JPH11124335A - Antineoplastic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antineoplastic agent useful for a treatment for a malignant tumor such as a gastric cancer, carcinoma of the esophagus, carcinoma of the colon and rectum, etc., excellent in antineoplastic effect and capable of avoiding a provision of any side effects and drug resistance by including a colloidal silver as an active ingredient. SOLUTION: This antineoplastic agent is obtained by including a colloidal silver with a diameter of pref. 1 to 500 nm. The colloidal silver is prepared by a dextrin reduction using a gelatin, etc., as a dispersant. The dose is pref. generally 0.1 to 1,000 mg/kg per adult and day. The antineoplastic agent is pref. used together with another antineoplastic agent containing, as an active ingredient, an antineoplastic compound having a positive electric charge in a neutral condition of cyanine dye and rhodacyanine dye, etc. The antineoplastic agent is useful for a treatment for a solid cancer such as colonic cancer and rectal cancer and a non-solid cancer such as leukemia and malignant lymphoma, and also applicable to a metastatic cancer or relapsed cancer along with a primary cancer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antitumor agent containing colloidal silver as an active ingredient.

[0002]

2. Description of the Related Art Various chemotherapeutic agents have been researched and developed for various tumors (cancer chemotherapy, current revieWn).
w, 1993-1994, edited by Takashi Tsuruo and Nagahiro Saijo, p.88-102 (Chugai Medical). However, many conventionally developed antitumor agents have problems such as serious side effects and development of drug resistance, and have not yet reached a satisfactory level. Therefore, development of an antitumor agent that can achieve a high therapeutic effect and avoids problems such as side effects and development of drug resistance has been desired.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a medicament effective for treating tumors. The present inventors have conducted intensive studies to solve the above-mentioned problems. As a result, colloidal silver has excellent antitumor activity and is useful as an antitumor agent. It has been found that an antitumor composition having more excellent antitumor activity can be provided by combining it with an active ingredient of an agent. Heretofore, colloidal silver has been widely used as a material for a yellow or black filter layer of a color negative film, for example, in the field of photographic light-sensitive materials. However, the present inventor has shown that this substance exhibits an excellent antitumor effect in vivo. Have not been reported so far. The present invention has been completed based on these findings.

[0004] That is, the present invention provides an antitumor agent containing colloidal silver as an active ingredient. According to a preferred embodiment of the present invention, the colloidal silver has a diameter of 1 nm to 5 nm.
An antitumor agent characterized by being in the range of 00 nm is provided. These antitumor agents are other antitumor agents used for treating a tumor, preferably an antitumor compound having a positive charge under neutral conditions (for example, selected from the group consisting of cyanine dyes and rhodacyanine dyes) When used in combination with an antitumor agent containing (an antitumor compound) as an active ingredient, a remarkable antitumor effect is achieved. Therefore,
According to the present invention, there is provided an action enhancer of an antitumor agent containing an antitumor compound as an active ingredient, the action enhancer containing colloidal silver as an active ingredient.

From another aspect, the present invention provides an antitumor composition comprising colloidal silver and an antitumor compound. According to a preferred embodiment of the present invention, the antitumor compound is a compound having a positive charge under neutral conditions; and the antitumor compound is selected from the group consisting of cyanine dyes and rhodacyanine dyes Provided are anti-tumor compositions that are compounds of the invention.

[0006] From still another viewpoint, a method for treating a tumor, comprising the steps of: providing an effective amount of an antitumor agent containing colloidal silver as an active ingredient or an antitumor composition containing colloidal silver and an antitumor compound; And a method for treating a tumor, comprising: an effective amount of an antitumor agent containing an antitumor compound as an active ingredient; and the above-mentioned effect enhancement comprising colloidal silver as an active ingredient. A method comprising administering an effective amount of an agent to a mammal, including a human, is provided. The invention also provides the use of colloidal silver for the manufacture of the antitumor agent, the antitumor composition, or the action enhancer.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The antitumor agent of the present invention is characterized by containing colloidal silver as an active ingredient. Colloidal silver, which is an active ingredient, is easily available, for example, in the field of photographic light-sensitive materials because it is widely used as a material for yellow or black filter layers of color negative films.

The method for producing colloidal silver is not particularly limited. For example, a method of reducing a soluble silver salt with hydroquinone in a gelatin solution disclosed in US Pat. No. 2,688,601; German Patent 1, 096, 1
No. 93, 913, a method of reducing a sparingly soluble silver salt with hydrazine; US Pat. No. 2,921,914.
A method of reducing silver with tannic acid as described in the specification; a method of forming silver particles by electroless plating as described in JP-A-5-134358. Also, Wiley & S
ons, New York, 1993, weise
The method of preparing yellow colloidal silver by the dextrin reduction method of Carey Le described in Colloidal Elements, r.

In these production methods, gelatin is widely used as a dispersant. However, the dispersant for producing colloidal silver contained in the medicament of the present invention is not limited to gelatin. For example, albumin, Proteins such as globulin and casein may be used. The diameter of the colloidal silver contained in the medicament of the present invention is not particularly limited.
It is in the range of 500 nm, preferably in the range of 5 nm to 50 nm. The diameter of the colloidal silver can be easily measured by observation with an electron microscope, X-ray diffraction, or the like.

[0010] Colloidal silver itself has excellent antitumor activity, but by using the antitumor agent of the present invention together with another antitumor agent containing an antitumor compound as an active ingredient, more excellent antitumor activity can be obtained. A tumor effect is achieved. Also, the antitumor composition containing colloidal silver and the antitumor compound provided by the present invention achieves an extremely excellent antitumor effect. As used herein, “anti-tumor” or a synonym thereof can exert a selective growth inhibitory action or a damaging action on tissues or cells of a malignant tumor and achieve reduction or elimination of tumor tissues or cells. It must be interpreted in the broadest sense, including the actions it can take.

The antitumor compound which can be used in combination with the antitumor agent of the present invention containing colloidal silver or the antitumor compound which can be blended with the antitumor composition of the present invention containing colloidal silver and an antitumor compound is Although not particularly limited, a positively charged antitumor compound can be preferably used. Particularly preferred compounds among the positively charged antitumor compounds include:
For example, doxorubicin, cyanine dyes, rhodacyanine dyes and the like can be mentioned.

[0012] Examples of cyanine dyes include those described in
The following general formula (1) disclosed in JP-A-5-69513:

Embedded image (Wherein Y and Y ′ each independently represent S, O, or a dimethylmethylene group [—C (CH ₃ ) ₂ —]; R and R ′ each independently represent an alkyl group or an alkenyl group; ^- represents an anion; n is an integer of 0 or 1 to _{4; R 1, R 2,} R 1 ', and R _2' each independently represent a hydrogen atom or a lower alkyl group; R ₁
And R ₂ and R ₁ ′ and R ₂ ′ may form a benzene ring or a naphthalene ring together with the adjacent carbon chain).

Further, as the cyanine dye, for example, the following general formula (2) disclosed in JP-A-54-157839:

Embedded image (Wherein the ring containing A on the left and the ring containing B on the right are nitrogen-containing heterocycles selected from the group consisting of benzothiazole, benzoselenazole, benzoxazole, naphthothiazole, and quinoline; Is 1 or 2
R ₁ and R ₂ are each independently a residue obtained by removing an anion of a quaternizing agent; X is an anion of a quaternizing agent; n Is 0 or a positive integer; the methine chain may have a substituent at the meso position).

As the rhodacyanine dye, for example, a compound represented by the following general formula (3) disclosed in US Pat. No. 5,360,803 can be used.

Embedded image Here, X ₁ and X ₂ are each independently O, S, -CH
= CH -, - C (R 4) (R 5) -, or -N (R ₆₎ - represents; Y ₁ is O, S, Se, or -N (R ₇₎ - represents a. R
₁ and R ₃ each independently represent an alkyl group having 1 to 15 carbon atoms. R ₂ is an alkyl group having 1 to 15 carbon atoms, an aryl group having 6 to 20 carbon atoms, or an imidazole ring, a thiazole ring, a pyrrole ring, a pyrazole ring, a furan ring, a thiophene ring, a piperidine ring, a morpholine ring,
It represents a hetero ring selected from the group consisting of a piperazine ring, a pyrazine ring, a pyridine ring, and a pyrimidine ring.

Z ₁ is -N (R ₁ )-(CH = CH) _m-
With C-X _1, thiazole ring, benzothiazole ring,
Naphthothiazole ring, oxazole ring, benzoxazole ring, naphthoxazole ring, selenazole ring, benzoselenazole ring, thiazoline ring, 2-pyridine ring, 4
-Pyridine ring, 2-quinoline ring, 4-quinoline ring, 1-
It represents any of an isoquinoline ring, a 3,3-alkylindolenin ring, an imidazole ring, a benzimidazole ring, and a naphthoimidazole ring.

Z ₂ is -X ₂ -C = (CH-CH) _n =
Together with N ⁺ -R ₃ , a thiazole ring, a benzothiazole ring, a naphthothiazole ring, an oxazole ring, a benzoxazole ring, a naphthoxazole ring, a selenazole ring,
Benzoselenazole ring, thiazoline ring, 2-pyridine ring, 4-pyridine ring, 2-quinoline ring, 4-quinoline ring, 1-isoquinoline ring, 3,3-alkylindolenine ring, imidazole ring, benzimidazole ring, or Represents any of naphthoimidazole rings.

L ₁ may represent a methine group, or L ₁ and R ₃ may form a ring such as pyrrole, tetrahydropyridine or oxazole. R ₄ and R ₅ each independently represent an alkyl group having 1 to 15 carbon atoms. R ₆ and R ₇ each independently have 1 to 15 carbon atoms.
Or an aryl group having 6 to 20 carbon atoms. Q represents a pharmacologically acceptable anion. m and n each independently represent 0 or 1.

Further, rhodacyanine dyes are disclosed in
Compounds represented by the following general formulas (4) to (9) disclosed in JP-A-117148 can be used.

Embedded image

Here, X ₁ is O, S, Se, or -N
R ₁₄ - a and; X ₂ is _{O, S, Se, -NR 15} -, - C
R ₁₆ R ₁₇ — or —CH = CH—; X ₃ is O,
X ₄ is —NR ₁₉ —, or —C
R ₂₀ R ₂₁ —; Y ₁ is O, S, Se, or —NR
₁₈ -, and; Z ₁ is 5-membered may be saturated or unsaturated to form a well also with other rings fused may have a substituent or 6
Z ₂ represents an atomic group necessary for forming a naphthalene ring, an anthracene ring or a phenanthrene ring which may have a substituent;
_{R 1, R 3, R 14} , R 15, and R ₁₉ each independently represent a substituted or unsubstituted alkyl group; R ₂ and R ₁₈ are each independently an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group Or an unsubstituted or substituted heterocycle.

L ₁ , L ₂ and L ₃ each independently represent an unsubstituted or substituted methine group, and when it is a substituted methine group, L ₁ and R ₁ and / or L ₃ and R ₃ are bonded to each other. R ₄ may form a saturated or unsaturated 5- or 6-membered ring;
And R ₅ each independently represent a hydrogen atom, an unsubstituted or substituted alkyl group, or an unsubstituted or substituted aryl group; R ₆ , R ₇ , R ₈ , and R ₉ each independently represent a hydrogen atom, an unsubstituted or substituted Represents an alkyl group, an unsubstituted or substituted aryl group, or R ₆ , R ₇ , R
Two groups selected from the group consisting of ₈ and R ₉ may combine to form a saturated or unsaturated 5- or 6-membered ring.

R_Ten, R₁₁, R₁₂And R₁₃Is German
Standing hydrogen atom, unsubstituted or substituted alkyl group, unsubstituted
Or substituted aryl group, unsubstituted or substituted alkoxy
Si group, unsubstituted or substituted aryloxy group, unsubstituted
Or substituted acyl group, unsubstituted or substituted alkoxyca
Rubonyl group, trifluoromethyl group, unsubstituted or substituted
Substituted benzoyl group, unsubstituted or substituted ureido group, no substitution
Substituted or substituted amino group, unsubstituted or substituted amide
Group, unsubstituted or substituted sulfamide group, unsubstituted
Is a substituted carbamyl group, unsubstituted or substituted sulfamoi
Group, halogen atom, nitro group, cyano group, hydroxyl group,
Represents a carboxyl group, or R_Ten , R₁₁, R₁₂
And R₁₃Two adjacent groups are bonded to each other to
It may form a saturated 5- or 6-membered ring, wherein said ring is substituted
May have a group or may form a condensed ring with another ring.
K; R₁₆, R₁₇, R₂₀, And R_{twenty one}Are independent
Q represents a substituted or substituted alkyl group;^-Is pharmaceutically acceptable
Represents 0 or 1;

The above described Japanese Patent Application Laid-Open No. 54-157839
And the cyanine dyes of the above general formula disclosed in JP-A-55-69513 and U.S. Pat.
Specific examples of rhodacyanine dyes disclosed in JP-A-360-803 and JP-A-5-117148 are described in detail in respective publications, and specific compounds disclosed in those publications are described in detail. Any of the compounds consisting of combinations of the substituents specifically exemplified can be compounded as an antitumor compound in the medicament of the present invention.

As the particularly preferred antitumor compounds, the following compounds 1 to 7 can be used, but the antitumor compounds which can be incorporated in the medicament of the present invention are not limited to the following compounds.

Embedded image

The mixing ratio of the colloidal silver and the antitumor compound in the antitumor composition containing the colloidal silver and the antitumor compound is not particularly limited. For example, the weight ratio of the antitumor compound / colloidal silver is 0.5 to 500. , And more preferably 10 to 50. The method for producing an antitumor composition containing colloidal silver and an antitumor compound is not particularly limited. For example, an antitumor compound to be mixed is dissolved in an appropriate solvent (water, physiological saline, alcohol, etc.). It is preferable that the mixture is added to colloidal silver and stirred at an appropriate temperature between 40 ° C. and 70 ° C., and then, if necessary, alcohol or the like is distilled off under reduced pressure and redispersed by ultrasonic irradiation. The antitumor composition of the present invention containing colloidal silver and an antitumor compound may contain one or more antitumor compounds.

The antitumor compound, preferably a positively charged antitumor compound, can exist as an isomer based on one or more asymmetric carbons and / or one or more double bonds. In this case, any stereoisomerically pure isomers (optical isomers, diastereoisomers, geometric isomers, etc.), mixtures of any isomers, and racemates can be used. When the antitumor compound can exist in the form of a salt, a substance in the form of a pharmacologically acceptable salt may be added to the antitumor composition of the present invention. Further, a hydrate or solvate of the antitumor compound in a free form or a salt form may be incorporated in the antitumor composition of the present invention.

The pharmaceutically acceptable salts include acid addition salts, base addition salts and amino acid addition salts. Examples of the acid addition salt include, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, oxalate, benzoate, methanesulfonate, p- Organic acid salts such as toluenesulfonate, maleate, fumarate, tartrate, citrate, succinate and lactate can be mentioned. As the base addition salt, for example, metal salts such as sodium salt, potassium salt, magnesium salt and calcium salt, and amine salts such as ammonium salt, methylamine salt and triethylamine salt can be used. As amino acid addition salts, for example, glycine, phenylalanine,
Addition salts such as aspartic acid and glutamic acid can be used.

The antitumor agent of the present invention containing colloidal silver as an active ingredient, or the antitumor composition containing colloidal silver and an antitumor compound can be administered orally or parenterally. The form of the composition, for example, tablets, pills,
Pharmaceutical preparations for oral administration such as powders, granules, capsules, solutions, suspensions and the like; or preparations for parenteral administration such as suppositories, injections, drops, inhalants, creams and ointments You. For the production of these pharmaceutical compositions, various pharmaceutical additives commonly used in the art can be used. For example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments, diluents, bases, solubilizers or dissolution aids, isotonic agents, pH regulators, stabilizers , A propellant, an adhesive and the like, which can be appropriately selected by those skilled in the art according to the form of the preparation.

The antitumor agent or antitumor composition of the present invention can be applied to various types of malignant tumors, and the applicable diseases are not particularly limited. For example, gastric cancer, esophageal cancer, colon cancer, colon cancer, rectal cancer, It can be applied to non-solid cancers such as lung cancer, liver cancer, kidney cancer, pancreatic cancer, brain tumor, skin cancer, tongue cancer, breast cancer, uterine cancer, prostate cancer, leukemia, malignant lymphoma, etc. In addition, the present invention is applicable to metastatic cancer or recurrent cancer. The dose of the antitumor agent or antitumor composition of the present invention should be appropriately increased or decreased depending on the administration route, the age and weight of the patient, and the type and malignancy of the tumor, and whether metastasis or recurrence occurs, Generally, the amount of colloidal silver per adult per day is about 0.1 to 1,000 mg / kg. The dose when the antitumor agent of the present invention is used in combination with another antitumor agent is also the same as described above.

[0029]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. Example 1 Production of Antitumor Agent (Injection) Containing Colloidal Silver An aqueous solution containing 17 g of silver nitrate was added to 700 mL of an aqueous solution containing 18 g of dextrin adjusted to pH 11.0,
Gelatin was added, washed with water at 30 ° C. by a known flocculation method, gelatin was added, and the mixture was heated to 60 ° C. to prepare colloidal silver. The average particle size of the colloidal silver was 10 nm. The obtained colloidal silver was diluted with physiological saline to a silver concentration of 2 mg / mL,
An antitumor agent in the form of an injection was produced by performing a normal sterilization operation.

Example 2 Preparation of Antitumor Composition (Injection) Containing Colloidal Silver and Cyanine Dye Compound 1 (100 mg) shown above as a particularly preferred antitumor compound is dissolved in 10 mL of ethanol, and a solution thereof is prepared. Was added to the colloidal silver (20 mg in terms of silver amount) obtained in Example 1, and the mixture was stirred at 60 ° C. for 1 hour. Ethanol was distilled off under reduced pressure, 10 mL of water was added, and the mixture was re-dispersed using a bath-type ultrasonic irradiation apparatus, and then subjected to ordinary sterilization operation to produce an antitumor composition in the form of an injection.

Example 3 Inhibition of In Vivo Tumor Growth Inhibition of in vivo tumor growth was evaluated using colon cancer cells.
Sections of human colon cancer strain LS174T were inoculated subcutaneously into the right axillary abdomen of balb / c-nu / nu mice as tumors. Each of the antitumor agent obtained in Example 1 or the antitumor composition obtained in Example 2 from the seventh day after tumor inoculation for 5 days (three injections every other day), 20 mg / silver per dose kg was administered subcutaneously around the tumor.
Tumor size in two directions was measured with calipers and tumor volume was quantified. Tumor volume was calculated by the following equation. Compound 1 (100 mg) was dissolved in 0.1 mL of ethanol using a bath-type ultrasonic irradiation device, dropped into 10 mL of water, and irradiated with ultrasonic waves for 1 hour using a bath-type ultrasonic irradiation device. The dispersion was administered as a positive control.

[0032]

## EQU1 ## Tumor volume = (major axis) × (minor axis) ² ÷ 2 T / C = (tumor volume of treated mouse / tumor volume of target mouse) × 100

Table 1 shows the tumor volume 7 days after the last injection.
Colloidal silver had a clear tumor growth inhibitory effect either alone (Example 1) or in combination with Compound 1 having antitumor activity (Example 2).

[0034]

[Table 1] ──────────────────────── Test group Tumor volume (mm ³ ) T / C (%) ──────── ──────────────── Subject (no administration) 1831 (100) Antitumor agent of Example 1 1566 86 Compound 1 administration group 1176 64 Antitumor composition of Example 2 630 34 ─ ───────────────────────

[0035]

EFFECT OF THE INVENTION Colloidal silver itself has an antitumor activity and is useful as an active ingredient of an anticancer agent. Also,
By administering colloidal silver to a patient together with an antitumor agent containing an antitumor compound as an active ingredient, or by administering an antitumor composition containing colloidal silver and an antitumor agent to a patient, an excellent antitumor The effect is achieved.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hitomi Ikenaga 210, Nakanuma, Minamiashigara, Kanagawa Prefecture Inside Fuji Photo Film Co., Ltd. (72) Inventor Tadao Shishido 210, Nakanuma, Minamiashigara, Kanagawa Prefecture Fuji Photo Film, Ashigara Research (72) Inventor Hiroshi Tamura 210 Nakanuma, Minamiashigara, Kanagawa Prefecture Fuji Photo Film Co., Ltd.Ashigara Research Laboratory (72) Inventor Tetsukawa Tetsukawa 2-17-9-105 Ebara Shinagawa-ku, Tokyo (72) Inventor Ikuo Hasegawa Tokyo 72 Funamachi, Shinjuku-ku, Tokyo (72) Inventor Koji Hasegawa 2 Funamachi, Shinjuku-ku, Tokyo

Claims (8)

[Claims] 1. An antitumor agent comprising colloidal silver as an active ingredient. 2. The antitumor agent according to claim 1, wherein the diameter of the colloidal silver is in the range of 1 nm to 500 nm. 3. An action enhancer for an antitumor agent comprising an antitumor compound as an active ingredient, wherein the action enhancer comprises colloidal silver as an active ingredient. 4. The action enhancer according to claim 3, wherein the antitumor compound is a compound having a positive charge under neutral conditions. 5. The action enhancer according to claim 3, wherein the antitumor compound is a compound selected from the group consisting of cyanine dyes and rhodacyanine dyes. 6. An antitumor composition comprising colloidal silver and an antitumor compound. 7. The antitumor composition according to claim 6, wherein the antitumor compound is a compound having a positive charge under neutral conditions. 8. The antitumor composition according to claim 6, wherein the antitumor compound is a compound selected from the group consisting of cyanine dyes and rhodacyanine dyes.