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WO2011089289A1 - Utilisation d'amitriptiline en tant qu'agent antitumoral pour le traitement du cancer du poumon - Google Patents

Utilisation d'amitriptiline en tant qu'agent antitumoral pour le traitement du cancer du poumon Download PDF

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Publication number
WO2011089289A1
WO2011089289A1 PCT/ES2011/000009 ES2011000009W WO2011089289A1 WO 2011089289 A1 WO2011089289 A1 WO 2011089289A1 ES 2011000009 W ES2011000009 W ES 2011000009W WO 2011089289 A1 WO2011089289 A1 WO 2011089289A1
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Prior art keywords
amitriptyline
cells
treatment
cancer
lung cancer
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Ceased
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PCT/ES2011/000009
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English (en)
Spanish (es)
Inventor
Manuel DE MIGUEL RODRÍGUEZ
Mario David Cordero Morales
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Universidad de Sevilla
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Universidad de Sevilla
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Anticipated expiration legal-status Critical
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    • 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
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • amitriptyline as an antitumor agent for the treatment of lung cancer.
  • the present invention is framed in the field of Pharmacy and Oncology and refers to the use of a pharmaceutical composition comprising the tricyclic antidepressant amitriptyline for the preparation of a medicament for the treatment and / or prophylaxis of a lung cancer process.
  • a pharmaceutical composition comprising the tricyclic antidepressant amitriptyline for the preparation of a medicament for the treatment and / or prophylaxis of a lung cancer process.
  • said lung cancer process is non-small cell and, more preferably, the non-small cell lung cancer process is large cell lung carcinoma.
  • Anti-cancer therapies based on cytotoxic drugs that damage the DNA of tumor and non-tumor cells, are not effective for certain tumors that have a highly efficient intrinsic DNA repair mechanism, such as brain tumors from glial cells, so It is resorting to other types of alternative therapies among which is oxidative therapy.
  • This therapy consists in inducing high levels of oxidative stress in tumor cells, taking advantage of the fact that they are more susceptible to oxidative attack than healthy cells due to their lower number of mitochondria and antioxidant enzymes.
  • Oxidative therapy is currently performed in two independent ways, increasing the concentration of reactive oxygen species (ROS), and by inhibiting the antioxidant systems of tumor cells. By generating high levels of ROS and inhibiting the antioxidant system of tumor cells, the defenselessness of the tumor cells is caused by oxidative stress and apoptotic death of these cells by activation of the caspases cascade.
  • ROS reactive oxygen species
  • anti-cancer therapies are being directed towards the mitochondria of tumor cells.
  • a drug that damages these organelles would cause an increase in oxidative stress and cell death.
  • Chlorimipramine belongs to the group of medicines called tricyclic antidepressants. Another compound that also falls into the same category is amitriptyline, a drug widely used in the clinic for the treatment of depression and as an analgesic.
  • Amitriptyline has a wide variety of pharmacological actions. Apart from its palliative effects, it has been currently studied for its cytotoxic effects, thus, different articles show the adverse effects that this drug causes in neuronal cells (Weiss and Sawyer, 1993. Toxicol. In Vitro, 653-667), liver cells (Yasuhara et al., 1979. Pharmacology, 18 (2): 95-102) or fibroblast cells (Cordero et al., 2009. Toxicology and Applied Pharmacology, 235: 329-337) among others. Although the cytotoxic effects that amitriptyline has on different cell models are being studied, the mechanism of action that causes its toxicity is not yet fully known.
  • Lung cancer is very difficult to control with current treatments. For this reason, many patients with this disease are encouraged to participate in clinical trials.
  • the selection of treatment depends mainly on the type of lung cancer and the stage. Lung cancer can be classified into two large groups:
  • laser therapy treatment in which a laser beam is used to destroy cancer cells
  • endoscopic placement of a shunt used to open an airway that is blocked by abnormal tissue
  • Non-small cell lung cancer treatment selection depends mainly on the size, site and grade of the tumor.
  • Surgery is the most common way to treat this type of lung cancer.
  • Four types of surgery are used: wedge resection (surgery to remove a tumor and a small amount of normal surrounding tissue), segmental resection (when a somewhat larger portion of tissue is taken), lobectomy (surgery to remove a lobe from the lung), pneumonectomy (surgery to remove a lung), cuff resection (surgery to remove a part of the bronchus), cryosurgery (treatment that freezes and destroys cancerous tissue, can be used to control symptoms in the last stages (stages) of the non-small cell lung cancer).
  • Radiation therapy and chemotherapy can also be used to slow the progression of the disease and to control symptoms.
  • biological therapy uses substances made by the body or synthetics to boost, direct or restore the body's natural defenses against cancer
  • laser therapy treatment that uses a laser beam to destroy cancer cells
  • photodynamic therapy PDT, a treatment that uses a medication and a specific type of laser beam to destroy cells cancerous
  • electrocautery treatment for which a stylet or needle heated with an electric current is used to destroy abnormal tissue.
  • the present invention relates to the use of a pharmaceutical composition comprising the tricyclic antidepressant amitriptyline for the preparation of a medicament for the treatment and / or prophylaxis of a lung cancer process (hereinafter, the term AMIT can be used to refer to the amitriptyline compound ).
  • a pharmaceutical composition comprising the tricyclic antidepressant amitriptyline for the preparation of a medicament for the treatment and / or prophylaxis of a lung cancer process
  • AMIT can be used to refer to the amitriptyline compound
  • said lung cancer process is non-small cell and, more preferably, the non-small cell lung cancer process is large cell lung carcinoma.
  • the present invention provides a new anti-cancer agent for oxidative therapy, amitriptyline, since, although, as we have seen, works focusing on the use of amitriptyline as a cytotoxic agent are appearing, so far the potential beneficial effects have not been developed. that this drug can have in tumor cells and, more specifically, in lung cancer.
  • this therapy although several molecules have already been studied as possible anti-cancer agents framed within the oxidative therapy strategy, this therapy, as we have seen, depends on the redox balances of the different tumors so the effectiveness of the anti-cancer agent depends on the tumor that we are trying.
  • this work demonstrates how amitriptyline offers better results in the lung tumor line H460 when compared to other agents already used to induce oxidative stress in tumor cells.
  • the present invention solves the technical problem posed by the effective treatment of lung cancer, by oxidative therapy with amitriptyline as an anticancer agent.
  • the treatment of this type of cancerous processes has special relevance because lung tumors usually acquire a high resistance against cytotoxic drugs such as those used in chemotherapy, which damage cellular DNA, because they find new DNA repair strategies very efficient
  • one aspect of the present invention relates to the use of a pharmaceutical composition comprising the tricyclic antidepressant amitriptyline for the preparation of a medicament for the treatment and / or prophylaxis of a lung cancer process.
  • lung cancer process refers to a set of diseases in which the body produces an excess of malignant cells (also known as cancer or cancer), with typical features of uncontrolled behavior and growth (growth and division beyond normal limits, invasion of surrounding tissue and, sometimes, metastasis).
  • Said cancerous process comprises any disease of an organ or tissue in a mammal, preferably man, characterized by a poorly controlled, or uncontrolled, multiplication of normal or abnormal cells in said tissue, and their effect on the entire body.
  • the cancerous lung process includes benign neoplasms, dysplasias, hyperplasias, as well as neoplasms that show metastases, or any other transformation such as, for example, leukoplasias that often precede the cancer outbreak.
  • Cells and tissues are cancerous when they grow and replicate more quickly than normal, moving or dispersing in the surrounding healthy tissue or any other body tissue, what is known as metastasis, assumes abnormal shapes and sizes, shows changes in its Nucleocytoplasmic ratio, nuclear polychromasia, and finally ceases.
  • Cancer cells and tissues can affect the body as a whole causing paraneoplastic syndromes, or if the cancerous process occurs in a vital organ or tissue, its normal function being disrupted or damaged, with possible fatal results.
  • the end result of the evolution of a cancer that involves a vital organ, whether primary or metastatic, is the death of the affected mammal.
  • the cancer tends to spread, and its extent is normally related to changes in disease survival.
  • cancer is in one of three states of growth: early or localized, when the tumor is still confined in the tissue of origin, or in its primary location; direct extension, when the cancer cells of the tumor have invaded adjacent tissue or have spread only to regional lymph nodes; or metastasis, when cancer cells have migrated to distant parts of the body from the primary location, through the circulatory or lymphatic system, and have been established in secondary locations.
  • cancer is malignant because of its tendency to cause death if it is not treated.
  • Benign tumors do not usually cause death, although they can do so if they interfere with the normal function of the body due to its characteristics or location, size or paraneoplastic effects.
  • benign lung tumors fall within the definition of cancerous process or lung cancer.
  • cancer cells divide at a higher rate than normal cells, but the distinction between the growth of normal and cancerous tissues is not so much that cell division is much faster, such as the partial or complete loss of stopping your growth and differentiate into a useful and limited tissue, of the type that characterizes the functional balance of normal tissue growth.
  • Cancer tissue can express certain receptor molecules and are probably influenced by susceptibility and immunity.
  • cancer includes benign, or malignant, neoplasms such as: squamous cell lung carcinoma, adenocarcinoma, bronchioloalveolar carcinoma, adenoescamosal carcinoma, papillary adenocarcinoma, mucoepidermoid carcinoma, cystic adenoid carcinoma, large cell carcinoma or giant starry cell carcinoma.
  • lung cancer Given its location, lung cancer can be located in the upper lobes and, especially in the anterior segment; in the lower lobes; in the middle lobe and lining.
  • Pancoast tumor is the malignant tumor located in the pulmonary apex. Lung cancers are classified into:
  • Central lung cancer appears at the level of the main, lobar and segmental bronchi.
  • the epidermoid variety (squamous cells) is a type of central lung cancer.
  • Peripheral lung cancer appears from the fifth generation bronchi.
  • Adenocarcinoma is a type of peripheral cancer. Rarely They get to be located in very remote areas, next to the pleura.
  • Amitriptyline a compound marketed as an antidepressant drug, is used within the anticancer strategy called oxidative therapy, therapy that consists in inducing high levels of oxidative stress in tumor cells, taking advantage of the fact that they are more susceptible to oxidative attack than healthy cells.
  • oxidative therapy therapy that consists in inducing high levels of oxidative stress in tumor cells, taking advantage of the fact that they are more susceptible to oxidative attack than healthy cells.
  • amitriptyline has the characteristics necessary to be used as an anti-cancer agent in oxidative therapy for the treatment of lung cancer.
  • H460 neoplastic cell line lung tumor line belonging to non-microcytic cells
  • results carried out on the H460 neoplastic cell line reveal that it not only increases ROS levels, because it causes a significant increase in the production of intramitochondrial ROS, but also produces a decrease significant of the antioxidant systems of the cells limiting the response of the cells to oxidative stress and, therefore, making them more sensitive to oxidative damage. It also induces apoptosis causing a marked decrease in cell population.
  • CPT camptothecin
  • DOXO doxorubicin
  • METO methotrexate
  • microcytic cell carcinomas their name derives from the size of their cells (microcytic: very small cells). Approximately 20% of lung cancers are of this type. It is preferably located in the central area of the lungs. - Non-small cell carcinomas: they represent approximately 80% of the remaining lung cancers. The most frequent types are:
  • Squamous or squamous cell carcinoma usually located in the central part of the lungs, has a relatively slow growth.
  • Adenocarcinoma it is usually located in more peripheral areas of the lungs, which frequently affects the pleura and chest wall.
  • a preferred embodiment of the present invention relates to the use of the pharmaceutical composition for treatment. and / or prophylaxis of a cancerous lung process where said process is non-small cell lung cancer.
  • the non-small cell lung cancer process is preferably large cell lung carcinoma.
  • Another preferred embodiment of the present invention relates to the use of the pharmaceutical composition where the medicament further comprises a pharmacologically acceptable excipient.
  • excipient refers to a substance that aids the absorption of amitriptyline, stabilizes said compound or helps the preparation of the drug in the sense of giving it consistency or providing flavors that make it more pleasant.
  • the excipients could have the function of keeping the ingredients together such as starches, sugars or cellulose, sweetening function, dye function, drug protection function such as to isolate it from air and / or moisture, function filling a tablet, capsule or any other form of presentation such as dibasic calcium phosphate, a disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph.
  • pharmaceutically acceptable refers to the compound referred to being allowed and evaluated so as not to cause damage to the organisms to which it is administered.
  • the vehicle must be pharmaceutically acceptable.
  • a “pharmaceutically acceptable carrier” refers to those substances, or combination of substances, known in the pharmaceutical sector, used in the preparation of pharmaceutical forms of administration and includes, but are not limited to, solids, liquids, solvents or surfactants.
  • the vehicle can be an inert substance or action analogous to any of the sequences of the present invention.
  • the function of the vehicle is to facilitate the incorporation of amitriptyline as well as other compounds, allow a better dosage and administration or give consistency and form to the pharmaceutical composition.
  • the presentation form is liquid, the vehicle is the diluent.
  • a more preferred embodiment relates to the use of the pharmaceutical composition where the pharmacologically acceptable carrier is at least one nanoparticle, a liposome, or micelles or microemulsions.
  • Amitriptyline can be associated, for example, but not limited to nanoparticles, liposomes, micelles or microemulsions.
  • a nanoparticle is a microscopic particle with a dimension smaller than 100 nm.
  • nanoparticles are an area of intense scientific research, due to a wide variety of potential applications in various fields among which are the biomedical field.
  • a liposome is a spherical vesicle with a phospholipid membrane. The liposome contains a core of aqueous solution.
  • the micelle is a spherical lipid that contains non-aqueous material. Both liposomes and micelles can be used as carriers of various substances between the outside and inside the cell.
  • microemulsions are defined as a system of water, oil and at least one amphiphilic compound that is presented as a simple liquid solution, optically isotropic and thermodynamically stable. These systems are also of interest because of their considerable potential to act as drug release vehicles that incorporate a wide variety of active molecules.
  • the incorporated amitriptyline could be applied to "vehicles" such as nanoparticles, liposomes, micelles or microemulsions that direct the drug to the tumors.
  • the address that brings the antitumor agent conjugated to the nanoparticle to the tumor can be passive or active.
  • the first one is based on the EPR (Enhanced Permeability and Retention) effect of macromolecules in solid tumors: the great permeability of the blood vessels of the tumor tissue and the poor lymphatic drainage leads to an accumulation of the macromolecules in the tumor tissue.
  • active targeting is based on ligands targeting receptors or antigens that are overexpressed in tumor cells.
  • compositions of the present invention and the combined preparation can be formulated for administration to an animal, and more preferably to a mammal, including man, in a variety of ways known in the state of the art.
  • they can be, without limitation, in sterile aqueous solution or in biological fluids, such as serum.
  • Aqueous solutions may be buffered or unbuffered and have additional active or inactive components. Additional components include salts to modulate ionic strength, preservatives including, but not limited to, antimicrobial agents, antioxidants, chelators, and the like, and nutrients including glucose, dextrose, vitamins and minerals.
  • the compositions can be prepared for solid administration.
  • compositions may be combined with various inert vehicles or excipients, including but not limited to; binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint or methyl salicylate.
  • binders such as microcrystalline cellulose, gum tragacanth, or gelatin
  • excipients such as starch or lactose
  • dispersing agents such as alginic acid or corn starch
  • lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • flavoring agents such as peppermint or methyl salicylate.
  • compositions or preparations and / or their formulations may be administered to an animal, including a mammal and, therefore, to man, in a variety of ways, including, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intracecal, intraventricular, oral, enteral, parenteral, intranasal or dermal.
  • the dosage to obtain a therapeutically effective amount depends on a variety of factors, such as the age, weight, sex or tolerance of the mammal.
  • the term "therapeutically effective amount” refers to the amount of amitriptyline, prodrugs, derivatives or analogs of amitriptyline that produce the desired effect and, in general, will be determined, among others, by the proper characteristics. of said prodrugs, derivatives or analogs and the therapeutic effect desired.
  • a preferred embodiment of the present invention relates to the use of the pharmaceutical composition where the medicament is presented in a form adapted to parenteral administration and another preferred embodiment of the present invention relates to the use of the pharmaceutical composition where the medicament is present in a form adapted to oral administration.
  • adapted form refers to how to adapt the medicament of the present invention so that it can be administered parenterally or orally.
  • the form adapted to oral administration is selected from the list comprising, but not limited to, drops, syrup, herbal tea, elixir, suspension, extemporaneous suspension, drinkable vial, tablet, capsule, granulate, seal, pill, tablet, tablet, tablet, troccus or lyophilized.
  • the form adapted to parenteral administration refers to a physical state that can allow its injectable administration, that is, preferably in a liquid state. Parenteral administration can be carried out by intramuscular, intraarterial, intravenous, intradermal, subcutaneous or intraosseous administration but not limited to these types of parenteral administration routes.
  • the medication is present in a form adapted to sublingual, nasal, intracatecal, bronchial, lymphatic, rectal, transdermal or inhaled administration.
  • the form adapted to rectal administration is selected from the list comprising, but not limited to, suppository, rectal capsule, rectal dispersion or rectal ointment.
  • the form adapted to transdermal administration is selected from the list comprising, but not limited to, transdermal patch or iontophoresis.
  • a more preferred embodiment of the present invention relates to the use of the pharmaceutical composition where the medicament is presented in a form adapted to parenteral administration intratumorally, intravenously, intraperitoneally or intramuscularly.
  • This drug can be applied directly by injection by any efficient route such as, but not limited to, intratumoral, intravenous, intraperitoneal or intramuscular, without waiting a priori for important side effects. According to preliminary tests in mice, no significant histological or biochemical damage is found when AMIT is injected intratumorally.
  • All medications have specific characteristics regarding their release, absorption, distribution, metabolism and elimination.
  • a drug When a drug is introduced into the body, it must overcome numerous biological barriers before reaching the receptor that depend on the route of administration. In order for a drug to exert its action, it must reach an adequate concentration and in the appropriate place in which a drug is in a position to interact with its receptors to perform its biological effect without the intervention of diffusion barriers.
  • the drug can penetrate the body in favor of the absorption processes, reach the plasma and, through it, distribute through the tissues in favor of the distribution processes.
  • the drug as soon as it penetrates the organism, is subjected to the elimination processes that essentially comprise two subtypes of mechanisms: elimination by natural routes (urine, bile, saliva, etc.) and enzymatic metabolism or biotransformation.
  • the concentration of said drug in the serum of the treated individual is usually measured.
  • the serum concentration experiences variations, depending on pharmacokinetic mechanisms such as the plasma level curve that describes the variations suffered by the concentration of a drug in the serum (or plasma), from its administration to Its disappearance from the organism.
  • Latency period time that elapses from the moment of administration until the pharmacological effect begins.
  • Intensity of the effect it is usually related to the concentration reached by the drug in the serum. It depends, therefore, on the height of the curve; The higher the height, the greater the effect.
  • Duration of the action or effect time elapsed between the moment at which the minimum effective concentration is reached at the time it falls below said concentration.
  • amitriptyline is a drug that is already marketed as an antidepressant, its pharmacokinetics is known. Thus, it is known that it is absorbed very well by the digestive tract and, although there are considerable interindividual variations, the maximum effects are achieved after several weeks of treatment, although adverse effects may manifest from the first dose.
  • AMIT binds strongly to plasma and tissue proteins. The half-life is 10 to 50 hours for AMIT and is distributed in the liver, lungs and brain. After a single dose, between 25 and 50% of the dose is excreted in the urine and a small part in the stool (Vademecum).
  • the compound amitriptyline is administered in various concentrations to a culture of H460 (non-small cell lung cancer) tumor cells. At these concentrations, amitriptyline not only increases ROS levels but also produces a significant decrease in the antioxidant systems of the cells making them more sensitive to oxidative damage and induces apoptosis by decreasing the cell population.
  • a concentration of 50 ⁇ of amitriptyline is equivalent to 13.85 pg / ml.
  • amitriptyline In humans, after a single oral dose of 75 mg of amitriptyline, the maximum concentration of amitriptyline in plasma is estimated at about 40 ng / ml, reaching 4 hours. If 150 mg of this drug is received daily for a month, stable plasma concentrations are usually reached by day 14, with plasma levels being about 80 ng / ml. The apparent average elimination half-life of amitriptyline is 22.4 hours. The recommended average dose of administration of amitriptyline would be between 25 and 250 mg / day, which would be reflected in a quantity of plasma amitriptyline of about 13 ng / ml and 33 ng / ml, respectively (Vademecum).
  • Another preferred embodiment of the invention relates to the use of the pharmaceutical composition of the invention where the medicament has an amount of amitriptyline capable of reaching a serum concentration of between 13 and 133 ng / ml.
  • AMIT amitriptyline.
  • CPT camptothecin.
  • DOXO doxorubicin.
  • METO methotrexate.
  • FIG. 2 Percentage of apoptotic cells.
  • AMIT amitriptyline.
  • CPT camptothecin.
  • DOXO doxorubicin.
  • METO methotrexate.
  • FIG. 3. ROS levels.
  • AMIT amitriptyline.
  • CPT camptothecin.
  • DOXO doxorubicin.
  • METO methotrexate.
  • FIG. 4. CoQ10 levels (antioxidant).
  • AMIT amitriptyline.
  • CPT camptothecin.
  • DOXO doxorubicin.
  • METO methotrexate.
  • FIG. 5 Levels of catalase (antioxidant).
  • FIG. 6 Mitochondrial membrane potential levels.
  • FIG. 7 Activity of the l + lll complex of the respiratory chain.
  • amitriptyline a drug with antitumor properties that would be framed within the anti-cancer strategy called oxidative therapy by induction of oxidative stress or autophagy.
  • CPT camptothecin
  • DOXO doxorubicin
  • METO methotrexate
  • Coenzyme Q10 (CoQ10), showed a drastic decrease in cultures of H460 tumor cells treated with AMIT 50 ⁇ , however, in cultures treated with CPT, DOXO or METO no decrease in this membrane antioxidant was observed, rather a small rise was seen to counteract the increases in ROS (Figure 4).
  • the damage caused by the increase in mitochondrial ROS induces the opening of the mitochondrial transition pore (MPT), thus increasing the permeability of the mitochondria with the consequent exit of proapoptotic proteins to the cytosol such as cytochrome c, smac / devil, etc., starting the intrinsic pathway of caspase-3 dependent apoptosis.
  • MPT mitochondrial transition pore

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Abstract

L'invention concerne une composition pharmaceutique qui comprend l'antidépressif tricyclique ou amitriptiline pour la préparation d'un médicament destiné au traitement et/ou à la prophylaxie d'un processus cancéreux du poumon. De préférence, ledit processus cancéreux du poumon est non microcytaire et, mieux encore, le processus cancéreux du poumon non microcytaire est un carcinome à grandes cellules du poumon.
PCT/ES2011/000009 2010-01-19 2011-01-19 Utilisation d'amitriptiline en tant qu'agent antitumoral pour le traitement du cancer du poumon Ceased WO2011089289A1 (fr)

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ESP201000061 2010-01-19
ES201000061A ES2363394B2 (es) 2010-01-19 2010-01-19 Uso de amitriptilina como agente antitumoral para el tratamiento de cáncer de pulmón.

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KR102861622B1 (ko) * 2021-07-06 2025-09-18 국립암센터 Cdk4/6 억제제 및 삼환계 항우울제를 포함하는 암의 예방 또는 치료를 위한 약학적 조성물

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2002043652A2 (fr) * 2000-11-29 2002-06-06 Ramot At Tel-Aviv University Ltd. Medicaments anti-proliferation
WO2008112297A2 (fr) * 2007-03-13 2008-09-18 Yale University Procédés de traitement du cancer par interférence avec la signalisation d'un récepteur d'igf-i

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002043652A2 (fr) * 2000-11-29 2002-06-06 Ramot At Tel-Aviv University Ltd. Medicaments anti-proliferation
WO2008112297A2 (fr) * 2007-03-13 2008-09-18 Yale University Procédés de traitement du cancer par interférence avec la signalisation d'un récepteur d'igf-i

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Title
DEBONIS, SALVATORE ET AL.: "In vitro screening for inhibitors of the human mitotic kinesin Eg5 with antimitotic and antitumor activities", MOLECULAR CANCER THERAPEUTICS, vol. 3, no. 9, 2004, pages 1079 - 1090, XP002476969 *

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