NL2024493B1 - Pharmaceutical composition for preventing or stopping metastases - Google Patents
Pharmaceutical composition for preventing or stopping metastases Download PDFInfo
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- NL2024493B1 NL2024493B1 NL2024493A NL2024493A NL2024493B1 NL 2024493 B1 NL2024493 B1 NL 2024493B1 NL 2024493 A NL2024493 A NL 2024493A NL 2024493 A NL2024493 A NL 2024493A NL 2024493 B1 NL2024493 B1 NL 2024493B1
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- Prior art keywords
- cancer
- pharmaceutical composition
- metastasis
- use according
- compound
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
The invention relates to a composition, and a medicament for preventing or stopping of metastases, in particular metastases originating from epithelia cancer, such as skin cancer, lung cancer, stomach cancer, brain cancer, breast cancer, colo—rectal 5 cancer, prostate cancer, pancreas cancer, and esophagus cancer. It has been found that the present composition irreversibly converts cancer cells with metastatic potential into harmless cells with no metastatic potential.
Description
FIELD OF THE INVENTION The invention relates to a composition, and a medicament for the prevention of metastasis or stopping of ongoing metastasis, in particular metastases originating from epithelial cancers, such as skin cancer, lung cancer, breast cancer, colo-rectal cancer, prostate cancer, liver cancer, stomach cancer, brain cancer, kidney cancer, gall bladder cancer, pancreas cancer, bladder cancer and esophagus cancer. It has been found that the present composition prevents or stops metastasis.
BACKGROUND OF THE INVENTION The occurrence of cancers is widely spread. For treatment of these cancers typically aggressive drugs are used, such as chemo-therapy, which pose many typically negative side-effects to the human body. The treatment of metastases is even worse, as these metastases are often spread throughout the body, and can therefore typically not be treated effectively, at least not without causing severe damage to the body.
Cancer relates to cells that proliferate in a largely uncontrolled manner, and therefore compared to other living cells they proliferate more rapid and also endlessly. Therewith a primary tumour is formed. In general metastasis relates to a spread from an initial cancer site to a different site within a living body. These different sites may then be referred to as metastases. This spread is caused by cancer cells which are able to circulate through the body towards other parts thereof. There they may form a secondary tumour, the metastatic tumour. The metastasis may have a small volume, but it is often widely spread through the body. Most cancers can metastasize of which some are in particular troublesome. The cells of the metastasis often resemble the cells of the original tumour, and therefore reference is made to the initial tumour when characterizing the metastasis. They could therefore in principle be treated likewise, but as they are widespread treatment may be cumbersome and to harmful to the body. However, metastases can acquire new characteristics making them unresponsive to anti-cancer drugs that are effective against the primary tumour, making them even more difficult to treat. Currently, primary tumours that have 40 not metastasized can effectively be treated by surgery, usually in combination with chemotherapy and/or radiation-therapy. This is the major reason why cancer patients often do not die from their primary tumour but from the metastases. Therefore, there is an unmet need for new treatments that can prevent metastasis or stop ongoing metastasis.
For treatment of cancer metastases often combined therapies are used, that is two or more chemicals are combined. These combined therapies are often more effective. Still typically for every individual human being such as therapy needs to be established, which often involves testing of therapies that after evaluation thereof are considered to be ineffective.
As therapies for treatment of metastases are scarce or ineffective, there still is a need for improved pharmaceuticals and treatments which overcome drawbacks of the prior art.
SUMMARY OF THE INVENTION It is an objective of the invention to provide a composition that is able to prevent metastasis or stop metastasis, such as stopping ongoing metastasis or stopping further metastasis, by irreversibly blocking the metastatic capacity of tumor cells.
The invention furthermore provides method of use of such composition, and for the prevention of metastasis and stopping of ongoing metastasis, especially if a mammal is prone to develop metastases, such as in cancer phase II or III, and for limiting or containing effects thereof.
The invention provides for a pharmaceutical composition for the prevention of metastasis and stopping of ongoing metastasis, comprising a first compound comprising at least one carbohydrate and containing more than one sulphate, and a second compound, different from the first compound, that can activate PPAR, preferably PPARy. The first compound preferably comprises two or more sulphates, and is more preferably an oligo-, or poly- sulphate comprising compound, such as comprising 3-20 sulphates, preferably containing 4-15 sulphates, more preferably containing 5-12 sulphates, such as 6-10 sulphates, e.g. 7-8 sulphates, such as (CsHeXi010S2)n, wherein X may be selected from single valence metal atoms, such as Na*, and K*, 1 being 2, and from double valence metal atoms, such as Ca?t, and Mg?*, 1 being 1, and n preferably being in the range of 2-20, more preferably 3-12, such as 4-8. When reference to the first compound is made the 40 references includes the oligo- and polysulphates, as indicated above. The molecular weight of the first compound is preferably not too large, such as <10 kDa, preferably <7 kDa, such as < 5kDa. A compound that can activate PPAR means that the PPAR receptor activity increases by at 2 to 3 times compared to a baseline situation without the PPAR activating compound. The compound that can activate PPAR is not a protein, or not a nucleic acid (NA)-strand compound. Suitable compounds that can activate PPAR include thiazolidinediones, NSAIDs, sulphonylureas and indoles.Inventors discovered that metastasis can be prevented or ongoing metastasis can be stopped by a compound according to the invention, comprising a carbohydrate comprising more than one sulphate group like Pentosan polysulphate in combination with a PPAR, preferably a PPARy agonist, like indomethacin or pioglitazone stimulated synergistically the formation of adipocytes with Beige/Brite and/or BAT characteristics, that is an irreversible transfer of cancer cells with metastatic potential into harmless cells. Such a transfer can be observed in the mesenchymal progenitor KS483 cell line, deposited at DSMZ, Inhoffenstr. 7B, D-38124 Braunschweig, Germany, under accession number DSM ACC3286 on January 13, 2016, but other cell lines of comparable origin can be used as well and also epithelial cancer cell lines with metastatic potential.
The invention therefore provides a pharmaceutical composition, comprising a compound comprising at least one carbohydrate (saccharide) and containing at least one sulphate, in combination with a second compound that can activate PPAR, preferably PPARy, for use in the prevention of metastasis or stopping of ongoing metastasis.
Hence, patients with cancers that are known to metastasize or that already have one or more metastases, benefit from use of the pharmaceutical composition of the invention because metastasis can be prevented or ongoing metastasis can be stopped.
Therefore, the invention also relates to the use of the pharmaceutical composition as described as a medicament.
Preferably, the invention further relates to the pharmaceutical composition of the invention, for use in the prevention of metastasis or stopping of ongoing metastasis of 40 these metastatic cancers.
DETAILED DESCRIPTION OF THE INVENTION In an exemplary embodiment the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis may comprise pentosan sulphate, and/or adedquan sulphate.
In an exemplary embodiment the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis may comprise indomethacin and/or pioglitazone.
In an exemplary embodiment the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis may comprise pentosan sulphate and/or adequan sulphate, and indomethacin and/or pioglitazone.
In an exemplary embodiment the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis may comprise pentosan sulphate and indomethacin, pentosan sulphate and pioglitazone, adequan sulphate and indomethacin, adequan sulphate and pioglitazone, as well as combinations thereof.
In an exemplary embodiment of the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis the first compound and second compound may be provided in a molar ratio of 0.01:1 to 1:0.01, preferably
0.2:1 to 1:0.2, more preferably 0.33:1 to 1:0.33, even more preferably 0.45:1 to 1:0.245, such as 0.5:1 to 1:0.5, e.g. 0.9:1 to 1:0.9.
In an exemplary embodiment of the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis the composition further comprises (iii) at least one pharmaceutically acceptable carrier.
In an exemplary embodiment of the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis the active pharmaceutical ingredients are in one dosage form, preferably comprising 1-10 mg active ingredients/kg body weight, preferably 2-5 mg active ingredients/kg body weight, such as 2-1000 mg active ingredients, preferably 10-500 mg active ingredients, more preferably 20-100 mg active ingredients.
In an exemplary embodiment of the present pharmaceutical 40 composition for use in the prevention of metastasis or stopping of ongoing metastasis the pharmaceutical composition may comprise separate dosage forms for individual pharmaceutical active ingredients, preferably 2-10 dosage forms, such as 3-5 dosage forms.
5 In an exemplary embodiment of the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis the composition may be in the form of a tablet, capsule, repository, or injectable.
In an exemplary embodiment of the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis the composition may be in the form of a tablet or capsule suitable for oral administration.
In an exemplary embodiment the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis may be formulated in a form, which, depending on its use, allows targeting of specific cells, tissues or organs, such as in the form of nanoparticles. For example, the nanoparticle may be any kind of nanodevice in which both compounds are packaged for targeted delivery. In a more preferred embodiment, targeting can be done by any specific molecule attached on the outside of the specific form, such as for example a nanoparticle, like an antibody, or other molecular or chemical entity that can target specific cells, tissues or organs.
In an exemplary embodiment the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis the dosage and dosage form are such that all metastases in a body are targeted.
In an exemplary embodiment of the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis the cancer metastasis may originate from epithelial cancers.
In an exemplary embodiment of the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis the cancer may be selected from skin cancer, stomach cancer, brain cancer, lung cancer, breast cancer, colo-rectal cancer, liver cancer, kidney cancer, gall bladder cancer, prostate cancer, bladder cancer, pancreas cancer, and esophagus cancer.
In an exemplary embodiment the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis may be for use as a medicament by administering said medicament in an effective amount to epithelial cancers for a sufficient period. Typically, the present pharmaceutical composition may be used over a period of 1 week-12 months, preferably 2 weeks- 6 months, such as 4 weeks -3 months. Thereafter the pharmaceutical composition may be used for an additional period of time, typically in a lower dosage, such as 10-50% of an initial dosage, wherein the additional period may be at least one month, and typically it may be used for more than a year, such as a five to ten years or even during a remainder of the life time of the pet or mammal.
In an exemplary embodiment of the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis the administration may be to a pet or mammal comprising said tissue, wherein the mammal preferably is a human with metastasis.
In an exemplary embodiment of the present pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis may be as a medicament.
More in particular, the invention also relates to pharmaceutical composition of the invention for use in the prevention of metastasis or stopping of ongoing metastasis.
The pharmaceutical composition according the invention may be a combination composition, wherein the active pharmaceutical ingredients are in one dosage form. The pharmaceutical composition may also comprise separate dosage forms for individual pharmaceutical active ingredients.
The compound comprising at least one carbohydrate and containing at least one sulphate preferably has anti- inflammatory effects, meaning that at least one of the inflammatory markers is reduced. Inflammatory markers are e.d. TNFa, IFN, cytokines, histamine, interleukins, chemokines, leukotrienes, lysosome granules and prostaglandins.
The compound that activates PPAR, preferably PPARy preferably is a compound that can activate PPAR, meaning the PPAR receptor activity increases by at least 2-3 times compared to a baseline situation without the PPAR activating compound.
The compound that activates PPAR, preferably PPARy preferably has anti-inflammatory effects, meaning that at least one of the inflammatory markers is reduced. Inflammatory markers are e.g. TNFx, IFN, cytokines, histamine, interleukins, chemokines, leukotrienes, lysosome granules and prostaglandins.
A carbohydrate is an organic compound comprising only carbon, hydrogen, and oxygen, usually with a hydrogen:oxygen atom ratio of 2:1 (as in water); with the empirical formula Cm(H20})n (where m could be different from n). Structurally it is more accurate to view carbohydrates as polyhydroxy aldehydes and ketones.
Carbohydrates as used in the present invention do not relate to glycosylated proteins or nucleoside compounds (like DNA, RNA or the like) The carbohydrate preferably is a Glycosaminoglycans (GAGs) or keratan. Glycosaminoglycans, or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of an amino sugar {N-acetylglucosamine or N-acetyl galactosamine) along with a uronic sugar {glucuronic acid or iduronic acid) or galactose.
Based on core disaccharide structures, GAGs may be classified into four groups.
Preferred types of sulphated saccharides are also known as heparin, heparan sulphate analogues, or heparin-like compounds.
Suitable compounds comprising a carbohydrate and a sulphate group can be derived from natural sources, or can be made - at least in part - synthetically.
Examples of sulphated compounds include single Sulphur containing agents like MSM (dimethylsulfon), dextran sulphate, or multiple Sulphur containing agents, like polysulphated glycosaminoglycan (adeguan sulphate), heparin like pentosan sulphate or the like.
Preferred sulphated saccharides compounds are polysulphated glycosaminoglycan (Adequan sulphate), heparin like pentosan polysulphate (Elmiron) or the like.
The second part of the present composition, is an agent that can activate PPAR, preferably PPARy. Preferred PPAR agonists include triglitazones (TZDs: triglitazone, rosiglitazone, pioglitazone etc.) and indomethacin.
Preferably, both the compound comprising at least one carbohydrate and containing at least one sulphate and the compound that activates PPARy preferably has anti-inflammatory effects, meaning that at least one of the inflammatory markers is reduced. Inflammatory markers are e.g. TNFa, IFN, cytokines, histamine, interleukins, chemokines, leukotriene, lysosome granules and prostaglandins.
Whether a compound is a PPAR, preferably PPARy agonist can be determined in a simple cell-based test.
By PPAR agonist is meant any compound that increases the biological activity or expression of one or more PPARs (e. J., PPARx, PPARy, and PPARB/S) in a cell by a least 10% relative.
Examples of PPARy agonists include any of the Thiazolidinediones, but particularly Rosiglitazone, Troglitazone and Pioglitazone and analogs thereof. Rosiglitazone is the preferred PPAR agonist. Additional examples of PPARy agonists include non-steroidal anti-inflammatory drugs, such as Indomethacin, Ibuprofen, Naprosyn and Fenoprofen and antioxidants such as vitamin E, vitamin C, S-adenosyl methionine, selenium, beta-carotene, idebenone, cysteine, dithioerythritol, dithionite, dithiothreitol, and pyrosulfite.
Examples of PPARx agonists include any of the fibrates (e.g., fenofibrate, bezafibrate, gemfibrozil, and analogs thereof), docosahexaenoic acid, and Wy 4643.
So, for example Pentosan sulphate in combination with one of these compounds could prevent metastasis or stop ongoing metastasis. More specifically PPARy agonistic action can be determined in a similar manner as described above, using a dual luciferase assay with a luciferase construct containing a PPARy responsive element.
This second compound is not a protein or nucleic acid-based compound.
Suitable PPARy agonists include thiazolidinediones, NSAIDs, sulphonyl ureas and indoles.
Thiazolidinediones (abbreviated as TZDs) are also known as glitazones. Suitable thiazolidinediones include rosiglitazone, pioglitazone, troglitazone, and ciglitazone, which are selective ligands for the nuclear transcription factor peroxisome proliferator- activated receptor (PPAR)y. Typical TZDs have the 40 formula as shown in fig. 5, where n is 1,2, or 3, Y and Z independently are O or NH; and E is a cyclic or bicyclic aromatic or non-aromatic ring, optionally containing a hetercatom selected from oxygen or nitrogen. Suitable TZDs are for example described in W02000/27401.
NSAIDs are a class of drugs that provides analgesic and antipyretic (fever-reducing) effects, and, in higher doses, anti-inflammatory effects. PPARy is activated by several endogenous ligands emerging from the metabolism of arachidonic acid and linoleic acid. Among the PPARy ligands represented are the lipoxygenase products 13{S)HODE (produced from linoleic acid by 15-L0OX-1) and 15(S)HETE (produced from arachidonic acid by both 15-LOX-1 and 15-L0OX-2, although 15-LOX-2 catalyzes this reaction much more efficiently). Induction of 15-LOX-1 activity by NSAIDs occurs independently of COX-2 inhibition NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action.
Suitable NSAIDs include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid {(oxicam) derivatives and fenamic acid derivatives, Suitable salicylates include aspirin (acetylsalicylic acid), diflunisal (Dolobkbid™), salsalate (Disalcid™) and choline magnesium trisalicylate (Trilisate™) Suitable propionic acid derivatives include ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, and loxoprofen.
Suitable acetic acid derivatives include Indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac and nabumetone (drug itself is non-acidic but the active, principal metabolite has a carboxylic acid group) Suitable enolic acid (oxicam) derivatives include piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
Suitable fenamic acid derivatives (fenamates } include mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid.
Sulfonylurea derivatives are a class of antidiabetic drugs 40 that are used in the management of diabetes mellitus type 2.
Examples include carbutamide, acetohexamide, chlorpropamide, tolbutamide, tolazamide, glipizide, gliclazide, glibenclamide {glyburide), glibornuride, gliquidone, glisoxepide, glyclopyramide and glimepiride. They act primarily by increasing insulin release from the beta cells in the pancreas. All sulfonylureas contain a central S-phenyl sulfonylurea structure with a p- substituent on the phenyl ring (R) and various groups terminating the urea N' end group (R2) (see figure 6).
Indoles include indole-derived agents which can bind to PPARy, and comprise mainly sulfonyl-indoles.
Dual alpha-gamma agonists are suitable as well, and include glitazars.
Suitable glitazars include aleglitazar, muraglitazar and tesaglitazar.
PPARx agonists include fibrates and biguadines.
Preferably, the compound comprising at least one saccharide and at least one sulphate can be present in the pharmaceutical composition such as in an amount of 0-10 wt.3 relative to a total weight.
Preferably, the PPARy agonist can be present in an amount of 0-10 wt.% relative to a total weight.
Preferably, the relative amounts between the two compounds (sulphated compound to PPARy agonist) are 1:1 to 1:5.
The pharmaceutically acceptable carrier can be present in an amount of 0.01% to 99.9%, preferably 0.1%-10%, and its amount will depend on the formulation.
In one embodiment, the medicament is in the form of a tablet, suitable for oral administration.
In another embodiment, the medicament is in a form suitable for local administration.
The medicament can comprise the components in the form of a solid, or liquid preparation.
The dosage form can be an immediate release or extended release formulation.
The invention furthermore relates to the pharmaceutical composition of the invention for use in the prevention of metastasis or stopping of ongoing metastasis.
The invention furthermore relates more specifically to the pharmaceutical composition of the invention for the use in the 40 prevention of metastasis or stopping of ongoing metastasis.
It is an advantage of the present invention that the constituents of the composition can be non-biologics, and several of the exemplary components are approved medicaments.
Pentosan polysulphate (PPS), manufactured from beech-wood, is an FDA-approved oral medication for the treatment of interstitial cystitis (IC), also known as painful bladder syndrome. PPS is known to have anti-inflammatory and pro- chondrogenic properties. Pentosan polysulphate is available as pills or as a direct infusion into the bladder.
Adequan sulphate, a polysulphated glycosaminoglycan, is a well known veterinary medicament for treating joint pain.
Indomethacin is an FDA-approved, non-steroidal anti- inflammatory drug (NSAID). It's commonly used to reduce fever, pain, stiffness and swelling. Furthermore, Indomethacin is a COX-inhibitor that blocks prostaglandin production and is used as an inhibitor of inflammation. In higher doses it can also induce adipogenesis in vitro in mesenchymal progenitor cells by activating PPARYyY.
Pioglitazone is a powerful PPARy agonist, and belongs to the class of thiazolidinediones, or glitazones, and was designed to treat type II diabetes by increasing the insulin sensitivity.
Summary of the Figures Figure 1 shows pictures of histological staining experiments, relating to the synergistic effect of the combination of Pentosan sulphate with Indomethacin.
Figure 2 shows pictures of histological staining experiments, relating to the synergistic effect of the combination of Pentosan sulphate with Pioglitazone.
Figure 3 shows pictures of histological staining experiments, relating to the synergistic effect of the combination of Adequan sulphate with Indomethacin.
Figure 4 shows in vitro measurement in relative light units (RLU) of PPAR transcriptional activity in KS-483 cells transfected with a dual PPAR reporter system and exposed to different compounds.
Figures 5 shows a schematic structure of Thiazolidinedion and figure 6 of sulfonylurea.
DETAILED DESCRIPTION OF THE FIGURES The invention will be elucidated with the following non- 40 limiting examples and experiments.
Figure 1-3 show the effect of the combined use of a compound comprising a carbohydrate containing more than one sulphate {Adequan sulphate or Pentosan sulphate), and Indomethacin or Pioglitazone. The concentrations of active compounds used to stimulate the cells are given in the pictures. The active compounds were added to the medium, and thereafter the cells were suspended in the medium. After 3 days, the cells were stained with Oil red O or Nile Red staining.
Oil Red O (Solvent Red 27, Sudan Red 5B, C.I. 26125, C26H24N40) is a lysochrome (fat-soluble dye) diazo dye used for staining of neutral triglycerides and lipids on frozen sections. The pictures show central nuclei, increasing lipid formation and droplets by the combined use of the composition of the invention, and therefore is indicative of conversion of cancer cells with metastatic potential into harmless cells. Nile red (also known as Nile blue oxazone) is a lipophilic stain accumulating in lipid globules inside the cell. Nile Red fluoresces strongly when partitioned into lipids, but practically not at all in an aqueous solution.
Figure 4 shows the effect of exposure of KS-483 cells to a compound comprising a carbohydrate and a sulphate (Adequan sulphate or Pentosan sulphate), and Indomethacin or Pioglitazone.
Similar experiments are performed on other cell lines, on organoids, and on assays, showing similar results.
Examples and experiments The genes in KS-483 cells were assessed for up- or downregulation after stimulation with the compound. Briefly, KS- 483 cells were cultured under standard culturing conditions in «o-MEM medium supplemented with glutamax, penicillin/streptomycin and 10% heat-inactivated Fetal Calf Serum (FCS).
From experiments with up- and downregulated genes, and their activity, it is clear that a composition, comprising (i) a compound comprising at least one carbohydrate and containing more than one sulphate, in combination with (ii) indomethacin and/or pioglitazone blocked metastasis development.
activity measurements KS-483 cells were used for activity measurements. From the RLU measured after exposure to single compounds it is clear that 40 a composition, comprising (i) a compound comprising at least one carbohydrate and containing more than one sulphate and indomethacin and/or pioglitazone lead to a significant increase in activity and transfer away from metastatic cells. The invention has been described by reference to certain embodiments discussed above. It will be recognized that these embodiments are susceptible to various modifications and alternative forms well known to those of skill in the art without departing from the scope of the invention. Accordingly, although specific embodiments have been described, these are examples only and are not limiting upon the scope of the invention, which is defined in the accompanying claims.
For the purpose of searching the following section is added, which may be considered embodiments of the present invention, and of which the subsequent section represents a translation into Dutch.
1. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis, comprising (i) a first compound comprising at least one carbohydrate and containing more than one sulphate preferably selected from multiple Sulphur containing agents with a molecular weight of < 10 kDa, in combination with (ii) a second compound selected from the group of thiazolidinediones, NSAIDs, sulphonylureas, and indoles.
2. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to embodiment 1, comprising pentosan sulphate, and/or adequan sulphate.
3. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to embodiment 1 or 2, comprising indomethacin and/or pioglitazone.
4. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to any of embodiments 1-3, wherein the first compound and second compound are provided in a molar ratio of 0.01:1 to 1:0.01.
5. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to any one of the preceding embodiments, wherein the composition further comprises (iii) at least one pharmaceutically acceptable carrier.
6. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to any one of the preceding embodiments, wherein the active pharmaceutical ingredients are in one dosage form, preferably comprising 1-10 mg active ingredients/kg body weight, such as 2- 1000 mg active ingredients.
7. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to any one of embodiments 1-6, comprising pentosan sulphate and/or adequan sulphate, and indomethacin and/or pioglitazone.
8. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to any one of embodiments 1-7, wherein the pharmaceutical composition comprises separate dosage forms for individual pharmaceutical active ingredients, and/or wherein the composition is in the form of a tablet, capsule, repository, or injectable.
9. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to embodiment 8, wherein the composition is in the form of a tablet or capsule suitable for oral administration.
10. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to any one of embodiments 1-9, formulated in a form, which, depending on its use, allows targeting of specific cells, tissues or organs, such as in the form of nanoparticles.
11. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to any one of embodiments 1-10, wherein the cancer originates preferably from epithelial tissue.
12. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to embodiment 11, wherein the cancer is selected from skin cancer, lung cancer, stomach cancer, brain cancer, breast cancer, kidney cancer, liver cancer, colo-rectal cancer, bladder cancer, gall bladder cancer, prostate cancer, pancreas cancer, melanomas, and esophagus cancer.
13. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis according to any 40 one of embodiments 1-12 for use as a medicament by administering sald medicament in an effective amount to cancer cells with metastatic potential for a sufficient period.
14. Pharmaceutical composition for use in the prevention of metastasis or stopping of ongoing metastasis of embodiment 13, wherein the administration is to a pet or mammal comprising said tissue, wherein the mammal preferably is a human with a cancer that has metastatic potential.
15. The pharmaceutical composition according to any one of embodiments 1-14 as a medicament for prevention of metastasis or for stopping of ongoing metastasis.
Claims (15)
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| EP20828165.9A EP4076439A1 (en) | 2019-12-18 | 2020-12-16 | Pharmaceutical composition for use in preventing or stopping metastases |
| US17/786,104 US20230023285A1 (en) | 2019-12-18 | 2020-12-16 | Pharmaceutical composition for use in preventing or stopping metastases |
| CN202080088159.7A CN114828846B (en) | 2019-12-18 | 2020-12-16 | Pharmaceutical composition for preventing or inhibiting metastasis |
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