CA2165454A1 - Food and/or pharmaceutical composition having a low polyamine content - Google Patents
Food and/or pharmaceutical composition having a low polyamine contentInfo
- Publication number
- CA2165454A1 CA2165454A1 CA002165454A CA2165454A CA2165454A1 CA 2165454 A1 CA2165454 A1 CA 2165454A1 CA 002165454 A CA002165454 A CA 002165454A CA 2165454 A CA2165454 A CA 2165454A CA 2165454 A1 CA2165454 A1 CA 2165454A1
- Authority
- CA
- Canada
- Prior art keywords
- composition
- composition according
- proteins
- human
- inhibitor
- 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.)
- Abandoned
Links
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
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/19—Dairy proteins
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
Abstract
An esculent composition consisting of a nutrient mixture having a low polyamine content, containing less than 50 picomoles/g of putrescine, spermidine, spermine and cadaverine, and containing (expressed in dry weight % on the basis of the overall dry weight) 10-35 % lipids, 8-30 % proteins, 35-80 % carbohydrates, and up to 10 % a mixture of vitamins, minerals and electrolytes. Said composition is advantageously enriched with or administered in combination with at least one intracellular polyamine synthesis inhibitor in an amount of no more then 15 wt % on the basis of the overall dry weight.
Description
FOOD AND/OR PHARMA~UTICAL COMPOSITION HAVING A LOW
POLYAMINE CONTENT
This invention relates to the food industry and the pharmaceutical industry.
Polyamines, and particularly putrescine (I), spermidine (II) and spermine (III) are present in all cells.
NH3 - ( CH2 ) 4 - NH3 ( I ) +NH3 - ( CH2 ) 3 - NH - ( CH2 ) 4 - NH3 ( I I ) NH3 - (CH2)3 - NH - (CH2)4 - NH - (CH2)3 - NH3+ (III) Although it has been believed for a long time that these molecules do not perform any physiological role and only represent a terminal step in tissular catabolism, a great deal of scientific work has shown that polyamines derived from decarboxylation of ornithine were actually biologically active molecules capable of acting at different and important levels in the life of the cell.
These molecules are found not only inside cells, they also occur in circulation within biological fluids in the organism such as blood, and are derived from three main sources:
- physiological cellular proliferation (growth and/or renewal of cells making up the organism), and tumorous cellulal proliferation, - food, - intestinal bacteria.
Intracellular polyamines are derived from a finely regulated metabolism related to the cellular cycle, rather than being obtained from passive transmembrane exchanges with biological fluids in the organism. An increase in the activity of the enzyme responsible for the main intracellular anabolic tract of polyamines, ornithine-decarboxylase (ODC) and therefore of the concentrations in putrescine, spermidine and spermine have actually been observed at the end of phase Gl and at the beginning of phase S, and at the beginning of phase G2 in the cellular replication cycle. The implication of the metabolism of polyamines in cellular replication and therefore in proliferative processes means that this metabolism is one of the preferred targets of anti-proliferative drugs, and is also the source of new circulation signals capable of revealing the existence of a neoplastic process within an organism.
It has been observed that tumorous growth is generally accompanied by a very significant increase in the intracellular anabolism of polyamines that are then found in increasing quantity in biological fluids.
Although the exact role of circulating polyamines as parameters involved in homeostatic regulation (or deregulation) of cellular proliferation is not yet clear, it has been demonstrated that the polyamine content of red cells may be considered and used as tumorous hyperplasic markers (see "Biological significance of circulating polyamines in oncology" -CA21 654~4 Moulinoux, J.-Ph. Quemener, V. and Khan, N.A.
Cellular and molecular biology - 37(8), 773-783, 1991).
Furthermore, this work has shown that circulating polyamines originating either from the cells_themselves or from the gastro-intestinal tract (food, intestinal bacteria) participate in maintaining the malignant proliferative condition.
Several ornithine-decarboxylase inhibitors are known In the current state of the art, and particularly irreversible selective inhibitors of this enzyme such as a-difluoromethylornithine (a-DFMO) marketed by the Marion Merrell Dow company under the name Eflornithine~. However, isolated administration of a-DFMO to patients or animals suffering from cancer without any other treatment has proved to be ineffective in halting the progress of a malignant tumor, although this polyamine synthesis inhibitor completely inhibited the proliferation of cancerous cells in vitro, while very significantly reducing intracellular contents of putrescine and spermidine.
The inability of a-DFMO to reduce the proliferation of malignant cells in vivo is very probably related to the fact that in the organism, cancerous cells restore the intracellular quantity of polyamines necessary to maintain their proliferation by capturing polyamines present in the extra-cellular environment, in other words in the various biological fluids such as blood.
This assumption was confirmed by work done by Person et al (Cancer Research, 1988, No. 48, pp. 4807 to 4811) 4 CA21 654~4 which demonstrated that unlike what was observed with L1210 abnormal cells, mice inoculated with muted L1210 cells made incapable of capturing extracellular polyamines responded well to a treatment inhibiting intracellular polyamines biosynthesis using a-DFMO.
Furthermore, various work has been carried out to show that joint administration to animals of:
- food with no polyamines, - a-DFMO, - a polyamine-oxydase (PAO) inhibitor eliminating oxidizing retroconversion of spermidine and spermine into putrescine, and - neomycine and metronidazole, almost entirely inhibits the tumorous progress of Lewis pulmonary carcinoma 3LL (Seiler N. et al, Cancer Research, 1990, No. 50, pp. 5077-5083), human glioblastoma U251 (Moulinoux J-Ph. et al, Anticancer Research, 1991, No. 11, pp. 175-180), Dunning prostate adenocarcinoma MAT-Lylu (Moulinoux J-Ph. et al, Journal of Urology, 1991, No. 146, pp. 1408, 1412) and human neuroblastoma neuro 2a (Quemener et al, "Polyamines in the gastro-intestinal tract", Dowling R.H., Falsch I.R.
and Laser C Ed., Kluwer Academic Publishers Boston, 1992, pp. 375-385).
It was also demonstrated in animals that polyamine depletion could considerably potentialize the anti-proliferative effects of conventional anti-tumorous drugs (methotrexate, cyclophosphamide, vindesine) while increasing the survival time of animals and possibly reducing the quantities of administered drugs while ~` _ 5 CA21654~4 maintaining the same anti-tumorous effects (Quemener V.
et al, "Polyamine deprivation enhances antitumorous efficacy of chemotherapy", Anticancer Research No. 12, 1992, pp. 1447-1454).
The object of the invention is to provide a composition administrable to man as food, food complement and/or a therapeutic nutrition product, in order to overcome the inefficiency of treatment in man done hitherto by isolated administration of a-DFMO.
More specifically, the object was to develop a composition efficient in man and, particularly, an accurate formulation of components of the inventive composition allowing a real synergy of caused effects, in man, by reducing outer polyamine contents and by inhibiting intracellular synthesis of these compounds.
This object is reached by a composition that can be ingested by man, characterized in that it consists of a nutrition mixture with a low polyamine content less than 50 picomoles/g of putrescine, of spermidine, of spermine and cadaverine, containing in percentage by dry weight with respect to the total dry weight : 10~
to 35~ of lipids, 8~ to 30~ of proteins, 35~ to 80~ of glucides, and up to 10~ of a mixture of vitamins, minerals and electrolytes.
This composition may be presented in dry form to be dissolved extemporaneously in a neutral vehicle suitable for oral or enteral administration, or in the form of a liquid ready for use. In all cases the composition is presented in sterile form.
-` 6 CA21654~4 This composition is particularly suitable for man and forms a food substitute that can efficiently create polyamine deprivation in patients. This composition could satisfactorily feed a patient whil~ creating polyamine deprivation, firstly by inhibiting intracellular polyamines synthesis and secondly by reducing the input of exogenic polyamines.
This composition brings, every day, at least 60 times less putrescine, 200 times less cadaverine, 700 less spermidine and spermine with respect to the human natural food which has the lowest polyamine content, but which nevertheless suits human nutrition needs.
This composition would strongly inhibit the endogenic synthesis of polyamines and very significantly reduce the input of these substances since its various constituents contain almost no polyamines. In order to also reduce polyamine inputs due to intestinal bacteria, this composition could be administered at the same time as a decontamination of the gastro-intestinal tract using antibiotic(s) and/or antiparasite product, for example such as neomycine and metronidazole. It would also be possible to consider including this type of antibiotic and/or antiparasite product directly into said composition, while remaining within the scope of the invention.
Nutrients used in the food composition according to the invention have a good nutritional value, even for sick patients.
- ~ 7 CA2 165454 The quantity of water used to make the composition is determined such that the composition is more or less liquid and can be easily ingested by the patient.
The percentage by weight of the mixture composed of vitamins, minerals and electrolytes is chosen so as to satisfy the necessary proportions, known to the expert in the subject, in a balanced diet.
This composition could be administered at the same time as at least one intracellular polyamines synthesis inhibitor.
In one attractive alternative of the invention, said composition is enriched with not more than 15~ by weight, and preferably between 0.2~ and 7~ by weight with respect to the total dry weight of the composition, of at least one intracellular polyamines synthesis inhibitor.
Usable ODC inhibitors are chosen particularly among the following compounds:
Pyri doxal phospha te antagonists - L-canaline - N-(5'-phosphopyridoxyl) ornithine Compe titi ve inhibi tors - a-hydrazino-ornithine - DL-a-hydrazino-~-aminovaleric acid - a-methylornithine (a-MO) - trans-3-dehydro-DL-ornithine -1.4-diamino-trans-2-butene -1.4-diaminobutanone Inhibi tors cont~; n i ng d i amin e -1.3-diaminopropane -1.3-diamino-2-propanol - bis(ethyl)spermine Suicide and irreversible inhibi tors - 2-difluoromethylomithine (DFMO) - monofluoromethylornithine - 2-monofluoromethyldehydro-ornithine - 2-monofluoromethyldehydro-ornithine methyl ester - 5-hexyne-1.4-diamine - trans-hex-2-en-5-yne-1.4-diamine - monofluoromethylputrescine - difluoromethylputrescine - a-allenylputrescine - (2R, 5R)-6-heptyne-2.5-diamine Among these inhibitors, competitive inhibitors are particularly preferred and particularly a-methylornithine (a-MO).
a-methylornithine has many advantages for the purposes proposed in this document. a-MO has the advantage of being an easily-synthesizable natural substance and with a high inhibition constant.
a-methylornithine also has the advantage that it inhibits the synthesis of polyamines in Escherischia coli, the most common bacteria naturally present in the intestinal tract, which in particular is not the case for a-DFMO.
Thus the use of a food composition according to the invention containing a-methylornithine as an - intracellular polyamines synthesis inhibitor, can - g CA216~454 reduce the exogenic input of polyamines by intestinal bacteria without needing to use an anti-biotherapy concomittently with administration of this composition, or at least reduce the administered dose of antibiotics.
Finally, a-MO has the advantage of being a simple competitive inhibitor of decarboxylase ornithine (which is contrary to methods currently being explored by the international scientific community) and strongly reduces the risk of the organism becoming accustomed by mutation leading to enhanced cellular resistance.
The original concept of the invention gave priority to searching for a synergy effect between several factors, namely particularly inhibition of the synthesis of intracellular polyamines and the depleted total input of these substances. From this point of view, it also appears that the best inhibitor is a-MO.
According to one alternative, the composition according to the invention is enriched in vitamins, particularly those provided by intestinal bacteria in a healthy human. The antibiotherapy that may accompany administration of said composition may also reduce the input of some vitamins. In this case it may be necessary to enrich the composition according to the invention with these vitamins in order to avoid causing a vitamin shortage caused by prolonged administration of said composition. In particular, it may be useful to enrich the composition in vitamins or in vitamin - lo CA2 165454 derivatives. Some derivatives of vitamin A (retinoic acid) are actually inhibitors of the ODC activity.
In preference, glucides of the composition belong to the group containing glucose polymers, maltodextrines, saccharose, modified starches, monohydrated glucose, dehydrated glucose syrup, glycerol monostearate and mixtures thereof. These glucides are actually digestible even in cases of digestive pathology or secondary functional anomalies caused by an anti-cancer treatment (chemotherapy or radiotherapy).
According to one alternative of the invention, proteins used belong to the group containing soluble milk proteins, soya proteins, serum peptides, powdered egg yolk, potassium caseinate, unphosphorylated peptides, casein peptides, mixed caseinate, soya isolate and mixtures thereof.
Preferably, lipids belong to the group containing butter oil, peanut oil, medium chain triglycerides, grape seed oil, soya oil, onager oil and mixtures thereof. Said lipids are advantageously composed of a mixture of at least one animal oil, at least one vegetable oil and glycerol stearate.
According to one alternative of the invention, said composition forms a daily food ration for one person and includes:
- possibly said intracellular polyamines synthesis inhibitor, with an amount of less than 50 g, and preferably between 1 and 10 g, - 11 CA2 1~5454 - between 75 g and 500 g of glucides, - between 20 g and 185 g of lipids, - between 20 g and 225 g of proteins, - sufficient quantities of vitamins, minerals and electrolytes to satisfy the daily nutritional needs of a human being.
Quantities of vitamins, minerals and electrolytes used are known to the expert in the subject and may easily be found in the literature (for example see "Apports nutritionnels conseillés" (Recommended nutritional inputs), Dupin, Abraham and Giachetti, second edition 1992, Ed. TEC and DOC Lavoisier).
This composition alone can satisfy the daily nutritional needs of a patient while reducing intra-cellular synthesis and external input of polyamines.It is then an independent food.
Obviously, this composition could be administered several times at intervals during the day, rather than all at once. Each ration will then be defined by weight so as to form a sub-multiple of the daily food ration of a human being and would include:
- possibly said intracellular polyamines synthesis inhibitor, with an amount of less than 50/X g, and preferably between 1/X and 10/X g, - between 75/X g and 500/X g of glucides, - between 20/X g and 185/X g of lipids, - between 20/X g and 225/X g of proteins, - sufficient quantities of vitamins, minerals and electrolytes to partially satisfy the daily nutritional néeds of a human being.
where X is an integer between 2 and 8, equal to the number of rations to be ingested by the patient to satisfy his daily nutritional needs.
The number of these rations could be _chosen to satisfy all of the patient's daily food requirements, or to supply only some of his nutritional needs, the other needs being satisfied by a natural food with low polyamine content (for example ham and pasta or rice).
In this case, the food composition will be used as a food complement.
Another purpose of the invention is an agent with 2 components A and B, component A having a composition that can be ingested by man consisting of a nutritive mixture with low polyamine content and containing less than 50 picomoles/g, of putrescine, of spermidine, of spermine, of cadaverine, and including 10~ to 35~ of lipids, 8~ to 30~ of proteins, 35% to 80~ of glucides and up to 10~ of a mixture composed of vitamins, minerals and electrolytes by dry weight as a percentage of the total dry weight, and a component B composed of an intracellular polyamines synthesis inhibitor preferably consisting of a-methylornithine, components A and B being used as combination products for use simultaneously, separately or with a time lag for the treatment of cancer, and particularly cancer of the prostate.
The composition or agent according to the invention may be used as a drug, food, food supplement or as a therapeutic nutrition product.
`~ 13 CA2 165454 The composition or agent according to the invention may create an antineoplasic activity in man. Since polyamine depletion potentiates the effects of conventional anti-cancer treatments, the com~osition or agent according to the invention can be used in combination with other cancer treatments, including treatments using polyamine metabolism inhibitors.
In particular, this type of composition or agent may be effective for treatment of cancer of the prostate.
The invention will be more easily understood by considering the following two examples of how the invention is created.
Example 1 The following composition is prepared (see table IV).
The following are dispersed in 150 liters of water, - 786 g of disodium phosphate, - 5.080 kg of peanut oil, - 0.300 kg of glycerol stearate, - 1.280 kg of butter oil, Stir and then add:
- 8.760 kg of milk soluble protein, and then 18.750 kg of maltodextrine and 7.000 kg of saccharose.
The complete mixture is cooled to ambient temperature, and 45 g of magnesium oxide, 13.8 g of calcium carbonate, 227.5 g of magnesium chloride, 6.7 g of iron sulfate, 40 g of vitamin premix and mineral salts, 73.6 g of choline chloride and 60.0 g of 30 ascorbic acid, are added. -The volume of the receptacle is topped up to 200 liters by adding water, and the pH is adjusted to 7.10 by the addition of a 2N sodium hydroxide solution.
After degassing, sterilization and homogeneization, the product is placed in crimped metal cans. 4.0 kg of a-methylornithine is added to this composition when a complete composition is required.
- 15CA2 ~ 65454 Ingredients Quantity (for 200 liters) Proteins Concentrate of milk 8.760 kg soluble proteins Glucides Maltodextrines 18.750 kg Saccharose 7.000 kg Lipids Butter oil 1.280 kg Peanut oil 5.080 kg Glycerol stearate 0.300 kg Vltamlns Vitamin A 106.000 mg Vitamin B 2.660 g Vitamin Kl 10.600 mg Vitamin C 20.000 g Vitamin B1 0.340 g Riboflavin 0.400 g Pantothenic acid 2.660 g Niacine 4.000 g Vitamin B6 0.540 g Folic acid 53.400 mg Biotine 39.000 mg Vitamin B12 0.540 mg Choline 54.000 mg Inositol 134.000 mg 16 CA2 ~ 65454 Minerals and electrolytes Sodium 100.000 g Potassium 200.000 g Calcium 100.000 g Phosphorus 134.000 g Magnesium 56.000 g Iron 1.340 g Zinc 1.600 g Copper 0.340 g Manganese 0.540 g Chlorides 90.000 g Iodine 20.000 mg Selenium 9.400 mg Chromium 16.600 mg Molybdenum 20.000 mg ODC inhibitor a-methylornithine 4000.000 g TABLE IV
^ 17 CA2 165454 The centesimal composition obtained is as follows:
Glucides: 12.500 g, including 9.000 g of maltodextrines and 3.500 g of saccharose;
Lipids: 3.330 g including 0.640 g of butter oil, 2.540 g of peanut oil and 0.150 g of glycerol stearate;
Proteins: 4.000 g added by a concentrate of milk soluble proteins.
Vitamins, minerals and electrolytes: 0.600 g;
a-methylornithine: 3.000 g;
water: 100 ml added as necessary.
The percentage by weight of vitamins, minerals and electrolytes used is chosen such that a daily consumption of four cans satisfies the nutritional requirements recommended by Dupin, Abraham and Giachetti (* Apports nutritionnels conseillés pour la population française" - Recommended nutritional input for the French population), second edition 1992, Editions TEC and DOC Lavoisier).
Example 2 A preparation with approximately the same ingredients as are given in table IV is prepared using the same procedure as described in Example 1. However the protein source is replaced by a mixture of soya isolate and egg yolk powder. Peanut oil is replaced by a mixture of corn sprouts oil and soya oil.
The centesimal composition per 100 ml can is as follows:
Glucides: 12.500 g including 9.000 g of maltodextrins and 3.500 g of saccharose;
Lipids: 3.330 g including 0.640 g of butter oil, 0.840 g corn sprouts oil, 1.700 g of soya oil and 0.150 g;
Proteins: 4.000 g including 3.380 g of soya isolate and 0.620 g of egg yolk powder;
Vitamins, minerals and electrolytes: 0.600 g a-methylonithine: 3.000 g Water: 100 ml added as necessary The purpose of the two examples of embodiments of the composition described above is not to restrict the scope of the invention. In particular, it may be decided to use an intracellular polyamines synthesis inhibitor other than a-methylornithine or a-DFMO, and to include this inhibitor with proportions by weight larger than those given in these examples. Other sources of glucides, lipids or proteins than those mentioned may also be envisaged, while remaining within the scope of the invention.
POLYAMINE CONTENT
This invention relates to the food industry and the pharmaceutical industry.
Polyamines, and particularly putrescine (I), spermidine (II) and spermine (III) are present in all cells.
NH3 - ( CH2 ) 4 - NH3 ( I ) +NH3 - ( CH2 ) 3 - NH - ( CH2 ) 4 - NH3 ( I I ) NH3 - (CH2)3 - NH - (CH2)4 - NH - (CH2)3 - NH3+ (III) Although it has been believed for a long time that these molecules do not perform any physiological role and only represent a terminal step in tissular catabolism, a great deal of scientific work has shown that polyamines derived from decarboxylation of ornithine were actually biologically active molecules capable of acting at different and important levels in the life of the cell.
These molecules are found not only inside cells, they also occur in circulation within biological fluids in the organism such as blood, and are derived from three main sources:
- physiological cellular proliferation (growth and/or renewal of cells making up the organism), and tumorous cellulal proliferation, - food, - intestinal bacteria.
Intracellular polyamines are derived from a finely regulated metabolism related to the cellular cycle, rather than being obtained from passive transmembrane exchanges with biological fluids in the organism. An increase in the activity of the enzyme responsible for the main intracellular anabolic tract of polyamines, ornithine-decarboxylase (ODC) and therefore of the concentrations in putrescine, spermidine and spermine have actually been observed at the end of phase Gl and at the beginning of phase S, and at the beginning of phase G2 in the cellular replication cycle. The implication of the metabolism of polyamines in cellular replication and therefore in proliferative processes means that this metabolism is one of the preferred targets of anti-proliferative drugs, and is also the source of new circulation signals capable of revealing the existence of a neoplastic process within an organism.
It has been observed that tumorous growth is generally accompanied by a very significant increase in the intracellular anabolism of polyamines that are then found in increasing quantity in biological fluids.
Although the exact role of circulating polyamines as parameters involved in homeostatic regulation (or deregulation) of cellular proliferation is not yet clear, it has been demonstrated that the polyamine content of red cells may be considered and used as tumorous hyperplasic markers (see "Biological significance of circulating polyamines in oncology" -CA21 654~4 Moulinoux, J.-Ph. Quemener, V. and Khan, N.A.
Cellular and molecular biology - 37(8), 773-783, 1991).
Furthermore, this work has shown that circulating polyamines originating either from the cells_themselves or from the gastro-intestinal tract (food, intestinal bacteria) participate in maintaining the malignant proliferative condition.
Several ornithine-decarboxylase inhibitors are known In the current state of the art, and particularly irreversible selective inhibitors of this enzyme such as a-difluoromethylornithine (a-DFMO) marketed by the Marion Merrell Dow company under the name Eflornithine~. However, isolated administration of a-DFMO to patients or animals suffering from cancer without any other treatment has proved to be ineffective in halting the progress of a malignant tumor, although this polyamine synthesis inhibitor completely inhibited the proliferation of cancerous cells in vitro, while very significantly reducing intracellular contents of putrescine and spermidine.
The inability of a-DFMO to reduce the proliferation of malignant cells in vivo is very probably related to the fact that in the organism, cancerous cells restore the intracellular quantity of polyamines necessary to maintain their proliferation by capturing polyamines present in the extra-cellular environment, in other words in the various biological fluids such as blood.
This assumption was confirmed by work done by Person et al (Cancer Research, 1988, No. 48, pp. 4807 to 4811) 4 CA21 654~4 which demonstrated that unlike what was observed with L1210 abnormal cells, mice inoculated with muted L1210 cells made incapable of capturing extracellular polyamines responded well to a treatment inhibiting intracellular polyamines biosynthesis using a-DFMO.
Furthermore, various work has been carried out to show that joint administration to animals of:
- food with no polyamines, - a-DFMO, - a polyamine-oxydase (PAO) inhibitor eliminating oxidizing retroconversion of spermidine and spermine into putrescine, and - neomycine and metronidazole, almost entirely inhibits the tumorous progress of Lewis pulmonary carcinoma 3LL (Seiler N. et al, Cancer Research, 1990, No. 50, pp. 5077-5083), human glioblastoma U251 (Moulinoux J-Ph. et al, Anticancer Research, 1991, No. 11, pp. 175-180), Dunning prostate adenocarcinoma MAT-Lylu (Moulinoux J-Ph. et al, Journal of Urology, 1991, No. 146, pp. 1408, 1412) and human neuroblastoma neuro 2a (Quemener et al, "Polyamines in the gastro-intestinal tract", Dowling R.H., Falsch I.R.
and Laser C Ed., Kluwer Academic Publishers Boston, 1992, pp. 375-385).
It was also demonstrated in animals that polyamine depletion could considerably potentialize the anti-proliferative effects of conventional anti-tumorous drugs (methotrexate, cyclophosphamide, vindesine) while increasing the survival time of animals and possibly reducing the quantities of administered drugs while ~` _ 5 CA21654~4 maintaining the same anti-tumorous effects (Quemener V.
et al, "Polyamine deprivation enhances antitumorous efficacy of chemotherapy", Anticancer Research No. 12, 1992, pp. 1447-1454).
The object of the invention is to provide a composition administrable to man as food, food complement and/or a therapeutic nutrition product, in order to overcome the inefficiency of treatment in man done hitherto by isolated administration of a-DFMO.
More specifically, the object was to develop a composition efficient in man and, particularly, an accurate formulation of components of the inventive composition allowing a real synergy of caused effects, in man, by reducing outer polyamine contents and by inhibiting intracellular synthesis of these compounds.
This object is reached by a composition that can be ingested by man, characterized in that it consists of a nutrition mixture with a low polyamine content less than 50 picomoles/g of putrescine, of spermidine, of spermine and cadaverine, containing in percentage by dry weight with respect to the total dry weight : 10~
to 35~ of lipids, 8~ to 30~ of proteins, 35~ to 80~ of glucides, and up to 10~ of a mixture of vitamins, minerals and electrolytes.
This composition may be presented in dry form to be dissolved extemporaneously in a neutral vehicle suitable for oral or enteral administration, or in the form of a liquid ready for use. In all cases the composition is presented in sterile form.
-` 6 CA21654~4 This composition is particularly suitable for man and forms a food substitute that can efficiently create polyamine deprivation in patients. This composition could satisfactorily feed a patient whil~ creating polyamine deprivation, firstly by inhibiting intracellular polyamines synthesis and secondly by reducing the input of exogenic polyamines.
This composition brings, every day, at least 60 times less putrescine, 200 times less cadaverine, 700 less spermidine and spermine with respect to the human natural food which has the lowest polyamine content, but which nevertheless suits human nutrition needs.
This composition would strongly inhibit the endogenic synthesis of polyamines and very significantly reduce the input of these substances since its various constituents contain almost no polyamines. In order to also reduce polyamine inputs due to intestinal bacteria, this composition could be administered at the same time as a decontamination of the gastro-intestinal tract using antibiotic(s) and/or antiparasite product, for example such as neomycine and metronidazole. It would also be possible to consider including this type of antibiotic and/or antiparasite product directly into said composition, while remaining within the scope of the invention.
Nutrients used in the food composition according to the invention have a good nutritional value, even for sick patients.
- ~ 7 CA2 165454 The quantity of water used to make the composition is determined such that the composition is more or less liquid and can be easily ingested by the patient.
The percentage by weight of the mixture composed of vitamins, minerals and electrolytes is chosen so as to satisfy the necessary proportions, known to the expert in the subject, in a balanced diet.
This composition could be administered at the same time as at least one intracellular polyamines synthesis inhibitor.
In one attractive alternative of the invention, said composition is enriched with not more than 15~ by weight, and preferably between 0.2~ and 7~ by weight with respect to the total dry weight of the composition, of at least one intracellular polyamines synthesis inhibitor.
Usable ODC inhibitors are chosen particularly among the following compounds:
Pyri doxal phospha te antagonists - L-canaline - N-(5'-phosphopyridoxyl) ornithine Compe titi ve inhibi tors - a-hydrazino-ornithine - DL-a-hydrazino-~-aminovaleric acid - a-methylornithine (a-MO) - trans-3-dehydro-DL-ornithine -1.4-diamino-trans-2-butene -1.4-diaminobutanone Inhibi tors cont~; n i ng d i amin e -1.3-diaminopropane -1.3-diamino-2-propanol - bis(ethyl)spermine Suicide and irreversible inhibi tors - 2-difluoromethylomithine (DFMO) - monofluoromethylornithine - 2-monofluoromethyldehydro-ornithine - 2-monofluoromethyldehydro-ornithine methyl ester - 5-hexyne-1.4-diamine - trans-hex-2-en-5-yne-1.4-diamine - monofluoromethylputrescine - difluoromethylputrescine - a-allenylputrescine - (2R, 5R)-6-heptyne-2.5-diamine Among these inhibitors, competitive inhibitors are particularly preferred and particularly a-methylornithine (a-MO).
a-methylornithine has many advantages for the purposes proposed in this document. a-MO has the advantage of being an easily-synthesizable natural substance and with a high inhibition constant.
a-methylornithine also has the advantage that it inhibits the synthesis of polyamines in Escherischia coli, the most common bacteria naturally present in the intestinal tract, which in particular is not the case for a-DFMO.
Thus the use of a food composition according to the invention containing a-methylornithine as an - intracellular polyamines synthesis inhibitor, can - g CA216~454 reduce the exogenic input of polyamines by intestinal bacteria without needing to use an anti-biotherapy concomittently with administration of this composition, or at least reduce the administered dose of antibiotics.
Finally, a-MO has the advantage of being a simple competitive inhibitor of decarboxylase ornithine (which is contrary to methods currently being explored by the international scientific community) and strongly reduces the risk of the organism becoming accustomed by mutation leading to enhanced cellular resistance.
The original concept of the invention gave priority to searching for a synergy effect between several factors, namely particularly inhibition of the synthesis of intracellular polyamines and the depleted total input of these substances. From this point of view, it also appears that the best inhibitor is a-MO.
According to one alternative, the composition according to the invention is enriched in vitamins, particularly those provided by intestinal bacteria in a healthy human. The antibiotherapy that may accompany administration of said composition may also reduce the input of some vitamins. In this case it may be necessary to enrich the composition according to the invention with these vitamins in order to avoid causing a vitamin shortage caused by prolonged administration of said composition. In particular, it may be useful to enrich the composition in vitamins or in vitamin - lo CA2 165454 derivatives. Some derivatives of vitamin A (retinoic acid) are actually inhibitors of the ODC activity.
In preference, glucides of the composition belong to the group containing glucose polymers, maltodextrines, saccharose, modified starches, monohydrated glucose, dehydrated glucose syrup, glycerol monostearate and mixtures thereof. These glucides are actually digestible even in cases of digestive pathology or secondary functional anomalies caused by an anti-cancer treatment (chemotherapy or radiotherapy).
According to one alternative of the invention, proteins used belong to the group containing soluble milk proteins, soya proteins, serum peptides, powdered egg yolk, potassium caseinate, unphosphorylated peptides, casein peptides, mixed caseinate, soya isolate and mixtures thereof.
Preferably, lipids belong to the group containing butter oil, peanut oil, medium chain triglycerides, grape seed oil, soya oil, onager oil and mixtures thereof. Said lipids are advantageously composed of a mixture of at least one animal oil, at least one vegetable oil and glycerol stearate.
According to one alternative of the invention, said composition forms a daily food ration for one person and includes:
- possibly said intracellular polyamines synthesis inhibitor, with an amount of less than 50 g, and preferably between 1 and 10 g, - 11 CA2 1~5454 - between 75 g and 500 g of glucides, - between 20 g and 185 g of lipids, - between 20 g and 225 g of proteins, - sufficient quantities of vitamins, minerals and electrolytes to satisfy the daily nutritional needs of a human being.
Quantities of vitamins, minerals and electrolytes used are known to the expert in the subject and may easily be found in the literature (for example see "Apports nutritionnels conseillés" (Recommended nutritional inputs), Dupin, Abraham and Giachetti, second edition 1992, Ed. TEC and DOC Lavoisier).
This composition alone can satisfy the daily nutritional needs of a patient while reducing intra-cellular synthesis and external input of polyamines.It is then an independent food.
Obviously, this composition could be administered several times at intervals during the day, rather than all at once. Each ration will then be defined by weight so as to form a sub-multiple of the daily food ration of a human being and would include:
- possibly said intracellular polyamines synthesis inhibitor, with an amount of less than 50/X g, and preferably between 1/X and 10/X g, - between 75/X g and 500/X g of glucides, - between 20/X g and 185/X g of lipids, - between 20/X g and 225/X g of proteins, - sufficient quantities of vitamins, minerals and electrolytes to partially satisfy the daily nutritional néeds of a human being.
where X is an integer between 2 and 8, equal to the number of rations to be ingested by the patient to satisfy his daily nutritional needs.
The number of these rations could be _chosen to satisfy all of the patient's daily food requirements, or to supply only some of his nutritional needs, the other needs being satisfied by a natural food with low polyamine content (for example ham and pasta or rice).
In this case, the food composition will be used as a food complement.
Another purpose of the invention is an agent with 2 components A and B, component A having a composition that can be ingested by man consisting of a nutritive mixture with low polyamine content and containing less than 50 picomoles/g, of putrescine, of spermidine, of spermine, of cadaverine, and including 10~ to 35~ of lipids, 8~ to 30~ of proteins, 35% to 80~ of glucides and up to 10~ of a mixture composed of vitamins, minerals and electrolytes by dry weight as a percentage of the total dry weight, and a component B composed of an intracellular polyamines synthesis inhibitor preferably consisting of a-methylornithine, components A and B being used as combination products for use simultaneously, separately or with a time lag for the treatment of cancer, and particularly cancer of the prostate.
The composition or agent according to the invention may be used as a drug, food, food supplement or as a therapeutic nutrition product.
`~ 13 CA2 165454 The composition or agent according to the invention may create an antineoplasic activity in man. Since polyamine depletion potentiates the effects of conventional anti-cancer treatments, the com~osition or agent according to the invention can be used in combination with other cancer treatments, including treatments using polyamine metabolism inhibitors.
In particular, this type of composition or agent may be effective for treatment of cancer of the prostate.
The invention will be more easily understood by considering the following two examples of how the invention is created.
Example 1 The following composition is prepared (see table IV).
The following are dispersed in 150 liters of water, - 786 g of disodium phosphate, - 5.080 kg of peanut oil, - 0.300 kg of glycerol stearate, - 1.280 kg of butter oil, Stir and then add:
- 8.760 kg of milk soluble protein, and then 18.750 kg of maltodextrine and 7.000 kg of saccharose.
The complete mixture is cooled to ambient temperature, and 45 g of magnesium oxide, 13.8 g of calcium carbonate, 227.5 g of magnesium chloride, 6.7 g of iron sulfate, 40 g of vitamin premix and mineral salts, 73.6 g of choline chloride and 60.0 g of 30 ascorbic acid, are added. -The volume of the receptacle is topped up to 200 liters by adding water, and the pH is adjusted to 7.10 by the addition of a 2N sodium hydroxide solution.
After degassing, sterilization and homogeneization, the product is placed in crimped metal cans. 4.0 kg of a-methylornithine is added to this composition when a complete composition is required.
- 15CA2 ~ 65454 Ingredients Quantity (for 200 liters) Proteins Concentrate of milk 8.760 kg soluble proteins Glucides Maltodextrines 18.750 kg Saccharose 7.000 kg Lipids Butter oil 1.280 kg Peanut oil 5.080 kg Glycerol stearate 0.300 kg Vltamlns Vitamin A 106.000 mg Vitamin B 2.660 g Vitamin Kl 10.600 mg Vitamin C 20.000 g Vitamin B1 0.340 g Riboflavin 0.400 g Pantothenic acid 2.660 g Niacine 4.000 g Vitamin B6 0.540 g Folic acid 53.400 mg Biotine 39.000 mg Vitamin B12 0.540 mg Choline 54.000 mg Inositol 134.000 mg 16 CA2 ~ 65454 Minerals and electrolytes Sodium 100.000 g Potassium 200.000 g Calcium 100.000 g Phosphorus 134.000 g Magnesium 56.000 g Iron 1.340 g Zinc 1.600 g Copper 0.340 g Manganese 0.540 g Chlorides 90.000 g Iodine 20.000 mg Selenium 9.400 mg Chromium 16.600 mg Molybdenum 20.000 mg ODC inhibitor a-methylornithine 4000.000 g TABLE IV
^ 17 CA2 165454 The centesimal composition obtained is as follows:
Glucides: 12.500 g, including 9.000 g of maltodextrines and 3.500 g of saccharose;
Lipids: 3.330 g including 0.640 g of butter oil, 2.540 g of peanut oil and 0.150 g of glycerol stearate;
Proteins: 4.000 g added by a concentrate of milk soluble proteins.
Vitamins, minerals and electrolytes: 0.600 g;
a-methylornithine: 3.000 g;
water: 100 ml added as necessary.
The percentage by weight of vitamins, minerals and electrolytes used is chosen such that a daily consumption of four cans satisfies the nutritional requirements recommended by Dupin, Abraham and Giachetti (* Apports nutritionnels conseillés pour la population française" - Recommended nutritional input for the French population), second edition 1992, Editions TEC and DOC Lavoisier).
Example 2 A preparation with approximately the same ingredients as are given in table IV is prepared using the same procedure as described in Example 1. However the protein source is replaced by a mixture of soya isolate and egg yolk powder. Peanut oil is replaced by a mixture of corn sprouts oil and soya oil.
The centesimal composition per 100 ml can is as follows:
Glucides: 12.500 g including 9.000 g of maltodextrins and 3.500 g of saccharose;
Lipids: 3.330 g including 0.640 g of butter oil, 0.840 g corn sprouts oil, 1.700 g of soya oil and 0.150 g;
Proteins: 4.000 g including 3.380 g of soya isolate and 0.620 g of egg yolk powder;
Vitamins, minerals and electrolytes: 0.600 g a-methylonithine: 3.000 g Water: 100 ml added as necessary The purpose of the two examples of embodiments of the composition described above is not to restrict the scope of the invention. In particular, it may be decided to use an intracellular polyamines synthesis inhibitor other than a-methylornithine or a-DFMO, and to include this inhibitor with proportions by weight larger than those given in these examples. Other sources of glucides, lipids or proteins than those mentioned may also be envisaged, while remaining within the scope of the invention.
Claims (23)
1. Composition that can be ingested by man, characterized in that it consists of a nutritive mixture low in polyamines and containing less than 50 picomoles/g of polyamines.
2. Composition according to claim 1, characterized in that it is enriched with at least an inhibitor of the intracellular polyamines synthesis up to 15% with respect to the total dry weight of the composition.
3. Composition according to claim 2, characterized in that it is enriched with said inhibitor up to 0.2%
to 3% in weight with respect to the total dry weight of the composition.
to 3% in weight with respect to the total dry weight of the composition.
4. Composition according to claim 2 or 3, characterized in that said inhibitor is a competitive inhibitor of decarboxylase ornithine.
5. Composition according to claim 4, characterized in that said competitive inhibitor is .alpha.-methylornithine
6. Composition according to one of claims 1 to 5, characterized in that it is enriched with vitamins.
7. Composition according to claim 1 to 6, characterized in that said glucides belong to the group including glucose polymers, maltodextrines, saccharose, modified starches, monohydrated glucose, dehydrated glucose syrup, glycerol monostearate and mixtures thereof.
8. Composition according to claim 1 to 7, characterized in that said proteins belong to the group including soluble proteins of milk, soya proteins, serum peptides, powdered egg yolk, potassium caseinate, unphosphorylated peptides, casein peptides, mixed caseinate, soya isolate and mixtures thereof.
9. Composition according to one of claims 1 to 8, characterized in that said lipids belong to the group including butter oil, peanut oil, medium chain triglycerides, grape seed oil, soya oil, onager oil and mixtures thereof.
10. Composition according to one of claims 1 to 9, characterized in that said lipids are constituted by a mixture of at least an animal oil, at least a vegetable oil and of glycerol stearate.
11. Composition according to one of claims 1, 6 to 10, characterized in that it is the daily food ration of a human being and it comprises :
- between 75 g and 500 g of glucides, - between 20 g and 185 g of lipids, - between 20 g and 225 g of proteins - vitamins, minerals and electrolytes in sufficient quantities to satisfy daily nutritional needs of a human being.
- between 75 g and 500 g of glucides, - between 20 g and 185 g of lipids, - between 20 g and 225 g of proteins - vitamins, minerals and electrolytes in sufficient quantities to satisfy daily nutritional needs of a human being.
12. Composition according to one of claims 1 to 10, characterized in that it is the daily food ration of a human being and it comprises :
between 75 g and 500 g of glucides, - between 20 g and 185 g of lipids, - between 20 g and 225 g of proteins - vitamins, minerals and electrolytes in sufficient quantities to satisfy daily nutritional needs of a human being.
between 75 g and 500 g of glucides, - between 20 g and 185 g of lipids, - between 20 g and 225 g of proteins - vitamins, minerals and electrolytes in sufficient quantities to satisfy daily nutritional needs of a human being.
13. Composition according to one of claims 1, 6 to 10, characterized in that it is a sub-multiple of a daily food ration of a human being and it comprises:
- between 75/X g and 500/X g of glucides, - between 20/X g and 185/X g of lipids, - between 20/X g and 225/X g of proteins, - sufficient quantities of vitamins, minerals and electrolytes to partially satisfy the daily nutritional needs of a human being.
where X is an integer between 2 and 8, equal to the number of rations to be ingested by the patient to satisfy his daily nutritional needs.
- between 75/X g and 500/X g of glucides, - between 20/X g and 185/X g of lipids, - between 20/X g and 225/X g of proteins, - sufficient quantities of vitamins, minerals and electrolytes to partially satisfy the daily nutritional needs of a human being.
where X is an integer between 2 and 8, equal to the number of rations to be ingested by the patient to satisfy his daily nutritional needs.
14. Composition according to any one of claims 1 to 10, characterized in that characterized in that it is a sub-multiple of a daily food ration of a human being and it comprises:
- less than 50/X g and preferably, between 1/X and 10/X g of said inhibitor of the intracellular polyamines synthesis, - between 75/X g and 500/X g of glucides, - between 20/X g and 185/X g of lipids, - between 20/X g and 225/X g of proteins, - sufficient quantities of vitamins, minerals and electrolytes to partially satisfy the daily nutritional needs of a human being.
where X is an integer between 2 and 8, equal to the number of rations to be ingested by the patient to satisfy his daily nutritional needs.
- less than 50/X g and preferably, between 1/X and 10/X g of said inhibitor of the intracellular polyamines synthesis, - between 75/X g and 500/X g of glucides, - between 20/X g and 185/X g of lipids, - between 20/X g and 225/X g of proteins, - sufficient quantities of vitamins, minerals and electrolytes to partially satisfy the daily nutritional needs of a human being.
where X is an integer between 2 and 8, equal to the number of rations to be ingested by the patient to satisfy his daily nutritional needs.
15. Composition according to one of claims 1 to 14, characterized in that it is in a dry form to be dissolved extemporaneously in a neutral vehicle.
16. Composition according to one of claims 1 and 14, characterized in that it includes a neutral vehicle making it ready for use.
17. Agent with two components A and B, component A
consisting of a composition that can be ingested by man according to one of claims 1, 6 to 11, 13, 15 or 16, and compound B consisting of an intracellular polyamines synthesis inhibitor, components A and B
being used as combination products for use simultaneously, separately or with a time lag.
consisting of a composition that can be ingested by man according to one of claims 1, 6 to 11, 13, 15 or 16, and compound B consisting of an intracellular polyamines synthesis inhibitor, components A and B
being used as combination products for use simultaneously, separately or with a time lag.
18. Composition according to one of claim 17, characterized in that said inhibitor is .alpha.-methylornithine.
19. Composition according to one of claims 1 to 18 for a use belonging to the group including food, food supplements and nutrition products.
20. Composition or agent according to any one of claims 1 to 18 usable as a drug.
21. Composition or agent according to any one of claims 19 or 20 usable as a therapeutic food product.
22. Composition or agent according to any one of claims 19 to 21, usable as an anti-cancer agent.
23. Composition or agent according to claim 22 usable for treatment of cancer of the prostate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9307586 | 1993-06-17 | ||
| FR9307586A FR2706254B1 (en) | 1993-06-17 | 1993-06-17 | Composition for food and / or pharmaceutical use poor in polyamines. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2165454A1 true CA2165454A1 (en) | 1995-01-05 |
Family
ID=9448437
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002165454A Abandoned CA2165454A1 (en) | 1993-06-17 | 1994-06-17 | Food and/or pharmaceutical composition having a low polyamine content |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0703732B1 (en) |
| AT (1) | ATE158149T1 (en) |
| AU (1) | AU7077094A (en) |
| CA (1) | CA2165454A1 (en) |
| DE (1) | DE69405742T2 (en) |
| DK (1) | DK0703732T3 (en) |
| ES (1) | ES2110244T3 (en) |
| FR (1) | FR2706254B1 (en) |
| GR (1) | GR3025699T3 (en) |
| NO (1) | NO955125L (en) |
| WO (1) | WO1995000042A2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2858231B1 (en) | 2003-07-31 | 2006-02-10 | Univ Rennes | NOVEL USE OF A POOR HUMAN FOOD COMPOSITION OF POLYAMINES FOR THE PRODUCTION OF A THERAPEUTIC FOOD |
| WO2008147214A1 (en) * | 2007-05-29 | 2008-12-04 | Nofima Akvaforsk-Fiskeriforskning As | Food article with improved shelf life |
| US9750563B2 (en) | 2009-09-22 | 2017-09-05 | Mederi Therapeutics, Inc. | Systems and methods for treating tissue with radiofrequency energy |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4112123A (en) * | 1976-07-21 | 1978-09-05 | Beatrice Foods Co. | Nutritionally balanced single food composition and method of production |
| US4207315A (en) * | 1976-10-20 | 1980-06-10 | University Patents, Inc. | Process for treating proliferative skin diseases using certain diamino compounds |
| US4201788A (en) * | 1976-10-20 | 1980-05-06 | University Patents, Inc. | Process for alleviating proliferative skin diseases |
| JPS5998015A (en) * | 1982-11-27 | 1984-06-06 | Microbial Chem Res Found | Immunoactivator |
| NZ212053A (en) * | 1984-05-17 | 1988-02-29 | Merrell Dow Pharma | Polyamine containing pharmaceutical compositions for treating neoplasms |
| US5162373A (en) * | 1986-01-17 | 1992-11-10 | Board Of Regents, The University Of Texas System | Methods and improved formulations for the determination and treatment of malignant disease in patients |
| JPS62263127A (en) * | 1986-05-06 | 1987-11-16 | メレルダウフア−マス−テイカルズ インコ−ポレ−テツド | Remedy for tumor by self-derived lak cell, interleukin-2 andornithine decarboxylase inhibitor |
-
1993
- 1993-06-17 FR FR9307586A patent/FR2706254B1/en not_active Expired - Fee Related
-
1994
- 1994-06-17 AT AT94919732T patent/ATE158149T1/en not_active IP Right Cessation
- 1994-06-17 DK DK94919732.1T patent/DK0703732T3/en active
- 1994-06-17 DE DE69405742T patent/DE69405742T2/en not_active Expired - Lifetime
- 1994-06-17 ES ES94919732T patent/ES2110244T3/en not_active Expired - Lifetime
- 1994-06-17 AU AU70770/94A patent/AU7077094A/en not_active Abandoned
- 1994-06-17 WO PCT/FR1994/000737 patent/WO1995000042A2/en active IP Right Grant
- 1994-06-17 EP EP94919732A patent/EP0703732B1/en not_active Expired - Lifetime
- 1994-06-17 CA CA002165454A patent/CA2165454A1/en not_active Abandoned
-
1995
- 1995-12-15 NO NO955125A patent/NO955125L/en unknown
-
1997
- 1997-12-17 GR GR970403350T patent/GR3025699T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0703732B1 (en) | 1997-09-17 |
| WO1995000042A2 (en) | 1995-01-05 |
| ATE158149T1 (en) | 1997-10-15 |
| AU7077094A (en) | 1995-01-17 |
| FR2706254B1 (en) | 1995-08-25 |
| DK0703732T3 (en) | 1998-05-11 |
| DE69405742T2 (en) | 1998-04-23 |
| NO955125D0 (en) | 1995-12-15 |
| EP0703732A1 (en) | 1996-04-03 |
| GR3025699T3 (en) | 1998-03-31 |
| NO955125L (en) | 1996-02-15 |
| FR2706254A1 (en) | 1994-12-23 |
| DE69405742D1 (en) | 1997-10-23 |
| ES2110244T3 (en) | 1998-02-01 |
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