JP2000229881A - Prognosis-improving agent for cancerous disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a prognosis-improving agent for cancerous diseases, not causing a side-effect. SOLUTION: This prognosis-improving agent includes lactoferrin an/or its hydrolyzate as an active ingredient and is orally administered to cancer patients. Cancerous disease is skin cancer, lung one, laryngeal one, tongue one, breast one, liver one, pancreatic one, esophagus one, stomach one, small intestinal one, colon one, kidney one, ovarian one, uterine one, prostatic one or urinary bladder one. Lactoferrin is preferably at least one kind selected from the group consisting of lactoferrin unsaturated with at least one metal, lactoferrin saturated with at least one metal and apolactoferrin, or a mixture of two or more kinds.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for improving the prognosis of cancer diseases, which comprises lactoferrin and / or a hydrolyzate of lactoferrin as an active ingredient. More specifically,
The present invention contains, as an active ingredient, metal-unsaturated lactoferrin, metal-saturated lactoferrin, or apolactoferrin (hereinafter sometimes collectively referred to as lactoferrins) and / or a hydrolyzate of lactoferrin as an active ingredient. The present invention relates to an agent for improving the prognosis of a cancer disease to be administered.

[0002]

2. Description of the Related Art Against the background of the recent aging society, new developments are required for treatment strategies for cancer diseases. Conventional cancer chemotherapy has been a powerful chemotherapy in which a large amount of an anticancer drug is administered to a patient in order to kill as many cancer cells as possible. As a result, it is a fact that it has made a certain contribution to certain blood cancers such as leukemia and malignant lymphoma.

However, for many solid cancers,
Although strong chemotherapy has been shown to shrink the tumor,
It has become clear that they do not necessarily lead to prolongation of life.
“Palliative cancer chemotherapy” with an emphasis on maintaining OL (quality of life) has been attracting attention (Cancer Therapy and Host, Vol. 6, pp. 165-176, 1994).
Year).

[0004] As the notion that the essence of cancer treatment lies in prolonging the life of patients and maintaining quality of life has become established, how to improve the prognosis of patients with advanced cancer disease and postoperative patients is a strategy for cancer treatment. Has become a major challenge.

[0005] Patients with advanced and recurrent cancers suffer from homeostasis and QOL due to various metabolic abnormalities starting with anorexia.
Is known to gradually decrease into cachexia (Mevio, Vol. 12, pages 8-15, 1
995) In such a state, the effect of the anticancer agent is no longer expected and the survival time is shortened.

[0006] Therefore, it is necessary to administer an anticancer agent with few side effects and a treatment intended to improve the cachectic condition to patients with advanced or recurrent cancer.

[0007] In the field of surgery, it is extremely important to improve the prognosis by performing treatment aimed at preventing postoperative recurrence and metastasis. Drugs used for improving the prognosis of such cancer patients have few side effects. There is a need for a drug that can maintain a patient's QOL for a long period of time (Experimental Medicine, Vol. 16 (extra number), pp. 193-202, 19).
1998), it can be said that an oral preparation is desirable from the viewpoint of convenience.

However, among the conventional oral anticancer drugs, a drug that can be expected to have a clear prognosis-improving effect is a 5-FU prodrug (5-FU) that has been suggested to have an effect of improving cachexia.
Currently, it is recognized only for some drugs such as deoxy-5-fuluorouridine: 5-DFUR (Ichiro Urushizaki, ed., "One pathological condition of cancer cachexia and the latest trends in treatment", No. 160- 169, Advanced Medicine, 1993).

On the other hand, lactoferrin is a harmless and natural iron-binding protein (capable of binding two iron ions per molecule) contained in tears, saliva, peripheral blood, milk and the like.
The molecular weight is 86,000 for bovine lactoferrin and 88,000 for human lactoferrin (edited by Kazutomo Imahori and Tamio Yamakawa, "Biochemical Dictionary", 2nd edition, p. 1390, Tokyo Kagaku Dojin, 1990). .

[0010] Lactoferrin is used for Escherichia coli, Candida fungi,
It is known to exhibit antibacterial activity against harmful microorganisms such as Clostridium fungi (Journal of Pediatrics, Vol. 94, page 1, 1979). In addition, lactoferrin is effective for colonizing useful bacteria such as bifidobacteria and lactic acid bacteria in human and animal intestines (Patent No. 2532911),
And Bifidobacterium growth factor (Japanese Patent Laid-Open No. 22-22 / 1990)
No. 5419) is also known.

Further, lactoferrin has been disclosed for various uses as follows.

1) Antibacterial, antiviral and antiparasitic agents JP-A-61-83131, JP-A-62-2499
No. 31, JP-A-63-56273, JP-A-63-56273
JP-A-3-284133, JP-A-1-44273, JP-A-1-221319, JP-A-1-233
226, JP 2-48534, JP 2
-191205, JP-A-2-233609, JP-A-3-181421, JP-A-3-193
708, JP-A-3-220130, JP-A-6-48956, JP-A-6-199698, JP-A-6-256221, JP-A-6-316
529, JP-A-7-206701, JP-A-7-316069, JP-A-9-2970,
JP-A-9-40578, JP-A-9-165342
And Japanese Patent Application Laid-Open No. 10-59865

2) Hematopoietic agent JP-A-62-125398, JP-A-63-225
No. 25, JP-A-2-6408, JP-A-3-1
JP 30060, JP-A-4-8269, JP-A-4-14067, and JP-A-4-95100

3) Skin and external preparations JP-A-1-135726, JP-A-7-19652
9, JP-A-8-59450, JP-A-8-2
JP-A-31462 and JP-A-8-333260

4) Oral and dental preparations JP-A-5-279266, JP-T-8-50609
No. 8, JP-A-8-217693

5) Ophthalmic agent WO 92/08477, JP-A-8-301785
And Japanese Patent Application Laid-Open No. 9-30966

6) Immunostimulants and immunostimulants JP-A-5-178759, JP-A-6-32743
JP, JP-A-6-145068 and JP-T-Hei-7
5077763, a gastrointestinal tract growth promoter (JP-A-1-93534), a bacterial toxin neutralizing agent (JP-A-2-20789 and JP-T-5-501416), an anti-aging agent (JP-A-5-501416). JP-A-4-58871 and JP-A-5-12498
0), antihypertensive (JP-A-4-316598), anti-rheumatic agent (JP-A-5-1866368), nerve growth factor production promoter (JP-A-5-32557).
JP), a gastrointestinal cell activator (JP-A-6-48955)
JP-A-6-172200), Arteriosclerosis Prevention Agent (JP-A-6-234655), Mucin Production Promoter (JP-A-9-12473), Angiogenic Treatment (JP-A-9-194388), an anti-abnormal crypt agent (JP-A-10-25249), an endotoxin-induced disease therapeutic agent (JP-A-10-194).
No. 114675), and a prophylactic and / or therapeutic agent for gastrointestinal disorders (Japanese Patent Application Laid-Open No. 10-130164).

In addition, the use of lactoferrin as an antitumor agent has already been described (see JP-A-63-5133).
No. 7), an oral cancer metastasis inhibitor (JP-A-10-598)
No. 64) is disclosed. However, lactoferrin is effective in improving the prognosis of cancer patients,
It is not known in the past and there is no literature.

On the other hand, the lactoferrin hydrolyzate is used as a virus infection inhibitor (JP-A-2-233609).
JP-A-5-32068), an antibacterial agent and a tyrosinase activity inhibitor (JP-A-5-32068), an antibacterial agent and a cosmetic containing the same (JP-A-6-279310), and an antioxidant (JP-A-6-279610). No. 1996687), an IgA production promoter (Japanese Patent Application Laid-Open No. 6-32743), an antifungal agent (Japanese Patent Application Laid-Open No.
No. 309774) is known.

As for the use of hydrolyzates of lactoferrins as antitumor agents, parenteral antitumor agents (JP-A-7-309771) are disclosed.

However, hydrolyzates of lactoferrins are not known to be effective for improving the prognosis of cancer patients, and there is no literature.

[0022]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies on substances that are effective in improving the prognosis of cancer patients. As a result, lactoferrins and hydrolysates of lactoferrins were converted into cachexia of terminal cancer. The present invention was found to be extremely effective in improving the prognosis and the postoperative prognosis, and completed the present invention.

An object of the present invention is to provide an agent for improving the prognosis of cancer patients which can be orally administered for a long period of time with almost no side effects.

[0024]

Means for Solving the Problems The present invention for solving the above problems is an agent for improving the prognosis of a cancer disease which is orally administered to a cancer patient, comprising lactoferrin and / or a lactoferrin hydrolyzate as an active ingredient. The cancer disease is skin cancer, lung cancer, laryngeal cancer, tongue cancer, breast cancer, liver cancer, pancreatic cancer, esophageal cancer, stomach cancer, small intestine cancer, colon cancer, kidney cancer, ovarian cancer, uterine cancer, prostate cancer or bladder cancer. That lactoferrin is one or a mixture of two or more selected from the group consisting of metal-unsaturated lactoferrin, metal-saturated lactoferrin, and apolactoferrin; and lactoferrin and / or a lactoferrin hydrolyzate has a body weight of 1 kg 1 per
In some embodiments, the administration is 20 mg to 15 g per day.

Next, the present invention will be described in detail.

[0026]

BEST MODE FOR CARRYING OUT THE INVENTION Lactoferrin used as an active ingredient of the present invention may be a commercially available product, such as colostrum and transition milk of mammals (eg, human, cow, buffalo, horse, goat, sheep, etc.). , Normal milk, end-stage milk, etc., skim milk which is a processed product of these, lactoferrin separated from whey etc. by a conventional method such as ion exchange chromatography, apolactoferrin obtained by removing iron from a lactoferrin by a conventional method, iron to apolactoferrin, Metal-unsaturated lactoferrin or metal-saturated lactoferrin obtained by partially or completely chelating metals such as copper, zinc, and manganese may be used.

Although natural human lactoferrin cannot be produced in large quantities, human lactoferrin produced by recombinant fungi, dairy cows (transgenic cows) and the like obtained by recombinant DNA technology is also available. It can be used in the present invention.

The hydrolyzate of lactoferrin used as the active ingredient of the present invention is produced by hydrolyzing the lactoferrin with an acid or an enzyme. The details are as follows.

In the hydrolysis with an acid, lactoferrin is dissolved in water, purified water or the like at a concentration of 0.1 to 20% (weight; hereinafter, the same unless otherwise specified), preferably 5 to 15%. Then, an acid (eg, an inorganic acid such as hydrochloric acid or phosphoric acid, or an organic acid such as citric acid) is added to the obtained solution, and the pH of the solution is adjusted.
Is adjusted to 1 to 4, maintained at a predetermined temperature, and hydrolyzed for a predetermined time. More specifically, when the pH is adjusted to 1 or more and less than 2, the temperature is maintained at 80 to 130 ° C., and when the pH is adjusted to 2 or more and less than 4, 80 to 130 ° C.
And hydrolyze for 1 to 120 minutes. Then
The reaction solution can be cooled and, if necessary, neutralized, desalted and decolorized.

In the hydrolysis with an enzyme, lactoferrin is dissolved in water, sterilized water, purified water or the like at a concentration of 0.5 to 20%, preferably 5 to 15%, and the optimum enzyme used for the hydrolysis is dissolved. The pH is adjusted, the enzyme is added, and hydrolysis is carried out while maintaining the enzyme at its optimum operating temperature. There are no particular restrictions on the enzyme used, and commercially available products, for example, Morcine F (trademark, manufactured by Seishin Pharmaceutical Co., optimal pH 2.5 to 3.0), pork pepsin (manufactured by Wako Pure Chemical Industries, Ltd., optimal pH 2) 3), SumiTeam AP
(Trademark, manufactured by Shin Nippon Chemical Co., Ltd., optimal pH 3.0), Amano A
(Trademark, manufactured by Amano Pharmaceutical Co., Ltd., optimum pH 7.0), endopeptidase such as trypsin (manufactured by Novo, optimum pH 8.0) or the like is used alone or in any combination.

Further, these enzymes include, for example,
A lactic acid bacterium-derived exopeptidase or a commercially available soy sauce enzyme containing peptidase (manufactured by Tanabe Seiyaku Co., Ltd.) produced by the method described in JP-A-8-43878 can also be used in combination. The amount of the enzyme used is in the range of 0.1 to 5.0% based on the substrate.

The hydrolysis by the enzyme is carried out at a temperature of 15 to 55 ° C., preferably 30 to 50 ° C., for 30 to 600 minutes, preferably 60 to 300 minutes. Next, the reaction solution is directly or neutralized, the enzyme is heated and inactivated by a conventional method, and if necessary, decolored to obtain a hydrolyzate.

The lactoferrins and hydrolysates of the lactoferrins obtained as described above can be used alone or in combination as active ingredients of the agent for improving the prognosis of cancer diseases of the present invention.

The prognosis-improving agent of the present invention containing lactoferrin and / or a hydrolyzate thereof as an active ingredient is formulated into various forms by a known method and orally administered. Specific preparations include tablets (including sugar-coated tablets, coated tablets, and buccal tablets), powders, capsules, (including soft capsules), granules (including coated ones), pills, and toro. -H, liquid preparations, or pharmaceutically acceptable sustained-release preparations thereof.

The above-mentioned preparation is prepared according to a known preparation method by using a pharmacologically acceptable carrier, excipient,
It is formulated as a pharmaceutical composition together with a disintegrant, a lubricant, a coloring agent and the like. Carriers and excipients used in these formulations include lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder,
Examples of binders such as gentian powder include starch, gelatin, syrup, polyvinyl alcohol, polyvinyl alcohol.
Examples thereof include ter, polyvinylpyrrolidone, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose and the like.

Examples of the disintegrant include starch, agar, gelatin powder, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crystalline cellulose,
Examples thereof include calcium carbonate, sodium hydrogen carbonate, and sodium alginate.

Further, as a lubricant, magnesium stearate, hydrogenated vegetable oil, macrogol, etc., and as a coloring agent, red 2 which is permitted to be added to pharmaceuticals.
No. 4, Yellow No. 4, Blue No. 1 and the like.

Further, tablets and granules may be used, if necessary, with sucrose, hydroxypropyl cellulose, purified shellac, gelatin, sorbitol, glycerin, ethyl cellulose.
, Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, methyl methacrylate, methacrylic acid polymer, etc. You can also.

The agent for improving the prognosis of a cancer disease of the present invention desirably contains at least 1 mg of lactoferrin and / or a decomposed product of lactoferrin as an active ingredient per 1 g of the drug. The dosage varies depending on age, symptoms and the like. It is orally administered at a rate of at least 1 mg / kg of human body weight, and preferably 20 mg to 15 g / day.

The prognostic agent for cancer disease of the present invention is derived from milk and has high safety. Therefore, other anticancer agents such as mitomycin C, cisplatin, fluorouracil, bleomycin, irinotecan, interferon, lentinan, and streptococci are used. When used in combination with an extract or the like, the dosage of these drugs can be reduced, and a synergistic effect can be expected in improving the prognosis of cancer diseases.

Next, the present invention will be described in detail with reference to test examples.

Test Example 1 In this test, the effect of lactoferrins and hydrolysates of lactoferrins on the improvement of the cachexia (significant decrease in body weight) associated with tumor growth was examined as an index of the effect of improving the prognosis. went.

[0043] 1) Experiment animals 4-week-old male CDF ₁ mice (Nippon Cha - Rusuriba - purchased from) divided into 10 animals per group of 30 mice were randomly made chow (Funabashi Farms) and allowed to freely take water They were reared for one week.

2) Tumor cells Colon cancer (colon 26: obtained from the Cancer Institute) was subcutaneously subcutaneously cut out of a mouse and cut out, washed with cold PBS (-) except for the necrotic part. Then, the mixture was made porridge with ophthalmic scissors, the same solution was added, and the mixture was filtered through a mesh (MESH 100).
The erythrocytes in the filtered cell solution were treated with 20 mM Tris-0.83.
The suspension was washed with PBS, and a cell suspension (1 × 10 ⁶ cells / ml) was prepared with the same solution.

3) Preparation of Sample Lactoferrin was produced as a commercial product (manufactured by Morinaga Milk Industry Co., Ltd.), and lactoferrin hydrolyzate was produced in the same manner as in Reference Example.
Lactoferrin and lactoferrin hydrolyzate in 0.2
The sample was dissolved in drinking water at a ratio of% to prepare a sample.

4) Test Method 0.5 ml of the above cell suspension (10 ⁵ cells) was transplanted subcutaneously into the abdomen of a mouse, and from the day of transplantation, one group was given drinking water containing lactoferrin (LF administration group), and Each group was allowed to freely drink lactoferrin hydrolyzate (LFH-administered group) -containing drinking water for 30 days. The remaining one group (control group) was fed normal drinking water.

Observations were made on the number of surviving days after transplantation, tumor weight and body weight fluctuation. For the number of days alive, the animals were observed twice daily for death and the number of days dead was recorded. Tumor weight was measured twice a week by measuring the major axis (L) and minor axis (S) of the tumor,
The estimated tumor weight was calculated from the formula (L × S ² ) / 2.

5) Test Results The test results are as shown in FIGS. FIG.
As is clear from the above, in the control group, there were deaths from day 20 after transplantation, and all the cases died on day 40. However, in the LF-administered group and the LFH-administered group, the survival time was prolonged.

The change in body weight is as shown in FIG. 2. In the control group, a marked decrease in body weight was observed from around 10 days after transplantation, and the lowest value was obtained on the 18th day.
In the treated group, weight loss was mild. From 19 days after transplantation, the weight of each group apparently increased due to the increase in tumor weight.

On the other hand, regarding the effect on tumor growth,
As shown in FIG. 3, no clear difference was observed among the three groups tested. This means that, when the results of FIGS. 1 and 2 are considered together, LF and LFH do not act on the tumor itself to kill the tumor, but LF and LFH have an effect on improvement after treatment. It proves that you are playing.

From the above results, it was found that lactoferrin and lactoferrin hydrolyzate clearly improved cachexia (significant decrease in body weight) expressed with tumor growth and contributed to prolongation of survival time. did.

The test was performed by changing the types of tumor cells, lactoferrins and hydrolysates of lactoferrins, and almost the same results were obtained.

Test Example 2 This test was conducted to examine the effect of lactoferrin and its hydrolyzate on the prognosis of surgery and combination therapy with chemotherapeutic agents.

1) Experimental animals Seven-week-old male C57BL / 6 mice (Nippon S.L.
40 animals were randomly divided into 10 animals per group, and solid feed (manufactured by Funabashi Farm) and water were freely taken and preliminarily reared for one week.

2) Tumor cells Lewis lung cancer cells (3LL, obtained from Dainippon Pharmaceutical) 5 ×
10 ⁴ mice were implanted into the tail vein of a mouse, and 3 to 4 lung metastases were excised 2 weeks later and meshed (FALCON2350)
And washed once with an RPMI 1640 culture medium containing 10% fetal bovine serum, suspended in the same culture medium, seeded in a culture flask (25 cm ² ), and subcultured 3 to 4 times to grow cancer cells. used.

3) Preparation of Sample Lactoferrin was produced as a commercial product (manufactured by Morinaga Milk Industry Co., Ltd.), and lactoferrin hydrolyzate was produced in the same manner as in Reference Example.
Lactoferrin and lactoferrin hydrolyzate in 0.2
The sample was dissolved in drinking water at a ratio of% to prepare a sample.

4) Test Method 2 × 10 ⁴ Lewis lung cancer cells were implanted subcutaneously in the right footpad of a mouse, and the right lower limb was cut (surgery) on the 7th day. MMC was abbreviated as 1.0 mg / kg. Lactoferrin (LF administration group) and lactoferrin hydrolyzate (L
FH-administered group) was taken from 7 days before the operation to 30 days after the operation.

Each group was treated as follows, and the survival days of each group were compared.

Group 1: group with only right lower limb amputation (surgery) alone Group 2: group with surgery + MMC (chemotherapeutic agent) administration Group 3: group with surgery + MMC + lactoferrin administration Group 4: operation + MMC + lactoferrin hydrolyzate administration group

5) Test Results The results of this test are as shown in FIG. As can be seen from FIG. 4, the third group, to which a chemotherapeutic agent was administered after the operation and further to lactoferrin orally, and the fourth group to which the lactoferrin hydrolyzate was also orally administered were MMC only after the operation. Compared with the second group administered orally, a prolonged survival effect was observed (improved survival rate).
In other words, Lewis lung cancer cells were used and M
The third group, in which MC was used twice and oral intake of lactoferrin before and after the operation, was the highest in the survival rate, and many healing survival cases were observed.

The survival rate of the second group, to which MMC was orally administered, was reduced compared to the first group, which was operated only by surgery.
Oral administration of lactoferrin or lactoferrin hydrolyzate reduced the toxicity of MMC and significantly improved the survival rate.

The test was carried out while changing the types of tumor cells, lactoferrin and its hydrolyzate, and almost the same results were obtained.

Reference Example 500 g of commercially available bovine lactoferrin (manufactured by Morinaga Milk Products)
Was dissolved in 9 l of purified water, the pH was adjusted to 2.5 with 0.1 N hydrochloric acid, and commercially available pork pepsin (manufactured by Sigma) 10
g was added and hydrolyzed at 37 ° C. for 6 hours. Then 0.
The pH was adjusted to 7.0 with 1N sodium hydroxide, heated at 75 ° C. for 10 minutes to inactivate the enzyme, then cooled to room temperature, and centrifuged at 15,000 rpm for 30 minutes. The supernatant was freeze-dried by a conventional method to obtain about 420 g of a hydrolyzed bovine lactoferrin.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples.

[0065]

Example 1 (Preparation of a tablet containing bovine lactoferrin) An agent for improving the prognosis of a tablet having the following composition was produced by the following method.

Bovine lactoferrin (manufactured by Morinaga Milk Industry Co., Ltd.) 18.0 (%) Lactose (manufactured by Morinaga Milk Industry Co., Ltd.) 18.5 Corn starch (manufactured by Nisshin Flour Milling Co., Ltd.) 52.7 Magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) 1.4 carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., Ltd.) 9.4 A mixture of bovine lactoferrin, lactose, corn starch and carboxymethylcellulose calcium is uniformly kneaded while appropriately adding sterile purified water. After drying at 50 ° C. for 3 hours, magnesium stearate was added to the obtained dried product, mixed, and tableted by a conventional method to obtain a tablet.

Example 2 (Preparation of syrup containing bovine lactoferrin) Bovine lactoferrin (manufactured by Mirai) 8.0 (%) Fructose dextrose liquid sugar (manufactured by Sanmatsu Kogyo) 12.4 Citric acid (Ueno Pharmaceutical company) 0.2 Sodium citrate (Maruzen Pharmaceutical) 0.2 Carboxymethylcellulose calcium (Gotoku Pharmaceutical) 0.2 Purified water (Otsuka Pharmaceutical) 79.0 A syrup was produced by a conventional method.

Example 3 (Preparation of Capsule Bovine Lactoferrin) 600 g of lactose (manufactured by Wako Pure Chemical Industries), 400 g of corn starch (manufactured by Nisshin Seifun KK), 400 g of crystalline cellulose (manufactured by Wako Pure Chemical Industries) and bovine -600 g of lactoferrin (manufactured by Mirai) is sieved with a 50-mesh sieve (manufactured by Yamato Scientific Co., Ltd.), placed in a 0.5 mm-thick polyethylene bag, and mixed by inversion.
re Made by Pedini. Using a press method, the above powder was encapsulated (manufactured by Elanco Japan, Inc., No. 1 gelatin capsule, Op.Yello)
w No.6 Body. Empty weight is 75mg) and content is 275mg
To obtain 7,000 capsules containing 82 mg of lactoferrin.

Example 4 (Preparation of human lactoferrin powder) 100 g of human lactoferrin powder (manufactured by Mirai Co.) and 500 g of lactose (manufactured by Morinaga Milk Co., Ltd.) previously sieved with a No. 6 sieve (manufactured by Inai Seikeido) were mortared. The mixture was mixed with 400 g of lactose (manufactured by Morinaga Milk Products Co., Ltd.) which had been sieved in advance using a No. 5 sieve (manufactured by Inuchi Seieido Co., Ltd.), and the whole amount was sieved again using a No. 5 sieve. 5g packing machine (Tokyo Shokai. OMP-90)
A), packaged by 10%, and 10% human lactoferrin powder 2
00 packets were obtained.

Example 5 (Preparation of tablet containing bovine lactoferrin hydrolyzate) Bovine lactoferrin hydrolyzate 16.5 (%) (manufactured by the same method as in Reference Example) Lactose (Morinaga Dairy) 18 5.5 Potato starch (manufactured by Kanto Kagaku Co., Ltd.) 54.2 Magnesium stearate (manufactured by NOF Corporation) 1.4 Carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., Ltd.) 9.4 Bovine lactoferrin, lactose, potato starch and carboxy The mixture of methylcellulose calcium is uniformly kneaded while appropriately adding sterilized purified water, dried at 55 ° C. for 2 hours, and magnesium stearate is added to the obtained dried product, mixed, and beaten in a conventional manner. Tablets were obtained to give tablets.

Example 6 (Preparation of syrup containing bovine lactoferrin hydrolyzate) Bovine lactoferrin hydrolyzate 6.5 (%) (manufactured by the same method as in Reference Example) Fructose dextrose liquid sugar (Sanmatsu) 14.0 Citric acid (manufactured by Tanabe Seiyaku) 0.2 Sodium citrate (manufactured by Iwaki Pharmaceutical) 0.2 Carboxymethylcellulose calcium (manufactured by Gotoku Yakuhin) 0.2 Purified water (Fuso Pharmaceutical) 78.9 Each component was mixed to produce a syrup in a conventional manner.

Example 7 (Preparation of tablet containing bovine lactoferrin and bovine lactoferrin hydrolyzate) Bovine lactoferrin (manufactured by Morinaga Milk Products) 10.0 (%) bovine lactoferrin hydrolyzate 8.0 ( Lactose (manufactured by Morinaga Milk Industry Co., Ltd.) 18.5 Potato starch (manufactured by Kanto Chemical Co., Ltd.) 52.7 Magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) 1.4 Carboxymethylcellulose-calcium ( 9.4 Bovine lactoferrin, bovine lactoferrin hydrolyzate, lactose, potato starch, and carboxymethylcellulose calcium are kneaded uniformly while appropriately adding sterilized purified water to the mixture at 50 ° C. After drying for 2 hours, magnesium stearate is added to the obtained dried product, mixed, and tableted by a conventional method. Obtained.

[0073]

As described in detail above, the present invention provides
It is a lactoferrin and / or a hydrolyzate of lactoferrin as an active ingredient and is an orally administered prognosis-improving agent for cancer diseases to cancer patients. The effects of the present invention are as follows. 1) Since it is a protein or a hydrolyzate thereof that is contained in milk or the like and is ingested on a daily basis, there are almost no side effects even if it is ingested continuously for a long period of time. 2) It has a significant effect on improving prognosis. 3) When used in combination with other anticancer agents, for example, mitomycin C, cisplatin, fluorouracil, bleomycin, irinotecan, interferon, lentinan, streptococcal extract, etc., the dosage of these drugs can be reduced and the synergistic effect of improving the prognosis. Can be expected. 4) The toxicity of the anticancer drug can be reduced by using it together with the anticancer drug.

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between the number of days after transplantation of tumor cells and the survival rate.

FIG. 2 is a graph showing the relationship between the number of days after tumor cell implantation and body weight.

FIG. 3 is a graph showing the relationship between the number of days after tumor cell implantation and the estimated tumor weight.

FIG. 4 is a graph showing the relationship between the number of days after tumor cell transplantation and the survival rate when each treatment was performed.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Tomohiro Hida 5-83, Higashihara, Zama City, Kanagawa Prefecture Morinaga Dairy Co., Ltd. Biological Science Research Institute F-term (reference) 4C084 AA02 AA03 BA33 BA43 BA44 CA38 DC50 MA17 MA35 MA37 MA41 MA43 MA52 NA06 NA10 NA14 ZB262

Claims (4)

[Claims] An agent for improving the prognosis of a cancer disease, which comprises lactoferrin and / or a hydrolyzate of lactoferrin as an active ingredient and is orally administered to a cancer patient. 2. The cancer disease is skin cancer, lung cancer, laryngeal cancer, tongue cancer, breast cancer, liver cancer, pancreatic cancer, esophageal cancer, stomach cancer, small intestine cancer, colon cancer, kidney cancer, ovarian cancer, uterine cancer, prostate cancer. 2. The agent for improving prognosis of a cancer disease according to claim 1, wherein the agent is bladder cancer. 3. The lactoferrin according to claim 1, wherein the lactoferrin is one or a mixture of two or more selected from the group consisting of metal-unsaturated lactoferrin, metal-saturated lactoferrin, and apolactoferrin. An agent for improving the prognosis of cancer diseases. 4. Lactoferrin and / or a hydrolyzate of lactoferrin are present in an amount of 20 mg to 1 mg / kg of body weight per day.
The agent for improving prognosis of a cancer disease according to any one of claims 1 to 3, which is administered in an amount of 5 g.