Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta

Definitions

• This invention relates to combinations useful for the enhancement of growth inhibition or killing of tumor cells. More particularly, this invention relates to combinations of natural or recombinant tumor necrosis factors ("TNF”) and broad spectrum antibiotics, such as chloramphenicol and tetracycline, which impede or inhibit protein syn ⁇ thesis in the mitochondria of the target cell. Accord ⁇ ing to this invention, these antibiotics are used to enhance the growth inhibiting or killing effect of TNFs on tumor cells.
• TNF tumor necrosis factors
• broad spectrum antibiotics such as chloramphenicol and tetracycline
• TNF is produced by macrophages and mono- nuclear phagocytes. It is cytotoxic or cytostatic for a broad range of animal and human cancer cells in vitro and induces hemorrhagic necrosis in certain animal tumors and heterotransplanted human tumors in vivo [K. Haranaka and N. Satomi, "Note: Cytotoxic Activity of Tumor Necrosis Factor (TNF) on Human Cancer Cells in vitro, " Japan J. Exp. Med. , 51, pp. 191-94 (1981); L. Old, "Cancer Immunology: The -2-
• Antibiotic agents may be classified on the basis of their chemical structure and mechanism of action. For example, agents that affect the function of ribosomes to inhibit or impede mitochondrial protein synthesis form a class of antibiotics which are useful in the combinations of this invention. This class includes chloramphenicols and tetracy- clines, aminoglycosidic antibiotics, the macrolide antibiotics (i.e., erythromycin), linco ycin, and its congener clindamycin.
• Tetracyclines comprise a class of broad- spectrum antibiotics with a wide-range of anti- microbial activity. They are metabolites or semi- synthetic derivatives of metabolites of Streptomyces aureofaciens. They have bacteriostatic, or, at high concentrations, bacteriocidal effects on many species of gram-positive and gram-negative bacteria, spiro- chetes, and rickettsiae.
• the site of action of tetracyclines is the ribosome. They inhibit protein synthesis by preventing the addition of amino acids to a growing peptide chain. Tetracyclines also impair protein synthesis in mammalian cells at high concen- trations [A. Goodman et al., The Pharmacological
• Chloramphenicol is an antibiotic produced by Streptomyces venezuelae. It is a broad spectrum antibiotic which also inhibits protein synthesis in bacteria by binding to the ribosomes of its target. Chloramphenicol can also inhibit mitochondrial protein synthesis in mammalian cells probably because mito ⁇ chondrial ribosomes resemble bacterial ribosomes [L. . Wheeldon and A. L. Lehninger, Biochemistry, 5, pp. 3533-45 (1966)]. -3-
• the a inoglycoside antibiotics include gentamicin, tobramycin, amikacin, kanamycin, strepto ⁇ mycin and neomycin. These antibiotics act directly on the ribosome, where they inhibit protein synthesis and decrease the fidelity of translation of the genetic code [Goodman and Gil an's, supra, pp. 1162-80].
• Erythromycin and other macrolide anti ⁇ biotics, lincomycin, and clindamy ⁇ in inhibit protein synthesis by binding to 50S ribosomal subunits.
• erythro ⁇ mycin, chloramphenicol and clindamycin can interfere with each other's binding at this site [Goodman and Gilman's, supra, pp. 1222-27].
• Conventional treatment of tumors include non-surgical treatments, such as chemotherapy and radiation, and surgical treatments. Typically, these treatments are characterized by various undesirable side effects. Non-surgical treatments having immuno- suppressant effects may increase the patient's susceptibility to secondary infections. Surgical treatments to excise transformed cells involve risks attendant with invasive procedures and may not effec ⁇ tively remove or eliminate the entire transformed cell population.
• Alternative methods of treatment for cancers and non-malignant tumors have involved the use of monoclonal antibodies to tumor specific antigens on the surface of transformed cells.
• various therapies have been directed to aug- - — meriting the body's immune response to tumorigenic cells by increasing the body's level of various lymphokines.
• TNF alone is known to inhibit the growth of or to kill tumor cells.
• combinations of human lymphotoxin and human gamma interferon have been reported to inhibit tumor growth [European patent application 128,009].
• Combi ⁇ nations of TNF and human interferon have also been reported to demonstrate a greater growth inhibitory or cytotoxic effect on human tumors than the sum of their separate effects [L.
• the present invention provides combinations and methods that cause the inhibition of tumor growth or the enhancement of tumor cell death to a far greater degree than TNF alone.
• broad spectrum anti ⁇ biotics which inhibit or impede protein synthesis in the target cell dramatically enhance the tumoricidal effect of TNF.
• Particularly useful combinations with such TNF treatments include the tetracyclines or chloramphenicol.
• TNF tumor necrosis factor
• TNF is a growth inhibitory or cytotoxic lymphokine. Natural TNF is a protein with a molecular weight of over 17,000. TNF has been produced in small quantities in vivo. For example, endotoxin may be used to trigger the release of TNF by activated macrophages. TNF can also be induced in established cell lines, i.e., U937 [D. J. Camerson, Reticuloenthel. Soc. , 34, pp. 45-52 (1983)]. TNF has been cloned and expressed in various host-vector systems [A. L. Mar enout et al., "Molecular Cloning And Expression Of Human Tumor Necrosis Factor And Com- parison With Mouse Tumor Necrosis Factor, " Eur. J.
• TNF includes all proteins, polypeptides, and peptides which are natural or recombinant TNFs, or derivatives thereof, and which are characterized by the tumoricidal activity of these TNFs. They include TNF-like com- pounds from a variety of sources, such as natural TNFs, recombinant TNFs, and synthetic or semi-syn ⁇ thetic TNFs.
• Tumor encompasses any undesirable proliferation of cells. Such proliferation includes malignant and non-malignant, solid or fluid tumors, carcinomas, -6- myelomas, sarcomas, leukemias, lymphomas,. and other cancerous, neoplastic, or tumorigenie diseases.
• Chloramphenicol is an antibiotic which impedes protein synthesis in bacteria and mammalian cells by attaching to bacterial ribo ⁇ somes or mitochondrial ribosomes, respectively, in order to cause cell death.
• chloramphenicol includes related derivatives, such as thioamphenicol, a more water-soluble and less toxic derivative of chloramphenicol.
• Tetracycline Tetracyclines are a class of antibiotics which impede protein synthesis in bacteria and mammalian cells by attaching to bacterial ribosomes or mitochondrial ribosomes, respectively, in order to cause cell death.
• tetracycline includes related members of the broad family of antibiotics generally known as tetracycline, as well as their derivatives. The term includes, for example, chlortetracycline, oxy- tetracycline, demeclocycline, methacycline, doxycycline and minocycline.
• This invention relates to combinations and methods for treating tumors and neoplastic diseases. More particularly, this invention relates to combi- nations of pharmaceutically effective amounts of TNF and pharmaceutically effective amounts of broad spectrum antibiotics that inhibit or impede protein synthesis in the target cell.
• those antibiotics are selected from the group of tetracyclines or chloramphenicol.
• TNFs useful in the combinations and treatments of this invention are the TNFs produced in vitro by a variety of cells in response to various inducers.
• these TNFs include compounds displaying TNF activity obtained from sera of mice -7- and rabbits which have been infected with Bacillus- Cal ette-Guerin (BCG) or Corynebacterium and treated with lipopolysaccharide (LPS) of Escherichia coli [E. A. Carswell et al., "An Endotoxin-Induced Serum Factor That Causes Necrosis Of Tumors", Proc. Natl. Acad. Sci. USA, 72, pp. 3666-70 (1975)].
• BCG Bacillus- Cal ette-Guerin
• LPS lipopolysaccharide
• human monocytes isolated from the blood of healthy human donors, and stimulated with lymphokines or LPS produce chemical agents having cytotoxic or cytostatic effects on mouse target cells and human transformed cells which are useful in the compositions of this invention
• lymphokines or LPS produce chemical agents having cytotoxic or cytostatic effects on mouse target cells and human transformed cells which are useful in the compositions of this invention
• TNFs useful in the combinations and treat ⁇ ments of this invention may also be produced and purified in large amounts using recombinant DNA tech ⁇ nology [L. Fransen et al., "Molecular Cloning Of Mouse Tumour Necrosis Factor cDNA And Its Eukaryotic Expres ⁇ sion," Nucl. Acid Res. , 13, pp. 4417 et seq. (1985); A. L. Marmenout et al., "Molecular Cloning And Expres- sion Of Human Tumor Necrosis Factor And Comparison With Mouse Tumor Necrosis Factor," Eur. J. Biochem, 152, pp. 515-22 (1985); see also D. Pennica et al., Nature, 312, pp. 724-28 (1984); T. Shirai, Nature, 313, pp. 803-06 (1985); A. M. Wang et al., Science, 228, pp. 149-54 (1985)].
• TNFs derived from the target species are preferably used.
• TNFs derived from other species may be used in the combinations and treatments of this invention if they are active in the target cells.
• mouse TNF has been shown to be active in human cell lines in vitro.
• mammals are treated with pharmaceutically effective amounts of the two active components — TNF and a broad spectrum antibiotic — of the combinations of this invention for a period of time sufficient to suppress tumor growth, and preferably to kill tumor cells.
• the mammals are treated with a composition comprising a combination of TNF and a broad spectrum antibiotic which impedes or inhibits ribosomal protein synthesis.
• they are treated sequentially with the two components.
• the particular sequence of treatment chosen does not appear to be important.
• mammals may be treated with sub ⁇ cutaneous, intravenous or intramuscular injections of TNF of between about 10 ⁇ g to 100 mg per patient per day.
• this dosage should be adjusted by the treating physician according to recognized medical standards, to accommodate the physical condition and acceptance level of the patient.
• they are also treated with a pharmaceutically effective amount of a broad spectrum antibiotic before, concurrently, of after treatment with TNF. Most commonly, the antibiotic is administered orally, its dosage being the standard one used against infection. [See Goodman and Gilman's, supra, pp. 1185, 1193 and 1222-27.] -10-
• Table I depicts the use of the combinations of this invention. More particularly, it shows the effect of recombinant TNF in combination with chlor ⁇ amphenicol, thioamphenicol (a more water-soluble and less toxic derivative of chloramphenicol) and tetra ⁇ cycline, on the B16B16, PG19 and Friend leukemia 745 cells.

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• 1986
  • 1986-12-05 WO PCT/EP1986/000710 patent/WO1987003489A1/en not_active Application Discontinuation
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