WO2008023362A2 - Traitement du cancer - Google Patents

Traitement du cancer Download PDF

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Publication number
WO2008023362A2
WO2008023362A2 PCT/IL2007/001009 IL2007001009W WO2008023362A2 WO 2008023362 A2 WO2008023362 A2 WO 2008023362A2 IL 2007001009 W IL2007001009 W IL 2007001009W WO 2008023362 A2 WO2008023362 A2 WO 2008023362A2
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Prior art keywords
tumor
meca
agonist
mtx
brain
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PCT/IL2007/001009
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English (en)
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WO2008023362A3 (fr
Inventor
Pnina Fishman
Sara Bar-Yehuda
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Can-Fite Biopharma Ltd.
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Publication of WO2008023362A2 publication Critical patent/WO2008023362A2/fr
Publication of WO2008023362A3 publication Critical patent/WO2008023362A3/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to the field of therapeutics and in particular to cancer therapy.
  • the A 3 adenosine receptor a G; protein-associated cell surface receptor, has been proposed as a target to combat cancer and inflammation.
  • the receptor is highly expressed in various tumor cell types while low expression was shown in adjacent normal tissues.
  • Activation of the receptor by a specific synthetic agonist induces de-regulation of signal transduction pathways which include the Wnt and the NF-IcB, resulting in tumor growth inhibition (1-5).
  • a 3 AR agonists inhibit the development of colon, prostate and pancreatic carcinomas as well as melanoma and hepatoma.
  • a 3 AR agonists were also shown to act as anti-inflammatory agents by ameliorating the inflammatory process in different experimental autoimmune models such as rheumatoid arthritis, Multiple sclerosis and Crohn's disease (6-10). It was proposed earlier that the A 2A and A 3 receptors mediate the anti-inflammatory effects of methotrexate (11).
  • a 3 adenosine receptor (A 3 AR) expression levels are elevated in cancer cells as compared to normal cells (12, 13). Thus, the A 3 AR expression level has been described as a mean for the diagnosis of cancer (14).
  • Methotrexate is a metabolic antagonist which interferes with the replication of rapidly dividing cells by preventing the conversion of folic acid to folinic acid, a building block for new DNA.
  • MTX was initially developed as therapeutic drug for malignant tumors and is currently used, in lower doses, for treating rheumatoid arthritis as well as other autoimmune and allergic diseases.
  • Combination therapies comprising MTX and an additional agent have been suggested: for example, the combination of MTX with an antibody or an inhibitor of ⁇ -4- 9
  • integrin 15, 16
  • MTX anti-TNF antibodies or TNF-binding protein in the treatment of TNF-mediated disorders, including autoimmune diseases (17, 18).
  • A3 AR agonist for the treatment of inflammation was also described (19).
  • the interaction of MTX with adenosine was also described (20, 21). Specifically, the anti-inflammatory actions of methotrexate were associated with the capacity of methotrexate to induce adenosine release. This interaction was suggested as a basis for the development of an additional class of anti-inflammatory drugs.
  • Brain and spinal cord tumors are abnormal growths of tissue found inside the skull or the bony spinal column. Individuals of any age can develop brain tumors. In fact, they are the second most common cause of cancer-related death in people up to the age of 35, with a slight peak in occurrence among children between the ages of 6 and 9.
  • brain tumors There are two types of brain tumors: primary brain tumors that originate in the brain and metastatic (secondary) brain tumors that originate from cancer cells that have migrated from other parts of the body.
  • Primary brain tumors are commonly located in the posterior cranial fossa in children and in the anterior two-thirds of the cerebral hemispheres in adults, although they can affect any part of the brain. They rarely spreads beyond the central nervous system, and death results from uncontrolled tumor growth within the limited space of the skull.
  • Metastatic brain cancer indicates advanced disease and has a poor prognosis.
  • AU cancerous brain tumors are life threatening (malignant) because they have an aggressive and invasive nature.
  • a non-cancerous primary brain tumor is life threatening when it compromises vital structures (e.g., an artery).
  • Treatment for brain tumor depends on the age of the patient, the stage of the disease, the type and location of the tumor, and whether the cancer is a primary tumor or brain metastases.
  • the treatment plan is developed by the oncology team and the patient. Treatment involves any combination of surgery, radiation, and chemotherapy. Some tumors require several different surgical procedures, and some can be treated with radiation alone. 9
  • BCNU chemotherapeutic agent that has proved to be effective.
  • BCNU chemotherapeutic agent that has proved to be effective.
  • the neurosurgeon places a wafer soaked with BCNU (Gliadel®, BiCNU®) into the surgical cavity after the tumor has been removed. By applying it directly to the diseased area of the brain, side effects are limited and the drug has a more beneficial effect.
  • Chemotherapy agents being tested for use in recurrent glial tumors include Taxol® (paclitaxel), irinotecan, topotecan, and high-dose tamoxifen with either carboplatin or procarbazine.
  • Other chemotherapeutic agents for the treatment of recurrent gliomas include interferon and retinoic acid.
  • a method of treating a subject having a tumor comprising administering to said subject an amount of methotrexate (MTX) and an amount of an agonist of the A 3 adenosine receptor (A 3 AR agonist), the amount of said MTX combined with the amount of said A 3 AR agonist being effective to cause an anti-cancer effect.
  • MTX methotrexate
  • a 3 AR agonist an agonist of the A 3 adenosine receptor
  • the tumor is a brain tumor.
  • a 3 AR agonists that may be used in accordance with the invention are IB-MECA and Cl-IB-MECA (also referred to herein by the terms CFlOl and CF102, respectively) as well as others, as detailed hereinafter.
  • a method of treating a subject having a tumor and being treated with MTX comprising administering to said subject an amount of an A 3 AR agonist effective to provide said treatment.
  • the tumor is a brain tumor.
  • a method of treating a subject having a tumor and indicated for treatment with an A 3 AR agonist comprising administering to the subject an amount of MTX effective to obtain said treatment.
  • the tumor is a brain tumor.
  • the invention also provides the use of an A 3 AR agonist for the preparation of a pharmaceutical composition for treating a subject having a tumor and being treated with MTX.
  • the invention provides for the use of MTX for the preparation of a pharmaceutical composition for treating a subject having a rumor and being treated with an A 3 AR agonist.
  • the invention also provides the use of an A 3 AR agonist for treating a subject having a tumor and being treated with MTX.
  • the invention provides for the use of MTX for treating a subject having a tumor and being treated with an A 3 AR agonist.
  • the tumor is a brain tumor.
  • the invention also provides a pharmaceutical composition for the treatment of tumor and being treated with MTX, comprising an amount of A 3 AR agonist effective to obtain said treatment as well as a pharmaceutical composition for treating a subject having a tumor being treated for said tumor with MTX, comprising an amount of an A 3 AR agonist effective to obtain said treatment.
  • the tumor is a brain tumor.
  • Fig. 1 is a bar graph showing the effect of combined treatment of MTX and
  • CF 102 (MTX+CF102) on proliferation of human Burkitt's lymphoma cells as compared to the effect of MTX alone (MTX) or CF 102 alone (CF102);
  • Fig. 2 is a bar graph showing the effect of combined treatment of MTX and CF 102 (MTX+CF102) on the development of human Burldtt's lymphoma cells brain metastases as compared to the effect of MTX alone (MTX) or CF102 alone (CF102);
  • Fig. 3 is a Western blot analysis of a protein extract from spleen cord of healthy animals (Control) or diseased animal treated with vehicle (Lymphoma+vehicle); CF 102 alone (Lymphoma+CF102), MTX alone (Lymphoma+MTX) or CF102+MTX (Lymphoma+CF102/MTX).
  • each one of the active agents, MTX and an A 3 AR agonist for the preparation of a pharmaceutical composition for administration to a subject having a tumor and being indicated for treatment by an anti-cancer treatment that comprises use of the other active agent; as well as a pharmaceutical composition for the treatment of a tumor indicated for treatment by one of these active agents, that comprises an effective amount of the other of these active agents and a pharmaceutically acceptable carrier.
  • an AsAR agonist includes one or more agonists.
  • composition consisting essentially of an A 3 AR agonist will not include or include only insignificant amounts (amounts that will have an insignificant effect on the anti-cancer effect of the composition) of other active ingredients that have an anti-cancer activity.
  • compositions consisting essentially of the active agents as defined herein would not exclude trace contaminants from the isolation and purification method, pharmaceutically acceptable carriers, such as phosphate buffered saline, excipients, preservatives, and the like. "Consisting of shall mean excluding more than trace elements of other elements. Embodiments defined by each of these transition terms are within the scope of this invention.
  • the invention is based on the finding that treatment of tumor bearing mice (injected with Human Burkitt's lymphoma cells) with IB-MECA, an A 3 AR agonist, in combination with MTX resulted in a combined anti-cancer effect, significantly larger than any of these drugs alone.
  • a method of treating a subject having a tumor comprising administering to said subject an amount of methotrexate (MTX) and an amount of an agonist of the A 3 adenosine receptor (A 3 AR agonist) the amount of said MTX combined with the amount of said A3 AR agonist being effective to provide an anti-cancer effect.
  • MTX methotrexate
  • a 3 AR agonist an agonist of the A 3 adenosine receptor
  • the tumor is a brain tumor.
  • a combined administration in the context of the present invention denotes administering to a patient the A 3 AR agonist and MTX within the same treatment course; namely during a treatment period, that can last weeks, months or years. Both active agents are given to the patients, each one according to its specific administration schedule, which may be the same or different, hi this context it is noted that MTX is typically given to patients once weekly, either orally or parentally.
  • An A 3 AR agonist may be administered to a patient orally or parentally, once daily, twice daily, several times daily, every other day, etc.
  • a combined treatment in accordance with the invention may involve, for example, weekly administration of MTX and once or twice daily administration of an A 3 AR agonist.
  • a combined treatment in accordance with the invention is a treatment involving the above combined administration, as further detailed hereinbelow.
  • a combined treatment according to the invention may be indicated to patients not previously treated by either MTX or an A 3 AR agonist, or to patients treated with either MTX or an A 3 AR agonist that are either not responding properly to the existing treatment or for the purpose of amplifying the therapeutic response.
  • the invention also pertains to the use of an A 3 AR agonist for the preparation of a pharmaceutical composition for treating a subject having a tumor and being treated with MTX, or alternatively, to the use of MTX for the preparation of a pharmaceutical composition for treating a subject having a tumor and being treated with an A 3 AR agonist.
  • the tumor is a brain tumor.
  • anti-cancer effect will be used to denote the disease modifying effect achieved by the combined administrations in alleviating the cancerous state including reducing the progression of the tumor (inhibiting tumor growth) or reversal, partially or totally, of the developed tumor e.g. by reducing tumor weight or size or even eliminating the tumor from the body, preventing tumor metastasis etc.
  • the reduction in tumor weight or size, the effect on tumor cell proliferation etc. may be determined on the basis of various parameters as known to the practitioner.
  • the parameters may include one or more of the following: physical examination for determining the existence of unusual lumps or swelling or reduction in mass of an already existing tumor lump (such as, for example, in malignant breast lumps), condition of lymph nodes, histological parameters of the solid tumor, blood parameters (such as protein levels indicative of a cancerous state), etc. It is understood that by treating the tumor that survival time of the subject undergoing treatment it typically prolonged.
  • tumor in accordance with the invention shall mean any condition in which cells proliferate at an abnormally high and uncontrolled rate, the rate being more rapid than normal tissue growth.
  • Tumors may be broadly classified into three major types: Malignant tumors arising from epithelial structures (called carcinomas); malignant tumors that originate from connective tissues such as muscle, cartilage, fat or bone (called sarcomas); and malignant tumors affecting hematopoietic structures (structures pertaining to the formation of blood cells) including components of the immune system (called leukemias and lymphomas).
  • Other neoplasms include but are not limited to neurofibromatosis.
  • solid tumor refers to any tumor which forms a mass.
  • Tumor mass may show partial or total lack of structural organization and functional coordination with normal tissue and may be a primary tumor mass or a secondary tumor mass (i.e. as a result of cell migration from the original tumor site through the blood and lymph vessels).
  • solid tumors include, but are not limited to, tumors of the brain, prostate, breast, colon, lung, kidney, bladder, liver, bone, head, neck, stomach, larynx, esophagus, cervix, rectum, colorectum and other sites in the gastrointestinal tract, uterus, ovary, skin (e.g., metastatic melanomas), lymphomas (including non-Hodgkin's, Burkitt's, diffuse large cell, follicular and diffuse Hodgkin's)) endometrium, pancreas and testes.
  • skin e.g., metastatic melanomas
  • lymphomas including non-Hodgkin's, Burkitt's, diffuse large cell, follicular and diffuse Hodgkin's
  • the tumor is selected to be of a type for which MTX has been or is currently indicated.
  • Some types include, without being limited thereto, breast cancer, head and neck cancer, lung cancer and brain cancer (brain lymphoma).
  • Brain tumor or "brain lymphoma”, as that term is used herein, refers to any intracranial tumor created by abnormal and uncontrolled cell division, normally either primary tumors found in the brain itself (neurons, gill cells, lymphatic tissue or blood vessels), in the cranial nerves (myelin producing Schwann cells), or in the brain envelopes (meninges), skull, pituitary and pineal glands, or spread from cancers primarily located in other organs to form secondary (metastatic) brain tumor.
  • the "subject" in accordance with the invention is any individual diagnosed as having a malignant tumor and indicated for anti-cancer treatment.
  • Anti-cancer treatment may include one or more of the following: surgery, chemotherapy, immunotherapy, radiation therapy, hormonal suppression, symptom control, cancer vaccines and complementary and alternative medicine.
  • the A 3 AR agonist is any compound that is capable of specifically binding to the adenosine A 3 receptor thereby fully or partially activating said receptor thereby yielding a therapeutic effect (in this particular case, an anti-inflammatory effect).
  • the A 3 AR agonist is thus a molecule that exerts its prime effect through the binding and activation of the A 3 AR. This means that at the doses it is being administered it essentially binds to and activates only the A 3 R. It should be noted that some A 3 AR agonists can also interact with and activate other receptors with lower affinities (namely a higher ICi).
  • a molecule will be considered an A 3 AR agonists in the context of the invention (namely a molecule that exerts its prime effect through the binding and activation A 3 R) if its affinity to the A 3 R is at least 3 times (i. e. its Ki to the A 3 R is at least 3 times lower), preferably 10 times, desirably 20 times and most preferably at least 50 times larger than the affinity to any other of the adenosine receptors.
  • the affinity of A 3 AR agonists to the human A 3 R as well as its relative affinity to the other human adenosine receptors can be determined by a number of assays, such as a binding assay.
  • binding assays include providing membranes or cells having the receptor and measuring the ability of the A 3 AR agonist to displace a bound radioactive agonist; utilizing cells that display the respective human adenosine receptor and measuring, in a functional assay, the ability of the A 3 AR agonist to activate or deactivate, as the case may be, downstream signaling events such as the effect on adenylate cyclase measured through increase or decrease of the cAMP level; etc.
  • an A 3 AR agonist is thus preferably administered at a dose such that the blood level that will be attained will give rise to essentially only A 3 R activation.
  • the A 3 AR agonist has a binding affinity (Ki) to the human A 3 AR of less than 1000 nM, desirably less than 500 nM, advantageously less 200 nM and even less than 100 nM, typically less than 50 nM, preferably less than 20 nM, more preferably less than 10 nM and ideally less than 5 nM.
  • Ki binding affinity
  • IB-MECA is the A 3 R agonist of choice
  • a therapeutic effect is achieved when IB-MECA is administered in an amount and for a time period sufficient to a maximal blood level of less than about 160 nM.
  • the dose of administered IB-MECA to achieve this maximal blood level can be easily gauged in a clinical study such as that described in US Patent Application publication No. 2005/0101560 (mentioned above); without being limited thereto.
  • individuals were given IB-MECA at different dosages and blood samples were taken in some time points and thereby the dose that yields " a blood level of IB-MECA of 160 nM were determined.
  • this absolute dose of IB- MECA will be different depending on the route of administration. For example, it is expected that intravenously administered IB-MECA will yield a blood level of 160 nM at a lower administered dose than following oral administration (as hi the case of the latter, the achieved blood level is limited by absorption through the digestive tract. Also, the total dose may dependent on factors such as age, gender, general health condition, etc. For example, it is expected that the total dose in children that will yield a blood level of 160 nM could be more or less than in adults.
  • the MTX and A 3 AR agonist are administered in amounts which are sufficient to achieve an anti-cancer effect.
  • the amount of each active agent is at least the amount which provides the desired anti-cancer effect when given alone, hi accordance with another embodiment, the invention may be contemplated to provide therapeutic combinations that may lower total dosage of each active agent than may be required when each individual drug is used alone. A reduction in adverse effects may also be noted.
  • the amount of each of the active agents will depend on the condition to be treated, the intended therapeutic regimen and the desired therapeutic dose. By way of example, where the dose is 1 mg per day and the desired administration regimen is once daily administration, the amount of the active agent in a pharmaceutical composition comprising same will be 1 mg. Where it is intended to divide this daily dose into 2 daily administrations, the amount of the active agent in the pharmaceutical composition will be 0.5 mg.
  • an amount effective to achieve the desired effect is determined by considerations known in the art.
  • An "anti-cancer effective amount" for purposes herein must be effective to achieve reduction or amelioration of signs and symptoms associates with cancer, such as local symptoms (unusual lumps or swelling, hemorrhage, pain and/or ulceration; symptoms of metastasis (enlarged lymph notes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms; and systemic symptoms such as weight loss, poor appetite and cachexia (wasting), excessive sweating anemia and specific paraneoplastic phenomena (i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes).
  • the anti-cancer effective amount must also be effective to achieve an anti-cancer effect as defined hereinabove.
  • the effective amount depends on a variety of factors including the affinity of the active agents to their corresponding receptor, their distribution profile within the body, a variety of pharmacological parameters such as half life in the body, on undesired side effects, if any, on factors such as age and gender of the subject to be treated, etc.
  • the effective amount is typically tested in clinical studies having the aim of finding the effective dose range, the maximal tolerated dose and the optimal dose. The manner of conducting such clinical studies is well known to a person versed in the art of clinical development.
  • the effective amount when the cancer state is brain cancer, the effective amount may be exhibited by reduction or elimination of one or more of the following signs associated with the existence of a tumor in the brain: headaches, nausea and vomiting, cognitive or physical impairment, and changes in personality.
  • the effective amount when the cancer state is breast cancer, the effective amount maybe exhibited by of one or more of the following parameters: elimination or reduction in size or thickness of an already existing breast lump, reduction or elimination of swelling, skin irritation or distortion; improvement in the shape of the breast (return to normal shape); improvement of the color of the skin of the breast, areola or nipple (return to normal color); cease or reduction in abnormal nipple discharge or tenderness.
  • An amount may also at times be determined based on amounts shown to be effective in animals. It is well known that an amount of X mg/Kg administered to rats can be converted to an equivalent amount in another species (notably humans) by the use of one of possible conversions equations well known in the art. Examples of conversion equations are as follows:
  • Rat (150g) to Man (70 Kg) is 1/7 the rat dose. This means that in the present case 0.001-0.4 mg/Kg in rats equals to about 0.14-56 microgram/Kg in humans; assuming an average weight of 70 Kg, this would translate into an absolute dosage of about 0.01 to about 4 mg.
  • the amounts equivalent to 0.001-0.4 mg/Kg in rats for humans are 0.16-64 ⁇ g/Kg ; namely an absolute dose for a human weighing about 70 Kg of about 0.011 to about 4.4 mg, similar to the range indicated in Conversion I.
  • Conversion III Another alternative for conversion is by setting the dose to yield the same plasma level or AUC as that achieved following administration to an animal.
  • IETMECA was given to healthy male volunteers it was concluded that a dose of 1 ⁇ /Kg - 400 ⁇ /Kg in mice in which IB-MECA was effective and is equivalent to a human dose of about 0.14 - 57 ⁇ /Kg, namely a total dose for a 70 Kg individual of 0.01 — 4 mg.
  • a preferred dosage range for IB- MECA and Cl-IB-MECA would be less than 4 mg, typically within the range of about 0.01 to about 2 mg (about 0.14 — 28 ⁇ /Kg, respectively) and desirably within the range of about 0.1 to 1.5 mg (about 1.4 - 21 ⁇ /Kg, respectively).
  • This dose may be administered once, twice or at times several times a day.
  • compositions in the context of the invention is intended to mean a combination of the active agent(s), together or separately, with a pharmaceutically acceptable carrier as well as other additives.
  • the carrier may at times have the effect of the improving the delivery or penetration of the active ingredient(s) to the target tissue, for improving the stability of the drug, for slowing clearance rates, for imparting slow release properties, for reducing undesired side effects etc.
  • the carrier may also be a substance that stabilizes the formulation (e.g. a preservative), that provides the formulation with an edible flavor, etc.
  • stabilizers and adjuvants see E.W.
  • MTX and the A 3 AR agonist may be administered to the subject by a variety of delivery modes as known in the art. While MTX may be administered orally or by parenteral injection, it is preferable that the A 3 AR agonist be administered orally.
  • the carrier will be selected based on the desired form of the formulation and the A 3 AR agonist composition may be in the form of a pill, capsule, in the form of a syrup, an aromatic powder, and other various forms.
  • IB-MECA formulated for oral delivery in an amount of up to about 5mg in a single daily dose or up to about 4 mg for twice daily administration.
  • the dosage form may comprise less than the desired administration dose such that an individual may need to take 2 or 3, etc. dosage forms of the composition to achieve his needed dose.
  • the dosage form may include 0.5 mg, 1 mg or 2 mg of IB-MECA and the individual will then need to take 4, 2 or 1 such dosage forms, respectively, to achieve the desired dose.
  • the treated individuals are adults
  • the administration rote is oral
  • IB-MECA for a single daily dose is less than about 5 mg and the dose of IB-MECA for twice daily dosing is less than 4 mg each dose (less than 8 mg total daily dose).
  • a preferred dose of IB-MECA, in accordance with this embodiment is in the range of about 0.1 to abovit 5 mg for a single daily administration; a preferred dose of IB-MECA for twice daily administration in the range of about 0.1 to about 4 mg (i.e. 0.2 to 8 mg total daily dose).
  • an effective amount of MTX is typically in the range of 5 to 25 mg, administered once weekly, orally or parentally.
  • the active ingredient is an A 3 AR agonist which exerts its prime effect through the A3 adenosine receptor and is a purine derivative falling within the scope of the general formula (I):
  • R 1 is C 1 -C 10 allcyl, C 1 -C 10 hydroxyalkyl, Ci-C 1 O carboxyalkyl or Ci-Ci 0 cyanoalkyl or a group of the following general formula (II):
  • Y is oxygen, sulfur atom or CHi -2 or , C(W)(W) where W and W could be same or different and are H or F or valence bond;
  • R' and R" are independently Ci-Ci 0 alkyl
  • R 2 is selected from hydrogen, halo, Ci-C 10 alkylether, amino, hydrazido, C 1 -Ci 0 alkylamino, C 1 -Ci 0 alkoxy, C 1 -Ci 0 thioalkoxy, pyridylthio, C 2 -Ci 0 alkenyl; C 2 -Ci 0 alkynyl, thio, and Ci-Ci 0 alkylthio, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 3 -C 8 cycloalkyl Ci-C 6 alkoxy, C 3 -C 8 cycloalkenyloxy, C 7 -Ci 2 bicycloalkyl Ci-C 6 alkoxy, C 7 -Ci 2 bicycloalkenyl Ci-C 6 alkoxy, C 6 -Ci 4 aryloxy, C 6 -Ci 4 aryl Ci-C 6 alk
  • R 3 is a -NR 4 R 5 group with R 4 being hydrogen or a group selected from alkyl, substituted alkyl or aryl-NH-C(Z)-, with Z being O, S, or NR a , and - when R 4 is hydrogen, R 5 being selected from Ci-C 6 alkyl, Ci-C 6 alkoxy, hydroxy, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl Ci-C 6 alkyl, C 3 -C 8 dicycloalkyl Cj-C 6 alkyl, C 7 -Ci 2 bicycloalkyl Ci-C 6 alkyl, C 7 -Ci 4 tricycloalkyl Ci-C 6 alkyl, C 6 -Ci 4 aryl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -Ci 4 diaryl Ci-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkoxy, heterocycl
  • C 3 -C 8 cycloalkyl wherein the aryl or heterocyclyl portion of R4 is optionally substituted with one or more substituents selected from the group consisting of halo, amino, Ci-C 6 alkyl, Ci-C 6 alkoxy, C 6 -Ci 4 aryloxy, hydroxy Ci-C 6 alkyl, hydroxy C 2 -C 6 alkenyl, hydroxy C 2 - C 6 alkynyl, aminocarbonyl Ci-C 6 alkoxy, and C 6 -Ci 4 aryl Ci-C 6 alkoxy, and any combination thereof; and the alkyl or cycloalkyl portion of Rl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, amino, and any combination thereof; or (R)- and (5)-l-phenylethyl, benzyl, phenylethyl or anilide groups, each said groups being unsubstituted or substituted in one or
  • R 5 is selected from the group consisting of substituted or unsubstituted heteroaryl-NR a -C(Z)-, heteroaryl-C(Z)-, alkaryl-NR a -C(Z)-, alkaryl-C(Z)-, aryl-NR-C(Z)- and aiyl-C(Z)-;
  • a 3 AR agonist is a xanthine-7-riboside derivative of the following general formula (V):
  • R a and R b may be the same or different and are selected from hydrogen, C 1 -C 10 alkyl, amino, C 1 -C 10 haloalkyl, Ci-C 10 aminoalkyl, and C 3 -Ci 0 cycloalkyl, or are joined together to form a heterocyclic ring containing two to five carbon atoms; and
  • R c is selected from C 1 -C 10 alkyl, amino, Ci-Ci 0 haloalkyl, Ci-Ci 0 aminoalkyl, C 1 - Ci 0 BOC-aminoalkyl and C 3 -Ci 0 cycloalkyl;
  • R 7 and R 8 may be the same or different and are selected from C 1 -C 1O alkyl, C 1 -Ci 0 cycloalkyl, (R)- or ( ⁇ S)-l-phenylethyl, an unsubstituted benzyl or anilide group, and a phenylether of benzyl group substituted in one or more positions with a substituent selected from C 1 -C 10 alkyl, amino, halo, C 1 -C 10 haloalkyl, nitro, hydroxyl, acetamido, C 1 - C 10 alkoxy, and sulfonic acid;
  • R 9 is selected from the group consisting of halo, benzyl, phenyl, C 3 -Ci 0 cyclalkyl, and Ci-C 10 alkoxy; or a suitable salt of any of the compounds defined above.
  • the A 3 AR agonist is a nucleoside derivative of the general formula (VII):
  • a 3 AR agonists in accordance with formula (VII) include, although not exclusively, N -benzyladenosine-5'-uronamide derivatives.
  • Some preferred N -benzyladenosine-5'- uronamide derivatives are N 6 -2-(4-aminophenyl)ethyladenosine (APNEA), N 6 -(4-arnino- 3- iodobenzyl) adenosine-5'-(N-methyluronamide) (AB-MECA) and l-deoxy-l- ⁇ 6- [( ⁇ 3- iodophenyl ⁇ methyl)amino]- 9H-purine-9-yl ⁇ -N-methyl- ⁇ -D-ribofuranuiOnamide (IB- MECA), 2-cmoro-N 6 -(3-iodobenzyl)adenosine- 5'-N-methlyuronamide (Cl-IB-MECA) as well as thio analogs
  • Non- limiting examples of thio analogs of the compound fo formula I include, although not exclusively, 2-[2-chloro-6-(iodobenzylamino)purin-9-yl]-3,4- dihydroxytetrahydrothiophene-2-carboxylic acid methyl amide (herein referred to by the abbreviation "thio-Cl-IB-MECA”) and 2-[2-6-(iodobenzylamino)purin-9-yl]-3,4- dihydroxytetrahydrotbiophene-2-carboxylic acid methyl amide (herein referred to by the abbreviation "thio-IB-MECA”).
  • the A 3 AR agonist is a nucleoside derivative of the general formula (VIII):
  • the A 3 AR agonist is a nucleoside derivative of the general formula (IX):
  • Agonists of A 3 AR in accordance with formula (IX) include, although not exclusively, bicyclic derivatives of IB-MECA 3 Cl-IB-MECA, such as, without being limited, 4'-(2-chloro-6- ⁇ [(3 -iodophenyl)methyl] amino ⁇ purin-9-yl)-2',3 '- dihydroxybicyclo[3.1.0]hexyl]-N-methylcarboxamide (herein referred to by the abbreviation "bicyclo-Cl-IB-MECA”), 4'-(6- ⁇ [(3-iodophenyl)methyl]amino ⁇ pnrin-9-yl)- 2',3'-dihydroxybicyclo[3.1.0]hexyl]-N-metliylcarboxamide (herein referred to by the abbreviation "bicyclo-IB-MECA”).
  • the A 3 AR agonist is N -benzyl-adenosine-5'- alkyluronamide-N 1 -oxide orN 6 -benzyladenosine-5'-N-dialyl-uronamide-N 1 oxide.
  • Example 1 Effect of a combined treatment of MTX and CF102 on the proliferation of human B-cell lymphoma.
  • the Human Burkitt's lymphoma cells were maintained in RPMI 1640 medium with 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 niM HEPES, and 1.0 mM sodium pyruvate, 90%; fetal bovine serum, 10%. Cells were transferred to a freshly prepared medium twice weekly.
  • MTT assay was used. Specifically, MTT stock solution (5mg/ml) was added (1 :10) to the culture system and incubated for 4 hours. Then the culture medium was removed and MTT solvent (HCL 0.05N in isopropanol) was added to the culture in an amount equal to the original volume. Absorbance of the converted dye was measured at 570nm.
  • Figure 1 provides the percent of inhibition of proliferation by the combined treatment compared to treatment with each agent alone.
  • MTX exerted an inhibitory effect of 21.5 ⁇ 0.5% on the growth of human Burkitt's lymphoma cells in vitro, while CFl 02 alone inhibited the proliferation of the cells by 31.33 ⁇ 1.2%.
  • the combined treatment of MTX+CF102 yielded higher cell growth inhibition of 47 ⁇ 2.55% in comparison to the two alone.
  • Example 2 Effect of a combined treatment of MTX and CF102 on the development of human B-cell lymphoma brain metastases
  • Severe Combined Immunodeficiency (SCID) female mice aged 6 weeks were used to test the effect of MTX in combination with CF 102 on the development of human Burkkti's lymphoma cells in a xenograft brain metastasis model.
  • Cells 1.5xlO 6 ) were intraveneously injected to the tail vein of the animals.
  • MTX group treated with MTX (2.5 mg/kg) administered intraperitoneal, once weekly
  • CF102 group treated with CF102 (100 ⁇ g/kg) administered daily, PO, throughout the whole study;
  • MTX+CF102 group treated simultaneously with MTX (2.5 mg/kg) administered intraperitoneal, once weekly and CFl 02 (100 ⁇ g/kg) administered daily, PO, throughout the whole study.
  • Figure 2 demonstrates the effect of MTX in combination with CF 102 on the development of Burkkti's lymphoma cells brain metastases in mice as was evaluated by the severity of paralysis observed.
  • the group treated with MTX+CF102 yielded a statistically significant paralysis savirity inhibition in comparison to that of MTX or CF102 alone, i.e., 87.5 % inhibition was observed in the combined treatment group whereas 45 % (p ⁇ 0.001) in the group treated with MTX alone and 60% in the CF 102 treated group.
  • the expression level of A 3 AR was measured in splenocytes protein extracts derived from all treated groups. In the vehicle treated group a high A 3 AR expression level was observed in comparison to healthy animals.
  • Treatment of MTX induced up- regulation of the receptor expression, thus making the cells more accessible to CFl 02 treatment.
  • Combined treatment of MTX and CF 102 resulted in down-regulation of A 3 AR expression level, indicating that receptor activation took

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Abstract

L'invention concerne le traitement thérapeutique d'un cancer par une administration combinée de méthotrexate et d'un agoniste du récepteur A3 de l'adénosine. L'invention concerne également des méthodes de traitement thérapeutique comprenant cette administration combinée, les compositions pharmaceutiques utiles dans ces procédés et aussi l'utilisation de n'importe lequel de ces agents actifs pour préparer cette composition pharmaceutique.
PCT/IL2007/001009 2006-08-21 2007-08-16 Traitement du cancer WO2008023362A2 (fr)

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EP2178369A2 (fr) * 2007-07-17 2010-04-28 Combinatorx, Incorporated Traitements de troubles prolifératifs des lymphocytes b
WO2011010306A1 (fr) 2009-07-21 2011-01-27 Ramot At Tel-Aviv University Ltd. Ligands du récepteur a3 de l’adénosine modulant la pigmentation
WO2011074903A2 (fr) * 2009-12-17 2011-06-23 이화여자대학교 산학협력단 Composition pharmaceutique incluant un agoniste de récepteur d'adénosine a3
WO2011096642A2 (fr) * 2010-02-02 2011-08-11 이화여자대학교 산학협력단 Composition pharmaceutique pour prévenir et traiter des maladies inflammatoires
KR101181627B1 (ko) * 2009-12-17 2012-09-10 이화여자대학교 산학협력단 Ａ3 아데노신 수용체 효능제를 포함하는 전립선암 치료용 약제학적 조성물
KR101192063B1 (ko) 2010-02-02 2012-10-17 이화여자대학교 산학협력단 염증성 질환의 예방 및 치료용 약제학적 조성물
KR101192097B1 (ko) 2009-12-17 2012-10-18 이화여자대학교 산학협력단 Ａ3 아데노신 수용체 효능제를 포함하는 대장암 치료용 약제학적 조성물
US8735407B2 (en) 2008-03-31 2014-05-27 The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Purine derivatives as A3 adenosine receptor-selective agonists
US8916570B2 (en) 2008-03-31 2014-12-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A3 adenosine receptor agonists and antagonists
JP2015007140A (ja) * 2008-09-26 2015-01-15 エージェンシー フォー サイエンス，テクノロジー アンド リサーチ ３−デアザネプラノシン誘導体
US9181253B2 (en) 2008-08-01 2015-11-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Adenosine receptor agonists, partial agonists, and antagonists
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EP2178369A2 (fr) * 2007-07-17 2010-04-28 Combinatorx, Incorporated Traitements de troubles prolifératifs des lymphocytes b
EP2178369A4 (fr) * 2007-07-17 2010-12-15 Combinatorx Inc Traitements de troubles prolifératifs des lymphocytes b
US8735407B2 (en) 2008-03-31 2014-05-27 The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Purine derivatives as A3 adenosine receptor-selective agonists
US8916570B2 (en) 2008-03-31 2014-12-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A3 adenosine receptor agonists and antagonists
US20110171130A1 (en) * 2008-08-01 2011-07-14 The United States of America, as represented by the Secretary ,Deptment of Health and HumanService A3 adenosine receptor antagonists and partial agonists
WO2010014921A2 (fr) * 2008-08-01 2010-02-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antagonistes et agonistes partiels des récepteurs de l'adénosine a<sb>3</sb> et agonistes partiels
US9181253B2 (en) 2008-08-01 2015-11-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Adenosine receptor agonists, partial agonists, and antagonists
JP2011529917A (ja) * 2008-08-01 2011-12-15 アメリカ合衆国 Ａ３アデノシン受容体アンタゴニストおよびａ３アデノシン受容体部分アゴニスト
WO2010014921A3 (fr) * 2008-08-01 2010-09-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antagonistes et agonistes partiels des récepteurs de l'adénosine a<sb>3</sb> et agonistes partiels
AU2009276411B2 (en) * 2008-08-01 2014-08-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A3 adenosine receptor antagonists and partial agonists
US8796291B2 (en) 2008-08-01 2014-08-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A3 adenosine receptor antagonists and partial agonists
JP2015007140A (ja) * 2008-09-26 2015-01-15 エージェンシー フォー サイエンス，テクノロジー アンド リサーチ ３−デアザネプラノシン誘導体
WO2011010306A1 (fr) 2009-07-21 2011-01-27 Ramot At Tel-Aviv University Ltd. Ligands du récepteur a3 de l’adénosine modulant la pigmentation
US9668959B2 (en) 2009-07-21 2017-06-06 Oradin Pharmaceutical Ltd. A3 adenosine receptor ligands for modulation of pigmentation
US9199102B2 (en) 2009-07-21 2015-12-01 Oradin Pharmaceutical Ltd. A3 adenosine receptor ligands for modulation of pigmentation
KR101192097B1 (ko) 2009-12-17 2012-10-18 이화여자대학교 산학협력단 Ａ3 아데노신 수용체 효능제를 포함하는 대장암 치료용 약제학적 조성물
US20120322815A1 (en) * 2009-12-17 2012-12-20 Ewha University-Industry Collaboration Foundation Pharmaceutical composition containing a3 adenosine receptor agonist
WO2011074903A2 (fr) * 2009-12-17 2011-06-23 이화여자대학교 산학협력단 Composition pharmaceutique incluant un agoniste de récepteur d'adénosine a3
KR101181627B1 (ko) * 2009-12-17 2012-09-10 이화여자대학교 산학협력단 Ａ3 아데노신 수용체 효능제를 포함하는 전립선암 치료용 약제학적 조성물
WO2011074903A3 (fr) * 2009-12-17 2011-11-10 이화여자대학교 산학협력단 Composition pharmaceutique incluant un agoniste de récepteur d'adénosine a3
KR101192063B1 (ko) 2010-02-02 2012-10-17 이화여자대학교 산학협력단 염증성 질환의 예방 및 치료용 약제학적 조성물
WO2011096642A3 (fr) * 2010-02-02 2011-11-10 이화여자대학교 산학협력단 Composition pharmaceutique pour prévenir et traiter des maladies inflammatoires
WO2011096642A2 (fr) * 2010-02-02 2011-08-11 이화여자대학교 산학협력단 Composition pharmaceutique pour prévenir et traiter des maladies inflammatoires
WO2024157246A1 (fr) * 2023-01-23 2024-08-02 Can-Fite Biopharma Ltd. Traitement du cancer du pancréas

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