Erythropoietin relieves toxicity in vivo induced by chemotherapy

FIELD: medicine, oncology.

SUBSTANCE: method involves administration of bleomycin and erythropoietin simultaneously in patients. Invention can be used for decreasing pulmonary cytotoxicity in patients treated with bleomycin. Invention provides improving functioning lung in patients of this category.

EFFECT: valuable medicinal properties of erythropoietin.

4 cl, 2 dwg, 2 ex


This application has priority in accordance with the preliminary application 60/282621 filed April 9, 2001, the disclosure of which is included here by reference in full.

The technical field to which the present invention

The present invention relates to a method of reducing organ cytotoxicity, such as pulmonary toxicity, the subject who is administered a cytotoxic agent, such as an antitumor agent.

Background of the invention

Erythropoietin (EPO) is a glycoprotein produced in the kidney, and is the main hormone responsible for stimulation of the formation of red blood cells (Erythro(cyto)SEZ). EPO stimulates the division and differentiation carried out erythroid cell precursors in the bone marrow. The normal level of erythropoietin in the plasma varies in the range from 0.01 to 0.03 units/ml may be elevated in 100-1000 times during hypoxia or anemia. Graber and Krantz, Ann. rev. Med. 29:51 (1978); Eschbach and Adamson, Kidney Intl. 28:1 (1985). Recombinant human erythropoietin (rHuEpo or epoetin alfa) commercially available in the form of Epogen® (Amgen Inc., Thousand Oaks, CA) and Procrit® (Ortho Biotech Inc., Raritan, NJ). EPO is often used to increase hematocrit cancer patients who become anemic because of their illness or as a result of treatment with chemotherapeutic drugs. EPO is indicated for cured what I anemia, including anemia associated with chemotherapy in cancer, chronic renal failure, malignization, rheumatoid arthritis in adult and juvenile rheumatoid arthritis, disorders of hemoglobin synthesis, prematurity and treatment of HIV infection zidovudine.

Pulmonary fibrosis is the most common manifestation of pulmonary toxicity in the use of chemotherapy drugs. Pulmonary fibrosis is a pathological accumulation of polymerized fibrin in the interstitial space. Its exact pathophysiology is not fully installed, although usually found in chronic inflammation, which occurs under the action of exogenous agents. Despite the fact that the lung damage associated with the action of many anticancer agents, bleomycin, nitrosamine, mitomycin, busulfan, ara-C, interleukin-2 and methotrexate are the chemotherapeutic agents most often associated with pulmonary toxicity. There is therefore a need for new ways to reduce organ toxicity associated with the introduction of a cytotoxic agent.

A brief statement of the substance of the invention

In accordance with the variants of implementation of the present invention the present invention is a method of decreasing body is Noah toxicity in the subject, which impose a cytotoxic agent, including simultaneous introduction with the cytotoxic agent erythropoietin (EPO; "active agent")that is administered in amount effective to reduce organ toxicity due to data cytotoxic agent. Generally, the cytotoxic agent is administered in an amount necessary to achieve a therapeutic effect, such as anti-tumor amount of the antitumor agent.

In accordance with the variants of implementation of the present invention organs that need to be treated or to be protected by the methods of the present invention include the liver, brain, kidneys and lungs, and the lungs are particularly preferred.

In accordance with other variants of implementation of the present invention antitumor agent is the agent that is cytotoxic to the lungs of the subject.

In accordance with the specific options of implementing the present invention, the antineoplastic agent is an antibiotic, nitrosamine, alkylsulfonate, similar citadine, Vinca alkaloid, epipodophyllotoxin, interleukin, an analogue of folic acid or combinations thereof.

In accordance with still some variants of implementation of the present invention the present invention includes the use of active agent, which is described above for the manufacture of a medicinal product for the above-described method.

The above and other embodiments of aspects of the present invention is explained in more detail in the following drawings and description.

Brief description of drawings

Figure 1 illustrates the effect of EPO and bleomycin on lung functioning after treatment for two weeks; and

Figure 2 illustrates the effect of EPO and bleomycin on lung functioning after treatment for four weeks.

Detailed description of preferred embodiments of the present invention

Entities that are treated using the method of the present invention include human and animal (e.g. dog, cat, cow, horse) and are the preferred subjects of the mammal.

As used in this text, introduction, at least one connection at a time, at least, with another connection means that the connection introduced almost simultaneously, so that the presence of one cheated on the biological action of another. Anyway, these two compounds can be administered simultaneously or sequentially. Sequential introduction allows you to enter the compound, effective to reduce the toxicity induced by chemotherapy as a preventive treatment before the introduction of a cytotoxic agent, or for treatment that reduces Toxics is here, induced by chemotherapy in the preceding introduction, at least one cytotoxic agent.

Cytotoxic agents. Cytotoxic agents that can be used in conjunction with the present invention, as a rule, are antineoplastic agents. Used herein, the term " antineoplastic or chemotherapeutic agent refers to agents that preferentially kill neoplastic cells or disrupt the life cycle of rapidly proliferating cells, and is used therapeutically to prevent or reduce growth of neoplastic cells. Used here chemotherapy involves only one treatment with a chemotherapeutic agent or combination of agents. For the subject in need of treatment, chemotherapy can be combined with surgical treatment or radiation therapy, or with other methods of cancer treatment.

Antitumor agents include agents, for the most part well-known experts in this field. Typical anticancer agents include, but are not limited to, Vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel (Taxol®, Bristol Myers Squibb), colchicine, cytochalasin, emetine, maytansine, amsacrine (or "mAMSA") and nitrosamine. the lass of Vinca alkaloid is described in Goodman and Gilman''s The Pharmacological Basis of Therapeutics 1277-1280 (7 thed. 1985) (hereinafter "Goodman and Gilman"). Examples of Vinca alkaloids include, but are not limited to, vincristine, vinblastine and vindesine. Class epipodophyllotoxins described in Goodman and Gilman, higher str-1281. Typical epipodophyllotoxin include, but are not limited to, etoposide, autopositioning and teniposide. The class of anthracycline antibiotics is described in Goodman and Gilman, higher str-1285. Examples of anthracycline antibiotics include, but are not limited to, daunorubicin, doxorubicin, mitoxantrone and bisantrene. Actinomycin D, also known as dactinomycin, described in Goodman and Gilman, higher str-1283. Plicamycin named mithramycin described in Goodman and Gilman, higher str-1288. Nitrosoanatabine include, but are not limited to, lomustin [CCNU] (CeeNU®, Bristol Myers Squibb), carmustine [BCNU] (BiCNU®, Bristol Myers Squibb), semustine [methyl-CCNU] and streptozocin.

Additional chemotherapeutic agents include, but are not limited to, cisplatin (Platinol®, Bristol Mayers Squibb); carboplatin (Paraplatin®, Bristol Mayers Squibb); mitomycin (Mutamycin®, Bristol Mayers Squibb); altretamine (Hexalen®, U.S. Bioscience, Inc.); cyclophosphamide (Cytoxan®, Bristol Mayers Squibb); busulfan (MYLERAN®, GlaxoSmithKline); cytarabine, such as ara-C, interleukin-2, and methotrexate.

Methods of administration of chemotherapeutic drugs vary depending on the specific agent used, from which the local experts in this field. Depending on the agent chemotherapeutic agents can be entered, for example, by injection (intravenous, intramuscular, intraperitoneal, subcutaneous, intratracheal, intratumoral, intrapleurally) or oral.

Erythropoietin. Used herein, the term " human erythropoietin (EPO) refers to the natural glycoprotein human erythropoietin and recombinant human erythropoietin (rHuEpo or epoetin alfa, commercially available in the form of Epogen® (Amgen Inc., Thousand Oaks, CA) and Procrit® (Ortho Biotech Inc., Raritan, NJ)). In the methods of the present invention can also be used peptide analogs of EPO. Used here, peptide analogues are compounds which, although they do not have amino acid sequences identical to sequences of EPO have similar three-dimensional structure. With regard to protein molecules that interact with the receptor, the interaction on the surface-accessible areas of stable three-dimensional molecules. Due to the ordering of essential residues in sites linking in a proper conformation, it is possible, in accordance with known methods, to design and synthesize peptides that mimic significant superficial signs of EPO binding sites. The molecule, which has a surface area the STI with the same in essence, molecular topology to the binding surface EPO capable of simulating the interaction of EPO receptor EPO. Methods for determining the three-dimensional structure of the peptide and its analogues are known and sometimes referred to as "methods for the rational design of drugs". See, for example, U.S. patent No. 4833092 Geysen; U.S. patent No. 4859765 Nestor; U.S. patent No. 4853871 Pantoliano; U.S. patent No. 4863857 Blalock (the inventors in this case imply that the content of the cited here all of the U.S. patents incorporated here by reference in full).

Peptides that mimic the biological activity of erythropoietin (peptide ligands EPO-receptor), can be replaced by EPO methods of the present invention. The sequence of these peptides may correspond to fragments of the full sequence of the EPO protein, fragments of which can communicate with the EPO-receptor and activate it. In addition, in the methods of the present invention can be used peptides with sequences that differ from the sequence of the EPO, because these peptides mimic the biological activity of EPO. Wrighton and co-authors reported the identification and characterization of small peptides that are associated with eritropoetinovmi receptor on the surface of target cells and activate it, despite the fact that consistently the tee these peptides differ from the primary sequence of EPO (Wrighton and co-authors, Science 273:458 (26 July 1996)). Data of peptide agonists presents the cyclic peptide of 14 amino acids, linked by a disulfide bond, with identifiable minimal consensus sequence. The structure of the complex of one such peptidomimetics with eritropoetinovmi receptor described in Livnah and co-authors, Science 273:464 (26 July 1996).

The EPO used in accordance with the methods of the present invention, it is possible to enter any suitable way that is obvious to the person skilled in the art. EPO can be entered systemically (e.g. intravenously) or locally (for example, by injecting into the tumor in the tissue directly surrounding the tumor, or in the anatomic area containing the tumor). In cases where, for example, the chemotherapeutic agent is delivered systemically, the number of EPO protects the endothelium, you can enter systemically via intravenous injection.

Dosage and time of introduction of EPO used in combination with a chemotherapeutic agent, also depends on the desired effect. The authors of the present invention have found that, depending on the time of the introduction of EPO (at the same time, before or after administration of a chemotherapeutic agent) and the dosage of EPO, EPO, or protects the endothelium from the inhibitory growth effects of chemotherapeutic agents or enhances the inhibition of vascular endothelial growth due to x is Biotherapeutics agents. Professionals in this field should be obvious how using a conventional experimentation to determine the dosage and the time of the introduction of EPO in combination with a particular chemotherapeutic agent to achieve the desired effect.

The maximum number of EPO, which you can enter one or more times, not installed. Input dose, up to 1500 units/kg for three to four weeks, have no toxic effects due to the actual EPO. Eschbach et al., in: Prevention of Chronic Uremia (Friedman and coauthors, eds.), Field and Wood Inc., Philadelphia, pp.148-155 (1989). The appropriate dose can vary from about 1, 10 or 100 units per kilogram (units/kg) to about 200, 1000 or 2000 units/kg

Pharmaceutical compositions. The above active compounds can be prepared for administration in a pharmaceutical carrier in accordance with known methods. See, for example, Remington, The Science And Practice of Pharmacy (9thEd. 1995). For the production of pharmaceutical compositions in accordance with the present invention the active compound (including its physiologically acceptable salts) are usually mixed, in particular, physiologically acceptable carrier. Of course, this carrier must be acceptable in the sense of compatibility with any of the other ingredients of the composition and should not harm the patient. The carrier may be solid or liquid, or that and the other, and it is preferable to prepare this compound in the form of a composition with a single dose, such as a tablet, which may contain by weight from 0.01 or 0.5% to 95% or 99% of the active compounds. One or more active compounds may be included in compositions of the present invention, which can be manufactured by any well-known pharmaceutical method, which is, in essence, the components are mixed, and optionally including one or more accessory ingredients.

Compositions of the present invention include compositions suitable for oral, rectal, local, buccal (e.g., sublingual), vaginal, parenteral (for example subcutaneous, intramuscular, intradermal or intravenous), local (i.e., for skin and mucosal surfaces, including surfaces of pneumatic paths) and percutaneous administration, although the most suitable way in any given case will depend on the nature and severity of the condition being treated and on the nature of the applied specific active connection.

Compositions suitable for oral administration may be presented as discrete units such as capsules, wafers, cake, or tablets, each containing a specified number of the given active compound; as a powder or granules; in the form of RA is down or suspension in an aqueous or nonaqueous liquid; or in the form of water-oil or inverse emulsion. Such compositions can be manufactured using any suitable pharmaceutical method which include stage Association the active compound and the carrier (which, as noted above, may contain one or more accessory ingredients). In General, the compositions of the present invention are produced by uniform and thorough mixing the active compound with a liquid or powdered solid carrier, or, if necessary, with both forming and getting the mix. For example, the tablet can be made by compressing or molding a powder or granules containing the active compound, optionally with one or more auxiliary ingredients. Pressed tablets can be manufactured by compression in the respective device of this compound in free-flowing form such as powder or granules, optionally mixed with a binder, a sliding agent, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be created using the stamping in the respective device this connection in the form of a powder, moistened inert binding liquid.

Compositions of the present invention suitable for parenteral administration, including the Ute sterile aqueous or non-aqueous injection solutions of the active compounds in this case, preparations should preferably be isotonic with respect to blood of the intended recipient. These preparations may contain antioxidants, buffers, antimicrobial additives and dissolved substances, which give this song isotonicity in relation to the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions may include suspendresume agents and thickeners. The resulting compositions can be presented in the form of packages with single/multiple doses, for example, sealed ampoules and vials, and can be stored in a lyophilized condition requiring only the addition of sterile liquid carrier, for example, saline or water for injection, immediately prior to use. Injection solutions and suspensions for immediate reception can be prepared from the above-described sterile powders, granules and tablets. For example, the first objective of the present invention is to obtain an injectable, stable, sterile composition comprising an active compound, or its salt, in the form of a dosage form in a sealed package. This compound or its salt is prepared in the form of a lyophilisate, which can recreate in liquid form with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for her any the options to the patient. The unit dosage form typically comprises from about 10 mg to about 10 g of this compound or its salts. If this compound or its salt is practically insoluble in water, you can eat an adequate amount of emulsifying agent which is physiologically acceptable, in sufficient quantity to emulsify the compound or its salt in an aqueous medium. One such suitable emulsifying agents is phosphatidylcholine.

In addition to the active agents or their salts, pharmaceutical compositions may contain other additives, for example, to bring the pH. In particular, agents for bringing the pH include, but are not limited to, acids such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate or sodium gluconate. In addition, the composition may contain antimicrobial preservatives. Suitable antimicrobial preservatives include, but are not limited to, methylparabene, propylparaben and benzyl alcohol. Antimicrobial preservatives are usually used if the composition is placed into the vial, intended for repeated use. Of course, it is shown that the pharmaceutical compositions of the present invention can be liofilizirovanny using methods, is all right known in the art.

Much more detail the present invention is illustrated in the following, not limiting examples.


Treatment Protocol

Female mice S B16 aged between 7 and 12 weeks with an approximate weight of 20 g is subjected to treatment with varying doses of EPO alone and in combination with bleomycin. The animals twice a week administered placebo, only EPO (5-40 µg/mouse, I.P. Pavlova.), only bleomycin (0,25-0,75 μg/mouse, I.P. Pavlova.) or EPO and bleomycin in combination. Animals put provocation test with methacholine (0-48 mg/ml) in 2 weeks, 4 weeks and 6 weeks. At these time points measured pulmonary function using plethysmograph for the entire volume of the body (Buxco, Niskayuna, NY). In this non-invasive method of investigation used a clear plastic chamber for the animal with two pneumotachometer and a sensor that is interfaced with a computer. Resistance to light and the volume change of the lung is assessed through the analyzer, which measures the flow and pressure, and reads the position equivalent to the volume of the lungs during inhalation and exhalation ("Iso-Volumetric Method"). Artifacts associated with motion or with atypical breathing (for example, "heavy breathing") in animals, are ignored in computer analysis using the parameters that you can set the circumstances for tidal volume and inspiratory time separate zivotnog is. The way plethysmography combined total volume of the body has been studied and it is shown that it gives a reliable indicator of the functioning of the lungs in mice (Hamelmann and co-authors, Am. J. Respir. Crit. Care Med. 156)3 Pt1) 776-75 (1997).


Experimental data

Found that bleomycin weakens the functioning of the lungs, which is reflected in the changes increase the amount of time ("Penh", substitute airway resistance). Twice a week for two weeks animals appoint bleomycin and put provocation test with methacholine (0-48 mg/ml), which is 2.6 times worse Penh values compared to the control animals (see Figure 1). EPO given in the absence of bleomycin, causes a small increase lung function. However, mice treated with a combination of bleomycin and erythropoietin, demonstrating a 60%improvement in lung function compared with mice treated only with bleomycin. A similar pattern of values Penh see if the registration of lung function are carried out through four weeks of treatment (see Figure 2).

The above is an illustration of the present invention, and not as any limitation. The present invention defines the following claims, with equivalents should also be covered by the specified formula.

1. A method of reducing pulmonary toxicity in the subject, which is administered b emycin, includes introduction bleomycin simultaneously with erythropoietin in an amount effective to reduce pulmonary toxicity.

2. The method according to claim 1, characterized in that bleomycin is an antineoplastic agent.

3. The method according to claim 1, characterized in that the anticancer cytotoxic agent to the lungs of the specified entity.

4. The method according to claim 1, characterized in that the introduction of erythropoietin include oral, rectal, outer, buccal, vaginal, parenteral, local or percutaneous introduction and combinations thereof.


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