JP3246670B2 - Anticancer agent comprising interleukin-2 and 5'-deoxy-5-fluorouridine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for treating a disease by enhancing immunity by administering a drug which makes use of the characteristics of each drug, avoids side effects on the living body, and exhibits a new medicinal effect which cannot be obtained by a single agent. More specifically, interleukin-2 (hereinafter, "interleukin-2" may be abbreviated as "IL-2") and 5'-deoxy-5-fluorouridine (5'-deoxy
-5-fluorouridine) (generic name doxifluridine, hereinafter 5 '
-May be abbreviated as DFUR).
The present invention relates to a therapeutic agent and a therapeutic method for cancer, various viral infections, and the like, which can be clinically applied.

[0002]

2. Description of the Related Art In recent years, immunopotentiators and various virus sensitizers have been developed.
Exempt from lymphokines such as IL-2 as anti-stain agents
Attempts have been made to use it as a drug to enhance epidemiological responsiveness
[Journal of Immunology (J. Immunol.),12
Five, 1904 (1980)]. Recently, as IL-2,
An IL-2 obtained by elementary engineering is known (Japanese Unexamined Patent Publication No.
0-115528 and 61-78799). On the other hand, 5 '
-Deoxy-5-fluorouridine was synthesized in 1979
However, it was found to be effective in clinical trials (cancer and chemotherapy).
Law, 12 (1), 2044, 1985].
Launched as an agent. Today, the treatment of cancer is surgical treatment and release.
Treatment with radiation therapy and hormonal therapy has been attempted,
Effective treatment for cancer, but cancer that has spread
Expect drug treatment for late-detected cancer
I have no choice. However, currently available anticancer drugs are:
Demonstrates useful medicinal effects, but also has strong side effects on the living body
Be completed as a satisfactory treatment for patients
Not in. In recent years, so-called phosphorus such as interleukin 2
Treatment of human malignant tumors using hokine as an antitumor agent
[Cancer and chemotherapy,13., 977 (198
6)) and its therapeutic effects have been reported [New England
Journal of Medesin (New England J. Me
d.),316, 889 (1987)].

[0003]

Means for Solving the Problems In order to enhance the therapeutic effect of malignant neoplasms by immunostimulatory action, the present inventors have conventionally used immunotherapeutic agents and chemotherapeutic agents for cancer as "IL-
Various treatments have been studied in combination with 2 ". As a result, among the various combinations, 5′-D
It has been found that when FUR and "IL-2" are administered in combination to a cancer-bearing animal, the respective effects are synergistically exerted and a strong therapeutic effect is obtained, and the present invention has been completed. That is, the present invention provides an effective amount of interleukin-2 and 5'-
An immunopotentiator comprising a combination of DFUR or a salt thereof, a method for treating a disease comprising administering the above immunopotentiator to an animal, and an interleukin-2 preparation and 5'-D
It is intended to provide a kit containing an FUR preparation. As the above-mentioned interleukin-2, any substance may be used as long as it has an IL-2 activity, that is, an action capable of maintaining T cells for a passage while maintaining their functions. For example, natural IL-2 produced in animals or animal cells, IL-2 produced by genetic recombination technology, and related substances thereof can be mentioned. When the above-mentioned IL-2 and their related substances are proteins, they may or may not have a sugar chain. Specifically, for example, the polypeptide (I) having the amino acid sequence shown in FIG. 1 (SEQ ID NO: 1) (human IL
-2) or a fragment consisting of a partial amino acid sequence necessary for its biological or immunological activity.
Examples of the fragment include polypeptide (I)
One amino acid from the amino terminus of EPC (EPC Publication 9153)
No. 9) or a fragment lacking four amino acids (JP-A-60-126088) or a fragment lacking a few amino acids at the carboxyl terminal (JP-A-60-26088).
-12,088). Further, polypeptides (I) having the amino acid sequence shown in FIG. 1 in which some of the constituent amino acids are deleted or replaced with other amino acids, for example, a cysteine residue at position 125 is replaced with a serine residue. (JP-A-59-93093).

[0004] The above-mentioned IL-2 may be chemically modified with a polyethylene glycol derivative or the like (for example, JP-A-60-226821). In particular, in the present invention, it is preferable to use human IL-2 which is produced by a genetic recombination technique and has the amino acid sequence shown in FIG. 1, and in this case, one having an additional methionine residue (Met) at its amino terminus. Mixtures with those not having (JP-A-60-115528, JP-A-61-7879)
No. 9), and those having no Met at the amino terminus and starting with alanine (Ala) (JP-A-61-7).
8799). Further, those having a sugar chain may be used. 5′-DFUR is a known compound, for example, Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 22, No. 11, pp. 1330-1335, 197
It has been described in 9 years, and is produced by the same method using 5-fluorouridine as a starting material. 5'-DF
It is known that UR has low toxicity to animals and particularly has little effect on immune organs (cancer and chemotherapy, 15
Vol. 5, No. 5, pp. 1747-1754, 1988). Interleukin-2 enhances the reactivity of lymphoid cells,
Because of its biological activity, combination with a drug having a small immunosuppressive effect among anticancer drugs is desired, and 5′-DF
UR was the drug for that purpose.

[0005] IL-2 used in the present invention has low toxicity.
For example, for IL-2, a mixture of human IL-2 having the amino acid sequence shown in FIG. 1 with and without Met at the amino terminus is disclosed in JP-A-61-7.
Human IL- having the amino acid sequence shown in FIG. 1 separated by isoelectric focusing similar to the method described in JP-A-8799.
2 at a dose of 10 mg / kg (1 mg
= 3.5 × 10 ⁴ units) No death occurred due to toxicity after administration. The 5'-DFUR used in the present invention has lower toxicity compared to other known chemotherapeutic agents, for example,
When administered to mice, no mortality was observed even with oral administration of 2000 mg / kg or intraperitoneal administration of 500 mg / kg. In addition, compounds that do not suppress the activity of natural killer cells even when administered to a living body and do not suppress this activity are very suitable for co-administration with IL-2.

[0006] Thus, the immunopotentiator of the present invention usually comprises
These active ingredients are used orally or parenterally as a pharmaceutical composition comprising a mixture with a pharmacologically acceptable carrier or excipient. For example, each active ingredient was previously made into an aqueous solution, each active ingredient was freeze-dried to obtain a solid mixture, and each aqueous solution was freeze-dried to obtain each solid one. Examples include a solid form in which either one is an aqueous solution and another active ingredient is freeze-dried, and a kit in which each active ingredient is separately formulated. The immunopotentiator of the present invention is administered as a single agent by mixing these active ingredients with a pharmaceutically acceptable diluent or excipient, if desired, according to a known pharmaceutical production method. it can. In addition, each active ingredient can be separately formulated as desired using a pharmaceutically acceptable diluent or excipient, if desired, and administered as a single agent using a diluent at the time of use. Furthermore, kits may be separately formulated as described above, and these may be separately, simultaneously, or with a time lag, administered in the same route or different routes to the same subject. it can.

When the immunopotentiator of the present invention is a solution,
It is manufactured by a conventional method using a solvent such as an aqueous solvent (eg, distilled water), a water-soluble solvent (eg, physiological saline, Ringer's solution), or an oily solvent (eg, sesame oil, olive oil). At this time, if necessary, a solubilizing agent (eg, sodium salicylate, sodium acetate), a buffer (eg, sodium citrate, glycerin), an isotonic agent (eg, glucose, invert sugar), a stabilizer (eg, human serum) albumin,
Additives such as polyethylene glycol), preservatives (eg, benzyl alcohol, phenol), and soothing agents (eg, benzalkonium chloride, procaine hydrochloride) can also be used. The concentration of IL-2 in the solution is preferably between about 3 and 500 mg / ml. 5'-DF in solution
The concentration of UR is preferably about 10-500 mg / ml. Compositions for oral administration further include tablets,
Pills, granules, powders, capsules, syrups, emulsions,
Suspending agents and the like. Such a composition is produced by a method known per se, and lactose, starch, sucrose, magnesium stearate and the like are used as carriers or excipients. For parenteral administration, for example, injections, suppositories, and the like can be used. Injections include, for example, intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like. Used. The injection solution is usually provided by filling in a suitable ampoule. Suppositories used for rectal administration are prepared by a method known per se. In formulating the immunopotentiator of the present invention, for example, a mixture of each formulation material is used for injection, as described in JP-A-62-228026, in order to prevent a decrease in the activity of IL-2. When dissolved in distilled water or physiological saline, it is desirable to add human serum albumin (HSA) at about 0.5-1%.

The immunopotentiator of the present invention has an activity of enhancing the immunity of mammals (eg, mice, cats, dogs, cows, horses, sheep, goats, rabbits, humans), and activates macrophages to infect various viruses. It is useful for the treatment or prevention of diseases and tumors, and has a profound effect on, for example, prolonging the life of a mammal holding a tumor. Such target diseases include various leukemias, malignant lymphoma, osteosarcoma, malignant melanoma, malignant villous epithelium, myoma, ovarian cancer, uterine cancer, prostate cancer, pancreatic cancer, gastrointestinal cancer such as stomach and intestine, lung cancer, esophageal cancer, Viral tumors such as cervical head tumors, brain tumors, and liver cancers. To administer the immunopotentiator of the present invention, when the composition is in the form of an aqueous solution, it is used as it is as a solution for injection. When the composition is in a solid form by freeze-drying, it is dissolved in distilled water or physiological saline and used as a solution for injection. If desired, the same monosaccharide as described above,
It contains sugar alcohols, amino acids, etc.
It can also be used after dissolution with a dissolution solution adjusted to H. When administering the immunopotentiator of the present invention, IL-2 and 5'-DF
The amount used with UR varies depending on the method of use, target tumor, and the like, but the amount of IL-2 protein is 10 μg [I
As the L-2 activity, 350 units (U) were used. As for the method for measuring the IL-2 activity, a mouse cell strain which proliferated depending on the IL-2 concentration was used as described in JP-A-60-115528. I did it. 5'-DFUR
Preferably, it is used in a ratio of about 0.1 to 100 mg,
More preferably, about 1 to 50 mg is used. The immunopotentiator of the present invention can be administered orally or parenterally to mammals including humans. The dose of the immunopotentiator of the present invention varies depending on the type of IL-2 used. For example, when administered as an injection based on the amount of IL-2 protein in mice, About 0.1 to 500 μg, about 0.001 for mammals other than mice
-4 μg, when administered as a suppository, about 0.01-20 μ /
kg, about 0.001 to 2 μg when administered as a drip
/ Kg when administered as an oral absorbent,
4 μg / kg are each preferred. On the other hand, 5'-DFUR
When administered as an injection on the basis of the dose (mg) of, for example, about 1 to 500 mg / day
/ Kg is preferred, and about 1 to 10 for mammals other than mice.
0 mg / kg is preferred. In the immunopotentiator of the present invention, separately formulated IL-2 and 5'-DFUR can be simultaneously administered to the same subject, or can be administered to the same subject at different times. In this case, the time difference may be, for example, about 12 to 24 hours, preferably about 3 to 9 hours, and more preferably about 2 hours or less.

The immunopotentiator of the present invention may further contain other chemotherapeutic agents and / or other immunotherapeutic agents,
Other chemotherapeutic agents include mitomycin, adriamycin, cisplatin, vindesine, vincristine,
Anticancer agents such as cyclophosphamide, ifomafamide, bleomycin, pepeomycin or etoposide. Examples of the immunotherapeutic agent include microbial or bacterial cell wall bone nucleus components; immunoactive polysaccharide natural type or cytokines obtained by genetic engineering techniques; and colony stimulating factors. Examples of the immunoactive polysaccharide include lentinan or schizophyllan Bacterial cell wall bone nucleus components include muramyl dipeptide derivatives and the like, microorganisms include lactic acid bacteria and the like, and natural or cytokines obtained by genetic engineering techniques include interferon and the like. When further containing other chemotherapeutic agents and / or other immunotherapeutic agents,
The amount usually used for the treatment is used.

[0010]

[Action] IL-2 and 5'-DFU with little immunosuppressive action
In combination with R, an immunopotentiator having a synergistic effect and less side effects can be obtained. The agent of the present invention containing IL-2 and 5'-DFUR exhibits remarkable immunopotentiating activities such as antitumor activity and macrophage activating activity. This is an effect that cannot be obtained. The immunopotentiator of the present invention is effective when used for treating a mammal having at least one kind of tumor.

[0011]

EXAMPLES The present invention will be described below in detail with reference to experimental examples and examples, but the present invention is not limited to these examples. In addition, IL-2 used in the experimental examples or examples was used.
Is human IL-2 having the amino acid sequence shown in FIG. 1, that is, IL-2 whose amino terminus starts with alanine. The IL-2 is expressed in a transformant Escheric coli.
hia coli) using N4830 / pTB285,
Culture was performed in the same manner as described in JP-A-1-78799, and highly purified by the same method as described in JP-A-60-115528.
Separated by isoelectric focusing in the same manner as in the method described in Japanese Patent Publication No. 9-99, and has a specific activity of about 3.5 × 1
0, which is the ⁴ units / mg. The transformant Escherichia
Cori N4830 / pTB285 was purchased on April 25, 1985.
The fermentation research institute (IFO) was granted accession number IF
Deposited as O14437, and April 30, 1985
From the Ministry of International Trade and Industry Ministry of Industry and Technology
RI No. FERM P-8199, which has been converted to a deposit based on the Budapest Treaty and stored at the same research institute (FRI) under the accession number FERMBP-852.

[0012]

[Experimental example 1] 5'-DFUR and I for subcutaneous transplant tumor
Comparative Experiment on Antitumor Activity of L-2 Mouse colon carcinsna26 (colon cancer No. 2) was subcutaneously injected into the hind leg calf of a male BALB / c mouse weighing about 25 g.
6) Tissue porridge (tumor cells in a suspended state by crushing the tumor with a homogenizer) was transplanted using a syringe, and those on which the tumor reached a certain size on day 12 after tumor transplantation were selected and divided into groups. The drug administration was started. IL-2 was administered subcutaneously once a day subcutaneously on the flank opposite the hind limb of the tumor implant 14
Went for days. IL-2 was dissolved in physiological saline (dissolution solution) containing 5% of normal mouse serum, and the solution was administered in an amount of 0.1%.
It was prepared to be ml / 20 g mouse body weight. 5'-DF
UR was orally administered once a day for 14 days from the first day of IL-2 administration. 5'-DFUR was suspended in physiological saline and prepared so as to have a dose of 0.2 ml / 20 g mouse body weight. The antitumor effect was evaluated after tumor transplantation.
The tumor weight on the day was measured, the average tumor weight of each experimental group was determined, and the tumor weight ratio (T / T) between the drug administration group (T, 5 mice per group) and the drug-untreated control group (C, 10 mice per group) was determined. C%). The daily dose of the drug was determined based on the weight of the drug per mouse (IL-2; μg, 5′-DFUR; μ).
g). Table 1 shows the experimental results.

[0013]

[Table 1]

[0014]

[Experimental example 2] 5'-DFUR and I for subcutaneous transplant tumor
Comparative Experiment on Antitumor Activity of L-2 A tissue porridge of colon cancer No. 26 was prepared subcutaneously in the flank of a female BALB / c mouse weighing about 20 g in the same manner as in Experimental Example 1, and an injection cylinder was prepared. On the 7th day after the tumor transplantation, those whose tumors reached a certain size were selected, divided into groups, and drug administration was started. IL-2 was administered subcutaneously once a day for 15 consecutive days on the flank opposite the tumor implantation site. 5'-D
FUR was orally administered once a day for 14 days from the first day of IL-2 administration. IL-2 has a normal mouse serum of 5
The solution was dissolved in physiological saline (dissolution solution) to which the solution was added in an amount of 0.1 ml / 20 g to give a mouse body weight. 5'-DFUR was suspended in physiological saline and prepared so as to have a dose of 0.2 ml / 20 g mouse body weight. The antitumor effect was evaluated by measuring the tumor weight on day 28 after tumor implantation, calculating the average tumor weight of each experimental group, and administering the drug-administered group (T, 5 mice per group) and the drug-untreated control group (C, 10 groups per group).
And the weight ratio (T / C%) of the tumor was determined. The daily dose of IL-2 is expressed in terms of the drug weight (μg) per mouse, and 5′-DFUR was also calculated for each mouse.
The amount per day was expressed by weight (μg). Table 2 shows the results of administration of IL-2 alone and IL-2 of the present invention and 5'-DFUR.

[0015]

[Table 2]

[0016]

[Experimental example 3] 5'-DFUR and I for subcutaneously transplanted tumor
Investigation of antitumor effect of L-2 in combination with other anticancer agents A tissue porridge of colon cancer No. 26 was transplanted subcutaneously in the abdomen of a female BALB / c mouse weighing about 20 g in the same manner as in Experiment 2. 5'-DFUR and IL-2 were administered once a day for 10 consecutive times from the 14th day after tumor implantation. 5'-DFUR was administered orally, and IL-2 was administered subcutaneously in the abdomen on the opposite side of the tumor implantation site, as in Experiment 2. In addition, mitomycin (hereinafter, referred to as MMC), adriamycin (hereinafter, ADR) and cyclophosphamide (hereinafter, CPA), which are anticancer drugs, were administered intravenously on days 7 and 10 after tumor implantation. All doses of drug are weight per mouse
(μg). The results showing that even when the 5'-DFUR and IL-2 of the present invention were administered for only 10 days in the late stage of tumor growth, when combined with other anticancer drugs, excellent effects could be exhibited (28 days after tumor transplantation). Table 3)
Shown in

[0017]

[Table 3]

[0018]

[Experimental example 4] 5'-DFUR, I for subcutaneous transplant tumor
Comparative Experiment on Life Prolonging Effect of Administration of L-2 and 5'-DFUR and IL-2 The colon porosity of colon cancer No. 26 was injected subcutaneously into the thigh of a male BALB / c mouse weighing about 25 g. Prepared in the same manner as above, transplanted using a syringe, and on day 20 after tumor implantation, those whose tumor reached a certain size were selected and divided into groups, and drug administration was started. IL-2 was administered subcutaneously once a day for 15 consecutive days on the flank opposite the tumor implantation site. 5'-
DFUR is daily 1 day for 15 days from the first day of IL-2 administration
Each dose was orally administered. IL-2 was dissolved in physiological saline (solution) containing 5% of normal mouse serum, and the amount of the solution was adjusted to be 0.1 ml / 20 g mouse body weight. 5'-DFUR was suspended in physiological saline and prepared so as to have a dose of 0.2 ml / 20 g mouse body weight. The antitumor effect was evaluated by observing the survival days of the tumor-bearing mice, calculating the average (median) survival days of each experimental group, and administering the drug-administered group (T, 5 animals per group) and the drug-untreated control group (C, one group). 5
And the number of surviving days (T / C%) was determined. The daily dose of IL-2 is expressed in terms of the drug weight (μg) per mouse, and 5′-DFUR was also calculated for each mouse.
The amount per day was expressed by weight (μg). Table 4 shows the results of administration of IL-2 or 5'-DFUR alone and administration of IL-2 and 5'-DFUR of the present invention.

[0019]

[Table 4]

[0020]

[Experimental example 5] 5'-DFUR and I for subcutaneously transplanted tumor
Comparative Experiment on Life Prolonging Effect of L-2 A tissue porridge of colon cancer No. 26 was prepared subcutaneously on the thigh of a male BALB / c mouse weighing about 25 g in the same manner as in Experimental Example 1, and a syringe was prepared. On the 14th day after tumor transplantation, those whose tumors reached a certain size were selected and divided into groups, and drug administration was started. IL-2 administration was administered subcutaneously on the flank opposite to the tumor implantation site once a week each day for 4 consecutive days.
Repeated for a week. For 5'-DFUR, oral administration once a day for 4 consecutive days each week was repeated for 5 weeks from the first day of IL-2 administration for 5 weeks. IL-2 was dissolved in physiological saline (dissolution solution) containing 5% of normal mouse serum, and the solution was administered in an amount of 0.1%.
It was prepared to be ml / 20 g mouse body weight. 5'-DF
UR is suspended in a physiological saline solution, and 0.2 m
1/20 g mouse body weight was prepared. To evaluate the antitumor effect, the number of surviving days of the tumor-bearing mice was observed, the average number of surviving days of each experimental group was determined, and the drug administration group (T, 5 to 10 animals per group)
The survival days ratio (T / C%) between the drug-untreated control group (C, 10 animals per group) was determined. The daily dose of IL-2 is represented by the drug weight per mouse (μg), and 5′-DFUR is also the weight per day per mouse (μg).
g). Table 5 shows the results of administration of IL-2 or 5'-DFUR alone and administration of IL-2 and 5'-DFUR of the present invention.

[0021]

[Table 5]

[0022]

[Experimental example 6] 5'-DFUR and I for subcutaneously transplanted tumor
Examination of antitumor effect by combining L-2 with other anti-cancer agent The tissue porridge of colon cancer No. 26 was subcutaneously applied to the thigh of female BALB / c mouse weighing about 25 g in the same manner as in Experimental Example 1. Prepared and transplanted. 5'-DFUR and IL-2 2 after tumor implantation
The administration for four consecutive days was repeated once a day from day 0 for four weeks. 5'-DFUR was administered orally, and IL-2 was administered subcutaneously in the abdomen on the opposite side of the tumor implantation site, as in Experimental Example 1. In addition, mitomycin (hereinafter referred to as MM) which is an anticancer drug
Called C. ) Was administered intravenously on days 17, 24, 31 and 38 after tumor implantation. The dose of each drug was expressed in terms of weight per mouse (μg). 5'-DFU of the present invention
Table 6 shows the results (experiment was performed twice) in which even when R and IL-2 were administered at a later stage of tumor growth, an excellent life-prolonging effect was exhibited when combined with other anticancer drug administration. .

[0023]

[Table 6]

[0024]

Embodiment 1 At this ratio, each component is mixed and dissolved in distilled water for injection or physiological saline, and human serum albumin (HSA)
Was added to a concentration of 0.5%, followed by filtration using a membrane filter (pore size: 0.22 μm). The obtained filtrate was aseptically dispensed in 1 ml portions into vials and freeze-dried to prepare an antitumor agent for injection. This preparation for injection is dissolved in 5 ml of distilled water for injection at the time of use.

[0025]

Embodiment 2 At this ratio, each component is mixed and dissolved in distilled water for injection or physiological saline, and human serum albumin (HSA)
Was added to a concentration of 0.5%, followed by filtration using a membrane filter (pore size: 0.22 μm). The obtained filtrate was aseptically dispensed in 1 ml portions into vials and freeze-dried to prepare an antitumor agent for injection. This preparation for injection is dissolved in 5 ml of distilled water for injection at the time of use.

[0026]

Embodiment 3 After mixing each component at this ratio, the mixture is dissolved in 1,000 ml of distilled water for injection or physiological saline, human serum albumin (HSA) is added to a concentration of 0.5%, and a membrane filter (pore size: 0.22 μm) is added. And filtered.
The obtained filtrate was aseptically dispensed into vials in 10 ml portions and freeze-dried to prepare antitumor agents for injection. This preparation for injection is dissolved in 10 ml of distilled water for injection at the time of use.

[0027]

Embodiment 4 After mixing each component at this ratio, the mixture is dissolved in 1,000 ml of distilled water for injection or physiological saline, human serum albumin (HSA) is added to a concentration of 0.5%, and a membrane filter (pore size: 0.22 μm) is added. And filtered.
The obtained filtrate was aseptically dispensed into vials in 10 ml portions and freeze-dried to prepare an antitumor agent for injection. This preparation for injection is dissolved in 10 ml of distilled water for injection at the time of use.

[0028]

Example 5 Kit preparation for injection: [A] IL-2 10 mg Lactose 85 mg HPC-L (oxypropylcellulose) 5 mg Total 100 mg After mixing the above three components in the above ratio, 1,000 ml of distilled water for injection or After dissolving in physiological saline, human serum albumin (HSA) is added to a concentration of 0.5%, followed by filtration using a membrane filter (pore size: 0.22 μm). The obtained filtrate is aseptically dispensed into vials of 5 ml each and freeze-dried to obtain Kit A. [B] 5'-DFUR 120,000 mg Sodium lauryl sulfate 20,000 mg Total 140,000 mg At the above ratio, the two were mixed and dissolved in 1,000 ml of distilled water for injection or physiological saline to obtain human serum albumin. (HSA) is added to a concentration of 0.5%, and the mixture is filtered using a membrane filter (pore size: 0.22 μm). The obtained filtrate is aseptically dispensed into vials of 5 ml each and freeze-dried to obtain Kit B. [C] 10 mg of distilled water for injection This kit is prepared by dissolving kit A using kit C at the time of use, and subsequently dissolving kit B to prepare a solution for injection.
Alternatively, kit B is dissolved using kit C, and then kit A is dissolved to prepare a solution for injection. Alternatively, kit A and kit B are separately dissolved using kit C to prepare two injection solutions, a kit A solution and a kit B solution, which are separately administered at the same time or at a certain time.

[0029]

EFFECTS OF THE INVENTION The immunopotentiator comprising the combination of IL-2 and 5'-DFUR of the present invention exerts a strong immunopotentiating action which cannot be obtained by using each of them alone.

[0030]

[0031]

[Sequence listing] SEQ ID NO: 1 Sequence length: 133

[0032]

[Type of sequence] Amino acid

[0033]

[Type of sequence] Protein

[0034]

[Sequence] Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu
Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr
Phe Lys Phe Tyr Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln
Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala
Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile
Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys
Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp
Ile Thr Phe Cys Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130.

[Brief description of the drawings]

FIG. 1 is a drawing showing an example of the amino acid sequence of IL-2 used in the present invention.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References Cancer and Chemotherapy, Vol. 14, No. 6 (1987), PART II II, p. 2111-2118 Cancer and Chemotherapy, Vol. 16, No. 1, (1987) ), P. 131-134 Cancer and Chemotherapy, Vol. 14, No. 5, (1987), PART I, p. 1252-1259 (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 38/20 A61K 31/70 CA (STN) MEDLINE (STN)

Claims (4)

(57) [Claims] 1. Interleukin-2 and 5'-deoxy-
An anticancer agent obtained by combining 5-fluorouridine or a salt thereof. 2. Interleukin-2 and 5'-deoxy-
The anticancer agent according to claim 1, which is obtained by mixing 5-fluorouridine or a salt thereof. 3. The kit according to claim 1, which comprises an interleukin-2 preparation and a preparation of 5'-deoxy-5-fluorouridine or a salt thereof. 4. The anticancer agent according to claim 1, further comprising another chemotherapeutic agent and / or another immunotherapy agent.