
• the cytostatic agent inhibits the proliferation of tumor cells.
• cytotoxic agent or "cytotoxic therapy” as used herein refers to a substance or therapy that is harmful to cells and ultimately causes cell death.
• the cytotoxic agent harms rapidly dividing cells such as tumor cells and causes tumor cell death, especially tumor cell death while not causing damage to or causing less damage to non-tumor cells.
• An example of a cytotoxic therapy is radiotherapy.
• drug resistant and “refractory” refer to a tumor cell which is unresponsive or partially unresponsive to treatments normally used to treat the cancer or kill the tumor cell.
• the term "in combination with” refers to the treatment of cancer or exposure of a tumor cell to at least two agents such that their effects on the tumor cell occur, at least in part, over the same time period. Administration of at least two agents may occur simultaneously in a single composition, or each agent may be simultaneously or sequentially administered in separate compositions.
• tumor cell growth is ceased or reduced and cell proliferation or cell division is ceased or reduced. This is also known as cytostasis.
• the growth of tumor cells can be measured in terms of weight or volume or cell number or cellular metabolic activity, i.e. MTT assay.
• malignant conversion refers to the conversion of benign tumors or benign tumor cells into malignant tumors or malignant tumor cells. Once malignant conversion has occurred, the tumor or tumor cells may invade other tissues or metastasize to other organs or tissues, and the subject has a cancerous tumor. Examples of benign tumors that undergo malignant conversion include colonic polyps and DCIS which may be converted to colon cancer or breast cancer respectively.
• the term "nutritional amount” includes an amount of selenium that provides an average daily intake. In the US, the average daily intake is 80-120 ⁇ g/day.
• pharmaceutically acceptable carrier it is meant a solid or liquid filler, diluent or encapsulating substance that may be safely used in topical, local or systemic administration.
• Suitable metal ion salts of selenate include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, iron, nickel, zinc, ammonium and alkylammonium salts.
• a preferred salt of selenate is the sodium salt, Na 2 SeO 4 .
• radiotherapy refers to the treatment or exposure of a tumor or tumor cells to high energy radiation.
• the effectiveness of radiotherapy may be enhanced by selenate or its pharmaceutically acceptable salt.
• radiotherapy may be further enhanced by administration of radiosensitizing agent.
• Illustrative examples of radiosensitizing agents include but are not limited to efaproxiral, etanidazole, fluosol, misonidazole, nimorazole, temoporf ⁇ n and tirapazamine.
• vertebrate subject refers to any subject, particularly a vertebrate subject and more particularly a mammalian subject, for whom prophylaxis or treatment is desired.
• Suitable vertebrate animals include, but are not limited to, primates, avians, livestock animals (e.g., pigs, sheep, cows, horses, donkeys), laboratory test animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats and dogs) and captive wild animals (e.g., foxes, deer, dingoes).
• a preferred subject is a human in need of treatment or prophylaxis of a benign tumor or may be at risk of a benign tumor undergoing malignant conversion to a malignant tumor.
• the aforementioned terms do not imply that symptoms are present.
• the average daily intake of selenium in the US is 80-120 ⁇ g/day.
• a supranutritional amount of selenium provides selenium to a subject at above the recommended daily allowance.
• a supranutritional amount of selenium may be 3 ⁇ g/kg to 20 mg/kg per day, 0.015 mg/kg to 20 mg/kg, 0.15 mg/kg to 20.0 mg/kg, 0.1 mg/kg to 14 mg/kg, 0.1 mg/kg to 13 mg/kg, 0.1 mg/kg to 12 mg/kg, 0.1 mg/kg to 10 mg/kg, 0.1 mg/kg to 9 mg/kg, 0.1 mg/kg to 8 mg/kg, 0.1 mg/kg to 7 mg/kg, 0.1 mg/kg to 6 mg/kg, 0.15 mg/kg to 5 mg/kg, 0.15 mg/kg to 4 mg/kg, 0.15 mg/kg to 3 mg/kg, 0.15 mg/kg to 2 mg/kg, 0.15 mg/kg to 1 mg/kg, especially 0.07 mg/kg to 6.5 mg/kg or 0.1 mg/kg to 14 mg/kg or 0.15 mg/kg to 5 mg/kg per day, and more especially 0.07 mg/kg to 2 mg/kg per day.
• an effective amount in the context of treating or preventing a benign tumor or inhibiting the growth of benign tumor cells is meant the administration of an amount of selenate or a pharmaceutically acceptable salt thereof, either in a single dose or as part of a series of doses, that is effective for inhibiting the growth and/or proliferation of benign tumor cells or for causing benign tumor cell death or for preventing metastatic conversion of a benign tumor to a malignant tumor.
• the effective amount will vary depending on the health and physical condition of the individual to be treated, the taxonomic group of the individual to be treated, and the formulation of the composition, the assessment of the medical situations and other relevant factors. It is expected that the amount will fall within a relatively broad range that can be determined through routine trials.
• an effective amount is a nutritional or supranutritional amount.
• an effective amount is an Akt-signaling pathway activation inhibiting amount or a Bcl-2 activity-reducing amount.
• the present invention is predicated in part on the determination that selenate, as opposed to other forms of selenium such as selenite, is effective in inhibiting the growth or proliferation of benign tumor cells, especially those in which the Akt signaling pathway is activated or in which Bcl-2 activity is elevated. Accordingly, in one aspect, the present invention provides methods for inhibiting the growth or proliferation of benign tumor cells, wherein the methods generally comprise exposing the tumor cells to an effective amount, such as an Akt signaling pathway activation-inhibiting amount or a Bcl-2 activity-reducing amount of selenate or a pharmaceutically acceptable salt thereof. In some embodiments of the invention, the amount of selenate or its pharmaceutically acceptable salt thereof is a nutritional amount.
• the amount of selenate or its pharmaceutically acceptable salt is a supranutritional amount, which is generally from about 0.015 mg/kg to 20.0 mg/kg, usually from about 0.07 mg/kg to 6.5 mg/kg or 0.1 mg/kg to 14 mg/kg or from about 0.15 mg/kg to 5 mg/kg, especially 0.07 mg/kg to 2 mg/kg per day.
• the present invention can be used effectively against various types of tumor cells.
• benign tumors that may be treated or prevented include, but are not limited to benign adenomas, angiofibromas, hemangiomas, leiomyomas, benign chorangiomas, cystadenomas, dermoid tumors, desmoid tumors, fibroadenomas, fibromas, benign ganglioneuromas, lipomas, meningiomas, myxomas, neurofibromas, nevus tumors, osteochondromas, pheochromocytomas, polyps, schwannomas, benign teratomas, benign thyomas and Brenner tumors.
• the tumor is a prostatic intraepithelial neoplasia, colonic polyps, atypical small acinar proliferative tumor cells, benign prostatic hyperplastic (hypertrophic) tumor cells (benign prostatic hyperplasia) or a ductal carcinoma in situ.
• the invention provides methods for treating or preventing a benign tumor in which Akt is activated, wherein the methods generally comprise administering to a subject in need thereof an Akt signaling pathway activation-inhibiting amount of selenate or a pharmaceutically acceptable salt thereof.
• the invention provides methods for treating or preventing a benign tumor in which Bcl-2 activity is elevated, wherein the methods generally comprise administering to a subject in need thereof a Bcl-2 activity-reducing amount of selenate or a pharmaceutically acceptable salt thereof.
• the amount of selenate or pharmaceutically acceptable salt thereof is a nutritional amount. In other embodiments, the amount is a supranutritional amount as broadly defined above.
• the tumor cell is drug resistant. In some embodiments, the tumor cell has an overactive Akt pathway.
• the selenate or its pharmaceutically acceptable salt is administered in combination with at least one cytostatic agent or cytotoxic agent.
• cytostatic agents are selected from: (1) kinase inhibitors, illustrative examples of which include Iressa®, Gleevec, TarcevaTM, (Erlotinib HCl), BAY-43-9006, inhibitors of the split kinase domain receptor tyrosine kinase subgroup (e.g., PTK787/ZK 222584 and SUl 1248); (2) receptor kinase targeted antibodies, which include, but are not limited to, Trastuzumab (Herceptin®), Cetuximab (Erbitux®), Bevacizumab (AvastinTM), Rituximab (ritusan®), Pertuzumab (OmnitargTM); (3) mTOR pathway inhibitors, illustrative examples of which include rapamycin and C
• the methods of the present invention may be employed in combination with other known treatments for benign tumors, for instance but not limited to, surgery, chemotherapy and radiotherapy.
• the selenate or its pharmaceutically acceptable salt is used in combination with radiotherapies, such as but not limited to, conformal external beam radiotherapy (50-100 Grey given as fractions over 4-8 weeks), either single shot or fractionated, high dose rate brachytherapy, permanent interstitial brachytherapy, systemic radio-isotopes (e.g., Strontium 89).
• the radiotherapy may be administered in combination with a radiosensitizing agent.
• radiosensitizing agents include but are not limited to efaproxiral, etanidazole, fluosol, misonidazole, nimorazole, temoporfin and tirapazamine.
• selenate or its pharmaceutically acceptable salt is used in combination with a tumorectomy.
• the cytostatic agent is a nucleic acid molecule, suitably an antisense or siRNA recombinant nucleic acid molecule.
• the cytostatic agent is a peptide or polypeptide.
• the cytostatic agent is small molecule.
• the cytostatic agent may be a cytotoxic agent that is suitably modified to enhance uptake or delivery of the agent.
• modified cytotoxic agents include, but are not limited to, pegylated or albumin-labelled cytotoxic drugs.
• the selenate or pharmaceutically acceptable salt thereof may be administered in combination with 5-alpha reductase inhibitors such as finasteride or dutasteride; alpha adrenergic receptor blockers such as terazosin (Hytrin), doxazosin (cardura), alfuzosin, tamsulosin (flomax) and Prazosin (Minipress); selective estrogen receptor modulators (SERMs) such as toremifene citrate (Acapodene), tamoxifen and raloxifen; selective androgen receptor modulators (SARMs) such as prostarine; or phytotherapeutics such as those derived from the American dwarf palm tree (saw palmetto or Serenoa repens), African plum tree (Pygeum africanum), pumpkin seeds, rye
• 5-alpha reductase inhibitors such as finasteride or dutasteride
• alpha adrenergic receptor blockers such as terazosin
• the selenate or pharmaceutically acceptable salt thereof may be administered in combination with non steroidal anti inflammatory drugs such as aspirin, ibuprofen, naproxene; or Cox-2 inhibitors such as sulindac, celocoxib (celebrex), refocoxib (vioxx) and lumiracoxib.
• non steroidal anti inflammatory drugs such as aspirin, ibuprofen, naproxene
• Cox-2 inhibitors such as sulindac, celocoxib (celebrex), refocoxib (vioxx) and lumiracoxib.
• the selenate or pharmaceutically acceptable salt thereof may be administered in combination with selective estrogen receptor modulators such as tamoxifen, raloxifen and toremifene citrate.
• the selenate or pharmaceutically acceptable salt thereof may be administered in combination with progesterone receptor antagonists such as mifepristone; immune modulating agents such as interferon; chemotherapy such as hydroxyurea and external beam radiation.
• progesterone receptor antagonists such as mifepristone
• immune modulating agents such as interferon
• chemotherapy such as hydroxyurea and external beam radiation.
• Certain embodiments of the present invention are directed to methods for treating or preventing a benign tumor in a subject, which methods generally comprise administering to the subject a therapeutically effective amount of selenate or a pharmaceutically acceptable salt thereof.
• the person managing the subject can determine the effective dosage form of selenate or its pharmaceutically acceptable salts for the particular condition and circumstances of the subject.
• a therapeutically effective amount of selenate is one that is effective for the treatment or prevention of the benign tumor, including the prevention of incurring a symptom (e.g., proliferation of tumor cells), holding in check such symptoms, and/or treating existing symptoms associated with the tumor (e.g., pain, tenderness, headaches, menstrual irregularity, urinary retention, cosmetic effect, shortness of breath, altered bowel habit, malena, haematemesis, focal neurological deficit).
• the therapeutically effective amount is a nutritional amount.
• the amount is a supranutritional amount of selenate or its pharmaceutically acceptable salt.
• the selenate is suitably in the form of the salt, sodium selenate (Na 2 SeO 4 ).
• the tumor to be treated may be determined by measuring one or more diagnostic parameters indicative of the course of the disease, compared to a suitable control.
• a "suitable control” may be the individual before treatment, or may be a human (e.g., an age-matched or similar control) treated with a placebo.
• the treatment or prevention of a benign tumor includes and encompasses without limitation: (i) preventing a benign tumor in a subject who may be predisposed to the benign tumor but has not yet been diagnosed with the benign tumor and, accordingly, the treatment constitutes prophylactic treatment for the benign tumor; (ii) inhibiting tumorigenesis, i.e., arresting the development of the benign tumor; (iii) relieving symptoms resulting from the benign tumor; or (iv) preventing malignant conversion of a benign tumor.
• the methods of the present invention are suitable for treating an individual who has been diagnosed with a benign tumor, who is suspected of having a benign tumor, who is known to be susceptible and who is considered likely to develop a benign tumor, who is considered likely to develop a recurrence of a previously treated benign tumor, or who has a benign tumor which may undergo malignant conversion to a malignant tumor.
• the benign tumor is a high grade prostatic intraepithelial neoplasia (HGPIN), colonic polyp or ductal carcinoma in situ (DCIS) that may undergo malignant conversion to prostate cancer, colon cancer or breast cancer respectively.
• the tumor to be treated may be a meningioma.
• Exemplary subjects for treatment with the methods of the invention are vertebrates, especially mammals.
• the subject is selected from the group consisting of humans, sheep, cattle, horses, bovine, pigs, dogs and cats.
• a preferred subject is a human.
• the selenate or pharmaceutically acceptable salt may be formulated by following any number of techniques known in the art of drug delivery.
• Selenate or its pharmaceutically acceptable salts may of course be administered by a number of means keeping in mind that all formulations are not suitable for every route of administration.
• Selenate or its pharmaceutically acceptable salts can be administered in solid or liquid form.
• the application may be oral, rectal, nasal, topical (including buccal and sublingual), or by inhalation.
• Selenate or its pharmaceutically acceptable salts may be administered together with conventional pharmaceutical acceptable adjuvant,, carriers and/or diluents.
• the solid forms of application comprise tablets, capsules, powders, pills, pastilles, suppositories and granular forms of administration. They may also include carriers or additives, such as flavors, dyes, diluents, softeners, binders, preservatives, lasting agents and/or enclosing materials. Liquid forms of administration include solutions, suspensions and emulsions. These may also be offered together with the above-mentioned additives.
• Solutions and suspensions of selenate or pharmaceutically acceptable salt thereof may be injected. Suspensions too viscous for injection may be implanted using devices designed for such purposes, if necessary. Sustained release forms are generally administered via parenteral or enteric means. Parenteral administration is another route of administration of the selenate or a pharmaceutically acceptable salt thereof used to practice the invention.
• Parenteral administration is another route of administration of the selenate or a pharmaceutically acceptable salt thereof used to practice the invention.
• Parenteral administration includes formulations suitable for injection and for nasal, vaginal, rectal, and buccal administration.
• the administration of selenate or its pharmaceutically acceptable salts may involve an oral prolonged dose formulation.
• Oral dose formulations are preferably administered once daily to three times daily in the form of a sustained release capsule or tablet, or alternatively as an aqueous based solution.
• Selenate or its pharmaceutically acceptable salt may be administered intravenously either daily, continuously, once a week or three times a week.
• the administration of selenate or its ' pharmaceutically acceptable salts may include daily administration, preferably once daily in the form of a sustained release capsule or tablet, or once daily as an aqueous solution.
• Combinations of selenate or its pharmaceutically acceptable salt and at least one cytostatic agent or a cytotoxic agent or a radiosensitizing agent may be administered in solid or liquid form in a single formulation or composition or in separate formulations or compositions.
• the selenate or its pharmaceutically acceptable salt and the cytostatic agent(s) or cytotoxic agent(s) or radiosensitizing agent(s) are administered orally as a single tablet or capsule or separate tablets or capsules.
• the selenate or its pharmaceutically acceptable salt and the cytostatic agent(s) or cytotoxic agent(s) or radiosensitizing agent(s) are administered intravenously in a single composition or separate compositions.
• the present invention also provides pharmaceutical compositions for treating or preventing a benign tumor or preventing a benign tumor undergoing malignant conversion, generally comprising a supranutritional amount, suitably from about 0.5 mg to about 1.0 g of selenate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
• the selenate or its pharmaceutically acceptable salt is in an amount of about 5.0 mg to about 700 mg or 5 mg to 450 mg.
• the selenate or its pharmaceutically acceptable salt is an amount of about 0.07 mg to 6.5 mg, 5 mg to 450 mg or 7.5 mg to 250 mg, especially 50 mg to 200 mg, for example, 50 mg to 100 mg or 100 mg to 150 mg for a single or divided daily dose.
• the pharmaceutical composition may be for treating a benign tumor in which Akt is activated or over-activated or a benign tumor in which Bcl-2 activity is elevated.
• the pharmaceutical compositions further comprise at least one cytostatic agent or cytotoxic agent.
• the pharmaceutical compositions may further comprise a radiosensitizing agent for use with radiotherapy.
• the pharmaceutical composition may further comprise a second agent that is suitable for treating a benign tumor, such as 5- ⁇ -reductase inhibitors, ⁇ -adrenergic receptor blockers, selective estrogen receptor modulators, selective androgen receptor modulators, phytotherapeutics, anti-inflammatory drugs, Cox-2 inhibitors, progesterone receptor antagonists, immune modulating agents or chemotherapy.
• the pharmaceutical composition of the present invention may include any additional components that are non-immunogenic and biocompatible with selenate, as well as capable of bioabsorption, biodegradation, elimination as an intact molecule.
• the formulation may be supplied in a ready-to-use form or may be supplied as a sterile powder or liquid requiring vehicle addition prior to administration. If sterility is desired, the formulation may be made under sterile conditions, the individual components of the mixture may be sterile, or the formulation may be sterile filtered prior to use.
• Such a solution can also contain appropriate pharmaceutically acceptable carriers, such as but not limited to buffers, salts, excipients, preservatives, etc.
• sustained release oral formulations are used for administering selenate or its pharmaceutically acceptable salt in the methods of the invention.
• These formulations generally comprise selenate or its pharmaceutically acceptable salt having decreased solubility in order to delay absorption into the bloodstream.
• these formulations may include other components, agents, carriers, etc., which may also serve to delay absorption of the selenate or its pharmaceutically acceptable salt.
• Microencapsulation, polymeric entrapment systems, and osmotic pumps, which may or may not be bioerodible, may also be used to allow delayed or controlled diffusion of the selenate or a pharmaceutically acceptable salt thereof from a capsule or matrix.
• the selenate or its pharmaceutically acceptable salts can be used solus or as part of another agent. Accordingly, the present invention also contemplates an agent that comprises selenate or a pharmaceutically acceptable salt thereof for the treatment of a benign tumor, especially one in which Akt is activated or in which Bcl-2 activity is elevated, or for the prevention of malignant conversion of a benign tumor to a malignant tumor.
• meningiomas will be established according to established protocols (Friend KE, Radinsky R, McCutcheon IE. Growth hormone receptor expression and function in meningiomas: effect of a specific receptor antagonist. J Neurosurg 1999; 91:93-9). [0068] Briefly, tumor tissue will be collected at the time of resection from patients with benign, or atypical, meningioma as determined by neuropathologic review using WHO 2000 criteria. Tumor fragments will be immediately transferred to the laboratory for further processing, carefully minced into small pieces, and treated with 0.4% trypsin/EDTA to dissociate the cells.
• the cells will be washed with PBS supplemented with 200 units/mL penicillin and 200 ⁇ g/mL streptomycin and transferred to 100-mm 2 tissue culture dishes containing DMEM supplemented with 10% FCS, 100 units/mL penicillin, and 100 ⁇ g/mL streptomycin.
• the cells will be grown in humidified incubators at 37 0 C with 5% CO 2 for 5 days, with periodic medium changes and then allowed to reach confluence. Low-passage cells ( ⁇ 7 passages) will used for proliferation experiments.
• Benign meningioma tumor growth curves will be analysed by allowing 2 x 10 5 tumor cells. The cells will be allowed to attach overnight in culture dishes. After 16 hours the medium will be changed to include sodium selenate in the presence of serum at the indicated concentrations and allowed to grow until specified time points. Supernatants and cells will then be harvested, combined and viable cells assessed by Trypan Blue exclusion assay. Experiments will be performed in triplicate.
• MTT Growth Assays will be performed by plating 1 x 10 3 meningioma tumor cells per well in a 96 well plate and allowing the cells to attach overnight. At 16 hours the medium will be replaced with fresh media containing sodium selenate (5-250 ⁇ M). For experiments determining the additional effect of PI3K inhibition on sodium selenate growth inhibition, LY294002 (Promega, Madison, WI, USA) will be added at a concentration of 10-50 ⁇ M with the sodium selenate. The controls for this experiment will then receive an equal volume of LY294002. diluent (DMSO). MTT growth assays will then be performed according to the manufacturer's protocol (Sigma). Experiments will be performed in triplicate.
• the prostate stromal (PrS) cell line was obtained from Cambrex Bio Science (Walkersville, MC, USA, www.cambrex.com) and was routinely cultured in Stromal Cell Medium BulletKit (Clonetics SCGM BulletKit, CC-3205) purchased from Cambrex. Complete growth medium was prepared from the BulletKit containing stromal cell basal medium supplemented with 0.1% human fibroblast growth factor B, 0.1% insulin, 5% fetal bovine serum and 0.1% gentamicin sulphate amphotericin-B according to supplier specification. Cells were cultured at 37 0 C in 5% CO 2 .

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