TW201215396A - Medicine for treating tumor and antitumor agent - Google Patents

Abstract

The object of the present invention is to provide a medicine for treating a tumor wherein the medicine exhibits therapeutic effects for nonresponder-patients of stomach cancer, colon cancer, rectal cancer, and small cell lung cancer, who show low response (sensitivity) to an antitumor agent comprising a protein polysaccharide derived from Coriolus as an active ingredient. The object of the present invention is solved by a medicine for treating a tumor, characterized by concomitantly administering: an antitumor agent comprising a protein polysaccharide derived from Coriolus as an active ingredient, and an immunesuppressor cell-inhibitory agent comprising a compound exhibiting inhibitory activity against immunesuppressor cells.

Description

201215396. In the following, the present invention relates to a tumor therapeutic agent or the like which uses an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient. [Prior Art] Proteoglycans extracted from Yunzhi exhibit antitumor activity and the like. An antitumor agent or the like having a proteoglycan of =2 cloud as an active ingredient is described in Japanese Laid-Open Patent Publication No. SHO 60-45533 (Patent Document No.). Among such proteoglycans, one of the proteoglycans derived from Yunzhi, the psK〇 main volume trademark) (commodity; δ "Krestin" (registered trademark)) is characterized not only by intradermal administration or vein Internal administration shows antitumor activity, and it can also be administered by oral administration to exhibit anti-tumor activity, and is also used clinically as a preparation for oral administration. PSK is a proteoglycan containing about 18 to 38% protein, and has a molecular weight of 5 Å or more (gel filtration method), for example, a molecular weight of 5 Å to 3 (9) (h) 〇 (gel filtration method). The sugar moiety of the main component is p_D_glucan, and the structure of the glucan moiety is a branched structure comprising a bond of 3, Μ and 卜6. It has been confirmed that an antitumor agent (for example, PSK) containing a proteoglycan derived from Yunzhi as an active ingredient is used in combination with chemotherapy for patients with gastric cancer (surgical cases) and colon and rectal cancer (healing resection). The prolonged effect of survival time and the prolonged effect of effective time by combination with chemotherapy for small cell lung cancer are recognized for the application of gastric cancer patients, colon, rectal cancer patients, and small cell lung cancer patients. [Prior Art Document] 158544.doc 201215396 [Patent Document 1] [Patent Document 1] Japanese Patent Laid-Open Publication No. SHO 60-45533 [Summary of the Invention] [Problems to be Solved by the Invention] However, in patients with gastric cancer, colon, and rectal cancer In patients with small cell lung cancer, there is a nonresponcier with a low effect of PSK administration. Namely, 'in gastric cancer patients, colon, rectal cancer patients, and small cell lung cancer patients', there is a non-responder having low reactivity (sensitivity) to an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient. Accordingly, it is an object of the present invention to provide a tumor therapeutic agent or an antitumor agent which exhibits a therapeutic effect even for such non-responders. Moreover, the application of PSK to cancer patients other than gastric cancer patients, colon and rectal cancer patients, and small cell lung cancer patients has not yet been approved. A further object of the present invention is to provide a tumor therapeutic agent or an antitumor agent using a proteoglycan derived from Yunzhi for a cancer patient who does not recognize PSK. [Means for Solving the Problem] The inventors of the present invention conducted intensive studies on a compound which can enhance the therapeutic effect of a proteoglycan derived from Yunzhi on a malignant tumor, and as a result, found that the inhibitory activity against immunosuppressive cells is obtained. The combination of the compound and the proteoglycan derived from Yunzhi can be used together to enhance the inhibition of cancer cell proliferation by the proteoglycan derived from Yunzhi, and it can be used as a therapeutic agent for tumors for many cancers. The present invention is based on such insights and includes the following invention.

The present invention relates to a medicament for treating a tumor, which comprises an immunosuppressive agent comprising a proteoglycan derived from a proteoglycan derived from Yunzhi as an active ingredient and a compound containing an inhibitory activity against immunosuppressive cells. Cytostatics. The agent for treating a tumor of the present invention exerts a high therapeutic effect even in a non-responder who has low reactivity with an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient. In the agent for tumor treatment of the present invention, it is preferred that the compound further has sputum tumor activity. By having antitumor activity of a compound having an inhibitory activity against immunosuppressive cells, a synergistic effect can be obtained in the treatment of tumors. Further, in the agent for tumor treatment of the present invention, preferably, the immunosuppressive cell is a bone marrow-derived suppressor cell (MDSC, Myeloicl_Derived Duppressor Ceil). By having the inhibitory activity of Mdsc in the above compound, the inhibition of the action of the antitumor agent containing the polysaccharide derived from the Yunzhi protein as an active ingredient by MDSC can be eliminated, and the therapeutic effect of the therapeutic agent for tumor therapy can be enhanced. Further, in the agent for tumor treatment of the present invention, preferably, the immunosuppressive cell is a control T cell (Treg, Reguiat〇ry τ eeUs). By having the Treg inhibitory activity of the above compound, the inhibition of the action of the antitumor agent containing the proteoglycan derived from Yunzhi as an active ingredient by Treg can be eliminated, thereby improving the therapeutic effect of the therapeutic agent for tumor therapy. In the agent for treating a tumor of the present invention, preferably, the compound is selected from the group consisting of gemcitabine, phosphodiesterase-5 (PDE-5) inhibitory compound, and all-trans-retinoic acid (ATRA). , arginase inhibition 158544.doc 201215396 compound, sunitinib, cyclophosphamide, denileukin diftitox, CTLA-4 inhibitory compound, CD25 inhibitory compound, and _ 2R inhibitor compound a compound in the middle. Further, the present invention relates to an antitumor agent characterized by comprising an immunosuppressive cytokine containing a proteoglycan derived from Yunzhi as an active ingredient and a compound having an inhibitory activity against immunosuppressive cells. And use it. The antitumor agent of the present invention exerts a high therapeutic effect even when it is not particularly reactive to an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient. Further, the present invention relates to a method for treating a tumor, which comprises combining an antitumor agent containing a proteoglycan derived from Yunzhi as an effective component and an immunosuppressive cell inhibitor containing a compound having an inhibitory activity against immunosuppressive cells. Agent. Further, the present invention relates to a kit for treating a tumor, which comprises a compound containing a plurality of active ingredients, and a compound containing a proteoglycan derived from Yunzhi and an inhibitory activity against immunosuppressive cells as the above activity. ingredient. [Effect of the Invention] The anti-tumor agent containing the proteoglycan derived from Yunzhi as an active ingredient and the immunosuppressive cell inhibitor containing a compound having an inhibitory activity against immunosuppressive cells are used in combination with the agent for treating a tumor of the present invention. When the agent is administered, the proliferation of cancer cells can be inhibited, and a higher therapeutic effect can be obtained. That is, the agent for tumor treatment of the present invention has low reactivity (sensitivity) to an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient.

S 158544.doc 201215396 Non-responders also exert a higher therapeutic effect. In addition, the tumor-treating agent of the present invention inhibits the proliferation of cancer cells even in the case of a tumor that does not recognize an antitumor agent containing a proteoglycan derived from a proteoglycan derived from Yunzhi, such as PSK, and thereby causes the cancer cells to subside. effect. For example, the present invention has not yet recognized the use of an antitumor agent containing a polysaccharide derived from Yunzhi as an active ingredient such as PSK, but the tumor therapeutic agent of the present invention can also inhibit the proliferation of cancer cells and further cause cancer cells to regress. Further, when the immunosuppressive cytostatic agent used in the present invention has immunosuppressive cell inhibitory activity and (direct) cell killing (damage) activity, the tumor therapeutic agent of the present invention exhibits that each of the compounds has the original The effect of synergy. [Embodiment] [1] Agent for tumor therapy The agent for tumor therapy of the present invention is an immunological anti-tumor agent containing a proteoglycan derived from Yunzhi as an active ingredient and a compound containing a compound having an inhibitory activity against immunosuppressive cells. Inhibitors of cytostatics. The details of the antitumor agent and the immunosuppressive cell inhibitor of the therapeutic agent for tumor treatment of the present invention are described below. In addition, the term "combination" in the present specification and the like refers to administration of a medicament for treating a tumor containing a proteoglycan derived from Yunzhi and a compound having an inhibitory activity against immunosuppressive cells as an elixir. Further, it also refers to an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient in an individual preparation form, and an immunosuppressive cytostatic agent containing a compound having an inhibitory activity of 158544.doc 201215396 having immunosuppressive cells. At the same time or staggered time, the administration was carried out in the form of 2 doses. In the latter case, the number of administrations of the antitumor agent and the immunosuppressive cell inhibitor may be the same or different. (Antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient) As an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient, for example, PSK can be mentioned. PSK is sold under the trade name "Krestin". It can be used as an aqueous solvent, such as hot water or an alkaline solution (for example, an alkali metal hydroxide, especially an aqueous solution of sodium hydroxide) against Yunzhi CM101 strain [FERM- The mycelium of P2412 (ATCC 20547)] was extracted, purified, and dried. The sugar moiety of the main component is β-D-glucan, and the structure of the glucan moiety is a branched structure comprising β 1 -3, β 1 -4 and β 1 - 6 linkages. The main constituent monosaccharide is glucose or mannose, which contains about 18 to 38% protein. Among the amino acids constituting the protein, acidic amino acids such as aspartic acid or glutamic acid, and neutral amino acids such as lysine or leucine are many, and alkalis such as amino acid or arginine are used. Less amino acid. In the present specification and the like, Yunzhi is not limited to the CM101 strain, and may be any one containing a proteoglycan having antitumor activity. Further, the antitumor agent containing the proteoglycan derived from Yunzhi as an active ingredient is not limited as long as it has antitumor activity. For example, it can be PSK, and ASKRE (曰医工), KREZYL POWDER (沢井制药), CHIORESTIN POWDER (长生堂), CHIORESTIN POWDER (TANABE SEIYAKU HANBAI), which are PSK's generic drugs (Generic Drug). , CARBOCRIN POWDER (Dayang Pharmaceutical Industry), and CARBOCRIN POWDER (Nippon Chemiphar). 158544.doc 5 201215396 It has been confirmed that an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient is used in combination with chemotherapy for patients with gastric cancer (surgical cases) and colon and rectal cancer (healing resection). The prolongation of survival time and the prolonged effect of effective time by combination with chemotherapy for small cell lung cancer have been recognized for the application of gastric cancer patients, colon, rectal cancer patients, and small cell lung cancer patients. (Immunostatic cytostatic agent containing a compound having an inhibitory activity against immunosuppressive cells) The immunosuppressive cytostatic agent used in the agent for treating a tumor of the present invention contains a compound having an inhibitory activity against immunosuppressive cells. The immunosuppressive cells are not particularly limited as long as they have a function of suppressing the immune response of the living body. Examples of the immunosuppressive cells include inhibitory cells derived from the bone marrow (hereinafter referred to as MDSC) and controllable tau cells (hereinafter referred to as Treg). The inhibitory cells derived from bone marrow and controllable tau cells are described below. (Inhibitory cells derived from bone marrow) MDSC is a generic term for bone marrow cell cells having immunosuppressive function. MDSC is a heterogeneous cell population that interacts with tau cells, macrophages, and natural killer cells. In addition, the report has an increase in peripheral blood and tumor tissues of cancer patients. The surface marker of the MDSC as a mouse is not particularly limited, and examples thereof include CDllb and Grl. Further, CD31 + & IL_4a can also be used as a marker. Further, the surface markers of human MDSCs are cdi ib+, Grl+, CD14仏, and HLA_DR丨. W, but no specific marker was identified. According to 158544.doc •10-201215396, the human MDSC is not limited to cells having the above-mentioned markers as long as it has any of the following immunosuppressive functions. The immunosuppressive function of MDSC is inducible nitric-oxide synthase 2 (hereinafter referred to as NOS2) and arginase-l (hereinafter referred to as ARG1) expressed in MDSC. Two enzymes are related. NOS2 inhibits IL-2 receptor signaling of T cells via NO production and induces programmed cell death. On the other hand, ARG1 inhibits the function of T cells by consuming arginine from the surrounding environment by using a metabolic enzyme of arginine. Further, as an immunosuppressive function of MDSC, immunosuppression caused by TGF-β and IL-10 secreted by MDSC and cysteine deficiency due to presence of MDSC are also reported. (controlled T cells)

Treg is a T cell that inhibits an immunologically active cell such as a T cell or a dendritic cell, and an increase in Treg is confirmed in human tumor tissue or peripheral blood. The surface marker of human Treg is not limited, and can be set as CD4+, CD25+ (IL_2 receptor alpha chain), and accounts for 5-10% of CD4+ cells of normal human peripheral blood. In addition, Treg blames glucocorticoid-induced TNF receptor (GITR) and Cytotoxic T lymphocyte antigen 4 (CTLA-4). And FOXP3. In CD4+Treg, IL-10-producing Tr1, TGF-β-producing Th3, naturally occurring Tregs (nTreg), and inducible Tregs (iTreg) were reported. nTreg prevents the onset of autoimmune diseases by physiologically inhibiting autoreactive T cells that escape central immunological tolerance in the thymus. s 158544.doc -11 - 201215396 (compound having inhibitory activity against immunosuppressive cells) The compound having an inhibitory activity against immunosuppressive cells includes, for example, a compound which inhibits the function of MDSC, a compound which inhibits the function of Treg, and A compound that inhibits the function of MDSC and Treg. In the present specification and the like, "inhibiting the function of MDSC" includes reducing cells of MDSC, suppressing immunosuppressive substances secreted from MDSC, inhibiting secretion of immunosuppressive substances against MDSC, or inhibiting antigen presentation ability and effect ability by MDSC. The suppression and the like. In addition, the "function of suppressing Treg" in the present specification and the like may be understood as the Treg in the description of the MDSC. In addition, the term "reduction" as used herein refers to the induction inhibition and elimination of MDSC or Treg. Examples of the compound which inhibits the function of MDSC. include gemcitabine, phosphodiesterase-5 (PDE-5) inhibitory compounds (e.g., sildenafil, tadalafil, and vardenafil). (vardenaifil)), all-trans-retinoic acid (hereinafter referred to as ATRA), or arginase-inhibiting compound (for example, boric acid derivative 2(S)-amino-6-side Boronic-acid derivative 2(S)-amino-6-boronohexanoic acid (ABH), S-(2 boroethyl)-L-cysteine (S-(2boronoethyl)-L-cysteine) BEC)), COX-2 (epoxidase-2) inhibitor (SC58236), KIT-specific antibody, Nitroaspirin, Vitamin D3, Avastin Vascular Endothelial Growth Factor _ VEGF-trap, Vascular Endoth'elial Growth Factor-trap, Doxorubicin, 5-1 Urine 158544.doc -12- 201215396 Pyrimidine (5-FU), cyclophosphamide. For example, ATRA differentiation induces MDSC' to inhibit the immunosuppressive activity of MDSC. Further, boric acid derivative 2(S)-amino-6-borocabonic acid (ΑΒΗ), and S-(2boroethyl)-L-cysteine (BEC) are analogs of arginine. Examples of the compound which inhibits the function of Treg include cyclophosphamide, Denierukin diftitox, CTLA-4 inhibitory compound (for example, anti-CTLA-4 antibody), CD25 inhibitory compound (for example, anti-CD25 antibody), and IL. -2R inhibiting compounds (eg, anti-il-2R antibodies). The interleukin is a fusion protein of il-2 and diphtheria, and kills CD25-positive cells. As a compound which inhibits the functions of MDSC and Treg, a compound having an inhibitory activity against sunitinib (Sunitinib) having immunosuppressive cells preferably has antitumor activity in addition to an inhibitory activity against immunosuppressive cells ( Direct cell killing activity). By inhibiting immunosuppressive cells, a compound having an inhibitory activity against immunosuppressive cells can enhance the antitumor effect of an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient, and can inhibit tumor cells by itself. . Therefore, a synergistic effect on inhibition of proliferation of tumor cells can be obtained by using a drug for tumor treatment containing an immunosuppressive cytostatic agent having a compound having antitumor activity in addition to an inhibitory activity against immunosuppressive cells. Examples of the compound having an inhibitory activity against immunosuppressive cells and having antitumor activity (direct cell killing activity) include gemcitabine, cyclophosphamide, and sunitinib. Inhibitory activity with immunosuppressive cells and

S 158544.doc -13· 201215396 In the compound having antitumor activity, when the effective amount of the inhibitory activity of the immunosuppressive cell is different from the effective amount showing the antitumor activity, p, 'the compound is administered at least to show Amount of inhibitory activity of immunosuppressive cells 0 (Gemcitabine) Gemcitabine is a compound represented by the following formula (1), and a pharmaceutical composition containing gemcitabine hydrochloride is used as a non-small cell cancer, pancreatic cancer, biliary tract cancer, It is approved and sold for urothelial cancer and antitumor agents for non-surgical or recurrent breast cancer (trade name: Gemzar). In addition, the report is also effective for breast cancer, bladder cancer, and nest cancer. Furthermore, the effects of cisplatin are inhibition of DNA synthesis, induction of programmed cell death, and reduction of MDSC. [Chemical 1]

Regarding the administration of gemcitabine as an anti-tumor agent, in the case of non-small cell lung cancer, pancreatic cancer, biliary tract cancer, urothelial cell carcinoma, intravenous infusion of 1 〇〇.〇rng by taking 30 minutes each time /m2 of gemcitabine. One dose per week was continued for 3 weeks, and the drug was discontinued at the 4th week. Take this as a course of treatment and 158544.doc •14- 201215396. Furthermore, it can be appropriately reduced according to the state of the patient. Further, in the case of inoperable or recurrent breast cancer, as gemcitabine, an intravenous infusion of 125 mg/m 2 of gemcitabine was administered for 30 minutes each time. In this case, the administration was performed once a week for 2 consecutive weeks, and the third week was discontinued. Take this as a course of treatment and repeat it. (Cyclophosphamide) Cyclophosphamide is a compound represented by the following formula (2), for multiple bone tumors, malignant lymphoma (Hodgkin's disease, lymphosarcoma, reticulum sarcoma), lung cancer, breast cancer The use of acute leukemia, polycythemia vera, cervical cancer, endometrial cancer, ovarian cancer, neurotumor (neuroblastoma, retinoblastoma), and bone tumors has been recognized. In addition, in chronic lymphocytic leukemia, chronic osteogenic leukemia, throat cancer, gastric cancer, adenocarcinoma, liver cancer, colon cancer, testicular tumor, chorionic disease (choriocarcinoma, destructive mole, mole), Among rhabdomyosarcoma and malignant melanoma, it is recognized in combination with other anti-malignant agents. Further, it is recognized in the combination therapy with other anti-malignant agents in breast cancer (preoperative or postoperative chemotherapy). Cyclophilamide is a compound which inhibits the function of Treg by a small amount of administration. [Chemical 2] C1\

(2)

S 158544.doc •15· 201215396 Regarding the administration of cyclophosphamide as an antitumor agent, in the case of separate administration, 100 mg of cyclophosphamide (in terms of anhydride) is injected into adults once a day. Go to the vein. In the case of patient tolerance, the dose per sputum is increased to 200 mg. The cyclophosphamide is administered in a total amount of 3000-8000 mg, and is as long as possible when the effect is found. (Sunitinib) Sunitinib is a compound represented by the following formula (3), against the imatinib gastrointestinal stromal tumor (GIST, Gastrointestinal Stromal Tumors), and renal cells that cannot be cured or metastasized The application of cancer is recognized and sold under the trade name SUTENT. Sunitinib is a compound that inhibits the function of Treg and MDSC. The main function is VEGF (Vascular Endothelial Growth Factor) receptor involved in angiogenesis and PDGF (Platelet-Derived Growth Factor) involved in tumor proliferation. A plurality of receptors such as a source growth factor receptor are used as targets. [Chemical 3]

158544.doc 16- 201215396 The administration of sunitinib as an anti-tumor agent was carried out by oral administration of 50 mg of sunitinib in adults for 4 weeks and 1 time. It was suspended for 2 weeks. Take this as a course of treatment and repeat it. Furthermore, the amount is appropriately reduced according to the state of the patient. (Advantages of a therapeutic agent for tumors) - It is generally considered that an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient exerts an antitumor effect by restoring and enhancing a living body defense function of a cancer patient, specifically an immune function. . Therefore, by immunizing a cancer patient with an immunosuppressive cytokine containing a compound having an inhibitory activity against immunosuppressive cells, immunosuppressive cells (e.g., MDSC or T> eg) of cancer patients can be inhibited. In this way, by suppressing the suppression of the immune function by the suppression of the immunosuppressive cells, the immunostimulating action of the antitumor agent containing the polysaccharide derived from the Yunzhi protein as an active ingredient can be further enhanced. Therefore, an immunosuppressive cytostatic agent containing a compound containing a proteoglycan derived from a protein and an immunosuppressive cytostatic agent containing a compound having an inhibitory activity against immunosuppressive cells can be used to contain a source derived from Yunzhi. An immunostimulatory action of an antitumor agent having a proteoglycan as an active ingredient is inhibited by an immunosuppressive cell (for example, a non-responder who is less responsive to treatment with an antitumor agent derived from a proteoglycan derived from Yunzhi) And the use of anti-tumor agents derived from Yunzhi's proteoglycans: cancer patients) to improve the therapeutic effect. Further, when the immunosuppressive cytostatic agent containing a compound having an inhibitory activity against immunosuppressive cells has antitumor activity, it is expected to cooperate with the antitumor activity of the antitumor agent derived from the proteoglycan derived from Yunzhi. 5 158544.doc 1<7 201215396 Same effect. Further, the use of an anti-tumor agent containing a proteoglycan derived from Yunzhi as an active ingredient has not been recognized for cancer patients, colon, rectal cancer patients, and cancer patients other than small cell lung cancer patients. Therefore, the object of the present invention is also to provide a tumor therapeutic agent to a cancer patient other than a gastric cancer patient, a colon, a rectal cancer patient, and a small cell lung cancer patient, which is a source of less side effects for cancer patients. The agent of the proteoglycan from Yunzhi can obtain a higher therapeutic effect. Here, 'when the immunosuppressive cell inhibitor has antitumor activity against the activity of tumors other than gastric cancer, colon, rectal cancer, and small cell lung cancer', even for lunar cancer, colon, rectal cancer, and small cell lung cancer A tumor other than 'can also obtain a therapeutic effect using an antitumor agent derived from a proteoglycan of Yunzhi. In other words, when the immunosuppressive cell inhibitor has antitumor activity (direct cell killing activity) even for tumors other than gastric cancer, colon, rectal cancer, and small cell lung cancer, the tumor therapeutic agent of the present invention is used. An antitumor agent using a proteoglycan derived from Yunzhi can be provided for the treatment of cancer patients other than gastric cancer, colon, rectal cancer, and small cell lung cancer. Further, even for a tumor in which an antitumor agent containing a proteoglycan derived from a proteoglycan derived from Yunzhi is not approved, and an immunosuppressive cell inhibitor which does not recognize an antitumor activity as an antitumor agent, The inventive therapeutic agent for tumors is also effective. (Formulation of a medicament for treating a tumor) The dosage form of the medicament for treating a tumor of the present invention may be a separate preparation of the antitumor agent and the cytostatic agent of the immunosuppressive 158544.doc -18-201215396, respectively, or may be An antitumor agent (proteoglycan derived from Yunzhi) is mixed with an immunosuppressive cell inhibitor (a compound having an inhibitory activity against immunosuppressive cells). The combination ratio of the proteoglycan derived from Yunzhi to the compound having the inhibitory activity of the immunosuppressive cell (the ratio in the tincture or the ratio of the use in the two doses) is as long as it is effective for the treatment of cancer. There is no particular limitation. (In the case where the agent for the treatment of the tumor is one dose), when the agent for the treatment of the tumor is one dose, the ratio of the proteoglycan derived from the Yunzhi protein and the compound having the inhibitory activity of the immunosuppressive cell is as long as the tumor The treatment is effective, and is not particularly limited. Further, the dosage form of the medicinal agent is not particularly limited, and for example, oral administration can be carried out in the form of a conventional pharmaceutical preparation such as a sac, a microcapsule, a granule, a granule, a fine granule, or a powder. Further, it may be administered by intravenous injection of a conventional pharmaceutical preparation such as an injection such as intramuscular injection, intramuscular injection, or subcutaneous injection (e.g., intravenous injection). Subcutaneous technique, intraperitoneal administration, rectal administration, transdermal preparations, excipients, wetting agents, disintegrating agents, surfactants, granules, preservatives, and dissolutions can be used. Auxiliary: agent: slowing agent, agent, etc., the above additives are produced by the common method, for example, gelatin of gelatin, carbonated town, synthetic stone acid, glucose, powder, talcum powder, stearic acid Magnesium, its total vitamins, methine cellulose or its salt _ methyl fibrillated Labo gum, polyethylene glycol, sugar

S 158544.doc 201215396 Glycerin, ethanol, propylene glycol, citric acid, sodium chloride, syrup, petrolatum,

In addition, the administration method and the administration interval of the tumor therapeutic agent can be appropriately set depending on the body weight of the patient, for example, the dosage, the administration amount, the age, the degree of the symptoms, and the like. In the case where the agent for tumor treatment is one dose, a compound derived from the proteoglycan and the inhibitory activity of the immunosuppressive cell may be contained as an active ingredient, and further contains a pharmaceutically acceptable carrier. The medicine, and the form of the σ substance are provided. The pharmaceutical composition is a novel pharmaceutical combination (the advantage when the tumor therapeutic agent is an expectorant). By administering the tumor therapeutic agent to one dose, it is possible to avoid administering a plurality of drugs to the patient. In other words, by administering the expectorant in the same manner as heretofore, the proliferation of cancer cells can be suppressed, and a high therapeutic effect can be obtained, so that the burden on patients who are administered with the drug can be avoided. (When the agent for tumor therapy is used as two doses) When the agent for treating a tumor is separated into two agents of an antitumor agent and an immunosuppressive cell inhibitor, the ratio of use of the antitumor agent to the immunosuppressive cell inhibitor is only There is no particular limitation on the treatment of malignant tumors. Further, the dosage form of the antitumor agent and the immunosuppressive cell inhibitor is not particularly limited, and the same dosage form as the above-mentioned one agent for the tumor therapeutic agent can be used. Further, the administration method, the administration amount, the administration time, and the administration interval can be appropriately set, for example, according to the patient's body weight, age, degree of symptoms, etc., using gemcitabine as a component. It is not necessary to be administered as a course of treatment, as long as, for example, when psk is used as an anti-tumor inhibitory cell inhibitor, administration can be carried out as follows: t-citabine is owed weekly, each intravenously The mgw was administered for 2 weeks, and the PSK system was continuously administered orally at 3 g from the 2nd week. Alternatively, it can be administered as follows. The gemcitabine system is administered once a week, each time intravenously to the brain mg/mm2 for 3 weeks, and the psK system starts from the second week. The oral administration was continued in a week with la 3 g. Tian Ran, the above-mentioned administration method is a list, and it can also be used for other administrations and dosages of human anti-tumor agents and immunosuppressive cell inhibitors, dosage, administration time, and administration interval. Ideally, it is determined based on the clinical treatment experience being managed. Further, the anti-tumor agent may be provided in the form of a pharmaceutical composition containing a proteoglycan derived from Yunzhi as an active ingredient and further containing a pharmaceutically acceptable carrier. Further, the immunosuppressive cytostatic agent may be provided as a pharmaceutical composition containing a compound having an inhibitory activity against immunosuppressive cells as an active ingredient and further containing a pharmaceutically acceptable carrier. (Advantages when the tumor therapeutic agent is used as two doses) In the case of using an immunosuppressive cytostatic agent having antitumor activity, by treating the tumor therapeutic agent into two doses, even if one drug is stopped It is also possible to continue to administer another agent during the period. For example, when the side effect of one drug is large and the side effect of the other drug is small, even if it is not necessary to administer a drug having a large side effect, it is necessary to administer a drug having a large side effect, and thus there is a burden on the patient. Increase the ambiguity. By making the tumor s 158544.doc •21 · 201215396 into 2 swords, it is possible to administer another agent with less side effects even during the period when the expectant agent with a large side effect is stopped. In this way, by treating the tumor with two doses, it is possible to suppress the proliferation of cancer cells to obtain a higher therapeutic effect, and to avoid an increase in the burden on the side effects of the patient. The appropriate combination ratio (mixing ratio, or use ratio) of each of the antitumor agent and the immunosuppressive cell inhibitor in the agent for treating a tumor of the present invention is set, and the administration period and the administration interval are set. Preferably, it is determined according to the clinical trial being controlled. The administration method, the administration amount, the administration period, and the administration interval for the combined use of the antitumor agent and the immunosuppressive cytostatic agent are described in the accompanying documents or instructions of the tumor therapeutic agent of the present invention. can. (The tumor to be treated by the agent for treating a tumor) The tumor to be treated by the agent for treating a tumor of the present invention is not particularly limited, and the following may be mentioned. Specific examples include breast cancer, squamous cell carcinoma, lung cancer (for example, small cell or non-small cell lung cancer), pancreatic cancer, glioblastoma, ovarian cancer, vulvar cancer, liver cancer, hepatocellular carcinoma, colorectal cancer, and uterus. Cancer (eg endometrial cell tumor, cervical cancer, endometrial cancer), salivary gland cancer, kidney cancer, thyroid cancer, bladder cancer, kidney cancer, head and neck cancer, stomach cancer, esophageal cancer, prostate cancer, biliary tract cancer, Neurological cancer (eg, neuroblastoma), retinal cancer, skin cancer, leukemia, urothelial carcinoma, brain tumor, osteosarcoma, or transitional epithelial cancer. More specifically, the following may be mentioned as cancers and other cancers to which PSK, gemcitabine, cyclophosphamide, or sunitinib are applied. 158544.doc •22- 201215396 (1) Cancer for PSK (stomach cancer, colon, rectal cancer, and small cell lung cancer) (2) Gemcitabine-based cancer (non-small cell carcinoma, pancreatic cancer, biliary tract cancer, road surface) Carcinoma, and inoperable or recurrent breast cancer) (3) Applicable to carbon cancer (multiple myeloma, malignant lymphoma (Hodgkin's disease, lymphosarcoma, reticulum sarcoma), lung cancer, breast cancer, Acute leukemia, polycythemia vera, cervical cancer, endometrial cancer, ovarian cancer, neurological tumor (neuronal blastoma, retinoblastoma), bone tumor, chronic lymphocytic leukemia, chronic myelogenous leukemia, throat cancer, stomach cancer , pancreatic cancer, liver cancer, colon cancer, testicular tumor, chorionic disease (chorionic cancer, destructive mole, hydatidiform mole), rhabdomyosarcoma, malignant melanoma, breast cancer (preoperative or postoperative chemistry of operable cases) Therapy)) (4) For the treatment of sunitinib (anti-imatinib gastrointestinal stromal tumor (GIST), and renal cell carcinoma that cannot be cured or metastatic) (5) other cancers (squamous Cancer, glioblastoma, vulvar cancer, liver cancer, hepatocellular carcinoma, colorectal cancer, uterine cancer (eg endometrial cell tumor, cervical cancer, or endometrial cancer), salivary gland cancer, kidney cancer, thyroid cancer , bladder cancer, head and neck, cancer, esophageal cancer, prostate cancer, neurological cancer (such as neuroblastoma), retinal cancer, skin cancer, leukemia, brain tumor, osteosarcoma, transitional epithelial cancer) The inflammatory mass of the therapeutic agent of the medicament is such non-small cell lung cancer, salivary gland cancer, biliary tract cancer, urothelial carcinoma 'gastric cancer, knotted, rectal cancer, small cell lung cancer. [2] An antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient. The anti-tumor derived from the proteoglycan derived from Yunzhi as an active ingredient in the third of April 158544.doc • 23· 201215396 Oncology and inclusion An immunosuppressive cytostatic agent having a compound having an inhibitory activity against immunosuppressive cells is used in combination. The antitumor agent containing the proteoglycan derived from Yunzhi as an active ingredient is the same as the antitumor agent in the above-mentioned tumor therapeutic agent, and thus detailed description thereof will be omitted. Further, as an immunosuppressive cytostatic agent to be administered in combination with an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient, the same immunosuppressive cell inhibitor as the above-mentioned tumor therapeutic agent can be used. The appropriate use ratio, administration amount, administration time, and administration interval of the antitumor agent in combination with the immunosuppressive cytokine inhibitor are preferably determined according to the controlled clinical test. The administration method, the administration amount, the administration time, the administration interval, and the like for the combined use of the antitumor agent and the immunosuppressive cytostatic agent may be described in the accompanying documents or instructions of the antitumor agent. The tumor to be treated as an antitumor agent is not particularly limited, and examples thereof include tumors to be treated for a tumor therapeutic agent, and are preferably non-small, 'field lung cancer, pancreatic cancer, biliary tract cancer, urothelial carcinoma. , gastric cancer, colon, rectal cancer, small cell lung cancer. Among the antitumor agents of the priming, it is preferred that the compound having the immunosuppressive cell I5 is active and has antitumor activity. By having an anti-tumor activity of a compound having an inhibitory activity against immunization of cells, a synergistic effect can be obtained in tumor/score therapy, and even if the anti-tumor agent of the present invention is not approved, treatment effect. Further, in the antitumor agent of the present invention, it is preferred that the immunosuppressive property is fine

》 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The anti-tumor agent of the present invention is used as an active ingredient to suppress the action of the anti-tumor agent derived from Yunzhi caused by MDSC, and the therapeutic effect. Further, in the anti-tumor agent of the present invention, it is preferably immunized. The inhibitory cell is a control T cell (Treg), and the compound having the inhibitory activity of the immunosuppressive cell has the inhibitory activity of Treg, and the protein polysaccharide derived from Yunzhi caused by (4) can be eliminated as an active ingredient. The anti-tumor agent is inhibited by the action of the anti-tumor agent, and the anti-tumor agent of the present invention is preferably a compound having the immunosuppressive activity of the anti-tumor agent. Free gemcitabine, phosphodiesterase _ 5 (PDE-5) inhibitory compound, all-trans retinoic acid (_ATRA), arginine inhibitory compound, sunitinib, cyclophosphamide a compound of a group consisting of Denileukin diftitox, a CTLA-4 inhibitory compound, a CD25 inhibitory compound, and an IL_2R inhibitory compound. [3] An immunosuppressive cytostatic agent containing a compound having an inhibitory activity against immunosuppressive cells The immunosuppressive cell inhibitor containing a compound having an inhibitory activity against immunosuppressive cells described in the present specification and the like is used in combination with an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient. An immunosuppressive cytokine inhibitor of a compound which inhibits activity is an immunosuppressive cytokine inhibitor in the above-mentioned tumor therapeutic agent, and an anti-tumor which is administered in combination with an immunosuppressive cytostatic agent containing a compound having an inhibitory activity against immunosuppressive cells Agent can use the above

S 158544.doc •25- 201215396 The tumor therapeutic agent contains a proteoglycan derived from Yunzhi as an anti-tumor agent with a six-component composition. According to the controlled clinical trial, the appropriate use ratio, administration amount, and administration time and administration interval of the immunosuppressive cytostatic agent and the antitumor agent in the immunosuppressive cytokine inhibitor of the present specification are set. = decided. The administration method or the method for administering an immunosuppressive cytostatic agent and an antitumor agent in combination with the immunosuppressive cytokine inhibitor of the present invention, the administration amount, the administration time, and the administration interval are described. [4] Method for treating tumors The present invention discloses a method for treating tumors, which comprises administering an effective amount of an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient to an object in need of tumor treatment, and containing immunosuppressive activity. An immunosuppressive cytostatic agent of a compound that inhibits activity of a cell. The immunosuppressive cell inhibitor used in the present therapeutic method preferably further has antitumor activity. Further, the immunosuppressive cells in the immunosuppressive cytostatic agent having activity of inhibition used in the present therapeutic method are, for example, osteoblast-inhibiting cells (MDSC) and control T cells (Treg). The immunosuppressive cytokine inhibitor may have an inhibitory activity against both MDSC and Treg, and may also have an inhibitory activity against β as a compound having inhibitory activity against immunosuppressive cells, and may be exemplified by gemcitabine or phosphodiesterase. _5 (PDE-5) inhibitory compound, all-trans-retinoic acid (ATRA), arginase inhibitory compound, sunitinib, cyclophosphamide, and dinileukin diftitox ), CTLA-4 inhibitory compound, CD25 inhibitory compound, and il-158544.doc -26-201215396 2R inhibitory compound. In the method for treating a tumor of the present invention, it is preferred that the compound having an inhibitory activity against immunosuppressive cells further has antitumor activity. Further, in the method for treating a tumor of the present invention, preferably, the immunosuppressive cell is a bone marrow-derived suppressor cell (MDSC). Further, in the method for treating a tumor of the present invention, preferably, the immunosuppressive cell is a control T cell (Treg). Further, in the method for treating a tumor of the present invention, preferably, the compound having an inhibitory activity against immunosuppressive cells is selected from the group consisting of gemcitabine, discoic acid diacetate-5 (PDE, 5) inhibitory compound, and all-trans retinoic acid. (4) i7^ acid ATRA), arginine inhibitory compound, sunitinib, denileukin diftitox, CTLA-4 inhibitory compound, CD25 inhibitory compound 4, and IL_2R inhibitory compound a compound in a group. [5] Tumor treatment kit The tumor treatment kit of the present invention is a combination of a plurality of active ingredients and contains a protein polysaccharide derived from Yunzhi and a compound having an inhibitory activity against immunosuppressive cells as the above-mentioned active ingredient. A compound derived from a protein body of Yunzhi and an inhibitory activity against immunosuppressive cells can be used as a proteoglycan derived from Yunzhi and a compound having an inhibitory activity against immunosuppressive cells in the above-mentioned tumor therapeutic agent. The tumor treatment kit of the present invention is a combination of a plurality of active ingredients and containing a protein polysaccharide derived from Yunzhi and a compound having an inhibitory activity against immunosuppressive cells as the above-mentioned active ingredient, and may further contain

S 158544.doc -27- 201215396 Instructions for administering a medicament to a patient simultaneously, continuously or individually. In the same manner as the agent for treating a tumor, it may contain a protein-derived polysaccharide derived from cloud and an inhibitory activity of immunosuppressive cells in the form of one dose, or may contain a proteoglycan derived from Yunzhi in two doses. And a compound having an inhibitory activity against immunosuppressive cells. Further, the administration method, the administration amount, the administration time, and the administration interval are not particularly limited. In the tumor treatment kit of the present invention, it is preferred that the compound having an immunosuppressive activity of the inhibitory activity of the fine moon L further has antitumor activity. Further, in the tumor treatment kit of the present invention, preferably, the immunosuppressive cells are bone marrow-derived suppressor cells (MDSC). Further, in the tumor treatment kit of the present invention, preferably, the immunosuppressive cells are control T cells (Treg), and in the tumor treatment kit of the present invention, preferably immunosuppressive cells are used. The inhibitory activity of the compound is selected from the group consisting of gemcitabine, phosphodiesterase-5 (PDE_5) inhibitory compound, all-trans retinoic acid (A), ruthenium acid (ATRA), arginine inhibiting compound, sunitinib a compound in a group consisting of a cyclic cans, a denileukin diftit x, a CTLa_4 inhibitory compound, a CD25 inhibitory compound, and a specific inhibitor compound. [6] Proteoglycan derived from Yunzhi A proteoglycan derived from Yunzhi as an active ingredient of an antitumor agent is used in a method for treating a tumor and is used in combination with a compound having an inhibitory activity against immunosuppressive cells. In the use of proteoglycans in the treatment of tumors, the compound having an inhibitory activity against immunogenicity of 158544.doc -28-201215396 is preferably further resistant to tumor activity. In the use of proteoglycans in tumor therapy methods, the immunosuppressive cells are preferably bone marrow-derived suppressor cells (MDsc). In the use of proteoglycans in tumor treatment methods, the immunosuppressive cells are preferably control T cells (Treg). In the use of proteoglycans in a method for treating tumors, the inhibitory active compound having immunosuppressive cells is preferably selected from the group consisting of gemcitabine, phospho-S-zyme-5 (PDE-5) inhibitory compound, and all-trans retinoic acid. (4) 丨 奶 ret retinoic acid . ATRA), arginine inhibitory compound, sunitinib, cyclophosphamide, dirithrin (Denileukin, ctla_4 inhibitory compound, CD25 inhibitory compound, and IL_2R inhibitory compound The present invention is not limited to the above-described embodiments, and various modifications can be made without departing from the scope of the invention, and the embodiments obtained by appropriately combining the technical means disclosed in the embodiments are also included in the technology of the present invention. In addition, the documents described in the present specification are hereby incorporated by reference. [Embodiment] The present invention is specifically described by the following examples, which are not intended to limit the scope of the invention. Example 1» In this embodiment, for the purpose of the invention, the tumor therapeutic agent is applied to a mouse transplanted with breast cancer cells. 'And study PSK and Gemcitabine 158544.doc •29·201215396 Bin (Gemzar injection) combined with the effect of the effect. For each female bALB / c mice, 1 x 1 〇 5 mice with breast cancer The cell line 4T1 was transplanted subcutaneously. At the time when breast cancer cells proliferated to 200 mm3, 8 animals in each group were divided into 4 groups (PSK and gemcitabine-administered groups, psk alone, group, gemcitabine alone, and non-injection). Gemcitabine is administered to the peritoneal cavity at a dose of 120 mg/kg after 7 days of collateralization. After gemcitabine is administered twice, it is 50 mg/kg three times a week from the next day. The dose was administered intraperitoneally to psk. In the non-administered group, physiological saline was administered intraperitoneally as a control for gemcitabine or pSK. The tumor volume after grouping, 7 days, 14 days, and 21 days was measured. On the next day of the administration, the necropsy was performed and the tumor weight was measured. The protocol and results are shown in Figure 丨. The figure shows the tumor volume of tumor treatment drugs in mice transplanted with breast cancer (Fig. 1B) and tumor weight. (Figure 1C) a graph of the inhibitory effect, and shows an anti-tumor And the scheme of the administration scheme of immunosuppressive cytostatics (Fig. 1A). The scheme of the scheme of Fig. 1 is for the PSK and the gemcitabine to find the group: the agent's investment plan. Furthermore, the investment plan "g" indicates that gemcitabine 'P' means PSK. That is, gemcitabine alone is administered to the group in the donation program without psk administration, and physiological saline is added instead of PSK. Another party, PSK The regimen of the gemcitabine was not administered alone in the administration program, and it was a regimen of administering physiological saline instead of gemcitabine. As shown in Figure 1, the PSK alone showed an anti-tumor tendency. However, no significant difference was confirmed. On the other hand, gemcitabine alone showed antitumor 158544.doc 201215396 tumor effect. Further, by combining gemcitabine with psk, the combined effect of tumor volume and tumor weight was confirmed. In addition, the gemcitabine in the sputum is administered separately to the group. As shown by the increase in tumor volume after the 14th, the growth of the tumor is promoted by the withdrawal of gemcitabine, but the PSK and gemcitabine are administered to the group at the stop of gemcitabine. During the drug period, proliferation promotion (recovery) is inhibited by administering only PSK. More specifically, the tumor volume was increased by about 600 mm3 in the gemcitabine alone. In contrast, the increase in tumor volume in the PSK and gemcitabine administration groups was suppressed to about 1 mm 3 . That is, when the gemcitabine is stopped, the proliferation of the tumor volume can be suppressed to about 1/6 by administration of PSK. In addition, if the PSK and gemcitabine-administered group, the PSK alone-administered group, the gemcitabine alone-administered group, and the non-administered group were used for tumor weight at the time of necropsy, PSK and gemcitabine-administered groups were compared with non-administered groups. The reduction in tumor weight is more than the reduction in the amount of PSK alone administered to the group, and the combination of the gemcitabine alone. It can be considered that the synergistic effect of the combined use of PSK and gemcitabine in the group is synergistic. Furthermore, the white triangle (Δ) in Fig. 1 indicates the PSK and gemcitabine-administered groups, the black horn (▲) indicates that Giesi reads the group separately, and the white diamond (◊) indicates that psk is administered separately to the group' and black. The diamond (♦) indicates a non-subject group. <<Example 2>> In the present example, the number of administrations of gemcitabine in Example 1 was increased, and the combined effect of PSK and gemcitabine was investigated. Change the investment of gemcitabine to just after grouping, after 7 days, after 14 days, and after 21 days, except this

The operation of Example 1 was repeated except for S 158544.doc -31-201215396. The investment plan and results are shown in Figure 2. Fig. 2 is a graph showing the inhibitory effect of tumor therapeutic agent on tumor volume (Fig. 2B) and tumor weight (Fig. 2C) in breast cancer transplanted mice, and an administration scheme indicating an antitumor agent and an immunosuppressive cytostatic agent. (Fig. 2A). The administration scheme shown in Fig. 2 is directed to the administration of each of the pSK and gemcitabine-administered agents. Furthermore, the rG of the investment scheme indicates gemcitabine, and the "P" indicates PSK. That is, gemcitabine alone is administered to the group as a solution for not investing in PSK in the administration plan. On the other hand, pSK alone is administered to the group in the administration program without the administration of gemcitabine, and it is a regimen of administering physiological saline instead of gemcitabine. In the present administration scheme, 'for 4Τ1 cells, PSK alone Although anti-tumor tendency was shown, no significant difference was confirmed, and gemcitabine alone showed an anti-tumor effect. Further, by using gemcitabine and PSK in combination, it is possible to clearly recognize the effect on the tumor volume and the tumor weight disc. As shown in Fig. 2, gemcitabine alone administered to the group increased tumor volume from day 7 to 21, but the pSK and gemcitabine administration groups of this example not only inhibited the increase of tumor volume, but also on the 7th to 21st. Reduce tumor volume. More specifically, the gemcitabine alone administered to the group increased the tumor volume by about 2〇〇mm3 during the period from 7th to 21st, compared to the 'PSK and gemcitabine administration group, the tumor volume was reduced to nearly 0°. After the 7th week, as the PSK administration started, the tumor volume began to decrease. Therefore, it was shown that PSK had a large effect on the reduction of tumor volume. 158544.doc •32· 201215396 Furthermore, the white triangle (△) in Fig. 2 indicates the pSK and gemcitabine-administered groups, the black triangle (▲) indicates that gemcitabine is administered separately, and the white diamond indicates that pSK is administered separately to the group 'and black The diamond (♦) indicates a non-subject group. <<Example 3>> In the present example, the effect of the combined use of PSK and gemcitabine (Gemzar injection) in the case of reducing the dose of gemcitabine was studied. For the dose of gemcitabine, the operation of Example 1 was repeated except that the amount of 60 mg/kg was used instead of the amount of 120 mg/kg. The results are shown in Fig. 3. Fig. 3 is a graph showing the inhibitory effect of a tumor therapeutic agent on tumor volume in a mouse transplanted mouse. As shown in Fig. 3, although the anti-tumor tendency was shown in the PSK alone administration group, no significant difference was observed, and on the other hand, gemcitabine alone showed an antitumor effect. Further, by using gemcitabine and PSK in combination, it is possible to clearly confirm the effect on the tumor volume. In addition, gemcitabine in Figure 3 was administered alone to the group. As shown by the increase in tumor volume after 14 days, the proliferation of tumors was promoted by the withdrawal of gemcitabine, but in the PSK and gemcitabine groups, in gemcitabine. Proliferation promotion (recovery) is inhibited by administration of PSK only during drug withdrawal. More specifically, in the gemcitabine alone administration group, the tumor volume was increased by about 500 mm3, whereas the tumor volume was hardly increased in the pSK and gemcitabine administration groups. Right comparison of PSK and gemcitabine-administered groups, PSK alone, group, gemcitabine alone, and non-administered groups on the day before the necropsy day, PSK and gemcitabine were compared to non-administered groups. The tumor volume is reduced more than PSK alone, and gemcitabine alone

S]58544.doc -33- 201215396 The addition of the group to the group can be considered to have a synergistic effect in the combination of PSK and gemcitabine. In addition, gemcitabine can achieve sufficient anti-tumor effects even at a dose of 6 mg/kg. Furthermore, the white square (□) in Fig. 3 indicates that pSK and gemcitabine (60 mg/kg) were administered to the group 'black squares' (not shown in gemcitabine (60 mg/kg) alone to the group 'white diamonds' (◊) PSK is administered separately to the group, and black diamonds (♦) indicate non-administered groups. <<Example 4>> In the present example, the effect of the combined use of PSK and gemcitabine (Gemzar injection) in the case of reducing the dose of gemcitabine was studied. The operation of Example 2 was repeated except that the amount of 60 mg/kg was used instead of 120 mg/kg for the administration of the drug. The results are shown in Fig. 4. Fig. 4 is a graph showing the inhibitory effect of a tumor therapeutic agent on tumor volume in a mouse transplanted mouse. As shown in Fig. 4, the administration of 4T1 cells to PSK alone showed an anti-tumor tendency, but no significant difference was confirmed. 'Gemcitabine alone showed an anti-tumor effect. Furthermore, by using gemcitabine and PSK together, it is obvious that the tumor volume can be tolerated and used together. As shown in Fig. 4, the tumor volume was increased on the 7th to 21st day of the gemcitabine alone administration group, but the tumor volume of the pSK and gemcitabine administration groups of the present example hardly increased from the 7th to the 21st. More specifically, the gemcitabine alone administered to the group increased the tumor volume by about 2 mm during the period from the 7th to the 21st. In contrast, the pSK and gemcitabine administration groups did not show an increase in tumor volume. Even if the dose of gemcitabine is reduced from 12 mg/kg to 6 mg/kg, a sufficient anti-tumor effect can be obtained. 158544.doc -34- 201215396 Furthermore, in the graph of tumor volume in Figure 4, white square (mouth) indicates PSK and gemcitabine (60 mg/kg) administered to the group, and black square () indicates gemcitabine (60 mg/). Kg) alone administered to the group, white diamond (◊) indicates pSK alone administered to the group, and 'black diamond (♦) indicates non-administered group. <<Example 5>> In the present example, in order to investigate the effect of the tumor therapeutic agent of the present invention in mice transplanted with pancreatic cancer cells, the combination of psk and gemcitabine (Gemzar injection) was studied. The effect of the vote. For each female BALB/c mouse, lxlO6 mouse pancreatic cancer cell line pAN_〇2 was transplanted subcutaneously. After 9 days of transplantation, 7 animals in each group were divided into 4 groups (psk and gemcitabine-administered group, PSK alone, group, gemcitabine alone, and non-administered group). Gemcitabine was administered to the peritoneal cavity at a dose of 6 〇 mg/kg after just after grouping and 7 weeks later. After gemcitabine was administered twice, pSK was administered intraperitoneally at a dose of 50 mg/kg three times a week starting from the next day. In the non-administered group, as a control of gemcitabine or PSK, physiological saline was administered intraperitoneally. Tumor volumes after grouping (9 days after transplantation), 13 days after transplantation, 17 曰, 20 曰, 24 曰, 27 曰, 31 曰 '34 曰 '38 曰, 41 曰, 45 曰, and 48 。 were measured. 48 days after tumor implantation, a necropsy was performed and the tumor weight was determined. The investment plan and results are shown in Figure 5. Fig. 5 is a graph showing the inhibitory effect of tumor volume (Fig. 5A) and tumor weight (Fig. 5B) in a tumor-treating agent in a mouse transplanted with adenocarcinoma. The administration scheme of the antitumor agent (PSK) and the immunosuppressive cell inhibitor (gemcitabine) is shown in Fig. 5A. Furthermore, the "G" of the investment scheme indicates that Gyxy s 158544.doc -35 - 201215396, and "P" indicates PSK. Gemcitabine alone was administered to the group in the administration protocol without the administration of PSK, and physiological saline was administered instead of PSK. On the other hand, PSK alone was administered to the group in the administration program without the administration of gemcitabine, and it was a regimen of administering physiological saline instead of gemcitabine. As shown in Fig. 5, with respect to the tumor volume, the PSK alone administered to the group showed p = 0.288" and the gemcitabine alone administered group showed ρ = 〇 · 292, which showed an anti-tumor tendency, but no significant difference was observed. Further, regarding the tumor weight, the PSK alone administered to the group and the gemcitabine alone administered to the group showed an anti-tumor tendency, but no significant difference was observed. On the other hand, by using gemcitabine and PSK in combination, it is possible to have a combined effect on tumor volume and tumor weight, specifically, p=0.034 in terms of tumor weight, and p=〇〇75 in tumor volume, which can be confirmed. The combination of gemcitabine and PSK. Furthermore, the white triangle (Δ) in Fig. 5A indicates the pSK and gemcitabine administration groups, the black triangle (▲) indicates that gemcitabine is administered alone, the white circle indicates that PSK is administered alone, and the black circle (·) indicates non-injection. To the group. «Example 6> In the present example, even if the administration start time of the tumor therapeutic agent of the present invention in Example 5 was postponed, the combination of pSK and gemcitabine was obtained and the effect was evaluated. The operation of Example 5 was repeated except that the administration of gemcitabine was started to be changed to 34%. Tumor volumes after grouping (34 移植 after transplantation), 36 曰, 40 曰, 43 曰, 47 曰, 50 曰, and 54 移植 after transplantation were measured. After 54 weeks of tumor transplantation, non-administered groups and 158544.doc _ 36 · 201215396 PSK alone were given to the group of mice to die. A graph showing the inhibitory effect of the tumor therapeutic agent on the tumor volume in a pancreatic cancer-transplanted mouse is shown in Fig. 6 . As shown in Fig. 6, in the pSK and gemcitabine alone, the anti-tumor tendency was shown, but no significant difference was observed. Furthermore, by using gemcitabine and PSK together, it is possible to clearly confirm the effect on the tumor volume. That is, the tumor volume of gemcitabine and PSK mice after 54 days after transplantation was compared with the control group, which was ρ=0·055, and there was a clear tendency to use the gemcitabine and PSK mice 50 days after transplantation. The tumor volume was compared with the control group, and p=〇.〇23, a significant difference was confirmed. In addition, gemcitabine in Figure 6 was administered alone to the group. As shown by the increase in tumor volume after 43 days, the proliferation of the tumor was promoted by the withdrawal of gemcitabine, but it was administered to the group of PSK and gemcitabine in gemcitabine. Proliferation promotion (recovery) is inhibited by administration of PSK only during drug withdrawal. More specifically, the tumor volume in the gemcitabine alone group was increased by about 350 mm3, whereas in the PSK and gemcitabine-administered groups, the increase in tumor volume was suppressed to about 2 mm 3 . That is, when the gemcitabine is stopped, the proliferation of the tumor volume can be suppressed by administering PSK. It can be considered that the combined effect of the PSK and gemcitabine in the group is synergistic. Furthermore, the white triangle (△) in Fig. 2 indicates the PSK and gemcitabine administration group, the black triangle (▲) indicates that gemcitabine is administered alone, and the white circle (〇) indicates that psK is administered separately to the group 'and black circle (·) Indicates a non-invested group. [Industrial Applicability] The agent for treating a tumor of the present invention can be preferably used as an improvement against the following

S 158544.doc -37-201215396 The agent for the therapeutic effect of the patient, the non-responder has low reactivity (sensitivity) to the antitumor agent containing psK as an active ingredient, and can be used as the currently unrecognized: containing PSK as effective A cancer patient with a compound of anti-tumor (4) has a higher therapeutic effect. The invention has been described above on the basis of specific aspects, and modifications or improvements are apparent to those skilled in the art. [Simple diagram of the diagram] Figure! (4) is a diagram showing the administration scheme of the antitumor agent and the immunosuppressive cell inhibitor, (8) is a graph showing the inhibitory effect of the tumor volume, and (C) is the inhibition of the tumor weight. A chart of the effects. Fig. 2 is a diagram showing the information relating to Example 2, (4) is a diagram showing an administration scheme of an antitumor agent and an immunosuppressive cell inhibitor, (B) is a graph showing the inhibitory effect of tumor volume, and (c) is a graph showing A graph of the inhibitory effect of tumor weight. Fig. 3 is a graph showing the effect of suppressing the tumor volume of the tumor therapeutic agent in Example 3. Fig. 4 is a graph showing the effect of suppressing the tumor volume of the tumor therapeutic agent of Example 4. Fig. 5 is a view showing the data relating to Example 5, wherein (a) is a graph showing the inhibitory effect of tumor volume, and (B) is a graph showing the effect of suppressing tumor weight. Fig. 6 is a graph showing the inhibitory effect of the tumor volume of the tumor therapeutic agent of Example 6. 158544.doc •38·

Claims (1)

201215396 VII 1. 2. 3. 4. 5. 6. 7. 8. Scope of application: A medicament for the treatment of tumors, characterized in that an antitumor agent containing a proteoglycan derived from Yunzhi as an active ingredient is used in combination with An immunosuppressive cytostatic agent comprising a compound having an inhibitory activity against immunosuppressive cells. The agent for tumor treatment according to claim 1, wherein the above compound further has antitumor activity. The agent for tumor treatment according to claim 1 or 2, wherein the immunosuppressive cell is a bone marrow-derived suppressor cell (MDSC). The tumor therapeutic agent according to claim 1 or 2 wherein the immunosuppressive cell is a control T cell (Treg). The tumor therapeutic agent according to claim 1 wherein the compound is selected from the group consisting of gemcitabine, phosphodiesterase-5 (PDE-5) inhibitory compound, all-trans-retinoic acid (ATRA), and fine A compound of the group consisting of an aminase inhibitory compound, sunitinib, a cyclamate, a deniieukin diftitox, a CTLA_4 inhibitory compound, a CD25 inhibitory compound, and an IL-2R inhibitory compound. An antitumor agent comprising a protein polysaccharide derived from Yunzhi as an active ingredient and used in combination with an immunosuppressive cytokine containing a compound having an inhibitory activity against immunosuppressive cells. A method for treating a tumor, which comprises using an antitumor agent containing a polysaccharide derived from Yunzhi as an active ingredient and an immunosuppressive cytostatic agent containing a compound having an inhibitory activity against immunosuppressive cells. A tumor treatment kit comprising a plurality of active ingredients in combination, and S 158544.doc 201215396 contains a protein polysaccharide derived from Yunzhi and a compound having an inhibitory activity against immunosuppressive cells as the above-mentioned active ingredient. 158544.doc