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EP1701719A1 - Agents de combinaison chp-gemcitabine et utilisation en tant qu' agents antitumoraux - Google Patents

Agents de combinaison chp-gemcitabine et utilisation en tant qu' agents antitumoraux

Info

Publication number
EP1701719A1
EP1701719A1 EP04816269A EP04816269A EP1701719A1 EP 1701719 A1 EP1701719 A1 EP 1701719A1 EP 04816269 A EP04816269 A EP 04816269A EP 04816269 A EP04816269 A EP 04816269A EP 1701719 A1 EP1701719 A1 EP 1701719A1
Authority
EP
European Patent Office
Prior art keywords
tumor
use according
chp
carcinoma
gemcitabine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04816269A
Other languages
German (de)
English (en)
Inventor
Zoser B. Salama
Dagmar Braun
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Esteve Pharmaceuticals GmbH
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP1701719A1 publication Critical patent/EP1701719A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to combination agents comprising cis-hydroxy-proline (CHP) and gemcitabine and the use of these agents in tumor prophylaxis and therapy.
  • CHP cis-hydroxy-proline
  • Tumors or cancer are localized increases in tissue volume and thus, in the broader sense, any localized swelling due to edema, acute or chronic inflammation, such as inflammation-related organ swellings, in the narrower sense tumors are new forms of tissue in the form of spontaneous, uninhibited, Autonomous and irreversible excess growth of the body's own tissue, which is usually associated with different degrees of loss of specific cell and tissue functions.
  • the consequences of this autonomous and irreversible excess growth lead to a considerable impairment of the organism, for example humans, and can lead to death.
  • Another difficulty in finding antitumor agents is that different derivatives or the original substance and its derivatives react and act differently, both in the animal model and also in humans.
  • various original substances are known which have no or only a slight antitumor effect, whereas their derivatives or derivatives can have a significant tumor-inhibiting but also a tumor-promoting effect.
  • Cis-hydroxy-proline has, for example, according to Klohe et al. (1985) did not find any properties that are necessary for an effective anti-tumor agent. Based on initial positive tests with this and other amino acids at the National Cancer Institute from 1933 to 1946, derivatives of proline and hydroxy-proline were synthesized in the following years to be used as a drug in cancer therapy (EP 02 23 850). Furthermore, because of the low activity of CHP (Klohe et al.), It has been proposed to use a combination of different CHP derivatives, since these should have a synergistic effect as a pharmaceutical agent in tumor treatment (US Pat. No. 6,066,665).
  • the described synergistic effects of the combination preparations proved to be only partially reproducible and, furthermore, the developed derivatives could only be used in very high concentrations - which are accompanied by side effects.
  • the object of the invention was therefore to provide a means and a method for cancer therapy based on CHP, which allow simple, safe and effective use.
  • a combination of CHP and gemcitabine has been found to have a high activity against tumor cells.
  • the invention therefore relates to the surprising teaching that a> compound, namely underivatized CHP, the antitumor properties of which have been described as insufficient in the prior art, in combination with the chemotherapeutic gemcitabine has an effect on cancer cells that is surprisingly higher than that of the individual compounds is.
  • CHP in the sense of the invention are ice isomers of 4-hydroxy-L-proline or its salts, without being CHP derivatives.
  • Gemcitabine in the sense of the invention is in particular gemcitabine hydrochloride, 2'-deoxy-2 ', 2'-di-fluorocytidine.
  • the combination agent in the sense of the invention can, for example, be such that CHP and gemcitabine are contained together in a solution or in a solid, such as a tablet.
  • the ratio of CHP and gemcitabine can vary freely. A ratio of CHP and gemcitabine in the range from 1: 10,000 to 10,000: 1 is preferred. Within this range, the ratio of CHP and gemcitabine can vary depending on the tumor or patient status.
  • the at least two components - CHP and gemcitabine - can also be introduced together into a solution or a solid in such a way that they are released with a time delay.
  • the combination agent in the sense of the invention can also consist of two separate solutions or two separate solids, one solution or one solid essentially gemcitabine and the other solution or other solid essentially CHP includes. It is possible that the two solutions or solids are associated with a common or with separate carriers. The two solutions and / or the two solids can be present, for example, in a capsule as a common carrier.
  • Such a formulation of the combination agent according to the invention is particularly advantageous if the CHP and the gemcitabine are to be administered with a time delay.
  • the organism is first brought into contact with CHP, for example by infusion or by oral administration, in order then to be brought into contact with the other constituent of the combination agent at a later time.
  • the combination agent it is also possible for the combination agent to be provided using customary pharmaceutical methods and processes in such a way that the organism is first brought into contact with gemcitabine and then with CHP. It is therefore preferred to sequentially bring the organism into contact with the components of the combination agent.
  • the time period between the administration of the two components of the combination agent according to the invention or the first release of CHP or gemcitabine depends on the age, gender, the overall constitution of the patient, the type of tumor or other parameters determined by the treating doctor, for example by preliminary tests can be.
  • the agent according to the invention may comprise customary auxiliaries, preferably carriers, adjuvants and / or vehicles.
  • the carriers can be, for example, fillers, extenders, binders, humectants, disintegrants, solution retarders, absorption accelerators, wetting agents, adsorbents and / or lubricants.
  • the combination agent is particularly referred to as a drug or pharmaceutical agent.
  • the agent comprises one or more additional agents from the group of antiviral, fungicidal or antibacterial agents and / or immune stimulators.
  • the agent can comprise further chemotherapy agents, preferably alitretinoin, aldesleukin (IL-2), alretamine, all-transretinoic acid (tretinoin), aminoglutethimide, anagrelide, anastrozole, asparaginase (E.
  • chemotherapy agents preferably alitretinoin, aldesleukin (IL-2), alretamine, all-transretinoic acid (tretinoin), aminoglutethimide, anagrelide, anastrozole, asparaginase (E.
  • coli azathioprine
  • bicalutamine amide bleomycin, busulfan
  • capecitabine carboplatin, carmustine, chlorambucil, cisplatin, cladribine (2-CDA), cyclophosphamide, cytarabine, dacarbazine, dactinomycin-d, daunorubicin (daunomycin), daunorubicin, lipethominone, doxinoxin, doxinoxin, doxinoxin, doxinoxin, doxinoxin, doxinoxin, doxinoxin liposomal, epirubicin, estramustine phosphate, etoposide (VP-16-213), exemestane, floxuridine, 5-fluorouracil,
  • Megestrol Acetate Melphalan (L-phenylalanine mustard), 6-Mercaptopurine, Methotrexate, Methoxsalen (8-MOP), Mitomycin-C, Mitotane, Mitoxantrone, Nilutamide, Nitrogen Mustard (Mechlorethamine hydrochloride), Octreotide, Paclitaxel, Pentostatin (2) 'deoxycoformycin), plicamycin, porfimer, prednisone, procarbazine, rituximab, streptozotocin, tamoxifen, teniposide (VM-26), 6-thio-guanine, thalidomide, thiotepa, topotecan, toremifene, trastuzumab, trimetrex or vinistine / vinistine / vinistine / viddlingline , It may also be preferred to partially or completely replace gemcitabine with one or more of the agents mentioned.
  • the invention also relates to the use of the agent according to the invention in the diagnosis, prophylaxis, follow-up, therapy and / or after-treatment of Growth, differentiation and / or division of related diseases.
  • this disease is a tumor, in particular a neoplastic tumor, an inflammatory tumor, an abscess, an effusion and / or an edema. It is particularly preferred that the tumor is a solid tumor or leukemia.
  • the agent according to the invention is used as a gel, powder, powder, tablet, slow-release tablet, premix, emulsion, infusion formulation, drops, concentrate, granules, syrup, pellet, bolus, capsule, aerosol, spray and / or Inhaled prepared and / or used in this form.
  • the tablets, coated tablets, capsules, pills and granules can be provided with the customary coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, if necessary with a delay, where, for example, polymer substances and waxes can be used as embedding compounds.
  • compositions of this invention can preferably be used for oral administration in any orally acceptable dosage form, including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • carriers that are used frequently include lactose and corn starch.
  • Lubricants such as magnesium stearate, are also typically added.
  • diluents which may be used include lactose and dried corn starch.
  • the active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.
  • Suppositories can contain the usual water-soluble or water-insoluble carrier substances in addition to the active substance or substances, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C 4 alcohol with C 16 fatty acid) or mixtures of these substances).
  • active substance or substances for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C 4 alcohol with C 16 fatty acid) or mixtures of these substances).
  • ointments, pastes, creams and gels can contain the usual excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances ,
  • powders and sprays can contain the usual carriers, for example lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these.
  • Sprays can also contain the usual blowing agents, for example chlorofluorocarbons.
  • solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydofurfuryl alcohol, poly- contain ethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
  • solvents such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol
  • suspensions can contain the usual carriers such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth or mixtures contain these substances.
  • liquid diluents for example water, ethyl alcohol, propylene glycol
  • suspending agents for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth or mixtures contain these substances.
  • the medicaments can be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oily suspension.
  • This suspension can also be formulated using methods known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally compatible diluent or solvent, for example as a solution in 1,3-butanediol.
  • Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, non-volatile oils are usually used as solvents or suspending media.
  • Any mild non-volatile oil including synthetic mono- or diglycerides, can be used for this purpose.
  • Fatty acids such as oleic acid and its glyceride derivatives, can be used in the production of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, in particular in their polyoxyethylated forms.
  • oils such as olive oil or castor oil, in particular in their polyoxyethylated forms.
  • These oil solutions or suspensions can also be one Long chain alcohol or a similar alcohol contain as a diluent or dispersant.
  • the formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
  • the active substances CHP and / or gemcitabine should preferably be present in the pharmaceutical preparations listed in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
  • the listed pharmaceutical preparations can contain other active pharmaceutical ingredients.
  • the pharmaceutical preparations listed above are prepared in a customary manner by known methods, for example by mixing the active ingredient (s) with the carrier (s).
  • the preparations mentioned can be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment, drops) and for the therapy of tumors.
  • Injection solutions, solutions and suspensions for oral therapy, gels, infusion formulations, emulsions, ointments or drops can be considered as suitable preparations.
  • ophthalmic and dermatological formulations silver and other salts, ear drops, eye ointments, powder or solutions can be used.
  • suitable formulations can also be ingested through feed or drinking water.
  • the medicaments or the combination agents can be incorporated into other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement.
  • CHP and / or gemcitabine are incorporated in a pharmaceutical preparation in a concentration of 0.1 to 99.5, preferably 0.5 to 95, particularly preferably 20 to 80% by weight. That is, CHP and / or gemcitabine are present in the pharmaceutical preparations listed above, for example tablets, pills, granules and others, preferably in a concentration of 0.1 to 99.5% by weight of the total mixture in a certain ratio.
  • the amount of active ingredient that is to say the amount of a compound according to the invention, which is combined with the carrier materials to produce a single dosage form, will be able to vary by the person skilled in the art depending on the patient to be treated and the particular mode of administration.
  • the proportion of the active compound in the preparation can be changed so that a maintenance dose is present which inhibits or prevents further growth of the tumor or suppresses metastasis and infiltration.
  • the dose or frequency of administration, or both as a function of symptoms can then be reduced to a level at which the improved condition is maintained. If the symptoms have been relieved to the desired level, treatment should stop. However, patients may need long-term interruption treatment after any recurrence of symptoms.
  • the proportion of the compounds, that is to say their concentration, in the overall mixture of the pharmaceutical preparation as well as their composition or combination is variable and can be modified and adapted by the person skilled in the art on the basis of his specialist knowledge.
  • the compounds according to the invention can be brought into contact with an organism, preferably a human or an animal, in various ways.
  • the pharmaceutical compositions can be administered in different dosages.
  • the application should be carried out in such a way that the disease is combated as effectively as possible or the outbreak of such a disease is prevented by prophylactic administration.
  • the concentration and the type of application can be determined by a person skilled in the art through routine experiments.
  • Preferred applications of the compounds according to the invention are oral application in the form of powder, tablets, juice, drops, capsules or the like, rectal application in the form of suppositories, solutions and the like, parenterally in the form of injections, infusions and solutions and locally in the form of Ointments, plasters, envelopes, rinses and the like.
  • the compounds according to the invention are preferably brought into contact prophylactically or therapeutically.
  • the suitability of the chosen forms of application as well as the dose, the application scheme, the choice of adjuvant and the like can be determined, for example, by taking serum alliquots from the patient, that is to say the human or the animal, and testing for the presence of cancer cells in the course of the treatment protocol become.
  • the condition of the liver, but also the amount of T cells or other cells of the immune system can be determined in a conventional accompanying manner in order to obtain an overview of the patient's immunological constitution and in particular the constitution of organs important for metabolism ,
  • the clinical condition of the patient can be observed for the desired effect.
  • the patient can be modified and further treated with agents according to the invention and other known medicaments, from which an improvement in the overall constitution can be expected.
  • agents according to the invention and other known medicaments, from which an improvement in the overall constitution can be expected.
  • injections for example intramuscularly or subcutaneously or into the blood vessels, are a further preferred route for the therapeutic administration of the compounds according to the invention.
  • delivery via catheters or surgical tubes can also be used.
  • CHP and / or gemcitabine can also be used in a total amount of preferably 0.05 to 500 mg / kg of body weight per 24 hours, preferably from 5 to 100 mg / kg body weight. This is advantageously a therapeutic amount which is used to prevent or improve the symptoms of a disorder or of a respectful, pathologically physiological condition.
  • the daily dose of 0.05 to 500 mg / kg body weight can be used once or several times to achieve the desired results.
  • pharmaceutical agents are typically used for administration approximately 1 to 10 times per Day or alternatively or additionally used as a continuous infusion. Such administrations can be used as chronic or acute therapy.
  • the amounts of active ingredient that are combined with the carrier materials to produce a single dosage form can of course vary depending on the host to be treated and the particular mode of administration. It is preferred to distribute the target dose over 2 to 5 applications, 1 to 2 tablets with an active ingredient content of 0.05 to 500 mg / kg body weight being administered for each application.
  • tablets can also be retarded, which reduces the number of applications per day to 1 to 3.
  • the active substance content of the retarded tablets can be 3 to 3000 mg. If, as stated, the active ingredient is administered by injection, it is preferred to bring the host into contact with the compounds according to the invention 1 to 10 times a day or by continuous infusion, amounts of 4 to 4000 mg per day being preferred are. The preferred total amounts per day have proven to be advantageous in human medicine and in veterinary medicine.
  • the pharmaceutical agent is used in a single dose of 1 to 100, in particular 2 to 50 mg / kg body weight.
  • the amount of the single dose per application can be varied by the person skilled in the art on the basis of his specialist knowledge.
  • the compounds used in accordance with the invention can be given in the stated individual concentrations and preparations together with the feed or with feed preparations or with the drinking water, also in veterinary medicine.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, half a daily dose or a third or a quarter of a daily dose.
  • the dosage units can accordingly preferably contain 1, 2, 3 or 4 or more single doses or 0.5, 0.3 or 0.25 of a single dose.
  • the daily dose of the compounds according to the invention is preferably divided into 2 to 10 applications, preferably to 2 to 7, particularly preferably to 3 to 5 applications. A permanent infusion of the agents according to the invention is of course also possible.
  • 1 to 2 tablets are given for each oral application of the compounds according to the invention.
  • the tablets according to the invention can be provided with coatings and casings known to the person skilled in the art and can also be composed in such a way that they only release the active ingredient (s) in a certain part of the host, if preferred.
  • the cancer or tumor being treated is prophylactically prevented. prevents or prevents its recurrence, selected from the group of cancers or tumors of the ear, nose and throat area, the lungs, the mediastinum, the gastrointestinal tract, the urogenital system, the gynecological system, the breast, the endocrine system, the Skin, bone and soft tissue sarcomas, mesotheliomas, melanomas, neoplasms of the central nervous system, cancer or tumor diseases in childhood, lymphomas, leukaemias, paraneoplastic syndromes, metastases with no known primary tumor (CUP syndrome), peritoneal carcinoma poses, immunosuppression and malignancy-related malignancies or tumor metastases.
  • CUP syndrome primary tumor
  • the tumors can be the following types of cancer: adenocarcinoma of the breast, prostate and colon; all forms of lung cancer that originate from the bronchi; Bone marrow cancer, melanoma, hepatoma, neuroblastoma; the papilloma; the apudome, the choristome, the branchchioma; the malignant carcinoid syndrome; the carcinoid heart disease; the carcinoma (for example Walker carcinoma, basal cell carcinoma, basosquam ⁇ ses carcinoma, Brown-Pearce carcinoma, ductal carcinoma, Ehrlich tumor, in situ carcinoma, cancer 2 carcinoma, Merkel cell carcinoma, mucus cancer, non- small cell bronchial carcinoma, oat cell carcinoma, papillary carcinoma, scarring carcinoma, bronchioloalveolar carcinoma, bronchial carcinoma, squamous cell carcinoma and transitional cell carcinoma); histiocytic dysfunction; Leukemia (for example in connection with B-cell leukemia, mixed-cell leukemia, zero-cell
  • Cystosarcoma phyllodes Cystosarcoma phyllodes; Hemangiosarkom; lymphangiosarcoma; Myxosarcoma, ovarian cancer; Sarcoma (for example, Ewing's sarcoma, experimental, Kaposi's sarcoma and mastline sarcoma); Neoplasms (e.g.
  • bone neoplasms bone neoplasms, breast neoplasms, digestive system neoplasms, colorectal neoplasms, liver neoplasms, pancreatic neoplasms, neoplasms of the appendages, testicular neoplasms, orbital neoplasms, neoplasms of the head and neck , the central nervous system, neoplasms of the hearing organ, pelvis, respiratory tract and urogenital tract);
  • Neurofibromatosis and cervical squamous dysplasia Neurofibromatosis and cervical squamous dysplasia.
  • the cancer or tumor which is being treated is prophylactically prevented or its recurrence is prevented is selected from the flu of cancer or tumor diseases which comprise cells which comprise the MUC1 in the definition according to the invention, selected from the group: tumors of the ear, nose and throat area including tumors of the inner nose, the paranasal sinuses, the nasopharynx, of the lips, the oral cavity, the oropharynx, the larynx, the hypopharynx, the ear, the salivary glands and paragangliomas, tumors of the lungs including non-small-cell bronchial carcinomas, small-cell bronchial carcinomas, tumors of the mediastinum, tumors of the gastrointestinal tract of the esophagus, stomach, pancreas, liver, gallbladder and biliary tract, small intestine, colon and rectal carcinomas and anal carcinomas, urogenital tumors including tumors of the kidneys, ureters, bladder,
  • the cancer or tumor which is treated, prevented prophylactically or whose recurrence is prevented is selected from the group comprising cancers or tumor diseases of breast cancer, gastrointestinal tumors, including colon cancer, gastric cancer, colon cancer and small bowel cancer. pancreatic carcinoma, ovarian carcinoma, liver carcinoma, lung cancer, renal cell carcinoma and multiple myeloma.
  • cell lines from the American Type Culture Collection were used and until confluent in a monolayer in an RPMI-1640 bicarbonate medium (Seromed, Berlin, Germany) in an incubator (5% H 2 0.37 ° C) cultivated.
  • the cells were examined for mycoplasma contamination.
  • the medium had 10% heat inactivated fetal calf serum (Seromed) and 4 mM glutamine.
  • the cells are cultivated and passaged using the usual methods (0.03% trypsin containing 0.02% EDTA, 3 times a week).
  • the cell number is determined using a TOA Sysmex microcell counter (TOA, Tokyo, Japan).
  • the chemicals are from Sigma (St. Louis, MO).
  • the components for testing are used as supplied.
  • CHP is used as a 5 mg / ml stock solution in PBS (phosphate buffered saline, Dulbecco) and frozen in aliquots at -20 ° C.
  • Related components are used as 2 mg / ml stock solution and are frozen at -20 ° C.
  • the cells are obtained by trypsinization, washed in PBS, in 70% ethanol at -20 ° C for 20 min. fixed. The cells are then washed again in PBS and transferred to a staining solution containing 20 ⁇ g / ml
  • PI Propidium odid
  • Monidet P40 / PBS 0.05% Monidet P40 / PBS
  • the washed cells are analyzed by flow cytometry (Coulter XL-MLC, Coulter, Miami, Florida) using the Multicycle AV software (Phoenix) for the calculation of the cell cycle distribution of PI histograms.
  • the percentage of cells in the Gl / 0 (resting phase), S phase (DNA synthesis) and G2M (mitotic cells) are determined. Apoptotic subGl cells were calculated from PI histograms. All experiments are carried out in duplicate.
  • the chemosensitivity assay is carried out with 10 4 cells per well in a 96-well microtiter plate with 100 ⁇ l medium, the components to be tested being in a lumens of 100 ⁇ l can be supplied. All components are diluted on the microtiter plates and the plates are incubated under cell culture conditions for 4 days, except for the tests, in which the relationship between application time and reaction is to be determined. Cell viability is determined using an MTT assay, including mitochaondrial activity, the ratio of cell survival to cell number. The tests were carried out according to the methods known to the person skilled in the art.
  • the apoptotic or necrotic cells were carried out by Annexin V / PI staining experiments according to the usual laboratory methods.
  • Combination agents according to the invention which release CHP and gemcitabine sequentially were also tested. These agents were prepared by the galenic methods known to those skilled in the art. Agents were used in cell cultures in which CHP is released first and gemcitabine is released 24 hours or 48 hours later. It was found that the pancreatic carcinoma cells, which were initially brought into contact with CHP, and which were therefore pretreated with CHP, showed resistance when subsequently brought into contact with gemcitabine. For example, the cells were about 5% more resistant at a higher gemcitabine concentration of more than 0.25 ⁇ g / ml and up to 20% more resistant at a lower gemcitabine concentration.
  • Table 2 shows the effect of the combination agents on PANC-1 cells.
  • pancreatic tumors are particularly promising if they are first brought into contact with gemcitabine and then with CHP, the CHP concentration being chosen to be low in accordance with the aforementioned.
  • the agents used were those which contain CHP and gemcitabine in differently dissolvable carriers and vehicles.
  • kits are used in which gemcitabine and CHP have been provided in separate solutions, which are described in accordance with an instruction given in the kit was included, were used sequentially.
  • Combination agents are thus available which, depending on the time-delayed release and the components or compounds released first or subsequently, have different specificities for different types of tumor.
  • the combination agent according to the invention modifies the respective cell cycle of the tumor cells.
  • the S phase or the G2M or Gl / 0 state was modified or lost.
  • the S phase or the G2M or Gl / 0 state was modified or lost.
  • several cells of the combination agent had switched to apoptotic / necrotic cells.
  • different specificities of the combination agent can be achieved if other chemotherapeutic agents such as oxoplatin or doxorubicin are used in addition to gemcitabine. This could also be shown when using combination agents in which the gereitabinin portion was completely replaced by oxoplatin or doxorubicin or another chemotherapeutic agent.
  • a further modification of the specificity of the combination agents was possible by using trans-hydroxy-proline instead of the ice form of the CHP.
  • combination agents disclosed according to the invention were also clinically tested in the human field. Good results have been achieved with the CHP-gemcitabine combination agent and the CHP-capecitabine combination agent. Gemcitabine was developed by the
  • myelosuppression which are caused by damage to the bone marrow, are called myelosuppression.
  • Other side effects include severe sweating, diarrhea, fever or symptoms similar to influenza, nausea, vomiting, diarrhea, shortness of breath, peripheral edema, hematuria, proteinuria, hair loss and rash and reactions at the injection site.
  • Treatment days 1 to 7 8 g daily CHP (intravenously)
  • the gemcitabin dose is 1000 mg / m 2 and is given intravenously on the 1st, 8th and 15th day
  • CHP is given orally, the dose being 4 g
  • a large number of patients suffering from colorectal adenocarcinomas and liver metastases can be treated with a combination therapy of capecitabine and CHP.
  • the standard treatment for these tumors is
  • Geiteitababe during a 21-day treatment cycle. Patients are treated for 14 days, followed by a 7-day rest period.
  • the recommended dose of capecitabine is 2,500 mg / m 2 per day.
  • the agent is given orally in two separate doses 30 minutes after a meal.
  • Capecitabine administration leads to a multitude of side effects that have already been listed for gemcitabine administration (see above).
  • the combination of capecitabine and CHP leads to good efficiency in the treatment of tumors and the
  • the combination therapy allows the use of a lower dose of capecitabine and shorter treatment cycles of only 10 days.
  • the Combination therapy is very well tolerated by the patients.
  • the success of the therapy was determined in the same way as with the CHP-gemcitabine combination therapy.
  • Both the CHP-gemcitabine and the CHP-capecitabine combination therapy showed good therapeutic success in tumor treatment, whereby the chemotherapeutic agents gemcitabine and capecitabine could be used in the presence of CHP in lower doses and shorter treatment cycles (compared to the isolated administration of individual pharmaceutical agents).
  • the side effects that occur in the gastrointestinal tract such as. B. abdominal pain, diarrhea including vomiting diarrhea, the breaking itself and the general symptoms of exhaustion as well as stomatitis, anemia and others were reduced.

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Abstract

L'invention concerne des agents de combinaison contenant cis-hydroxyproline (CHP) et gemcitabine ainsi que l'utilisation de ces agents dans la prophylaxie et la thérapie tumorale.
EP04816269A 2003-12-12 2004-12-13 Agents de combinaison chp-gemcitabine et utilisation en tant qu' agents antitumoraux Withdrawn EP1701719A1 (fr)

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DE10359828A DE10359828A1 (de) 2003-12-12 2003-12-12 CHP-Gemcitabin- Kombinationsmittel und ihre Verwendung als Antitumorwirkstoffe, insbesondere Antimetastasierungswirkstoffe
PCT/DE2004/002760 WO2005056005A1 (fr) 2003-12-12 2004-12-13 Agents de combinaison chp-gemcitabine et utilisation en tant qu'agents antitumoraux

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WO2005120495A1 (fr) * 2004-06-14 2005-12-22 Salama Zoser B Composition anticancereuse composee de proline ou de ses derives et d'un anticorps antitumoral
HUE027443T2 (en) 2007-09-10 2016-10-28 Boston Biomedical Inc A novel class of Stat3 pathway inhibitors and tumor stem cell inhibitors
JP6433085B2 (ja) 2013-04-09 2018-12-05 ボストン バイオメディカル， インコーポレイテッド がんの処置に使用するための２−アセチルナフト［２，３−ｂ］フラン−４，９−ジオン
WO2015026813A1 (fr) * 2013-08-19 2015-02-26 Taris Biomedical Llc Dispositifs d'administration de médicament à multiples unités et procédés
CN105030682B (zh) * 2015-06-24 2018-02-09 广州复大医疗股份有限公司 一种纳米微粒胶体及其制备方法与用途
US11299469B2 (en) 2016-11-29 2022-04-12 Sumitomo Dainippon Pharma Oncology, Inc. Naphthofuran derivatives, preparation, and methods of use thereof
WO2018213424A1 (fr) 2017-05-17 2018-11-22 Boston Biomedical, Inc. Méthodes pour le traitement du cancer

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CA1281288C (fr) * 1984-11-05 1991-03-12 Wilhelm Hoerrmann Traitement des tumeurs
US6153643A (en) * 1984-11-05 2000-11-28 Hoerrmann; Wilhelm Anti-cancer-substance
DE59702322D1 (de) * 1996-03-11 2000-10-12 Wilhelm Hoerrmann Kombination aus cis-4-hydroxy-l-prolin und n-methyl-cis-4-hydroxy-l-prolin zur anwendung als therapeutischer wirkstoff insbesondere für die krebstherapie
WO2001034134A2 (fr) * 1999-11-11 2001-05-17 Eli Lilly And Company Combinaisons oncolytiques pour traitement du cancer
WO2001034198A2 (fr) * 1999-11-11 2001-05-17 Eli Lilly And Company Combinaisons oncolytiques pour traitement des cancers
EP1258248A3 (fr) * 2001-05-18 2003-06-04 TAP Pharmaceutical Products, Inc. Traitement de tumeurs avec un dérivé de fumagillol et un autre agent antinéoplastique

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DE10359828A1 (de) 2005-07-28
AU2004296129A1 (en) 2005-06-23
RU2006125081A (ru) 2008-01-20
AU2004296129A2 (en) 2005-06-23
MXPA06006717A (es) 2007-05-04
CA2548605A1 (fr) 2005-06-23
ZA200605707B (en) 2008-02-27
WO2005056005A1 (fr) 2005-06-23
CN1889946A (zh) 2007-01-03
JP2007513894A (ja) 2007-05-31
US20070207980A1 (en) 2007-09-06
BRPI0417513A (pt) 2007-03-06

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