FR2535609A1 - ANTITUMOR ACTION MEDICINE BASED ON POLYHEXAMETHYLENEGUANIDINE - Google Patents
ANTITUMOR ACTION MEDICINE BASED ON POLYHEXAMETHYLENEGUANIDINE Download PDFInfo
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- FR2535609A1 FR2535609A1 FR8218494A FR8218494A FR2535609A1 FR 2535609 A1 FR2535609 A1 FR 2535609A1 FR 8218494 A FR8218494 A FR 8218494A FR 8218494 A FR8218494 A FR 8218494A FR 2535609 A1 FR2535609 A1 FR 2535609A1
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- cancer
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- polyhexamethyleneguanidine
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- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 5
- 239000010452 phosphate Substances 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 3
- 239000002504 physiological saline solution Substances 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 abstract 2
- 239000011149 active material Substances 0.000 abstract 1
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- 230000015572 biosynthetic process Effects 0.000 description 5
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 206010006417 Bronchial carcinoma Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000009956 adenocarcinoma Diseases 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000010534 mechanism of action Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 3
- 201000000274 Carcinosarcoma Diseases 0.000 description 3
- 208000001792 Sarcoma 37 Diseases 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 208000002847 Surgical Wound Diseases 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
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- 201000011549 stomach cancer Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 238000002679 ablation Methods 0.000 description 2
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- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- 208000009033 Leukemia L5178 Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- 230000001085 cytostatic effect Effects 0.000 description 1
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- 230000008021 deposition Effects 0.000 description 1
- 230000001909 effect on DNA Effects 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
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- 210000000952 spleen Anatomy 0.000 description 1
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- 238000001356 surgical procedure Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
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
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
LA PRESENTE INVENTION A TRAIT A LA PHARMACIE, ET ELLE SE RAPPORTE PLUS PRECISEMENT A UN NOUVEAU MEDICAMENT A ACTION ANTITUMORALE. SELON L'INVENTION, LE MEDICAMENT A ACTION ANTITUMORALE COMPORTE UNE MATIERE ACTIVE, A SAVOIR LE PHOSPHATE DE POLYHEXAMETHYLENEGUANIDINE DE FORMULE SUIVANTE:DANS LAQUELLE :N EST DE 2 A 5, R EST UN GROUPE NH OU NH - C - NH -;ET R EST UN GROUPE NH OU NH - C - NHTHE PRESENT INVENTION RELATES TO PHARMACY, AND IT RELATES MORE PRECISELY TO A NEW MEDICINAL PRODUCT WITH ANTITUMOR ACTION. ACCORDING TO THE INVENTION, THE MEDICINAL PRODUCT WITH ANTITUMOR ACTION CONTAINS AN ACTIVE MATERIAL, Namely POLYHEXAMETHYLENEGUANIDINE PHOSPHATE OF THE FOLLOWING FORMULA: IN WHICH: N IS FROM 2 TO 5, R IS AN NH OR NH - C - NH - GROUP; AND R IS AN NH OR NH - C - NH GROUP
Description
À La présente invention a trait à la pharmacie, etThe present invention relates to pharmacy, and
plus précisément elle se rapporte à un nouveau médica- more specifically it relates to a new drug.
ment à action antitumorale, destiné au traitement du cancer du tube digestif, du cancer du sein, ainsi que pour le traitement de la plaie opératoire à la suite de antitumor action, for the treatment of cancer of the digestive tract, breast cancer, as well as for the treatment of the operative wound as a result of
l'ablation totale de la tumeur.total removal of the tumor.
On-connalt actuellement différents produits à ac- There are currently various products available
tion antitumorale D'après leur mécanisme d'action, on divise ces produits en 4 classes: les antimétabolites, les agents alkylants, les agents intercalants et les According to their mechanism of action, these products are divided into four classes: antimetabolites, alkylating agents, intercalating agents, and anti-tumor agents.
inhibiteurs de la mitose Le mécanisme d'action des pro- inhibitors of mitosis The mechanism of action of
duits mentionnés relève essentiellement de leur effet sur la synthèse et l'activité des acides nucléiniques The quantities mentioned are mainly related to their effect on the synthesis and activity of nucleic acids
("Chimiothérapie des tumeurs malignes", sous la rédac- ("Chemotherapy of malignant tumors", under the drafting
tion de N N Blokhine, Moscou, Edition Méditsina, 1977). N N Blokhine, Moscow, Meditsina Edition, 1977).
Dans la majorité des cas, les médicaments connus In the majority of cases, known drugs
présentent une faible sélectivité d'action sur les cel- have a low selectivity of action on the cells
lules tumorales, compte tenu de ce qu'ils agissent éga- tumor cells, taking into account that they also
lement sur le métabolisme des cellules normales, d'o l'apparition de phénomènes toxiques à la suite de leur application clinique Par ailleurs, ces produits n'ont pas d'action efficace sur certaines formes de tumeurs malignes d'incidence fréquente (telles que le cancer These products have no effective action on certain forms of malignant tumors with frequent incidence (such as the cancer
bronchique, le cancer gastrique, le cancer du pancréas). bronchial, gastric cancer, pancreatic cancer).
On connaît certains polycations, comme par exem- Some polycations are known, for example
ple la polyéthylénimine, la polypropylimine, la polyly- polyethylenimine, polypropylimine, poly-
sine-et autres, qui confèrent une action électrostatique et cytostatique directe sur les cellules cancéreuses qui portent une charge négative plus forte que les cellules normales (H Morosov Polycation treated tumor cells in vivo and in vitro Cancer Res, 1971, v 31, No 3, p. 373-383; F M Mehrishi Effect of lysine polypeptides on the surface change of normal and cancer cells Eur. sine-and-others, which confer direct electrostatic and cytostatic action on cancer cells that carry a stronger negative charge than normal cells (H Morosov Polycation treated tumor cells in vivo and in vitro Cancer Res, 1971, v 31, No. 3 , pp. 373-383; FM Mehrishi Effect of lysine polypeptides on the surface of normal and cancer cells Eur.
J Cancer, 1969, v 5, No 3, p 427-435). J Cancer, 1969, v. 5, No. 3, pp. 427-435).
Toutefois, les composés mentionnés ci-dessus n'ont However, the compounds mentioned above have not
pas trouvé d'utilisation pratique à cause de leur effi- not found practical because of their effectiveness.
cacité insuffisante et de l'apparition de différents ef- insufficient capacity and the appearance of different ef-
fets secondaires.secondary fetuses.
Le médicament objet-de la présente invention est un produit original qui n'est pas décrit dans la litté- rature. The drug object of the present invention is an original product which is not described in the literature.
Le problème, posé dans la présente invention, con- The problem posed in the present invention
siste à élaborer un nouveau produit anticancéreux ayant un large éventail d'action, présentant un effet sur les formes de cancer résistant aux médicaments connus, et develop a new anti-cancer product with a wide range of action, with an effect on cancer forms that are resistant to known drugs, and
possédant une action de contact sur la cellule cancéreuse. possessing a contact action on the cancer cell.
Ce problème est résolu par le fait que le médica- This problem is solved by the fact that
ment à action antitumorale, comportant une matière active et un diluant pharmaceutique, selon l'invention, comporte antitumor action, comprising an active ingredient and a pharmaceutical diluent, according to the invention, comprises
à titre de matière active le phosphate de polyhexaméthy- as the active ingredient, polyhexamethyl phosphate is
lèneguanidine de formule suivante: R (CH 2)6 -f NH C NH (CH 2)6 R IR' I NH dans laquelle N est de 2 à 5; R est un groupe NH 2 ou NH 2 -C NH; et NH leneguanidine of the following formula: R (CH 2) 6 -f NH C NH (CH 2) 6 wherein: N is 2 to 5; R is NH 2 or NH 2 -C NH; and NH
R' est un groupe NH 2 ou NH 2 -C NH -. R 'is NH 2 or NH 2 -C NH -.
NH Le produit objet de la présente invention peut The product which is the subject of the present invention can
être utilisé sous diverses formes de présentation (solu- be used in various forms of presentation (
tés injectables, solutions, onguents, sunppositoires). injectables, solutions, ointments, suppositories).
On utilisera de préférence le médicament suivant l'in- The drug should preferably be used according to the
vention sous forme de solutés injectables ayant une te- in the form of injectable solutions having a
neur en matière active égale à 1,5 % en poids Le pro- active ingredient equal to 1.5% by weight.
duit objet de l'invention comportera, de préférence, à titre de diluant pharmaceutique, de l'eau distillée ou object of the invention will preferably comprise, as a pharmaceutical diluent, distilled water or
du soluté physiologique.physiological saline.
Le produit suivant l'invention est destiné au The product according to the invention is intended for
traitement des malades atteints de cancer du tube diges- treatment of patients suffering from cancer of the digestive tract
25356 O 925356 O 9
tif et de cancer du sein Il est actif sur les formes de tif and breast cancer It is active on the forms of
tumeurs résistantes à l'action des médicaments connus. tumors resistant to the action of known drugs.
Le produit possède une action de contact sur la cellule The product has a contact action on the cell
cancéreuse et peut être utilisé pour le traitement di- cancerous and can be used for the treatment of
rect de la plaie chirurgicale à la suite de l'ablation rect of the surgical wound as a result of the ablation
de la tumeur.of the tumor.
L'activité antitumorale du produit suivant l'in- The antitumor activity of the product according to
vention fut étudiée sur 6 systèmes tests: la leucémie vention was studied on 6 test systems: leukemia
lymphoide L-1210, le carcinosarcome de Walker, l'adéno- lymphoid L-1210, Walker's carcinosarcoma, adeno-
carcinome 755, le sarcome 37, le carcinome bronchique de Lewis et le mélanome B 16 La leucémie lymphoide L-1210 carcinoma 755, sarcoma 37, bronchial carcinoma of Lewis and melanoma B 16 L-1210 lymphoid leukemia
était implantée par la voie intraopéritonéale à des sou- implanted by the intraoperitoneal route to
ris BDF des deux sexes, à raison de 106 cellules par souris L'adénocarcinome 755 et le mélanome B 16 étaient greffés sur des souris femelles BDF, à raison de 50 mg de suspension tumorale par souris Le sarcome 37 était BDF of both sexes, at a rate of 106 cells per mouse Adenocarcinoma 755 and B16 melanoma were grafted on BDF female mice, at 50 mg of tumor suspension per mouse Sarcoma 37 was
implanté par la voie intra-abdominale à des souris blan- implanted by the intra-abdominal route to white mice
ches des deux sexes, sans lignée, à raison de 10 cellu- both sexes, without lineage, at the rate of 10 cells
les par souris Le carcinome bronchique de Lewis était greffé sur des souris BDF 1 par la voie sous-cutanée à raison de 50 mg de suspension tumorale par souris Le mice by mouse Bronchial carcinoma of Lewis was grafted on mice BDF 1 by the subcutaneous route at a rate of 50 mg of tumor suspension per mouse.
carcinosarcome de Walker était greffé par la voie sous- Walker's carcinosarcoma was grafted by the
cutanée sur des rats blancs sans lignée des deux sexes cutaneous on white rats without lineage of both sexes
et à raison de 100 mg de suspension tumorale par animal. and at a rate of 100 mg of tumor suspension per animal.
La première injection du produit suivant l'invention é- The first injection of the product according to the invention
tait réalisée 24 heures après la greffe de la tumeur ou de la leucémie On mettait le produit en solution dans 24 hours after the tumor or leukemia transplantation.
de l'eau distillée de façon extemporanée et on l'admi- extemporaneously distilled water and adminstered it
nistrait par la voie intrapéritonéale ou intraveineuse une fois par jour Les résultats de l'étude de l'activité antitumorale du produit suivant l'invention sont résumés was administered intraperitoneally or intravenously once a day The results of the study of the antitumor activity of the product according to the invention are summarized
dans le tableau 1.in table 1.
TABLEAU 1TABLE 1
N Souche tumorale Dose par Jours des Prolongement Voie d'ordre injection, injections de la vie, % d'administration mg/kg N Tumor Strain Dose per Days of Prolongation Route of Injection, Life Injection,% of Administration mg / kg
1 Leucémie lympha-1 Lymphatic leukemia
tique 24,9 1 175 intrapéritonéaletick 24.9 1 175 intraperitoneal
2 L-1210 4,2 1,2,3,4,7 125 -"-2 L-1210 4,2 1,2,3,4,7 125 - "-
3 Sarcome 37 3,0 1 85 -"-3 Sarcoma 37 3.0 1 85 - "-
4 -" 1,8 1,2,3,4,7 48 -"-4 - "1,8 1,2,3,4,7 48 -" -
-" 2,0 1,5,9 40 intraveineuse 6 Carcinosarcome de Walker 2,3 1,2,3,4,7 55 intrapéritonéale - "2.0 1.5.9 40 intravenous 6 Walker Carcinosarcoma 2.3 1,2,3,4,7 55 intraperitoneal
7 Adénocarcinome 755 5,0 1,2,3,4,7 68 -"- 7 Adenocarcinoma 755 5,0 1,2,3,4,7 68 - "-
8 _"_ 5,0 1,5,9 55 intraveineuse 9 Mélanome B 16 5,0 3,4,5,6,7 53 intrapérîtonéale 5.0 1.5.9 55 Intravenous 9 Melanoma B 16 5.0 3.4.5.6.7 53 Intraperitoneal
Carcinome bron-Bronchial carcinoma
chique de Lewis 5,0 1,5,9 20 intraveineuse ru en ts Lo classy Lewis 5.0 1.5.9 20 intravenous ru en ts Lo
2535609.2535609.
Les propriétés antitumorales du produit, objet Antitumor properties of the product, object
de la présente invention, furent étudiées sur les modè- of the present invention were studied on the models
les des hétérotrans Dlants subrénaux de tumeurs humaines. the subchrenous deleterious heterotransts of human tumors.
On utilisa à cette fin les prélèvements d'échantillons tumoraux cliniquessuivants: cancer du sein 4 échan- tillons, cancer gastrique 2, cancer du rectum 2, cancer bronchique 2 On prélevait de ces échantillons des microfragments de 103 cellules, que-l'on greffait sous la capsule rénale des souris BDF 1 On injectait le produit, suivant l'invention, aux 2, 4 et 6 èmes jours The following clinical samples were used for this purpose: breast cancer 4 samples, gastric cancer 2, rectal cancer 2, bronchial carcinoma 2 These samples were taken from microfragments of 103 cells, which were grafted under the renal capsule of BDF 1 mice The product according to the invention was injected at 2, 4 and 6 th days.
après la greffe tumorale à la dose de 12 mg/kg par in- after tumor transplantation at a dose of 12 mg / kg
jection. On assista à une inhibition de la croissance de la masse tumorale de 50 à 100 % dans 3 cas sur 4-pour le Eject. Tumor growth inhibition was 50 to 100% in 3 out of 4 cases.
cancer du sein, dans 2 cas sur 2 pour le cancer gastri- breast cancer, in 2 out of 2 cases for gastric cancer
que et 2 cas sur 2 pour le cancer du rectum L'inhibi- and 2 out of 2 for rectal cancer
tion fut insignifiante cour le cancer bronchique. was insignificant in bronchial cancer.
On étudia la sensibilité des cellules cancéreuses, prélevées au cours de l'intervention chirurgicale chez 22 oatients souffrant de cancer bronchique, à l'égard du The sensitivity of cancer cells taken during surgery to 22 patients with bronchial cancer was studied in the
médicament suivant l'invention.drug according to the invention.
A la suite de l'incubation de la suspension des cellules cancéreuses en présence du médicament suivant l'invention, en une quantité correspondant à la dose d'administration ( 5 mg/kg), on détermina au moyen d'un Following the incubation of the suspension of the cancer cells in the presence of the drug according to the invention, in an amount corresponding to the dose of administration (5 mg / kg), it was determined by means of a
compteur à scintillation en phase liquide et après in- liquid phase scintillation counter and after
troduction de thymidine et d'uridine marquées le degré de perturbation des processus de synthèse des ADN et thymidine and uridine tritition labeled the degree of disruption of DNA synthesis processes and
ARN dans les cellules cancéreuses par rapport aux cel- RNA in cancer cells compared to
lules servant de témoins.lules serving as witnesses.
La sensibilité des cellules cancéreuses en fonc-, The sensitivity of cancer cells in function,
tion de la structure histologique de la tumeur est don- tion of the histological structure of the tumor is
née au tableau 2.born in table 2.
TABLEAU 2TABLE 2
N Forme histologique Nombre Sensibles Non sen- N Histological form Number Sensitive Not sen-
d'or du cancer bronchique d'échan au produit sibles dre tillons au étudies Droduit gold from bronchogenic lung cancer to the products of the Droduit studies
1 2 3 4 51 2 3 4 5
2 Epithéliome pavi-2 Paved epithelioma
menteux 14 9 5 3 Adénocarcinome 6 1 5 4 Epithéliome peu 14 9 5 3 Adenocarcinoma 6 1 5 4 Little epithelioma
différencié 2 2 -differentiated 2 2 -
On réalisa l'étude de la toxicité générale du pro- The study of the general toxicity of the
duit de l'invention La DL 50 est égale à 70 mg/kg chez According to the invention, the LD 50 is 70 mg / kg
la souris.the mouse.
Les études de l'action biochimique du produit sui- Studies of the biochemical action of the product
vant l'invention chez des souris hybrides portant la for- the invention in hybrid mice bearing the
me ascitique de la leucémie L-5178 y et L-1210 montrent que l'administration intrapéritonéale à une reprise de la dose thérapeutique ( 5 mg/kg) du produit apporte une ascitic leukemia L-5178 and L-1210 show that intraperitoneal administration at once of the therapeutic dose (5 mg / kg)
inhibition de la biosynthèse des ADN, ARN et de la pro- inhibition of the biosynthesis of DNA, RNA and
téine dans les cellules tumorales à un degré plus net que dans les cellules normales des tissus du foie, de la in the tumor cells to a greater degree than in the normal cells of liver tissues,
rate, de la muqueuse de l'intestin grêle. spleen, mucosa of the small intestine.
Dans les expériences "in vitro", il fut également démontré que le produit, à des concentrations de 1 10-3 In "in vitro" experiments, it was also demonstrated that the product, at concentrations of 1 10-3
1.10-6 M, inhibe de façon significative ( 60 % par rap- 1.10-6 M, significantly inhibits (60% compared with
port à la série témoin) la biosynthèse des ADN, ARN et de la protéine dans les cellules de l'adénocarcinome d'Erlich et de la lympholeucémie L- 1210 Ceci s'explique the control series) the biosynthesis of DNA, RNA and protein in Erlich adenocarcinoma cells and L-1210 lympholeukemia This is explained
par la perturbation du transport des précurseurs radio- by the disruption of the transport of radio precursors
actifs de la synthèse des macromolécules dans la cellule tumorale. Les investigations de l'influence du produit objet de l'invention sur les cellules de la lympholeucémie L-5178 y ont établi que le produit, à des concentrations de 25 et 50 microg/ml, réduit la charge négative de la membrane Dlasmatique des cellules tumorales, et à des concentrations de 75 à 500 microg/ml, il recharge la active in the synthesis of macromolecules in the tumor cell. Investigations of the influence of the product object of the invention on L-5178 lympholeukemia cells established that the product, at concentrations of 25 and 50 microg / ml, reduces the negative charge of the cell membrane Dlasmatique tumors, and at concentrations of 75 to 500 microg / ml, it recharges the
surface des membranes.surface of the membranes.
Aux concentrations mentionnées ci-dessus, on as- At the concentrations mentioned above,
siste à l'expulsion des ions K+ et Na+ de la cellule expels the K + and Na + ions from the cell
dans le fluide extracellulaire.in the extracellular fluid.
Toutes ces études montrèrent que le mécanisme d'action du produit suivant l'invention relève de son All these studies showed that the mechanism of action of the product according to the invention lies in its
effet sur la membrane de la cellule cancéreuse. effect on the membrane of the cancer cell.
Le médicament suivant l'invention réduit la charge néeative de la membrane plasmatique de la cellule et par The medicament according to the invention reduces the neeative charge of the plasma membrane of the cell and by
là même perturbe le transport des précurseurs de la bio- the same disturbs the transport of the precursors of the bio-
synthèse des macromolécules dans la cellule cancéreuse, synthesis of macromolecules in the cancer cell,
tandis que le mécanisme d'action antitumorale des médi- while the mechanism of antitumor action of
caments connus s'explique par leur effet sur l'ADN (soit en étant des analogues des substrats, soit en se liant known because of their effect on DNA (either by being analogues of substrates or by binding
aux principaux centres des ADN en modifiant leur symé- the main DNA centers by changing their sym-
ti-ie).ti-ie).
Grâce au mécanisme d'action susmentionné, le pro- Thanks to the aforementioned mechanism of action, the
duit objet de l'invention exerce son effet sur les formes object of the invention exerts its effect on the forms
de cancer résistant à l'action des médicaments; connus. cancer resistant to the action of drugs; known.
Par ailleurs, à la différence des produits connus, le produit de l'invention possède une action de contact sur la cellule cancéreuse et peut donc être utilisé pour le Moreover, unlike the known products, the product of the invention has a contact action on the cancer cell and can therefore be used for
traitement direct de la plaie chirurgicale après l'abla- direct treatment of the surgical wound after ablation
tion de la tumeur.tumor.
Le produit suivant l'invention est destiné à l'ad- The product according to the invention is intended for use
ministration par la voie intraveineuse ou intramusculaire ainsi que pour le traitement des plaies opératoires Il peut être utilisé sous forme de solutions, de solutés intravenous or intramuscular administration as well as for the treatment of surgical wounds It can be used in the form of solutions, solutes
injectables, de suppositoires et d'onguents. injectables, suppositories and ointments.
A titre de diluant ou d'excipient pour préparer As a diluent or excipient for preparing
l'onguent, on peut avoir recours à n'importe quel sol- ointment, you can use any soil
vant ou excipient pharmaceutique approprié On aura de appropriate pharmaceutical excipient or excipient.
préférence recours à l'emploi du produit sous forme in- preference for the use of the product in the form of
jectable On prépare des solutés injectables ayant une teneur en matière active égale à 1,5 % en poids On uti- lise de préférence à titre de diluant l'eau distillée ou le soluté physiologique La dose journalière du produit suivant l'invention est égale à 150 mg, la dose pour un Injectable solutions having an active ingredient content of 1.5% by weight are preferably used. Dilute water or physiological saline is preferably used as diluent. The daily dose of the product according to the invention is equal to 150 mg, the dose for one
traitement est de 1500 mg.treatment is 1500 mg.
On prépare le médicament suivant l'invention par The drug according to the invention is prepared by
les procédés connus.known methods.
On obtient la substance active du produit suivant l'invention, le phosphate de polyhexaméthylèneguanidine The active substance of the product according to the invention is obtained, polyhexamethyleneguanidine phosphate
comme suit.as following.
On Polymérise des quantités équimoléculaires d'he- Polymerizes equimolecular quantities of
xaméthylèneguanidine et de chlorhydrate de guanidine à une température de 160 à 170 C pendant 23 heures Il se forme le chlorhydrate de polyhexaméthylèneguanidine qui a l'aspect d'une masse visqueuse et qui se solidifie après refroidissement On dissout le chlorhydrate de polyhexaméthylèneguanidine dans de l'éthanol, et on xamethyleneguanidine and guanidine hydrochloride at a temperature of 160.degree. C. to 170.degree. C. for 23 hours. Polyhexamethyleneguanidine hydrochloride, which has the appearance of a viscous mass and which solidifies after cooling, is dissolved. The polyhexamethyleneguanidine hydrochloride is dissolved in ethanol, and
ajoute à la solution ainsi obtenue une solution alcooli- adds to the solution thus obtained an alcoholic solution
que d'éthylate de sodium dans un rapport de chlorhydrate de polyhexaméthylèneguanidine et d'éthylate de sodium égal à 1:5 On filtre le dépôt de chlorure de sodium qui sodium ethoxide in a ratio of polyhexamethyleneguanidine hydrochloride and sodium ethoxide equal to 1: 5 is filtered the deposition of sodium chloride which
s'est formé et on additionne au filtrat de l'acide phos- formed and added to the filtrate phosphoric acid
phorique dans un rapport de 1:5 respectivement. phoric in a ratio of 1: 5 respectively.
On filtre le sédiment blanc de phosphate de poly- The white sediment of polyphosphate
hexaméthylèneguanidine qui se dépose, on le rince avec hexamethyleneguanidine which settles, is rinsed with
de l'éther et on le sèche sous vide On réalise la puri- ether and dried under vacuum.
fication du produit par reprécipitation (eau-éthanol). fication of the product by reprecipitation (water-ethanol).
On sépare par filtration le produit fini, on le rince The finished product is filtered off, rinsed
sur le filtre avec de l'éther et on le sèche sous vide. on the filter with ether and dried under vacuum.
Le rendement du produit désiré est égal à 71,6 % (en The yield of the desired product is equal to 71.6% (in
équivalent de chlorhydrate de polyhexaméthylèneguanidine). equivalent of polyhexamethyleneguanidine hydrochloride).
Le phosphate de polyhexaméthylèneguanidine ainsi obtenu est une substance finement cristalline de couleur The polyhexamethyleneguanidine phosphate thus obtained is a finely crystalline substance of color
blanche, inodore, de consistance solide, de masse molé- white, odorless, of solid consistency, of
culaire moyenne de 1070 à 1130, facilement soluble dans l'eau; insoluble dans les solvants organiques La subs- tance est stable au stockage et après lyophilisation de average ocular of 1070 to 1130, easily soluble in water; Insoluble in organic solvents The substance is stable in storage and after lyophilization of
ses solutions aqueuses.its aqueous solutions.
2535609.2535609.
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/SU1982/000020 WO1984000105A1 (en) | 1982-06-21 | 1982-06-21 | Medicinal preparation having antitumoral effect |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2535609A1 true FR2535609A1 (en) | 1984-05-11 |
| FR2535609B1 FR2535609B1 (en) | 1985-03-15 |
Family
ID=21616776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8218494A Granted FR2535609A1 (en) | 1982-06-21 | 1982-11-04 | ANTITUMOR ACTION MEDICINE BASED ON POLYHEXAMETHYLENEGUANIDINE |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS59501110A (en) |
| CA (1) | CA1194802A (en) |
| CH (1) | CH660964A5 (en) |
| DE (1) | DE3249514T1 (en) |
| FR (1) | FR2535609A1 (en) |
| GB (1) | GB2134783B (en) |
| NL (1) | NL8220420A (en) |
| SE (1) | SE437931B (en) |
| WO (1) | WO1984000105A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1110948A3 (en) * | 1999-12-20 | 2002-01-09 | SK Corporation | Polyhexamethyleneguanidine phosphate powder, method of making the same and antimicrobial resin containing the same |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5344846A (en) * | 1992-12-30 | 1994-09-06 | The United States Of America As Represented By The Department Of Health And Human Services | Compositions and methods for inhibiting deoxyhypusine synthase and the growth of cells |
| DE19628641C2 (en) * | 1996-07-16 | 1998-12-17 | Fresenius Ag | Use of PHMB for the treatment of tumor diseases |
| RU2144024C1 (en) * | 1998-10-28 | 2000-01-10 | Иркутский институт химии СО РАН | Method of preparing polyhexamethylene guanidine |
| KR100725004B1 (en) * | 1999-12-24 | 2007-06-04 | 에스케이 주식회사 | Disinfectant Disinfectant Composition and Method of Use thereof |
| AT505312A1 (en) | 2007-05-15 | 2008-12-15 | Recticel Schlafkomfort Gmbh Sc | POLYURETHANE MATERIAL WITH BIOCIDAL EQUIPMENT |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5341426A (en) * | 1976-09-27 | 1978-04-14 | Asahi Chem Ind Co Ltd | Fungicidal and bactericidal agents |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3824288A (en) * | 1961-06-09 | 1974-07-16 | Hoffmann La Roche | Substituted hydrazine derivatives and process for the manufacture thereof |
| BR6457241D0 (en) * | 1963-12-23 | 1973-06-26 | Rohm & Haas | PROCESS FOR THE PREPARATION OF T-OCTIL-GUANIDINES |
| GB1492678A (en) * | 1975-08-11 | 1977-11-23 | Ici Ltd | Guanidine derivatives |
-
1982
- 1982-06-21 DE DE19823249514 patent/DE3249514T1/en not_active Withdrawn
- 1982-06-21 WO PCT/SU1982/000020 patent/WO1984000105A1/en not_active Ceased
- 1982-06-21 JP JP57503491A patent/JPS59501110A/en active Pending
- 1982-06-21 NL NL8220420A patent/NL8220420A/en not_active Application Discontinuation
- 1982-06-21 CH CH90284A patent/CH660964A5/en not_active IP Right Cessation
- 1982-06-21 GB GB08403257A patent/GB2134783B/en not_active Expired
- 1982-10-07 CA CA000413032A patent/CA1194802A/en not_active Expired
- 1982-11-04 FR FR8218494A patent/FR2535609A1/en active Granted
-
1984
- 1984-01-30 SE SE8400453A patent/SE437931B/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5341426A (en) * | 1976-09-27 | 1978-04-14 | Asahi Chem Ind Co Ltd | Fungicidal and bactericidal agents |
Non-Patent Citations (1)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 89, no. 19, 6 novembre 1978, page 175, résumé no. 158758a COLUMBUS OHIO (US) & JP - A - 78 41 426 (ASAHI CHEMICAL INDUSTRY CO. LTD.)(14-04-1978) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1110948A3 (en) * | 1999-12-20 | 2002-01-09 | SK Corporation | Polyhexamethyleneguanidine phosphate powder, method of making the same and antimicrobial resin containing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| SE8400453L (en) | 1985-03-25 |
| CH660964A5 (en) | 1987-06-30 |
| FR2535609B1 (en) | 1985-03-15 |
| DE3249514T1 (en) | 1984-05-17 |
| SE8400453D0 (en) | 1984-01-30 |
| CA1194802A (en) | 1985-10-08 |
| GB2134783A (en) | 1984-08-22 |
| SE437931B (en) | 1985-03-25 |
| JPS59501110A (en) | 1984-06-28 |
| GB8403257D0 (en) | 1984-03-14 |
| NL8220420A (en) | 1984-05-01 |
| WO1984000105A1 (en) | 1984-01-19 |
| GB2134783B (en) | 1985-10-30 |
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