WO2010003308A1 - Utilisation de l’oxyde nitrique et de son système de transduction des signaux dans la préparation de médicaments destinés à une thérapie ciblée de tumeurs malignes - Google Patents

Utilisation de l’oxyde nitrique et de son système de transduction des signaux dans la préparation de médicaments destinés à une thérapie ciblée de tumeurs malignes Download PDF

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WO2010003308A1
WO2010003308A1 PCT/CN2009/000691 CN2009000691W WO2010003308A1 WO 2010003308 A1 WO2010003308 A1 WO 2010003308A1 CN 2009000691 W CN2009000691 W CN 2009000691W WO 2010003308 A1 WO2010003308 A1 WO 2010003308A1
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nitric oxide
malignant tumors
drug
targeted therapy
tumor
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费瑞德·穆拉德
卞卡
李桃·洁西卡
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卞化石
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    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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Definitions

  • Nitric Oxide and Its Information Transmission System in Preparation of Targeted Therapeutic Drugs for Malignant Tumors
  • the invention relates to biotechnology, in particular to the application of nitric oxide and its information transmission system in preparing a targeted therapy for treating malignant tumors.
  • Nitric Oxide is widely involved in information transmission activities closely related to life activities. Therefore, the association between NO and tumor growth has always attracted international attention.
  • Nobel Prize for Nitric Oxide was achieved, there has been no fundamental breakthrough in the relationship between NO and the diagnosis and treatment of malignant tumors. The main reason is:
  • Nitric oxide is an inorganic gas radical that has attracted attention in recent years. NO contains a pair of unpaired electrons, so it has the characteristics of free radicals. Because of its unique physical and chemical properties, NO has a biological diversity under normal conditions and affects almost all systems. N0 is highly soluble in fat and easily diffuses into adjacent tissue cells to react with target substances, producing a range of biological effects. NO is widely involved in the transmission of physiological information (for example, expanding blood vessels and acting as neurotransmitters). At the same time, excessive production of NO in pathological conditions causes extensive damage to the body.
  • Solid malignant tumor tissue consists of two major parts: a) tumor cells (parenchyma), and b) peripheral tissues (stroma). These two parts of nitric oxide biology are fundamentally different.
  • cGMP can be synthesized by at least 4 enzymes, and the decomposition system of cGMP is very complicated, and the non-physiological characteristics of malignant tumors increase the difficulty of analysis. Therefore, the existence and role of NO in malignant tumors have not been known so far.
  • ROS reactive oxygen species
  • RNS reactive nitrogen species
  • the technical problem to be solved by the present invention is to study and design the application of nitric oxide and its information transmission system in the preparation of antitumor drugs.
  • the invention provides a nitric oxide and an information transmission system thereof for use in preparing a targeted therapy for malignant tumors.
  • the present invention uses seven key biological target sequences in the nitric oxide cell information system: inducible nitric oxide synthase and other nitric oxide synthase subtypes; cellular protein oxidation and nitration; cyclic guanosine monophosphate (cGMP) Soluble ornithine cyclase (sGC); Receptors for natriuretic peptides (NPs) and other cell membranes of ornithine cyclase (pGC); phosphodiesterase subtypes; serine/threonine Specific changes in gene expression and protein function of acid-specific protein kinases [series; including protein kinase G (PKG)] in malignant tumor tissues serve as biotherapeutic targets.
  • inducible nitric oxide synthase and other nitric oxide synthase subtypes cellular protein oxidation and nitration
  • cGMP cyclic guanosine monophosphate
  • the regulatory drugs can be combined according to the target detection conditions to form an anti-malignant tumor based on a nitric oxide cell information system. Tumor-targeted therapeutic drug combination. This treatment can be used for primary lesions of tumors and other organ metastasis sites.
  • the seven key biological target series and related drug development details of the present invention include:
  • These drugs are drugs that alter the level of cyclic guanosine monophosphate in malignant tumors.
  • This class of drugs is a gene that changes the soluble guanylate cyclase subtypes of malignant tumors: ⁇ 1, ⁇ 2; ⁇ ⁇ 2, ⁇ 3 subunit, or a target drug that changes its enzymatic activity.
  • These drugs are genes or protein expressions that alter the subtypes of cell membrane ornithine cyclase in malignant tumors, or target drugs that alter their enzymatic activity.
  • Such drugs are targets for altering the expression of genes or proteins of specific subtypes of diuretic diesterase in malignant tumors, or for altering the protein function of specific subtypes of phosphodiesterase in malignant tumors.
  • These drugs are genes or protein expressions that alter the serine/threonine-specific protein kinase family, or target drugs that alter the protein function of the serine/threonine-specific protein kinase family in malignant tumors.
  • Such drugs include tumor treatment drugs for ligands or activators of guanylate cyclase/sodium peptide receptors (Table 1) and analogs thereof.
  • This class of drugs includes the PDE family and its inhibitors (Table 2); other phosphodiesterase inhibitor complexes such as methylxanthine (caffeine, theophylline, theobromine, aminophylline, choline, 2 Tumor therapy for hydroxypropyl theophylline), astragalus and its analogues.
  • PDE PDE family and its inhibitors
  • other phosphodiesterase inhibitor complexes such as methylxanthine (caffeine, theophylline, theobromine, aminophylline, choline, 2 Tumor therapy for hydroxypropyl theophylline), astragalus and its analogues.
  • These drugs include nitric oxide donors, nitric oxide precursors (such as nitrite, nitrate nitrate) and their analogs.
  • Such drugs include nitric oxide tinctures, or nitric oxide scavengers and analogs thereof.
  • Such drugs include tumor therapeutic drugs for cyclic guanosine monophosphate isomers and analogs thereof.
  • Phosphorylase kinase is a serine/threonine-specific protein kinase that converts phosphorylase b to phosphorylase a.
  • One of the enzymes activated by phosphorylase kinase is glycogen phosphorylase.
  • the gene for phosphorylase kinase ⁇ is PHKA1, ⁇ 2, and the gene for phosphorylase kinase ⁇ is ⁇ , phosphoric acid.
  • Kinase ⁇ gene is PHKG1, PKHG2 0 phosphorylase kinase by phosphorylation of reversible allosteric regulation and regulation.
  • PKA Protein kinase A
  • cAMP Protein kinase A
  • the level of cAMP is low, the whole enzyme remains intact and is not activated by the contact reaction.
  • the cAMP concentration is increased (eg, the G protein coupled receptor couples Gs to activate adenylate cyclase, inhibits the phosphodiesterase that degrades cAMP), cAMP binds to two sites of the regulatory subunit, thereby Causes a conformational change that releases the catalytic subunit.
  • PKA Protein kinase B
  • Aktl Akt2
  • Akt3 Akt3
  • Aktl participates in the cell survival pathway by inhibiting the process of apoptosis. Aktl also induces protein synthesis pathways and is therefore a key signaling protein in the cellular pathway that causes excessive proliferation of skeletal muscle and tissue growth. Because it blocks apoptosis, it promotes cell survival. Aktl is also a major cause of many types of cancer. Akt (now known as Aktl) was originally thought to be an oncogene in retroviral transformation.
  • Akt2 is an important signaling molecule in the insulin signaling pathway, a regulatory enzyme necessary for inducing glucose transport.
  • mice with null Aktl and normal Akt2 glucose homeostasis is undisturbed, but animals are smaller in size, which is consistent with Aktl's primary role in growth.
  • mice with normal Aktl and knocked out Akt2 had only slight growth defects, but showed a diabetic phenotype (insulin resistance), which is consistent with the view that Akt2 is specific for the insulin receptor in the signaling pathway.
  • the role of Akt3 is not known, but it is clearly expressed in the brain. It has been reported that mice lacking Akt3 have smaller brains.
  • PLC Protein kinase C
  • Classical PKC - includes alpha, beta, beta and gamma subunits. Its activation requires Ca2+, diglycerides (DAG) and phospholipids such as lecithin.
  • DAG diglycerides
  • PKC- ⁇ PRKCG
  • the novel (n) PKCs include the ⁇ , ⁇ , ⁇ and ⁇ subunits, which require DAG for activation but do not require Ca2+.
  • both classical and novel PKCs like phospholipase C, are activated by the same signal transduction pathway.
  • Non-classical PKC - Ca2+ and DAG are not required for activation.
  • PK-N1 (PKN1)
  • PK-N2 (PKN2)
  • Ca2+/calmodulin-dependent protein kinase or CaM kinase is mainly regulated by the Ca2+/calmodulin complex.
  • CaM kinases There are two types of CaM kinases:
  • CaM kinase For example, myosin light chain kinase (MLCK), which phosphorylates myosin, causes muscle contraction.
  • MLCK myosin light chain kinase
  • the multifunctional CaM kinase also known as CaM kinase II, plays an important role in many processes, such as neurotransmitter release, transcription factor regulation, and glucose metabolism. About 1% to 2% of the protein in the brain is CaM kinase II.
  • Mitogen-activated protein kinases act under extracellular stimuli (mitogens) and regulate a variety of cellular activities such as gene expression, mitosis, differentiation, and cell survival/apoptosis.
  • MAP is associated with most non-nuclear oncogene activities and is closely related to cellular responses to growth factors such as BDNF or nerve growth factor.
  • Extracellular stimulation leads to AP kinase activation through a signaling cascade (MAPK cascade) consisting of MAP kinase, MAP kinase kinase (MKK or MAP2K) and AP kinase kinase kinase (MKKK or AP3K).
  • Extracellular stimulation causes phosphorylation of the MAP2K serine and threonine residues, resulting in activation of MAP3K; MAP2K then activates AP kinase by phosphorylating its serine and tyrosine residues. From yeast to mammals, the AP kinase signaling cascade is well developed.
  • Extracellular signal-regulated kinase ERK1, ERK2
  • ERKs aka MAP kinase
  • growth factors and phorbol esters a tumor growth promoter
  • JNKs c-Jun N-terminal kinases
  • MAPK8 MAPK9, MAPK10
  • SAPKs stress-activated protein kinases
  • JNK and p38 signaling pathways are involved in stress, such as cytokines, UV irradiation, heat shock, and osmotic shock, and are associated with cell differentiation and apoptosis.
  • ERK5 ERK5 (MAPK7) was recently discovered and is activated by growth factors and stress stimuli and is involved in cell proliferation.
  • ERK3/4 ERK3 (MAPK6) and ERK4 (MAPK4) are structurally related to atypical MAPKs, and there are SEG motifs on the active loop. The main difference is only in the C-terminal extension.
  • ERK3 and EKR4 are mainly cytosolic proteins that bind, translocate and activate MK5 (PPAR, MAP2K5). Unlike the relative stability of ERK4, ERK3 is unstable.
  • ERK7/8 (MAPK15) is the newest member of the MAPKs family and functions similarly to atypical MAPKs. ERK7/8 has a C-terminus similar to ERK3/4.
  • Mos/Raf kinase is part of the APKK kinase family and is activated by growth factors. The function of this enzyme is to stimulate cell growth. The current inhibition of Raf has become a target for novel anti-tumor metastatic drugs that can reduce cell proliferation by inhibiting APK cascades.
  • Pelle is a serine/threonine kinase that phosphorylates itself, as does Tube and Toll.
  • the malignant tumor includes - Brain malignant tumors: astrocytoma, oligodendroglioma, ependymoma, brain (ridge) membrane, and embryo (tissue) tumor.
  • Lung cancer is the primary cause of human death from cancer s
  • Thyroid cancer There are four types of thyroid cancer, one of which is follicular carcinoma. Hurthle cell thyroid cancer, unlike follicular thyroid cancer, has an incidence of about 4% in thyroid cancer.
  • Bladder cancer is the most common malignant tumor of the urinary tract.
  • Hodgkin's disease is a malignant tumor derived from lymph nodes. It occurs at any age, but is more common in children and adolescents.
  • Bone cancer Most bone tumors are secondary tumors that develop from the spread of primary malignant tumor cells in other parts of the body to the bone.
  • Bone marrow cancer The vast majority of myeloma is a secondary tumor that is caused by the spread and metastasis that occurs in other parts of the body. '
  • Gallbladder cancer According to the American Cancer Society, gallbladder cancer is the fourth most common malignant tumor in the gastrointestinal tract, accounting for about 2 to 3% of all cancers in the United States.
  • Colon and rectal cancer is the third most common malignant tumor in men and the second most common malignant tumor in women.
  • Esophageal cancer It usually occurs between 50 and 70 years old.
  • Gastrointestinal tumors The gastrointestinal tract, or the digestive system, digests the food we eat, absorbs nutrients, and excretes the residue as a form of feces.
  • Kidney cancer means a part related to the kidney; “Cancer” refers to a type of malignant tumor that occurs in glandular, dermal, and mucosal epithelial cells.
  • Leukemia is a malignant tumor of hematopoietic tissue. Hematopoietic tissues include bone marrow, lymph nodes, and spleen. Although leukemia is the leading cause of death in children aged 3 to 14 years, leukemia is also common in adults.
  • Lymphoma is a malignant tumor of the lymphatic system.
  • the lymphatic system includes lymph nodes, lymph glands, and spleen, which are spread throughout the body and are connected to each other by capillary lymphatic vessels.
  • Oral, pharyngeal and laryngeal cancers include leukoplakia or erythema, mucosal ulceration of the mouth and throat.
  • Pancreatic cancer is a gland located behind the stomach.
  • Pancreatic juice secreted by the pancreas includes enzymes that can digest food, as well as insulin secretion from islet cells, which helps regulate blood sugar levels.
  • Rectal Cancer The American Cancer Society believes that the United States is one of the countries with the highest incidence of rectal cancer in the world, second only to prostate cancer, lung cancer and skin cancer.
  • Sarcoma A malignant tumor that occurs in muscle, bone, cartilage, and fibrous tissue. The sarcoma is named after the type of tissue it was originally grown on.
  • Gastric cancer is common worldwide, and in the past 40 years, the incidence of gastric cancer in the United States has decreased significantly.
  • Pharyngeal cancer The most common throat tumor is laryngeal cancer.
  • Ureteral Tumor The ureter is a conduit that connects the kidneys to the bladder and delivers urine to the bladder through muscle contraction.
  • Eye cancer is relatively rare. It affects many areas of the eye: the orbit and its protective tissues, the eyeballs, the eye mask and the eyelids.
  • the malignant tumor targeted therapeutic agent of the present invention comprises oral, parenteral, transdermal, topical, rectal, subcutaneous, intramuscular, intravenous, vaginal, intranasal. , bronchial administration, direct infiltration, peritoneal administration or local perfusion of drugs.
  • ANP cardiac natriuretic peptide
  • BNP brain natriuretic peptide
  • GC-A NPRA dirty, adrenal gland, heart, pulmonary vascular bed, ovary, GC/ P (guanylate ring
  • Type A natriuretic peptide receptor testis Type A natriuretic peptide receptor testis, Leydig tumor (MA-10) cells, neuroblastoma cells, brain, intestine, olfactory nerve and other tissues
  • GC-B/NPRB vascular bed fibroblasts, heart, lung, adrenal gland,
  • B-type natriuretic peptide receptor brain, ovary, cartilage and other tissues
  • ODA Olfactory nerve epithelium
  • ODA OAA development of skeletal muscle, lung, intestine, kidney and other tissues
  • NO nitrogen oxide
  • CO carbon monoxide CO carbon monoxide
  • the invention clarifies the substantial relationship between the NO information system and the malignant tumor in the international arena, and develops the core technology for the treatment of malignant tumors related to the NO Nobel Prize theory.
  • This core therapeutic technique is closely related to the diagnostic techniques described in the inventor's other patent. After the diagnosis and distribution of NO information system-related molecules in malignant tumors are clearly diagnosed, combined with the cell division cycle and differentiation characteristics of malignant tumors, the concept of comprehensive treatment and system biology of Chinese medicine is absorbed, and the malignant tumor target based on the biological regulation of nitric oxide is performed.
  • the directional treatment drugs comprehensively reveal that nitric oxide has the targeting, wideness, effectiveness, low toxicity or no toxicity, and has great clinical value.
  • FIG 1 Schematic diagram of the relationship between inflammation, iNOS, protein tyrosine nitration and malignant tumors
  • Figure 2 Non-reactive sGC stimulation and reduction of cGMP levels in malignant tumors
  • FIG. 8 Schematic diagram of the natriuretic peptide family and receptors
  • FIG. 9 and Figure 10 ANP, BNP plus phosphodiesterase inhibitors IBMX treated different concentrations of glioma cells and detected their proliferation on days 4 and 6, respectively.
  • CON is a blank control group.
  • Example 1 Inducible expression of nitric oxide synthase in malignant tumors
  • the present inventors performed a sample of human benign and malignant tumors approved by a tumor pathologist in the United States, and used only primary tumor cells or tumor tissues for biological analysis of nitric oxide. Revealed the inducibility of variation in malignant tumors. Nitric oxide synthase expression lays the foundation for the use of iNOS detection in the treatment of malignant tumors. Experimental results show that there is no or only a very small amount of inducible nitric oxide synthase (iNOS) expression in benign tumors. However, as the degree of malignancy of the tumor increased, the expression of inducible nitric oxide synthase (iNOS) was also correlated (Fig. 1).
  • iNOS reactive oxygen species
  • RNS reactive nitrogen species
  • NO combines with 0 2 - to form 0N00_, while 0N00 - is highly oxidizing and can react with proteins, lipids, carbohydrates and nucleic acids in shock, inflammation, ischemia-reperfusion injury, respiratory diseases and neurodegenerative diseases It plays an important role.
  • 0N00 can also react with active molecules in the body, such as endogenous antioxidants (ascorbic acid, vitamin E), sulfonium groups and aromatic compounds.
  • Cyclic guanosine monophosphate can be soluble in ornithine cyclase (sGC) or membranous ornithine cyclase (pGC) synthesized. Soluble ornithine cyclase synergistically produces enzyme activity from two subunits, ⁇ and ⁇ .
  • Cyclic guanosine monophosphate cGMP
  • PKGs cGMP-dependent protein kinases
  • CNGs Cyclic mediated ion channels
  • PDEs cGMP-regulated phosphodiesterase
  • SDSPAGE protein electrophoresis and specific antibodies were used to detect the protein expression of soluble ornithine cyclase alpha and beta subunits in benign and malignant tumors.
  • the results showed that soluble ornithine cyclase ⁇ and ⁇ were found in malignant tumors.
  • the protein expression of the subunits disappeared or was extremely weak (Fig. 3 and Fig. 4).
  • RNA expression of soluble ornithine cyclase alpha and beta subunits in benign and malignant tumors 7700 Prizm Sequence Detector System
  • cGMP cyclic guanosine monophosphate
  • sGC soluble ornithine cyclase
  • cGMP cyclic guanosine monophosphate
  • sGC soluble ornithine cyclase
  • Human telomerase reverse transcriptase The present inventors also used benign and malignant tumor samples for human telomerase Reverse transcriptase (hTERT) RT-PCR (7700 Prizm Sequence Detector System) detection. As shown in Figure 5, human telomerase reverse transcriptase gene expression is very high in malignant tumors, while benign tumor samples are extremely weak. The reliability of human benign and malignant tumor samples approved by the inventors of the United States for examination by a tumor pathologist is further demonstrated.
  • hTERT human telomerase Reverse transcriptase
  • Example 3 Treatment of malignant tumors by regulating intracellular cyclic guanosine monophosphate (cGMP) levels
  • cGMP cyclic guanosine monophosphate
  • the present invention firstly carried out experiments on the supplementation of cGMP with malignant tumors (Fig. 6).
  • 8-bromoguanosine 3',5-cyclic monophosphate (8Br-cGMP) is a cyclic guanosine preparation that can pass through the cell membrane, and is treated with 8Br-cGMP for benign (M71) and malignant tumors (M6 and D54).
  • Example 4 Natriuretic peptide family receptor and its membrane membranous ornithine cyclase
  • Natriuretic peptides mainly include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), c-type natriuretic peptide, CNP And synthetic natriuretic peptide (VAP), a group of peptides that are important in maintaining the body's water and salt balance, blood pressure stability, cardiovascular and kidney functions.
  • the natriuretic peptide family acts on it.
  • the two receptors are cell membrane ornithine cyclase (pGC) g
  • cGMP cyclic guanosine monophosphate
  • the present inventors conducted a comprehensive analysis of the expression of the receptor gene (mRNA) of the natriuretic peptide family in benign and malignant tumors.
  • mRNA receptor gene
  • real-time RT-PCR (7700 Prizm Sequence Detector System) results showed no correlation between the expression of the natriuretic peptide family receptor and the malignancy of the tumor.
  • the experimental data used the natriuretic peptide family receptor.
  • cyclic guanosine monophosphate provides a basis for the relationship between the natriuretic peptide family receptor and its membrane membranous ornithine cyclase and malignant tumors, suggesting that the expression of soluble ornithine cyclase in malignant tumors Mutation, and thus, whether the tumor expresses the natriuretic peptide family receptor or which type of natriuretic peptide family receptor is expressed, is not only directly related to the level of production of the cyclic guanosine monophosphate (cGMP) of the tumor tissue, but also the natriuretic peptide family.
  • Receptor ligands are used to provide a basis for the detection of malignant drug preparation.
  • Phosphodiesterase activity is directly related to the intracellular second messenger, cAMP and cGMP concentrations.
  • cAMP intracellular second messenger
  • cGMP cGMP
  • the use of phosphodiesterase inhibitors opens up new hopes for the treatment of a variety of diseases, depending on the cell and tissue distribution of each phosphodiesterase subtype, and the altered expression under various pathological conditions. Summarize the clinical application in recent years and analyze its mechanism of action to provide a basis for further development applications.
  • Atrial natriuretic peptide ABP
  • brain natriuretic peptide BNP
  • NPR-A/GC-A and NPR-B/GC-B can cause intracellular cyclic guanosine monophosphate (cGMP) levels Increase (Fig. 9, 10), but when the inventors used atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) alone, the inhibitory effect on the growth of malignant tumors was not significant.
  • cGMP cyclic guanosine monophosphate
  • Atrial natriuretic peptide ABP
  • brain natriuretic peptide BNP
  • IBMX phosphodiesterase inhibitor
  • results indicate that by determining the expression variation of phosphodiesterase subtypes in malignant tumors, it provides a basis for targeting the increase of the level of cGMP production in tumor tissues, and the detection of phosphodiesterase subtypes as Targeted inhibitors provide a basis for drugs for detecting malignant tumors.

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  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Enzymes And Modification Thereof (AREA)

Abstract

La présente invention a pour objet l’utilisation de l’oxyde nitrique et de son système de transduction des signaux dans la préparation de médicaments destinés à une thérapie ciblée de tumeurs malignes. Les médicaments sont choisis parmi des médicaments ciblés qui peuvent modifier l’expression ou l’activité de NOS inductibles, de NOS endothéliaux et de NOS neuraux et ainsi de suite.
PCT/CN2009/000691 2008-07-10 2009-06-22 Utilisation de l’oxyde nitrique et de son système de transduction des signaux dans la préparation de médicaments destinés à une thérapie ciblée de tumeurs malignes WO2010003308A1 (fr)

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CN200810128400 2008-07-10

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