Pharmaceutical composition for tumor treatment

Abstract

To provide a novel pharmaceutical composition for treating tumors.SOLUTION: Homoarginine or a pharmaceutically acceptable salt or derivative thereof is used, in conjunction with a) and / or b) below, to treat and / or prevent a tumor in a subject: a) administration of an antitumor agent; b) radiation exposure.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition used for treating and / or preventing tumors. [Background technology]

[0002] Numerous antitumor drugs have been developed for use in chemotherapy of malignant tumors. Antitumor drugs are classified according to their mechanism of action into DNA synthesis inhibitors, DNA replication inhibitors, microtubule inhibitors, hormone analogs, biologics (cytokines), molecularly targeted drugs, etc. The drug to be used and its administration method are selected taking into account numerous factors, such as the tumor's location, nature, and target molecule. Depending on the tumor's location, systemic administration can sometimes be difficult to deliver a therapeutically effective concentration of the drug to the tumor without causing serious side effects. In particular, for tumors of the central nervous system, such as brain tumors, the influence of the blood-brain barrier often makes it difficult for systemically administered drugs to reliably reach the tumor. To circumvent the influence of the blood-brain barrier, various drug delivery systems have been developed (e.g., Non-Patent Document 1).

[0003] Homoarginine is a cationic amino acid derived from lysine and is known as a precursor of nitric oxide (NO). It also inhibits arginase, thereby increasing the intracellular concentration of L-arginine, the main substrate of NO synthase. Homoarginine has also been suggested to be related to endothelial function enhancement, platelet aggregation inhibition, and insulin secretion promotion. Non-Patent Document 2 reports that homoarginine is associated with cardiovascular risk. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Takayasu Kamei, Mariko Takeda, Drug Delivery System, 28-4, pp. 287-299 (2013) [Non-patent document 2] Maerz, et al., Circulation, Vol. 122, Issue 10, 2010 Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention aims to provide a novel pharmaceutical composition for treating and / or preventing tumors. [Means for solving the problem]

[0006] The present invention provides the following: (1) A pharmaceutical composition comprising homoarginine or a pharmaceutically acceptable salt or derivative thereof, which is used to treat and / or prevent a tumor in a subject in combination with the following a) and / or b): a) administration of antitumor agents; b) Radiation exposure. (2) The pharmaceutical composition according to (1), wherein the tumor is a brain tumor, leukemia, or breast cancer. (3) The pharmaceutical composition according to (2), wherein the tumor is a brain tumor and the brain tumor is glioblastoma. (4) The pharmaceutical composition according to any one of (1) to (3), wherein the antitumor agent is a brain tumor therapeutic agent. (5) The pharmaceutical composition according to (4), wherein the antitumor agent is at least one agent selected from the group consisting of temozolomide, temsirolimus, decitabine, PD173074, AMI-1, orlistat, and pharmaceutically acceptable salts or derivatives thereof. (6) The pharmaceutical composition according to (1) or (2), wherein the antitumor agent is a therapeutic agent for treating leukemia. (7) The pharmaceutical composition according to (6), wherein the antitumor agent is daunorubicin. (8) A pharmaceutical composition used to enhance the effects of one or more tumor treatments, comprising homoarginine or a pharmaceutically acceptable salt or derivative thereof as an active ingredient. (9) A pharmaceutical composition comprising homoarginine or a pharmaceutically acceptable salt or derivative thereof and an antitumor agent. (10) The pharmaceutical composition according to (9), which is used to treat and / or prevent a tumor in a subject. (11) A pharmaceutical composition comprising an antitumor agent, the pharmaceutical composition being used to treat and / or prevent a tumor in a subject in combination with the administration of homoarginine or a pharmaceutically acceptable salt or derivative thereof. (12) The pharmaceutical composition according to (11), wherein the antitumor agent is a brain tumor therapeutic agent. (13) The pharmaceutical composition according to (12), wherein the antitumor agent is at least one agent selected from the group consisting of temozolomide, temsirolimus, decitabine, PD173074, AMI-1, orlistat, and pharmaceutically acceptable salts or derivatives thereof. (14) The pharmaceutical composition according to (11), wherein the antitumor agent is a therapeutic agent for treating leukemia. (15) The pharmaceutical composition according to (14), wherein the antitumor agent is daunorubicin. (16) A method for treating and / or preventing a tumor in a subject, comprising administering homoarginine or a pharmaceutically acceptable salt or derivative thereof and the following a) and / or b): a) administration of antitumor agents; b) Radiation exposure. [Effects of the Invention]

[0007] The present invention makes it possible to provide a novel pharmaceutical composition for treating and / or preventing tumors. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 is a schematic diagram showing the standard treatment for glioblastoma. [Figure 2]This graph shows the effect of temozolomide (TMZ) on sphere formation in glioblastoma cells in the presence and absence of homoarginine (hArg). The number of spheres formed was calculated relative to the number of spheres formed under the same conditions without TMZ, which was set at 1.0. The experiment was performed in triplicate. In the figure, "****" and "***" indicate P<0.0001 and P<0.001, respectively, in a one-tailed paired Student's t-test. [Figure 3] This graph shows the effect of temozolomide (TMZ) on sphere formation in normal human neural progenitor cells in the presence or absence of homoarginine (hArg). The number of spheres formed is shown as the number of spheres formed per 1000 cells. The experiment was performed in triplicate. In the figure, "ns" indicates that there was no significant difference in the Student's t-test. [Figure 4] FIG. 1 is a schematic diagram showing the administration schedule of homoarginine and temozolomide to glioblastoma model mice. [Figure 5] Kaplan-Meier survival curves for glioblastoma model mice treated with homoarginine and / or temozolomide. A control group was also monitored in the same manner. Each group consisted of 5 mice. [Figure 6] This graph shows the effect of temsirolimus on sphere formation by glioblastoma cells in the presence and absence of homoarginine (hArg). The number of spheres formed was calculated relative to the number of spheres formed under the same conditions without temsirolimus, which was set at 1.0. The experiment was performed in triplicate. In the figure, "**" and "*" indicate P<0.01 and P<0.05, respectively, in a one-tailed paired Student's t-test. [Figure 7] This graph shows the effect of decitabine on sphere formation in glioblastoma cells in the presence or absence of homoarginine (hArg). The number of spheres formed was calculated relative to the number of spheres formed under the same conditions without decitabine, which was set at 1.0. The experiment was performed in triplicate. In the figure, "*" indicates P<0.05 in a one-tailed paired Student's t-test. [Figure 8]This graph shows the effect of PD173074 on sphere formation by glioblastoma cells in the presence or absence of homoarginine (hArg). The number of spheres formed was calculated relative to the number of spheres formed under the same conditions without PD173074, which was set at 1.0. The experiment was performed in triplicate. In the figure, "***" and "*" indicate P<0.001 and P<0.05, respectively, in a one-tailed paired Student's t-test. [Figure 9] This graph shows the effect of AMI-1 on sphere formation by glioblastoma cells in the presence or absence of homoarginine (hArg). The number of spheres formed was calculated relative to the number of spheres formed under the same conditions without AMI-1, which was set at 1.0. The experiment was performed in triplicate. In the figure, "*" indicates P<0.05 in a one-tailed paired Student's t-test. [Figure 10] This graph shows the effect of orlistat on sphere formation by glioblastoma cells in the presence or absence of homoarginine (hArg). The number of spheres formed was calculated relative to the number of spheres formed under the same conditions without orlistat, which was set at 1.0. The experiment was performed with n = 3. In the figure, "*" indicates P < 0.05 in a one-tailed paired Student's t-test. [Figure 11] This is a graph showing the effect of daunorubicin (DNR) on the proliferation of leukemia cells in the presence or absence of homoarginine (hArg). The vertical axis shows the absorbance (OD) measured using the Cell Counting Kit-8. The test was performed in triplicate. [Figure 12] This graph shows the effect of X-ray irradiation on sphere formation in glioblastoma cells in the presence and absence of homoarginine (hArg). The number of spheres formed was calculated relative to the number of spheres formed under the same conditions without X-ray irradiation, which was set at 1.0. The experiment was performed with n = 3. In the figure, "****" and "***" indicate P<0.0001 and P<0.001, respectively, in a paired Student's t-test (one-tailed). DETAILED DESCRIPTION OF THE INVENTION

[0009] 1 Definition As used herein, the term "derivative" refers to a compound whose structure has been modified to enhance the desired activity of the compound, reduce side effects (e.g., cytotoxicity), increase water solubility, or increase stability, without losing the desired activity. Applicable modifications include, but are not limited to, PEG modification, amino acid modification, peptide modification, biotin modification, methylation, etc.

[0010] As used herein, "salt" refers to basic salts such as salts with inorganic bases, such as alkali metal salts and alkaline earth metal salts, and salts with organic bases, including salts with sodium, potassium, calcium, magnesium, ammonium, or diethanolamine, ethylenediamine, etc. Alternatively, as used herein, "salt" refers to acidic salts, including salts with inorganic acids, such as salts of mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids, such as methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid, gluconic acid, and palmitic acid; and salts with acidic amino acids, such as aspartic acid and glutamic acid.

[0011] As used herein, a "subject" refers to an individual for whom tumor treatment and / or prevention is to be performed, specifically a human or an animal (e.g., a mammal such as a dog, cat, cow, horse, pig, sheep, monkey, or ferret, or a bird such as a chicken), preferably a human.

[0012] As used herein, the term "tumor" includes any lesion in which cells grow excessively regardless of the body's control, but particularly refers to malignant tumors. This also includes lesions known as cancers and malignant neoplasms. In this specification, the tumors to be treated and / or prevented are not particularly limited in terms of their site of occurrence or nature, and include leukemias such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL); lymphomas such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, and multiple myeloma; as well as sarcoma, skin cancer, melanoma, bladder cancer, brain cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colorectal cancer, cervical cancer, liver cancer, head and neck cancer, esophageal cancer, pancreatic cancer, kidney cancer, adrenal cancer, gastric cancer, testicular cancer, gallbladder cancer and biliary tract cancer, thyroid cancer, thymic cancer, bone tumors, and brain tumors (glioma, astrocytoma, glioblastoma), etc.

[0013] 2. Pharmaceutical composition for treating and / or preventing tumors containing homoarginine (first embodiment) A first embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition comprising homoarginine or a pharmaceutically acceptable salt or derivative thereof, which is used for treating and / or preventing a tumor in a subject in combination with the following a) and / or b): a) administration of antitumor agents; b) Radiation exposure.

[0014] As a result of extensive research, the present inventors have found that the therapeutic effects of tumors induced by the administration of an antitumor agent and / or radiation can be enhanced by the concomitant use of homoarginine, which can provide clinical benefits such as improved therapeutic outcomes of the antitumor agent, reduced dosage of the antitumor agent to alleviate side effects, and reduced dosage or frequency of radiation exposure to alleviate side effects.

[0015] In the pharmaceutical composition of this embodiment, the tumor to be treated and / or prevented (hereinafter also referred to as "treatment, etc.") is not particularly limited, but is preferably a brain tumor, leukemia, or breast cancer. The brain tumor is preferably glioblastoma. The leukemia is preferably acute myeloid leukemia.

[0016] The pharmaceutical composition of this embodiment is a pharmaceutical composition containing homoarginine or a pharmaceutically acceptable salt or derivative thereof (hereinafter also simply referred to as "homoarginine"). Homoarginine, more specifically L-homoarginine, has a structure represented by the following formula (I): [ka]

[0017] The homoarginine content varies depending on the dosage form and administration method, but can be, for example, 1 to 50 mg / kg body weight / day, particularly 2 to 40 mg / kg body weight / day, 3 to 35 mg / kg body weight / day, 4 to 25 mg / kg body weight / day, or 5 to 20 mg / kg body weight / day. In the case of a salt or derivative, the content here refers to the free homoarginine equivalent.

[0018] In addition to homoarginine, the pharmaceutical composition of this embodiment may contain a pharmaceutically acceptable carrier as needed. Here, "pharmaceutically acceptable carrier" refers to additives commonly used in the pharmaceutical technology field. Examples include excipients, binders, disintegrants, fillers, emulsifiers, flow additives, lubricants, etc.

[0019] Examples of excipients include sugars such as monosaccharides, disaccharides, cyclodextrins, and polysaccharides (more specifically, but not limited to, glucose, sucrose, lactose, raffinose, mannitol, sorbitol, inositol, dextrin, maltodextrin, starch, and cellulose), metal salts (e.g., sodium chloride, sodium or calcium phosphate, calcium sulfate, magnesium sulfate, calcium carbonate), citric acid, tartaric acid, glycine, low-, medium-, and high-molecular-weight polyethylene glycols (PEG), Pluronic®, kaolin, silicic acid, or combinations thereof.

[0020] Examples of binders include starch paste using corn, wheat, rice, or potato starch, simple syrup, glucose solution, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, shellac, and / or polyvinylpyrrolidone.

[0021] Examples of disintegrants include the above-mentioned starches, lactose, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, laminaran powder, sodium hydrogen carbonate, calcium carbonate, alginic acid or sodium alginate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, or salts thereof.

[0022] Examples of fillers include the above-mentioned sugars and / or calcium phosphate (for example, tricalcium phosphate or calcium hydrogen phosphate).

[0023] Examples of emulsifiers include sorbitan fatty acid esters, glycerin fatty acid esters, sucrose fatty acid esters, and propylene glycol fatty acid esters.

[0024] Examples of flow regulators and lubricants include silicates, talc, stearates or polyethylene glycol.

[0025] Such carriers are primarily used to facilitate the formation of the dosage form and to maintain the dosage form and pharmacological effect, and may be used appropriately as needed. In addition to the above-mentioned additives, flavoring agents, solubilizing agents, suspending agents, diluents, surfactants, stabilizers, absorption enhancers, bulking agents, wetting agents, humectants, adsorbents, disintegration inhibitors, coating agents, coloring agents, preservatives, antioxidants, perfumes, flavoring agents, sweeteners, buffers, etc. may also be included as needed.

[0026] The pharmaceutical composition of this embodiment may also contain other drugs, such as other antitumor agents, anti-inflammatory agents, etc., in amounts that do not impair the effects of homoarginine.

[0027] The dosage form of the pharmaceutical composition of this embodiment is not particularly limited as long as it does not inactivate the active ingredient homoarginine and other additional active ingredients. For example, it may be any liquid, solid, or semisolid. Specific dosage forms include oral dosage forms such as liquids, powders, granules, tablets, capsules, sublingual tablets, and lozenges, and parenteral dosage forms such as injections, suspensions, emulsions, eye drops, nasal drops, creams, ointments, plasters, patches, and suppositories.

[0028] The pharmaceutical composition of this embodiment can be administered by any suitable method that does not inactivate the active ingredient contained therein. For example, it may be administered orally or parenterally (e.g., by injection, aerosol, topical application, eye drops, or nasal drops). Oral administration is particularly preferred.

[0029] The administration period of the pharmaceutical composition of this embodiment is not particularly limited and can be appropriately set depending on the type and period of the concomitant treatment.

[0030] The frequency of administration of the pharmaceutical composition of this embodiment is not particularly limited as long as it provides sufficient therapeutic or preventive effects on tumors and does not cause serious side effects, but is preferably, for example, once every three days to five times a day, and particularly once to three times a day. The administration period of the pharmaceutical composition of this embodiment is not particularly limited and is determined carefully taking into consideration the clinical effect and the level of side effects.

[0031] 2-1 Combination with antitumor agents The pharmaceutical composition of this embodiment may be used in combination with an antitumor agent. The "antitumor agent" referred to here is not particularly limited as long as it is a drug known to be effective in treating tumors, and the type and dosage can be appropriately selected and determined depending on the tumor to be treated and the condition of the subject (patient). The pharmaceutical composition of this embodiment may be administered in combination with only the antitumor agent, or may also be administered in combination with radiation.

[0032] When the tumor to be treated is glioblastoma, the antitumor agent to be used is not particularly limited as long as it is an antitumor agent known to be effective in treating glioblastoma, and can be appropriately selected depending on the condition of the patient to be treated. Examples of antitumor agents for glioblastoma include temozolomide, temsirolimus, decitabine, PD173074, AMI-1, orlistat, bevacizumab, carmustine, etc. Alternatively, the antitumor agent may be a pharmaceutically acceptable salt or derivative of any of these compounds.

[0033] When the tumor to be treated, etc. is leukemia, the antitumor agent to be used is not particularly limited as long as it is an antitumor agent known to be effective in the treatment, etc., of leukemia, particularly acute myeloid leukemia, and can be appropriately selected depending on the condition of the patient to be treated, etc. Examples of antitumor agents for leukemia include daunorubicin, cytarabine, idarubicin, enocitabine, etc. Alternatively, the antitumor agent may be a pharmaceutically acceptable salt or derivative of any of these compounds.

[0034] When the tumor to be treated is breast cancer, the antitumor agent to be used is not particularly limited as long as it is an antitumor agent known to be effective in treating breast cancer, and can be appropriately selected depending on the condition of the patient to be treated. Examples of antitumor agents for breast cancer include epirubicin, doxorubicin, paclitaxel, docetaxel, fluorouracil, eribulin, cyclophosphamide, gemcitabine, carboplatin, pemprolizumab, and atezolimumab. Alternatively, the antitumor agent may be a pharmaceutically acceptable salt or derivative of any of these compounds.

[0035] The dose and administration period of the antitumor agent can be the known dose and administration period for the antitumor agent used. Figure 1 shows an example of treatment of primary glioblastoma with temozolomide and radiation. In the illustrated example, temozolomide is administered at a dose of 75 mg / m along with radiation. 2 It will be administered once daily for 42 days, followed by a 4-week rest period. 2 The drug is administered orally to the body surface area of ​​200 mg / m² once daily for 5 consecutive days, followed by a 23-day rest period. This total of 28 days constitutes one course, and from the next course onwards, the dose is 200 mg / m². 2 Alternatively, depending on the degree of effect of the combination with the pharmaceutical composition of this embodiment, a lower dose and / or a shorter administration period than known in the art may be used.

[0036] The pharmaceutical composition of this embodiment, i.e., a pharmaceutical composition containing homoarginine, is administered simultaneously or on the same day as the start of administration of an antitumor agent, or 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days or more before the start of administration of the antitumor agent. Administration may be initiated before, 19 days before, 20 days before, 21 days before, 22 days before, 23 days before, 1 day after, 2 days after, 3 days after, 4 days after, 5 days after, 6 days after, 7 days after, 8 days after, 9 days after, 10 days after, 11 days after, 12 days after, 13 days after, 14 days after, 15 days after, 16 days after, 17 days after, 18 days after, 19 days after, 20 days after, 21 days after, 22 days after, or 23 days after. Alternatively, administration of the pharmaceutical composition of this embodiment may be terminated simultaneously or on the same day as the end of administration of the antitumor agent, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 days before, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 days after the end of administration of the antitumor agent. It is preferable that the administration of the pharmaceutical composition of this embodiment is started simultaneously with the start of administration of the antitumor agent, and is completed simultaneously with the completion of administration of the antitumor agent.

[0037] 2-2 Combined use with radiation The pharmaceutical composition of this embodiment may be used in combination with radiation irradiation. The "radiation irradiation" referred to here can be any known method for treating tumors. The type of radiation to be irradiated can be appropriately selected and set depending on the tumor to be treated, etc., and the condition of the subject (patient). The administration of the pharmaceutical composition of this embodiment may be combined with radiation irradiation alone, or may further be combined with an antitumor agent.

[0038] Radiation irradiation is broadly divided into two types: external irradiation and internal irradiation. Examples of external irradiation include intensity-modulated radiation therapy (IMRT) and stereotactic radiation therapy (SRT). Examples include proton therapy and heavy ion therapy. Internal irradiation is a treatment in which radiation is applied to a lesion site from inside the body, and examples include brachytherapy. The pharmaceutical composition of this embodiment can be combined with either type of radiation irradiation.

[0039] The dose and duration of radiation exposure can be the known dose and duration for the tumor being treated. Figure 1 shows an example of treatment of primary glioblastoma with temozolomide and radiation exposure. In the illustrated example, radiation exposure is 75 mg / m 2 In addition to administering temozolomide to the body surface area once daily for 42 days, radiation of 2 Gy is administered once daily for a total of 30 times during the 42-day period. Alternatively, depending on the degree of effect of the combination with the pharmaceutical composition of this embodiment, the radiation dose may be lower than the known radiation dose and / or the radiation period may be shorter than the known radiation dose.

[0040] The pharmaceutical composition of this embodiment, i.e., a pharmaceutical composition containing homoarginine, is administered simultaneously or on the same day as the start of the radiation exposure period, or 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 ​​days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92 days, 93 days, 94 days, 95 days, 96 days, Administration may be initiated 8 days, 19 days, 20 days, 21 days, 22 days, 23 days before, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, or 23 days later. Alternatively, administration of the pharmaceutical composition of this embodiment may be terminated simultaneously with or on the same day as the end of the radiation irradiation period, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 days before, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 days after the end of the radiation irradiation period. It is preferable that administration of the pharmaceutical composition of this embodiment is started at the same time as the start of the radiation exposure period, and is completed at the same time as the end of the radiation exposure period.

[0041] 3. Pharmaceutical composition for enhancing the effect of one or more tumor treatments, comprising homoarginine (Second embodiment) A second embodiment of the present invention is a pharmaceutical composition for use in enhancing the effectiveness of one or more tumor treatments, comprising homoarginine or a pharmaceutically acceptable salt or derivative thereof as an active ingredient.

[0042] More specifically, the pharmaceutical composition of this embodiment is used in combination with one or more tumor treatments selected from the following a) and b), thereby enhancing the effectiveness of the tumor treatment. a) administration of antitumor agents; b) Radiation exposure.

[0043] In the pharmaceutical composition of this embodiment, the dosage of homoarginine varies depending on its dosage form and administration method, but can be, for example, 1 to 50 mg / kg body weight / day, particularly 2 to 40 mg / kg body weight / day, 3 to 35 mg / kg body weight / day, 4 to 25 mg / kg body weight / day, or 5 to 20 mg / kg body weight / day. In the case of a salt or derivative, the dosage referred to here refers to the free homoarginine equivalent.

[0044] The pharmaceutical composition of this embodiment may contain, in addition to homoarginine, a pharmaceutically acceptable carrier as needed. The "pharmaceutically acceptable carrier" referred to here is synonymous with the carrier described in the section "Pharmaceutical composition for treating and / or preventing tumors containing 2 homoarginine (first embodiment)" unless otherwise specified. Furthermore, the conditions for the administration period, administration frequency, etc. of the pharmaceutical composition of this embodiment are also the same as those described in the section "Pharmaceutical composition for treating and / or preventing tumors containing 2 homoarginine (first embodiment)" unless otherwise specified.

[0045] Unless otherwise specified, the conditions for administering an antitumor agent, such as the type of antitumor agent, dosage, and administration period, are the same as those described in Section "2-1 Combination Use with Antitumor Agents." Furthermore, the conditions for irradiating radiation, such as the type of radiation, dosage, and irradiation period, are the same as those described in Section "2-2 Combination Use with Radiation."

[0046] 4. Pharmaceutical composition containing homoarginine and an antitumor agent (third embodiment) A third embodiment of the present invention is a pharmaceutical composition comprising homoarginine or a pharmaceutically acceptable salt or derivative thereof and an antitumor agent. The pharmaceutical composition of this embodiment is specifically used for treating and / or preventing tumors in a subject. By containing homoarginine and an antitumor agent as active ingredients, the pharmaceutical composition of this embodiment simultaneously administers these active ingredients to a subject, thereby enabling a greater antitumor effect to be achieved than a pharmaceutical composition containing an antitumor agent alone.

[0047] In the pharmaceutical composition of this embodiment, the tumor to be treated is not particularly limited, but is preferably a brain tumor, leukemia, or breast cancer. The brain tumor is preferably glioblastoma. The leukemia is preferably acute myeloid leukemia.

[0048] The pharmaceutical composition of this embodiment contains homoarginine. The content of homoarginine varies depending on the dosage form and administration method, but can be, for example, a content such that the dosage is 1 to 50 mg / kg body weight / day, particularly 2 to 40 mg / kg body weight / day, 3 to 35 mg / kg body weight / day, 4 to 25 mg / kg body weight / day, or 5 to 20 mg / kg body weight / day. In the case of a salt or derivative, the dosage referred to here refers to the free homoarginine equivalent.

[0049] The pharmaceutical composition of this embodiment contains an antitumor agent. The antitumor agent is not particularly limited as long as it can be administered in the same dosage form as homoarginine, but it is preferable that the antitumor agent be one that does not cause problems such as loss of efficacy when coexisting with homoarginine.

[0050] When the tumor to be treated is glioblastoma, the antitumor agent contained in the pharmaceutical composition is not particularly limited as long as it is an antitumor agent known to be effective in treating glioblastoma, and can be appropriately selected depending on the condition of the patient to be treated. Examples of antitumor agents for glioblastoma include temozolomide, temsirolimus, decitabine, PD173074, AMI-1, orlistat, bevacizumab, carmustine, etc. Alternatively, the antitumor agent may be a pharmaceutically acceptable salt or derivative of any of these compounds.

[0051] When the tumor to be treated, etc. is leukemia, the antitumor agent contained in the pharmaceutical composition is not particularly limited as long as it is an antitumor agent known to be effective in the treatment, etc., of leukemia, particularly acute myeloid leukemia, and can be appropriately selected depending on the condition of the patient to be treated, etc. Examples of antitumor agents for leukemia include daunorubicin, cytarabine, idarubicin, enocitabine, etc. Alternatively, the antitumor agent may be a pharmaceutically acceptable salt or derivative of any of these compounds.

[0052] When the tumor to be treated is breast cancer, the antitumor agent contained in the pharmaceutical composition is not particularly limited as long as it is an antitumor agent known to be effective in treating breast cancer, and can be appropriately selected depending on the condition of the patient to be treated. Examples of antitumor agents for breast cancer include epirubicin, doxorubicin, paclitaxel, docetaxel, fluorouracil, eribulin, cyclophosphamide, gemcitabine, carboplatin, pemprolizumab, and atezolimumab. Alternatively, the antitumor agent may be a pharmaceutically acceptable salt or derivative of any of these compounds.

[0053] The content of the antitumor agent in the pharmaceutical composition of this embodiment can be an amount that results in a known dosage of the antitumor agent, or can be an amount that results in a dosage that is less than the known dosage.

[0054] The administration period and frequency of the pharmaceutical composition of this embodiment can be the same as the known administration period and frequency of the antitumor agent, or can be shorter and / or less than the known administration period and frequency of the antitumor agent.

[0055] The pharmaceutical composition of this embodiment may contain, in addition to homoarginine and an antitumor agent, a pharmaceutically acceptable carrier as needed. Unless otherwise specified, the "pharmaceutically acceptable carrier" herein has the same meaning as the carrier described in the section "2. Pharmaceutical composition for treating and / or preventing tumors, containing homoarginine (first embodiment)."

[0056] The administration of the pharmaceutical composition of this embodiment may be performed in combination with radiation. Regarding radiation irradiation, the conditions such as the type of radiation, the dose, and the duration of irradiation are the same as those described in the section "2-2. Concomitant use with radiation irradiation," unless otherwise specified.

[0057] The pharmaceutical composition of this embodiment, i.e., a pharmaceutical composition containing homoarginine and an antitumor agent, is administered simultaneously or on the same day as the start of the radiation exposure period, or 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, or 18 days before the start of the radiation exposure period. Administration may be initiated before, 18 days before, 19 days before, 20 days before, 21 days before, 22 days before, 23 days before, 1 day after, 2 days after, 3 days after, 4 days after, 5 days after, 6 days after, 7 days after, 8 days after, 9 days after, 10 days after, 11 days after, 12 days after, 13 days after, 14 days after, 15 days after, 16 days after, 17 days after, 18 days after, 19 days after, 20 days after, 21 days after, 22 days after, or 23 days after. Alternatively, administration of the pharmaceutical composition of this embodiment may be terminated simultaneously with or on the same day as the end of the radiation irradiation period, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 days before, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 days after the end of the radiation irradiation period. It is preferable that administration of the pharmaceutical composition of this embodiment is started at the same time as the start of the radiation exposure period, and is completed at the same time as the end of the radiation exposure period.

[0058] 5. Pharmaceutical composition containing an antitumor agent (fourth embodiment) A fourth embodiment of the present invention is a pharmaceutical composition comprising an antitumor agent, which is used to treat and / or prevent tumors in a subject in combination with the administration of homoarginine or a pharmaceutically acceptable salt or derivative thereof. The pharmaceutical composition of this embodiment comprises an antitumor agent, and when administered in combination with homoarginine or a pharmaceutically acceptable salt or derivative thereof, it is possible to achieve a stronger antitumor effect than conventional antitumor agents.

[0059] In the pharmaceutical composition of this embodiment, the tumor to be treated is not particularly limited, but is preferably a brain tumor, leukemia, or breast cancer. The brain tumor is preferably glioblastoma. The leukemia is preferably acute myeloid leukemia.

[0060] When the tumor to be treated is glioblastoma, the antitumor agent contained in the pharmaceutical composition is not particularly limited as long as it is an antitumor agent known to be effective in treating glioblastoma, and can be appropriately selected depending on the condition of the patient to be treated. Examples of antitumor agents for glioblastoma include temozolomide, temsirolimus, decitabine, PD173074, AMI-1, orlistat, bevacizumab, carmustine, etc. Alternatively, the antitumor agent may be a pharmaceutically acceptable salt or derivative of any of these compounds.

[0061] When the tumor to be treated, etc. is leukemia, the antitumor agent contained in the pharmaceutical composition is not particularly limited as long as it is an antitumor agent known to be effective in the treatment, etc., of leukemia, particularly acute myeloid leukemia, and can be appropriately selected depending on the condition of the patient to be treated, etc. Examples of antitumor agents for leukemia include daunorubicin, cytarabine, idarubicin, enocitabine, etc. Alternatively, the antitumor agent may be a pharmaceutically acceptable salt or derivative of any of these compounds.

[0062] When the tumor to be treated is breast cancer, the antitumor agent contained in the pharmaceutical composition is not particularly limited as long as it is an antitumor agent known to be effective in treating breast cancer, and can be appropriately selected depending on the condition of the patient to be treated. Examples of antitumor agents for breast cancer include epirubicin, doxorubicin, paclitaxel, docetaxel, fluorouracil, eribulin, cyclophosphamide, gemcitabine, carboplatin, pemprolizumab, and atezolimumab. Alternatively, the antitumor agent may be a pharmaceutically acceptable salt or derivative of any of these compounds.

[0063] The content of the antitumor agent in the pharmaceutical composition of this embodiment can be an amount that results in a known dosage of the antitumor agent, or can be an amount that results in a dosage that is less than the known dosage.

[0064] The administration period and frequency of the pharmaceutical composition of this embodiment can be the same as the known administration period and frequency of the antitumor agent. Alternatively, the administration period and frequency of the pharmaceutical composition of this embodiment can be shorter than the known administration period and / or lower than the known administration frequency of the antitumor agent by administering it in combination with homoarginine.

[0065] The pharmaceutical composition of this embodiment is administered to a subject in combination with homoarginine. The dosage of homoarginine varies depending on its dosage form and administration method, but can be, for example, 1 to 50 mg / kg body weight / day, particularly 2 to 40 mg / kg body weight / day, 3 to 35 mg / kg body weight / day, 4 to 25 mg / kg body weight / day, or 5 to 20 mg / kg body weight / day. In the case of a salt or derivative, the dosage referred to here refers to the free homoarginine equivalent.

[0066] The pharmaceutical composition of this embodiment, i.e., a pharmaceutical composition containing an antitumor agent, is administered simultaneously or on the same day as the start of administration of homoarginine, or 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 ​​days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92 days, 93 days, 94 days, 95 days, 96 Administration may be initiated 8 days, 19 days, 20 days, 21 days, 22 days, 23 days before, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, or 23 days later. Alternatively, administration of the pharmaceutical composition of this embodiment may be terminated simultaneously or on the same day as the end of administration of homoarginine, or 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days before, 1 day after, 2 days after, 3 days after, 4 days after, 5 days after, 6 days after, 7 days after, 8 days after, 9 days after, 10 days after, 11 days after, 12 days after, 13 days after, 14 days after, 15 days after, 16 days after, 17 days after, 18 days after, 19 days after, 20 days after, 21 days after, 22 days after, or 23 days after the end of administration of homoarginine. It is preferable that the administration of the pharmaceutical composition of this embodiment is started simultaneously with the start of administration of homoarginine, and is completed simultaneously with the completion of administration of homoarginine.

[0067] The pharmaceutical composition of this embodiment may be used for the treatment of a tumor in a subject in combination with radiation in addition to the administration of homoarginine. The pharmaceutical composition of this embodiment may be administered simultaneously or on the same day as the start of the radiation irradiation period, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 days before, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 days after the start of the radiation irradiation period. Alternatively, administration of the pharmaceutical composition of this embodiment may be terminated simultaneously with or on the same day as the end of the radiation irradiation period, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 days before, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 days after the end of the radiation irradiation period. It is preferable that administration of the pharmaceutical composition of this embodiment is started at the same time as the start of the radiation exposure period, and is completed at the same time as the end of the radiation exposure period.

[0068] 6. Method for treating and / or preventing tumors (Fifth embodiment) A fifth embodiment of the present invention is a method for treating and / or preventing tumors, characterized in that the method comprises administering homoarginine or a pharmaceutically acceptable salt or derivative thereof and the following steps a) and / or b): a) administration of antitumor agents; b) Radiation exposure. According to the method of this embodiment, by including the administration of homoarginine, it is possible to achieve a higher therapeutic and / or preventive effect than treatments involving the administration of antitumor agents, radiation exposure, or a combination thereof.

[0069] Unless otherwise specified, the conditions for administering homoarginine, administering an antitumor agent, and irradiating are the same as those described in the sections "2. Pharmaceutical composition for treating and / or preventing tumors containing homoarginine (first embodiment)," "2-1. Combination use with an antitumor agent," and "2-2. Combination use with radiation." [Example]

[0070] [Example 1] Examination of the influence of homoarginine on the antitumor effect of temozolomide on glioblastoma cells (1-1) Cell culture A known patient-derived human glioblastoma cell line (TGS04) and normal human neural progenitor cells (obtained from Lonza, Basel, Switzerland) were cultured as spheroids in NSPC medium (DMEM / F12, 1x B27, 20 ng / mL hEGF, 20 ng / mL hbFGF, 1x GlutaMax™, penicillin / streptomycin) at 37°C, 5% CO2, and 5% O2. These cell lines were maintained by subculture every 3–4 days.

[0071] (1-2) Sphere formation assay of TGS04 NSPC media containing 1% methylcellulose were prepared with or without 20 mM homoarginine (hArg) and temozolomide (TMZ) at concentrations of 0, 2, 3, or 4 μM. TGS04 cells were dispersed and added to each medium. After mixing by rotation, the cells were transferred to a 96-well plate and cultured for 10–14 days. Sphere formation was measured using a Keyence BZ-9000 fluorescence microscope. Experiments were performed in triplicate.

[0072] The number of spheres in each medium is shown in Figure 2. Figure 2 shows the relative number of spheres under each condition, calculated with the number of spheres in the presence or absence of hArg and without TMZ set to 1. In the figure, "****" and "***" indicate P<0.0001 and P<0.001, respectively, in a paired Student's t-test (one-tailed). This demonstrates that the effect of TMZ was significantly enhanced by administration of hArg.

[0073] (1-3) Sphere formation assay of normal human neural progenitor cells NSPC media containing 1% methylcellulose were prepared with or without 30 mM homoarginine (hArg) and temozolomide (TMZ) at concentrations of 0, 2.5, 5.0, 7.5, or 10 μM. Normal human neural progenitor cells were dispersed and added to each medium. After mixing by rotation, the cells were transferred to a 96-well plate and cultured for 10–14 days. Sphere formation was measured using a Keyence BZ-9000 fluorescence microscope. Experiments were performed in triplicate.

[0074] The number of spheres formed in each medium is shown in Figure 3. Figure 3 shows the number of spheres per 1,000 cells under each condition. "ns" in the figure indicates that no significant difference was observed between the groups with and without hArg. As shown in Figure 3, regardless of the concentration of TMZ added, there was no significant difference in the number of spheres formed with or without hArg. This indicates that hArg enhances the effect of TMZ on glioblastoma cells but does not affect the effect of TMZ on normal human neural progenitor cells, demonstrating that the enhancement effect is tumor-specific.

[0075] [Example 2] Examination of the influence of homoarginine on the antitumor effect of temozolomide in glioblastoma model mice (2-1) Construction of glioblastoma model mice TGS04 cells were infected with a retrovirus derived from the pBabe retroviral vector containing the firefly luciferase gene to obtain luciferase-expressing cells. Luciferase-expressing cells were implanted intracranially into 4-week-old female Balb / c nu / nu mice (1 × 10 5 D-luciferin (150 mg / kg) was intraperitoneally administered to mice, and luminescence of the mice was confirmed by image analysis using an IVIS Lumina III imaging system (PerkinElmer, Waltham, MD).

[0076] (2-2) Drug administration The constructed mouse model was administered hArg and / or TMZ, and the behavior of intracranial glioblastoma cells and the survival rate of the mice were observed. Figure 4 shows an outline of the administration schedule for hArg and TMZ to mice. After tumor implantation, mice were intraperitoneally administered hArg at a dose of 200 mg / kg / day from day 1 to day 14, and / or TMZ at a dose of 1.5 mg / kg / day from day 7 to day 14 after tumor implantation. The mice were then observed. Control mice not administered hArg or TMZ were also observed in the same manner. The study was performed with n=5.

[0077] Luminescence in mouse glioblastoma cells was observed. Four weeks after the start of follow-up, intracranial luminescence was observed in the control and hArg-administered groups, but not in the TMZ-administered or hArg+TMZ-administered groups. However, after six weeks of follow-up, intracranial luminescence was observed in the TMZ-administered group. However, no intracranial luminescence was observed in the hArg+TMZ-administered group within the six-week follow-up period (data not shown).

[0078] Figure 5 shows Kaplan-Meier survival curves for mice under each condition. In the control group and the hArg-administered group, all mice died by day 40, and in the TMZ-administered group, all mice died by day 50. However, in the hArg+TMZ-administered group, the survival rate remained 100% until day 60, and some mice were still alive on day 80. These results demonstrate that hArg alone does not have significant antitumor activity, but that its combination with TMZ has high antitumor activity.

[0079] [Example 3] Examination of the influence of homoarginine on the antitumor effects of various antitumor agents on glioblastoma cells (3-1) Cell culture A human glioblastoma cell line (TGS04) derived from a known patient was cultured as spheroids in NSPC medium (DMEM / F12, 1x B27, 20 ng / mL hEGF, 20 ng / mL hbFGF, 1x GlutaMax™, penicillin / streptomycin) at 37°C, 5% CO2, and 5% O2. These cell lines were maintained by subculture every 3–4 days.

[0080] (3-2) Sphere formation assay of TGS04 NSPC media containing 1% methylcellulose and containing various antitumor agents (temsirolimus, decitabine, PD173074, AMI-1, and orlistat) at designated concentrations, with or without 25 mM homoarginine (hArg), were prepared. TGS04 cells were dispersed and added to each medium. After mixing by rotation, the cells were transferred to a 96-well plate and cultured for 10–14 days. Sphere formation was measured using a Keyence BZ-9000 fluorescence microscope. Each experiment was performed in triplicate.

[0081] Figure 6 shows the relationship between temsirolimus concentration and sphere number in the presence and absence of hArg. Figure 7 shows the relationship between decitabine concentration and sphere number in the presence and absence of hArg. Figure 8 shows the relationship between PD173074 concentration and sphere number in the presence and absence of hArg. Figure 9 shows the relationship between AMI-1 concentration and sphere number in the presence and absence of hArg. Figure 10 shows the relationship between orlistat concentration and sphere number in the presence and absence of hArg. Each figure shows the relative number of spheres under each condition, calculated with the number of spheres in the absence of an antitumor agent set to 1, with and without hArg. In the figures, "***", "**", and "*" indicate P<0.001, P<0.01, and P<0.05, respectively, in a paired Student's t-test (one-tailed). The results in Figures 6 to 10 demonstrate that the effects of various antitumor agents are significantly enhanced by the addition of hArg.

[0082] [Example 4] Examination of the influence of homoarginine on the antitumor effect of daunorubicin on human acute monocytic leukemia cells RPMI medium containing 10% FBS and daunorubicin (DNR) at the indicated concentrations was prepared with or without 25 mM homoarginine (hArg). Each medium was dispensed at 200 μL per well into a 96-well plate, and human acute monocytic leukemia cell line (MOLM14) was seeded at 10,000 cells per well. After 48 hours of culture at 37°C, 5% CO2, and 5% O2, absorbance was measured using Cell Counting Kit-8 (Dojindo Laboratories). Absorbance shows a positive correlation with cell number. Experiments were performed in triplicate.

[0083] The optical density (OD) of each medium is shown in Figure 11. It was confirmed that the number of leukemia cells was significantly suppressed in the presence of hArg compared to the absence of hArg. This indicates that the antitumor effect of hArg is not limited to glioblastoma.

[0084] [Example 5] Examination of the influence of homoarginine on the antitumor effect of X-ray irradiation on glioblastoma cells (5-1) Cell culture A human glioblastoma cell line (TGS04) derived from a known patient was cultured as spheroids in NSPC medium (DMEM / F12, 1x B27, 20 ng / mL hEGF, 20 ng / mL hbFGF, 1x GlutaMax™, penicillin / streptomycin) at 37°C, 5% CO2, and 5% O2. These cell lines were maintained by subculture every 3–4 days.

[0085] (5-2) Sphere formation assay of TGS04 NSPC media containing 1% methylcellulose with or without 15 mM homoarginine (hArg) were prepared. TGS04 cells were dispersed and added to each medium. After mixing by rotation, the cells were transferred to a 96-well plate and irradiated with 0, 2, 3, or 4 Gy of X-rays. After 10–14 days of culture, the spheres formed were measured using a Keyence BZ-9000 fluorescence microscope. Each experiment was performed in triplicate.

[0086] Figure 12 shows the effect of X-ray irradiation on sphere formation in glioblastoma cells in the presence and absence of homoarginine (hArg). The number of spheres formed was calculated relative to the number of spheres formed under the same conditions without TMZ, which was set at 1.0. In the figure, "****" and "***" indicate P<0.0001 and P<0.001, respectively, in a paired Student's t-test (one-tailed). The results in Figure 12 demonstrate that the effect of radiation irradiation is significantly enhanced by the addition of hArg.

Claims

1. 1. A pharmaceutical composition comprising homoarginine or a pharmaceutically acceptable salt or derivative thereof, which is used for treating and / or preventing a tumor in a subject in combination with: a) and / or b) of the following: a) administration of an antitumor agent; b) Irradiation.

2. The pharmaceutical composition of claim 1, wherein the tumor is a brain tumor, leukemia, or breast cancer.

3. The pharmaceutical composition of claim 2, wherein the tumor is a brain tumor, and the brain tumor is a glioblastoma.

4. The pharmaceutical composition according to claim 1 , wherein the antitumor agent is a brain tumor therapeutic agent.

5. 5. The pharmaceutical composition according to claim 4, wherein the antitumor agent is at least one agent selected from the group consisting of temozolomide, temsirolimus, decitabine, PD173074, AMI-1, orlistat, and pharmaceutically acceptable salts or derivatives thereof.

6. The pharmaceutical composition according to claim 1, wherein the antitumor agent is a leukemia therapeutic agent.

7. 7. The pharmaceutical composition of claim 6, wherein the antitumor agent is daunorubicin.

8. A pharmaceutical composition for use in enhancing the effect of one or more tumor treatments, comprising homoarginine or a pharmaceutically acceptable salt or derivative thereof as an active ingredient.

9. A pharmaceutical composition comprising homoarginine or a pharmaceutically acceptable salt or derivative thereof and an antitumor agent.

10. The pharmaceutical composition according to claim 9, which is used to treat and / or prevent a tumor in a subject.

11. A pharmaceutical composition comprising an anti-tumor agent, the pharmaceutical composition being used to treat and / or prevent tumors in a subject in combination with the administration of homoarginine or a pharmaceutically acceptable salt or derivative thereof.

12. The pharmaceutical composition according to claim 11, wherein the antitumor agent is a brain tumor therapeutic agent.

13. 13. The pharmaceutical composition of claim 12, wherein the antitumor agent is at least one agent selected from the group consisting of temozolomide, temsirolimus, decitabine, PD173074, AMI-1, orlistat, and pharmaceutically acceptable salts or derivatives thereof.

14. The pharmaceutical composition according to claim 11, wherein the antitumor agent is a leukemia therapeutic agent.

15. 15. The pharmaceutical composition of claim 14, wherein the anti-tumor agent is daunorubicin.

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