Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • 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
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/243—Platinum; Compounds thereof
• • 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
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the invention relates to pharmaceutical combination preparations that inhibit the abnormal growth of tumor cells.
• These combination preparations comprise, as active ingredients, compounds which have glutaminase activity in combination with certain antineoplastic agents.
• the invention relates to combination preparations of compounds having glutaminase activity with cytostatically active compounds.
• cancer encompasses a large number of different malignant diseases which are characterized by the fact that cells grow uncontrollably, cell differentiation is lacking and neighboring tissues are penetrated and metastases are formed. 15 Almost any tissue can be the source of such a malignant disease.
• antineoplastic agents not only damage tumor cells, but also healthy, rapidly growing cells, such as Mucous membranes, cells of the hematopoietic system (bone marrow) and hair follicles. Treatment with antineoplastic agents is therefore usually included
• Glutamine is the most common amino acid in the bloodstream and plays a major role as a nitrogen and energy source and as a basic component for many cell-based syntheses. Because of their strong growth, tumor cells in particular rely on glutamine from the bloodstream.
• Lung carcinomas act (McGregor, W & Roberts, J (1989): Proc. Amer. Assoc. Cancer Res. 30, 578). It has also been shown that treatment with glutaminase delays resistance to methotrexate (Roberts, J., Schmid, F.A. & Rosenfeld, H.J. (1979): Cancer Treat. Rep. 63: 1045-1054).
• the object of the present invention was therefore to increase the effect of antineoplastic agents and to provide preparations which can be used in concentrations which give rise to no or low toxicities and antibody formation.
• antineoplastic agents in combination with compounds with glutaminase activity are suitable for solving this problem.
• the combinations have a synergistic, direct or indirect toxic effect on dividing cells and can therefore be used for antineoplastic therapy.
• the component having glutaminase activity serves as an enhancer, which lowers the required dose of antineoplastic agents and reduces the side effects and the late effects.
• Platinum complexes in particular cis-platinum, oxaliplatin, carboplatin or derivatives thereof, or anthracyclines, in particular doxorubicin or daunomycin or derivatives thereof, are used as antineoplastic agents.
• the invention relates to combination preparations from
• Cytostatics have long been a recognized and widely used treatment principle in antineoplastic therapy. They are used to destroy malignant cells with uninhibited growth behavior. Normal and healthy cells should be damaged as little as possible.
• compounds which have glutaminase activity include the proteins or enzymes glutaminase; Glutaminase-asparaginase; Glutaminase analogues; Understand derivatives and modifications that either occur naturally or are synthetically produced and that inhibit glutamine production.
• the connections can be modified or provided with protective substances.
• Polyethylene glycol-modified compounds are preferably used.
• Genetically engineered glutaminase or / and Pseudomonas glutaminase are particularly preferably used.
• Glutaminases which can preferably be used according to the invention are described in WO 94/13817.
• Antineoplastic agents are understood to mean substances which are suitable and are used to damage or destroy microorganisms, parasites or tumor cells. Cytostatics and their derivatives from the following groups should be mentioned in particular:
• Alkylating and cross-linking compounds they irreversibly damage DNA; these include nitrogen mustard derivatives such as cyclophosphamide, ifosfamide, N-nitroso compounds such as carmustine,
• Ethyleneimine (aziridine) derivatives such as thiotepa, methanesulfonates such as busulfan, platinum complexes such as cis-platinum, oxaliplatin or carboplatin, as well as procarbazine, melphalan and others 2.
• Antimetabolites They displace natural building blocks; for example folic acid antagonists such as methotrexate, nucleoside analogues such as mercaptopurine, fluorouracil and others
• Mitosis inhibitors They inhibit the build-up or breakdown of the core spindles, especially vinca alkaloids (for example vincristine, vinblastine) and taxanes (for example paclitaxel)
• anthracyclines e.g. daunorubicin
• Doxorubicin damage the cell, among others. by intercalation in DNA and inhibition of topoisomerases (e.g. etaposide) and actinomycins, e.g. Actinomycin D and mitoxantrone
• Hormones and hormone antagonists They are used for tumors whose growth is hormone-dependent; This subheading includes (anti) estrogens (e.g. tamoxifen) including aromatase inhibitors such as formestan, gestagens and antiandrogens such as Flutamide.
• estrogens e.g. tamoxifen
• aromatase inhibitors such as formestan, gestagens and antiandrogens such as Flutamide.
• the present invention relates to the use of antineoplastic agents
• such combinations of active ingredients consist of a glutaminase-asparaginase, preferably Pseudomonas 7A glutaminase-asparaginase, and one or more antineoplastic agents from the above-mentioned groups.
• Combinations of this invention are characterized in that the antiturnoral effect of conventional antineoplastic agents is significantly increased by combination with a compound having glutaminase activity and the protein active substance itself can be used in concentrations which do not produce any toxic effects.
• the combination preparations can be used for cancer therapy.
• sub-therapeutic doses of a compound with glutaminase activity and antineoplastic agents can be used which synergistically inhibit tumor cell growth.
• the combination of the active ingredients has a significantly greater antineoplastic activity than an active ingredient of this active ingredient class alone.
• the antineoplastic active substances which are suitable for a combination include platinum complexes, in particular cis-platinum oxaliplatin, carboplatin or derivatives thereof, and anthracyclines, e.g. Actinomycin D, mitoxantrone, and in particular the DNA intercalators doxorubicin and daunomycin (daunorubicin).
• antineoplastic agents that can be used for a combination include the DNA alkylating agents cyclophosphamide, ifosfamide, melphalan; the antimetabolites methotrexate, 5-fluorouracil; the spindle or microtubule poisons vincristine, vinblastine, paclitaxel; the topoisomerase inhibitor etoposide; the antibiotics actinomycin D, mitomycin, mitoxantrone; the hormones tamoxifen and flutamide.
• a combination therapy using the pharmaceutical preparations of the present invention offers the advantage of synergistically enhancing the antitumor activity of the individual substances. This also results in the possibility of reducing the doses and thus the toxicities of the individual substances while at the same time maintaining the antitumor activity when combining the individual substances.
• a Combination therapy of the above-mentioned individual therapy principles also offers the possibility of overcoming resistance to cytostatic agents, both substance group resistance and multiple resistance (pleiotropic cytostatic resistance) being considered.
• the synergistic effect observed according to the invention is based on the following mechanism of action.
• Alkylating cytostatics e.g. Platinum preparations have an effect on cancer cells, especially during cell division.
• Energy depletion due to glutamine deprivation by means of glutaminase and the lack of glutamine in DNA synthesis by glutaminase lead to an increase in cell division time and thus to an extension of the vulnerable phase of cancer cells for alkylating substances.
• the cancer cells only grow in the medium from a certain concentration of glutamine.
• Flow cytometry was also used to determine that acute myeloid leukemia particularly affected cytostatic therapies in the early morning.
• the cancer cell lacks an important antioxidant due to the glutamine withdrawal in the cell as well as outside, which further contributes to the vulnerability to cytostatics.
• combination therapy it is possible to combine the active substances in a so-called fixed combination, i.e. to be administered in a single pharmaceutical formulation in which both active ingredients are contained, or to select a so-called free combination in which the active ingredients can be administered in the form of separate pharmaceutical formulations simultaneously or else in succession.
• the active substances are solids, the active substances can be prepared in the usual way
• Processes for solid pharmaceutical preparations are processed, for example, by mixing both active ingredients together and pressing them together with conventional carriers or auxiliaries, for example into tablets. But it is it is also possible to provide the active ingredients separately from one another in a ready-for-sale packaging unit, the packaging unit containing the two active ingredients in separate pharmaceutical formulations.
• the active substances are made available in the form of injection solutions, these can already contain the active substance combinations in question in ready-to-injectable, dissolved form. In principle, however, it is also possible to provide a parenteral formulation for each active substance in a packaging unit, so that the injection solutions can optionally be applied separately from one another. If the active substances are incompatible with one another, this form of application is the preferred method.
• the active compounds can also be in substance, if appropriate together with customary pharmaceutical auxiliaries, for example in lyophilized form, and can be reconstituted or solubilized by adding pharmaceutically identical injection media.
• the pharmaceutical preparations come in liquid or solid form for enteral or parenteral application. All the usual forms of application are possible here, for example tablets, capsules, dragees, syrups, solutions, suspensions.
• Water is preferably used as the injection medium, which contains the additives, such as stabilizers, solubilizers and buffers, which are customary for injection solutions.
• additives are e.g. Tartrate and citrate buffers, ethanol, complexing agents such as Ethylenediaminetetraacetic acid and its non-toxic salts, as well as high molecular weight polymers such as liquid polyethylene oxide for viscosity control.
• Injection solutions must be sterile and are preferably filled into ampoules.
• Solid carriers are, for example, starch, lactose, silicic acids, higher molecular fatty acids such as stearic acid, gelatin, agar, Calcium phosphate, magnesium stereate, animal and vegetable fats, solid high-molecular polymers such as polyethylene glycols; Preparations suitable for oral administration can optionally contain flavorings and sweeteners.
• the dosage can depend on various factors such as the mode of administration, species, age and individual condition.
• the daily doses are 0.005 - 100 mg / kg body weight per individual component.
• the ratio between the active ingredients can vary within a very wide range. For example, molar ratios between 1:10 to 1: 1000 and 10: 1 to 1000: 1 are possible, depending on the effectiveness of the active substances in question. In the case of combination with cytostatics, a ratio between 1: 100 and 100: 1 is preferred.
• the present invention relates to a pharmaceutical combination preparation consisting of at least one compound with glutaminase activity and at least one platinum complex, in particular cis-platinum. It was found that platinum complexes in combination with glutaminase, in particular Pseudomonas glutaminase, show synergistic effects on different Tu cell lines up to a factor of 120 in tissue cultures. The dose of cis-platinum and glutaminase can thereby be significantly reduced in each case compared to the dose amounts required for individual therapies.
• the therapeutic dose for glutaminase in the combination preparations according to the invention is preferably 50-150 IU / m 2 , in particular 100-130 IU / m 2 .
• the dose of platinum complex, in particular cis-platinum, in the combination preparations according to the invention is preferably 1-20 mg / m 2 , in particular 2-15 mg / m 2 and even more preferably 5-10 mg / m 2 body surface area. At such doses, a response from solid tumors is already observed after five days of administration. When given for three weeks the dose is preferably 10-100 mg / m 2 , in particular 20-50 mg / m 2 .
• the dose for glutaminase is again preferably 50-150 IU / m 2 , in particular 100-130 I.UJm 2 body surface.
• the amount of doxorubicin is advantageously 1 to 20 mg / m 2 , in particular 2 to 15 mg / m 2 and even more preferably 5 to 10 mg / m 2 of body surface with once weekly application.
• the preferred dose is 5-60 mg / m 2 , in particular 10-50 mg / m 2 and even more preferably 15-30 mg / m 2 body weight.
• the cell growth by means of absorption of the bound sulforhodamine dye was determined at 575 nm '.
• the percentage growth was calculated as follows:
• T means the amount of cells treated
• t stands for the number of cells at time 0 and after 48 hours.
• Figure 1 shows the anti-tumor effect of 0.026 ⁇ g / mL mitomycin on cells of a CNS tumor (SF-539) and breast (MCF7) tumor alone and in combination with 0.001 U / mL glutaminase.
• Mitomycin alone shows no effect on CNS cells, in combination with glutaminase the growth is reduced to 7% compared to the control.
• Mitomycin reduces the growth of MCF7 breast tumor cells to 66% compared to the control.
• growth is reduced to 40%.
• Figure 2 shows the anti-tumor effect of 0.3 ⁇ g / mL mitoxantrone on cells of a breast (MCF7), lung (NCI-H460) and colon (SW-60) tumor alone and in combination with 0.001 U / mL glutaminase , Glutaminase alone shows little effect on the three tumors.
• Mitoxantron reduces tumor cell growth alone to 23% to 47%. In combination, the growth of breast, lung and colon tumor cells is reduced to 1%, 9% and 25%, respectively.
• Figure 3 shows the anti-tumor effects of 2 ⁇ g / mIL cis-platinum on cells from a lung (A549), breast (MCF7) and colon (HAT29) tumor alone and in combination with 0.001 U / mL glutaminase.
• cis-platinum alone reduces growth to 41%, 86% and 65%, respectively.
• glutaminase the growth of the tumor cells is reduced to 15%, 18% and 2%.
• Figure 4 shows the anti-tumor effects of 2.3 ⁇ g / mL etoposide on cells from lung (A549 and NCI-1-123) and breast (MCF7) tumors alone and in combination with 0.001 U / mL glutaminase.
• Etoposide alone reduces the growth of these cells alone to about 40% compared to the control.
• glutaminase the growth of the tumor cells is reduced to 18% and 6% and 26%, respectively.
• Figure 5 shows the anti-tumor effect of 68 ⁇ g / mL melphalan on cells of a lung (NCI-H23) tumor alone and in combination with 0.001 U / mL glutaminase. Melphalan reduces tumor growth to 34%. In combination with glutaminase, growth is reduced to 10%.

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