JP3120187B2 - Endovascular embolic agent containing angiogenesis inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intravascular embolic agent containing an angiogenesis inhibitor effective for treating a malignant tumor.

[0002]

2. Description of the Related Art In particular, for an unresectable tumor, an intravascular embolizing agent is administered to its artery to block nutrients supplied, or a combination of an anticancer agent and an intravascular embolizing agent is administered. Chemoembolization, which is expected to simultaneously maintain a high anticancer drug concentration in a tumor, is well known as an effective therapy. Examples of such intravascular embolizing agents include degradable starch microparticles (DSM) (Cancer, 50, 631 (19)
82)), iodized poppy oil (Cancer Res., 44, 2115).
(1984)), cross-linked collagen fibers (Cancer Res., 4 ).
8 , 2446 (1988)) and ethylcellulose microcapsules (Cancer, 46, 14 (1980)). However, even if the tumor-controlling artery is embolized in these therapies, the tumor is recruited by the formation of collateral arteries due to the secretion of tumor-derived angiogenic factors, which is an important characteristic of tumors. It is feared that the effect cannot be obtained. Therefore, development of an intravascular embolic agent that further improves the treatment results of embolization therapy is desired.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide an intravascular embolic agent which contains an angiogenesis inhibitor and an intravascular embolic material, and enhances the anticancer effect of embolization therapy. That is, an object of the present invention is to provide an intravascular embolic agent which can be used alone or in combination with another intravascular embolic agent or an anticancer agent and which can obtain a stronger anticancer effect.

[0004]

[Means for Solving the Problems] In view of such circumstances,
The present inventors have conducted intensive studies on obtaining an intravascular embolic agent that enhances the anticancer effect. As a result, by adding an angiogenesis inhibitor to the intravascular embolic agent, less administration than the angiogenesis inhibitor alone was performed. It was unexpectedly found that the amount can enhance the anti-cancer effect, and further studies based on this result have completed the present invention. That is, the present invention provides an intravascular embolic agent containing an angiogenesis inhibitor and an intravascular embolic material. For example, the angiogenesis inhibitor used in the present invention is as follows: 1) Angiogenic factors are released or leaked in a tissue where a tumor exists. 2) Angiogenic factors increase the activity of vascular endothelial cells such as plasminogen activator, plasmin and collagenase. 3) The activated protease degrades the basement membrane surrounding blood vessels. 4) Endothelial cells migrate toward angiogenic factors, and endothelial cells proliferate behind them. Endothelial cells take the form of a tube arranged vertically with a tube. 5) A bond is formed between the formed vascular buds, and a loop is formed. 6) Blood flows through the loop. 7) Pericytes become visible outside the blood vessels, and a new basement membrane is formed. A substance that inhibits any step in the mechanism of angiogenesis. The angiogenesis inhibitor does not act directly on cancer cells, but has an effect different from conventional anticancer drugs that suppresses cancer growth for the first time by inhibiting angiogenesis of solid cancer (Nature, 348 , 555
(1990)). Examples of the angiogenesis inhibitor include extracts of cartilage tissue or aortic wall exhibiting collagenase inhibitory activity (Science, 221 , 1185 (1983)),
Protamine (Nature, 297 , 307 (1982)),
Angiostatic steroids (Science, 221 , 7
19 (1983)), a protein obtained from retinal pigment epithelial cells (Arch. Ophthalmol., 103 , 1870 (1)
985)), anti-tumor factors derived from cultured chondrocytes (protein nucleic acid enzyme, 33 , 1803 (1988)), and anti-inflammatory drugs such as indomethacin (Anticancer Res., 6 , 251 (1)
986)), a ribonuclease inhibitor (Proc. Natl. Ac
ad, SCi. USA, 84 , 2238 (1987)), drugs that affect collagen metabolism (Biochem. Biophys. Res. C
ommun., 1 33, 911 ( 1985) and Lab. Inves
t., 59 , 44 (1988)), a complex of polysaccharide sulfate and peptidoglycan (for example, JP-A-63-119500), a gold preparation for rheumatism, herbimycin A (JP-A-6-1988).
JP-A-3-295509) and fumagillin produced by microorganisms (for example, JP-A-1-2798).
No. 28) or a chemically synthesized fumagillol derivative (for example, EP-A-359036, EP-A-3).
57061, EP-A-386667, EP-A-41
5294). Of these, fumagillol derivatives are preferred, for example, those represented by the general formula (I)

[0005]

Embedded image

Wherein R ¹ is hydrogen, R ² is halogen, N
^{(O) mR 5 R 6,} N + R 5 R 6 R 7 · X -, S (O) nR 5 or S
⁺ R ⁵ R ⁶ .X ⁻ (wherein, R ⁵ , R ⁶ and R ⁷ each represent a hydrocarbon residue or a heterocyclic group which may have a substituent, X ⁻ represents a counter anion, and m represents 0. Or n is an integer of 0 to 2. R ⁵ and R ^{6 form} a nitrogen-containing or sulfur-containing heterocyclic ring which may be condensed with an adjacent nitrogen atom or sulfur atom. May be
These condensed nitrogen-containing or sulfur-containing heterocyclic rings may have a substituent. ) Or a bond represented by R ¹ and R ² , R ³ represents a 2-methyl-1-propenyl group or an isobutyl group, and A represents O or NR
⁸ (wherein R ⁸ represents hydrogen or a lower alkyl or aryl group which may have a substituent), and R ⁴
Represents hydrogen, a hydrocarbon residue which may have a substituent or an acyl group which may have a substituent. ] Is particularly preferable.

In the above formula (I), examples of the halogen represented by R ² include fluorine, chlorine, bromine and iodine.
When R ¹ and R ² are bonded, they form an epoxy ring. Examples of the hydrocarbon residue of the optionally substituted hydrocarbon residue represented by R ⁵ , R ⁶ or R ⁷ include a straight-chain or branched alkyl group having 1 to 6 carbon atoms (eg, , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), an alkenyl group having 2 to 6 carbon atoms (eg, vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-
Pentenyl, 4-pentenyl, 5-hexenyl and the like),
An alkynyl group having 2 to 6 carbon atoms (eg, ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-2-yl,
1-pentyn-3-yl, 3-pentyn-1-yl, 4
-Pentin-2-yl, 3-hexyn-1-yl and the like), a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and a cycloalkenyl group having 3 to 6 carbon atoms ( Examples, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl and the like), an aralkyl group having 7 to 13 carbon atoms (eg, benzyl, 1-phenethyl, 2-phenethyl and the like), an aryl group having 6 to 10 carbon atoms (eg, Phenyl, naphthyl, etc.).

The heterocyclic group of the optionally substituted heterocyclic group represented by R ⁵ , R ⁶ or R ⁷ includes 1 to 4 hetero atoms (eg, nitrogen, oxygen, sulfur, etc.). 5- or 6-membered heterocyclic group (eg, 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4
-Thiadiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), and the heterocyclic group is 5 or 6
Membered ring group (eg, benzene, pyridine, cyclohexane, etc.)
To form a bicyclic fused ring group (eg, 8-quinolyl, 8-purinyl, etc.).

The nitrogen-containing heterocyclic ring which R ⁵ and R ⁶ may form together with an adjacent nitrogen atom includes a 4- to 7-membered nitrogen-containing heterocyclic ring (eg, pyrrolidin-1-yl, piperazino ,
Morpholino, 4-methylpiperazin-1-yl and the like).

The sulfur-containing heterocyclic ring which R ⁵ and R ⁶ may form together with an adjacent sulfur atom includes a 4- to 7-membered sulfur-containing heterocyclic ring (eg, tetrahydrothiophen-1-yl,
1,4-thioxan-1-yl and the like).

The nitrogen-containing or sulfur-containing heterocyclic ring which R ⁵ and R ⁶ may form together with an adjacent nitrogen atom or sulfur atom is a 5- or 6-membered ring group (eg, benzene, pyridine, pyrazine, pyridazine, Condensed with cyclohexane)
Cyclic condensed ring group (eg, isoindolin-2-yl, 2-isoquinolyl, 1,3-dihydrobenzo [c] thiophene-2
-Yl, 2,3-dihydrobenzo [b] thiophen-1-yl, 3,4-dihydro-1H-2-benzopyran-2-
Yl, 3,4-dihydro-2H-1-benzopyran-1
-Yl, 1,2,4,5-tetrahydro-3-benzothiepin-3-yl, 1,3-dihydrothieno [3,4-c] pyridin-2-yl, 5,7-dihydrothieno [3,4-b ]
Pyrazin-6-yl, 5,7-dihydrothieno [3,4-
d] pyridazin-6-yl).

The lower alkyl group of the lower alkyl group which may have a substituent represented by R ⁸ has 1 to 1 carbon atoms.
6 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.).

The aryl group of the optionally substituted aryl group represented by R ⁸ includes aryl groups having 6 to 10 carbon atoms (eg, phenyl, naphthyl, etc.).

The hydrocarbon residue optionally having a substituent represented by R ⁴ includes the hydrocarbon residue optionally having a substituent represented by R ⁵ , R ⁶ and R ⁷ described above. Described in detail. When the hydrocarbon residue represented by R ⁴ is an alkenyl group, unsubstituted one is preferable.

Examples of the optionally substituted acyl group represented by R ⁴ include residues of an optionally substituted acyl group such as acyl carboxylate, acyl sulfonate, carbamoyl, thiocarbamoyl and sulfamoyl. Groups,
For example, alkanoyl, aroyl, heterocyclic carbonyl, carbamoyl, thiocarbamoyl, arylsulfonyl, alkylsulfonyl, sulfamoyl, alkoxycarbonyl, aryloxycarbonyl, each of which may have a substituent, are exemplified.

Examples of the alkanoyl group of the alkanoyl group which may have a substituent include an alkanoyl group having 1 to 6 carbon atoms (eg, formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.). No. Examples of the aroyl group of the aroyl group which may have a substituent include an aroyl group having 7 to 11 carbon atoms (eg, benzoyl, 1-naphthoyl, 2-naphthoyl and the like).

The heterocyclic carbonyl group in the optionally substituted heterocyclic carbonyl group includes a heteroatom
5 or 6 containing 1 to 4 (eg, nitrogen, oxygen, sulfur, etc.)
And a membered heterocyclic carbonyl group (eg, 2-furoyl, 2-thenoyl, nicotinyl, isonicotinyl, etc.).

The arylsulfonyl group of the arylsulfonyl group which may have a substituent has 6 to 1 carbon atoms.
0 arylsulfonyl group (eg, benzenesulfonyl,
1-naphthylsulfonyl, 2-naphthylsulfonyl and the like).

The alkylsulfonyl group of the alkylsulfonyl group which may have a substituent has 1 to 6 carbon atoms.
(Eg, methylsulfonyl, ethylsulfonyl, etc.).

The alkoxycarbonyl group of the alkoxycarbonyl group which may have a substituent has 2 carbon atoms.
To 7 alkoxycarbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, etc.).

The aryloxycarbonyl group of the optionally substituted aryloxycarbonyl group includes:
An aryloxycarbonyl group having 7 to 11 carbon atoms (eg,
Phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.).

A hydrocarbon residue or a heterocyclic group which may have a substituent represented by R ⁵ , R ⁶ or R ⁷ ,
R ⁵ and R ⁶ may be formed together with an adjacent nitrogen atom or sulfur atom, and may be a condensed nitrogen-containing or sulfur-containing heterocyclic group, each having a substituent represented by R ^8. A lower alkyl group or an aryl group which may be substituted, and a hydrocarbon residue or an acyl group which may have a substituent represented by R ⁴ (alkanoyl group, aroyl group, heterocyclic carbonyl group, carbamoyl group, A thiocarbamoyl group, an arylsulfonyl group, an alkylsulfonyl group, a sulfamoyl group, an alkoxycarbonyl group, or an aryloxycarbonyl group)
May have one or more substituents.

Examples of the substituent include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), a C _2-6 alkenyl group ( For example, vinyl,
Allyl, 2-butenyl, methylallyl, 3-butenyl,
2-pentenyl, 4-pentenyl, 5-hexenyl, etc.), C _2-6 alkynyl group (eg, ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-2-yl, 1
-Pentyn-3-yl, 3-pentyn-1-yl, 4-
Pentin-2-yl, 3-hexyn-1-yl and the like),
C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _3-6 cycloalkenyl group (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), C _6-10 aryl Group (eg, phenyl, naphthyl, etc.), amino, C _1-6 alkylamino group (eg, methylamino, ethylamino, isopropylamino, etc.), diC _1-6
Alkylamino group (eg, dimethylamino, diethylamino, etc.), azide, nitro, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl, C _1-4 alkoxy group (eg, methoxy, ethoxy, etc.), C _{6 -10} aryloxy group (eg, pheninoxy, naphthyloxy, etc.), C
_1-6 alkylthio group (e.g., methylthio, ethylthio, propylthio, etc.), _C6-10 arylthio group (e.g., phenylthio, naphthylthio, etc.), cyano, carbamoyl group,
Carboxyl group, C _1-4 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C _7-11
Aryloxycarbonyl group (eg, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.), carboxy C _1-4 alkoxy group
(Eg, carboxymethoxy, 2-carboxyethoxy, etc.), C _1-6 alkanoyl group (eg, formyl, acetyl,
Propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.), _C7-11 aroyl group (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C
_6-10 arylsulfonyl group (e.g., benzenesulfonyl,
1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, etc.), C _6-10 arylsulfinyl group (eg, benzenesulfinyl, 1-naphthylsulfinyl, 2- Naphthylsulfinyl), C
_1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), 5- or 6-membered heterocyclic group containing 1-4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) (eg, 2-
Furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazole-2-
Yl, 1-methyl-5-tetrazolyl), a 5- or 6-membered heterocyclic carbonyl group containing 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) (eg, 2-furoyl, 2-thenoyl, A 5- or 6-membered heterocyclic thio group containing 1 to 4 hetero atoms (eg, nitrogen, oxygen, sulfur, etc.) (eg, 4-pyridylthio, 2-pyrimidylthio, 1,3,4- Thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio, etc.), and a heterocyclic thio group is a bicyclic fused ring thio group (eg, 2-benzothiazolylthio,
8-quinolylthio).

When R ⁴ represents a disubstituted carbamoyl group, a thiocarbamoyl group or a sulfamoyl group, a nitrogen-containing heterocyclic ring (for example, pyrrolidine-) together with the nitrogen atom of the carbamoyl, thiocarbamoyl or sulfamoyl group. 1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl and the like)
May be formed.

Further, a substituent in a hydrocarbon residue or a heterocyclic group which may have a substituent represented by R ⁵ , R ⁶ or R ⁷ , a nitrogen atom in which R ⁵ and R ⁶ are adjacent to each other or A substituent in a nitrogen-containing or sulfur-containing heterocyclic group which may be formed together with a sulfur atom, and which may be condensed, a lower alkyl group which may have a substituent represented by R ⁸ or A substituent in the aryl group, and a hydrocarbon residue optionally having a substituent represented by R ⁴ , an alkanoyl group, an aroyl group, a heterocyclic carbonyl group, a carbamoyl group, a thiocarbamoyl group, an arylsulfonyl group, an alkyl Substituents in the sulfonyl group, sulfamoyl group, alkoxycarbonyl group, or aryloxycarbonyl group may have 1 to 3 substituents at further substitutable positions. It may have.

As the substituent, R ⁵ , R ⁶ or R
^A substituent on a hydrocarbon residue or a heterocyclic group which may have a substituent represented by ⁷ , each of R ⁵ and R ⁶ may be formed together with an adjacent nitrogen atom or sulfur atom, and A substituent in a nitrogen-containing or sulfur-containing heterocyclic group which may be cyclic, a substituent in a lower alkyl group or an aryl group which may have a substituent represented by R ⁸ , and a substituent represented by R ⁴ A hydrocarbon residue optionally having a substituent, an alkanoyl group, an aroyl group, a heterocyclic carbonyl group, a carbamoyl group, a thiocarbamoyl group, an arylsulfonyl group, an alkylsulfonyl group, a sulfamoyl group, an alkoxycarbonyl group, or an aryl The substituents exemplified for the substituent in the oxycarbonyl group are applied as they are.

Examples of the counter anion represented by X ⁻ include a halogen ion (eg, iodine ion, bromide ion, chloride ion, etc.), sulfate ion, phosphate ion, nitrate ion, perchlorate ion, tetrafluoroborate ion, Methane sulfate ion, p-tolyl sulfate ion, benzene sulfate ion, hydroxyl ion, carboxylate ion of organic acid (eg, oxalate ion, maleate ion, fumarate ion,
Succinate ion, citrate ion, lactate ion, trifluoroacetate ion, lactobionate ion, acetate ion, propionate ion,
(Tartarate ion, ethyl succinate ion, etc.)
And the like.

Compound (I) has an asymmetric center in the molecule and has optical activity, but its absolute structure is based on fumagillol as a raw material. Unless otherwise specified, a compound having the same structure as that of fumagillol is used. means.

[0029]

Embedded image

When the compound (I) has a di-lower alkylamino group, a nitrogen-containing heterocyclic group or a nitrogen-containing aromatic heterocyclic group in the molecule, the nitrogen atom in these substituents is further substituted with alkyl. quaternary ammonio group is of (eg, trimethylammonio, N- Mechirupirijinio, N- methylpyrrolidin-1-ylium, etc.) may be in the form, the foregoing X as counter anion ^- and the counter anion shown by Similar counter anions are mentioned. In compound (I), R ¹ and R ² are a bond, or R ¹ is hydrogen and R ² is N (O) mR ¹ R ² , N ⁺ R ¹ R ² R ^3.
Wherein X ^- preferably, especially ^{S + R 1 R 2 · X} - -, S (O) nR 1 and ^{S + (O) mR 1 R} 2 · X by R ⁵ and R ⁶ are a hydrocarbon residue And a compound wherein X ^- is halogen.

A is preferably O or NH, R ³ is preferably 2-methyl-1-propenyl, and R ⁴ is preferably carbamoyl or ureido having a substituent. The compound represented by the general formula (I) is a hydrolysis product of fumagillol (fumagillin) produced by a microorganism, fumagillol (f
umagillol) [Tarbell, DSet al., Journal of
American Chemical Society (J. Am. Chem. So
c.) 83 , 3096 (1961)] as a starting material, the preparation method, physicochemical and biological properties of which are described in detail in the aforementioned publications and in the application. Of these compounds, 6-O- (N
-Chloroacetylcarbamoyl) fumagillol, 6-O
-(N-chloroacetylcarbamoyl) -4 ', 5'-dihydrofumagillol, 6α- (N'-chloroacetylureido) -6-desoxyfumagillol, 4- (N-chloroacetylcarbamoyloxy)- 2- (1,2-epoxy-1,5-dimethyl-4-hexenyl) -1- (1,3-dihydrobenzo [c] thiophen-2-ylio) methyl-
3-methoxycyclohexanol chloride, 4-
(N'-chloroacetylureido) -2- (1,2-epoxy-1,5-dimethyl-4-hexenyl) -1- (1,3-
Dihydrobenzo [c] thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride is preferred.

The angiogenesis inhibitor may form a salt. Examples of the salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a base. Salts with an acidic or acidic amino group are used. Inorganic bases capable of forming these salts include alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), and organic bases such as trimethylamine, triethylamine, pyridine, picoline, and the like. N, N-dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine and the like; inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; Formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., and basic or acidic amino acids such as arginine, lysine, ornithine, asparagine , And glutamic acid.

The intravascular embolic material used in the present invention includes:
Oils commonly used in injections such as poppy oil, sesame oil and corn oil, ordinary metals such as iron and ferrite, insoluble salts of metals such as barium sulfate, hydroxy-calcium apatite sintered bodies and calcium triphosphate sintered bodies Ceramics such as sintered calcium phosphate fine particles, cholesterol, glycerol esters of fatty acids,
Wax such as silicon and activated carbon are used. Furthermore, those prepared by a method known per se such as solidifying as it is or using a cross-linking agent such as formaldehyde to cure the particles using ordinary natural and synthetic polymers as exemplified below are also used in the present invention. Can be used as an intravascular embolic material. Such polymers include polypeptides, polysaccharides, polyfatty acid esters, polyamino acids,
Examples thereof include polyaldehyde, polyvinyl-based polymer, and maleic anhydride-based polymer. The molecular weights of these polymers vary greatly depending on the type, and furthermore, upon molding, they vary greatly depending on whether or not an insolubilization treatment such as cross-linking or complex formation is performed, so it cannot be said unconditionally, but it is approximately 1,000 to 1,000. 2,000, more preferably 2,000
About 000 to 800,000.

Examples of the polypeptide include gelatin, collagen, elastin, albumin, hemoglobin, transferrin, globulin, fibrin, fibrinogen, keratin sulfate and the like.

Examples of polysaccharides include dextran, agarose, pullulan, chitosan, mannan, carrageenan, alginic acid, starch, amylose, amylopectin, pectin, lentinan, hyaluronic acid, hylan, ether cellulose (methylcellulose, ethylcellulose, carboxymethylcellulose, carboxyethylcellulose, Hydroxyethyl cellulose, hydroxypropyl cellulose and the like).

Examples of the polyfatty acid ester include homopolymers and copolymers of lactic acid, glycolic acid, hydroxybutyric acid, malic acid, citric acid, tartaric acid and the like.

For example, the copolymer of polylactic acid and lactic acid-glycolic acid has a lactic acid / glycolic acid ratio (molar ratio) of 100/0 to 30/70, and more preferably 100/0 to 30/70.
40/60, and a molecular weight of about 1,000 to 100,000, more preferably about 2,000 to 80,000.

Examples of polyamino acids include poly-γ-benzyl-L-glutamic acid and poly-γ-methyl-L-glutamic acid.

As the polyvinyl polymer, ethylene,
Propylene, butadiene, acrylic acid, acrylic acid ester, methacrylic acid, methacrylic acid ester, vinyl acetate, vinyl chloride, vinyl alcohol, vinyl pyrrolidone, vinyl ether, vinyl carbazole, styrene,
Examples include homopolymers and copolymers of styrene derivatives, α-cyanoacrylate, acrylamide, divinylbenzene and the like.

Of these, gelatin, albumin, collagen, starch, hyaluronic acid, polylactic acid, lactic acid-glycolic acid copolymer which is a polymer which gradually dissolves or decomposes in vivo is preferable.

The intravascular embolizing agent of the present invention can be administered intravascularly in the form of an oil solution, emulsion or suspension, as described in detail below. When the intravascular embolizing agent of the present invention is an emulsion or a suspension, the particles contained therein preferably have a particle size of 10 to 1000 μm.

The intravascular embolizing agent of the present invention may be a mixture of an angiogenesis-inhibiting substance and an intravascular embolizing substance, or may be a method known per se. Adsorbed or contained,
The latter is more preferred. In order to more strongly adsorb the angiogenesis inhibitor on the surface of the intravascular embolic material, an ion exchange resin may be used as the intravascular embolic material. For example, as a support, dextran, agarose, cellulose, polystyrene and the like can be mentioned.
E Sephadex, QAE Sephadex, DEAE Sepharos
e, DEAE Cellulose, QAE Cellulose and various types of Amberlite-IRA, Dowex-1 and the like are available as cation types such as CM Sephadex, CM Sephadex, CM
Cellulose and various types of Amberlite-IR, Dow
ex-50W (all manufactured by Sigma).
In this case, the intravascular embolizing agent of the present invention can be produced by simply mixing the ion exchange resin and the angiogenesis inhibitor.

The amount of the angiogenesis inhibitor used depends on the strength of its pharmacological action and may be any effective amount and may be 50 μg to 2 g, more preferably 200 μg to 1 g per dose.
g, but is not particularly limited. For example, as angiogenesis inhibitors, 6-O- (N-chloroacetylcarbamoyl) fumagillol and 4- (N'-chloroacetylureido) -2- (1,2-epoxy-1,5-
Dimethyl-4-hexenyl) -1- (1,3-dihydrobenzo [c] thiophen-2-ylio) methyl-3-
When a fumagillol derivative such as methoxycyclohexanol chloride is used, a single dose is 0.5 to 50.
Selected from 0 mg. In the case of the above-mentioned compound, a sufficient effect can be obtained by administering 500 mg to an adult once a month. In addition, the concentration of the angiogenesis inhibitor in the intravascular embolizing agent depends on its pharmacological effect activity, solubility in water or an organic solvent,
Although it depends on the particle formability, etc., 0.0
It is preferably from 1 to 95% by weight, especially from 0.1 to 90% by weight.

There are many methods known per se as a method for incorporating an angiogenesis inhibitor into an intravascular embolic material, and details thereof will be described in Examples. For example, an intravascular embolic material soluble in an organic solvent and an angiogenesis can be used. In the case of an inhibitor, dissolve it in, for example, dichloromethane, chloroform, ethyl acetate, isopropyl ether, etc., and disperse it in an aqueous phase containing a surfactant, protective colloid, etc., or spray dry to evaporate the organic solvent. And solidified to form a granular intravascular embolic agent. In this case, the angiogenesis inhibitor may not be partially dissolved. The surfactant or protective colloid used here is not particularly limited as long as it can form a stable oil / water emulsion.
For example, anionic surfactants (sodium oleate,
Sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants (polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, etc.), polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, lecithin, gelatin, etc. These may be used alone or in combination of two or more. Among them, polyvinyl alcohol, carboxymethyl cellulose and gelatin are preferred. The concentration is selected from 0.01 to 20%, more preferably 0.05 to 10%.

Further, in order to contain an angiogenesis inhibitor soluble in an organic solvent and a soluble angiogenesis inhibitor in water,
For example, an aqueous solution of an angiogenesis inhibitor is finely dispersed in an embolic substance dissolved in the above organic solvent, and the organic solvent is volatilized and solidified to obtain a granular intravascular embolic agent in the same manner as in the above method. Also in this case, the angiogenesis inhibitor may not be partially dissolved.

The concentration of the intravascular embolic material soluble in these organic solvents is not particularly limited, and may be within a range that gives a viscosity of dispersing as fine particles when dispersing in an aqueous phase for desolvation. 80%, more preferably 5-60%
Selected from

In order to include a water-soluble intravascular embolic substance and an organic solvent containing a soluble angiogenesis inhibitor,
The angiogenesis inhibitor is dispersed as it is in an aqueous solution of an intravascular embolic substance, for example, an albumin aqueous solution, or the angiogenesis inhibitor is dissolved in a volatile organic solvent, for example, isopropyl ether, and dispersed as fine particles in the albumin aqueous solution. Further, it is dispersed and solidified in an oil phase such as soybean oil or silicone oil to form a granular (microsphere) intravascular embolizing agent. There are several known methods for curing, for example, a method of heating to 120 to 160 ° C. or a method of crosslinking with formaldehyde, glutaraldehyde, or the like. Surfactants such as sorbitan monooleate and sorbitan sesquioleate may be added to form a stable water / oil emulsion. The concentration is selected from up to 20%.

Further, when any substance is dissolved in water, both substances are dissolved in water and dispersed in an oil phase such as the above-mentioned silicone oil, and solidification is performed in the same manner as described above to obtain an intravascular embolizing agent.

The concentration of the water-soluble intravascular embolic material is not particularly limited as long as it is within a range that gives a viscosity of being dispersed as fine particles when dispersed in the oil phase.
80%, more preferably 2% to 60%.

It is more effective to use an intravascular embolic agent containing the angiogenesis inhibitor of the present invention and an intravascular embolic agent together with an anticancer agent due to its anticancer effect. The anticancer agent may be mixed with the above-mentioned intravascular embolizing agent, or may be adsorbed or contained in the intravascular embolizing agent. As for the method of incorporating the substance into the inside, it can be encapsulated by a method known per se depending on whether the substance is water-soluble or organic solvent-soluble as in the method of encapsulating the angiogenesis inhibitor in the intravascular embolizing agent. In this case, an intravascular embolizing agent containing the angiogenesis inhibitor and the anticancer agent at the same time may be administered, or an intravascular embolizing agent containing each of them may be mixed and administered. The anticancer agent referred to herein includes, for example, nitrogen mustard hydrochloride-N-oxide, cyclophosphamide, thiotepa, carbone, chlorambucil,
Nimustine hydrochloride, ifosfamide, melphalan, dacarbazine, uracil mustard, mannomustine, dopan, BCNU, triethylene melamine, azatepa, trenimon, isoprocuone, busulfan, dimethylmirellan, piposulfan, etogluside, epoxypropidine, epoxypiperazine, hexamethylmelamine , Dibromomannitol, pipobroman, etc., aminopterin, methotrexate, carmofur, guanine, 8-azaganine, mercaptopurine, thioinosine, azathioprine, uracil, fluorouracil, tegafur, cytarabine, ancitabine hydrochloride, enocitabine, azacerin, diazomycin Antimetabolites, actinomycin D, cyclomycin,
Antibiotics such as mitomycin C, daunomycin, daunorubicin hydrochloride, doxorubicin hydrochloride, bleomycin hydrochloride, bleomycin sulfate, neocartinostatin, pepromycin sulfate, aclarubicin hydrochloride, chromomycin A3, epirubicin hydrochloride, ansamycin, cardinophilin, pirarubicin, vinblastine sulfate , Plant alkaloids such as vincristine sulfate, vindesine sulfate and etoposide, platinum complexes such as cisplatin and carboplatin, other Hg-hematoporphyrin, Co-protoporphyrin, procarbazine hydrochloride, sodium estramustine phosphate, ranimustine, mitoxantrone, doxyfluridine, L-asparaginase and the like. The amount of the anticancer drug used depends on its pharmacological action,
Any effective amount may be used, and 50 μg to 2
g, but is not particularly limited. For example, doxorubicin hydrochloride, cisplatin, mitomycin C,
In the case of a commonly used anticancer agent such as bleomycin hydrochloride, a single dose is selected from 0.1 to 500 mg. The concentration of the anticancer agent in the intravascular embolic agent depends on the strength of its pharmacological activity, the solubility in water or an organic solvent, the particle formability, and the like.
Is desirable.

The intravascular embolizing agent containing the angiogenesis-inhibiting substance of the present invention is used as it is or after dispersing it in a suitable dispersion medium or a contrast agent such as iodized poppy oil at the time of use. Examples of the dispersion medium include a dispersant (eg, polyoxysorbitan fatty acid ester, carboxymethyl cellulose, etc.), a preservative (eg, methyl paraben, propyl paraben, etc.), and a tonicity agent (eg, sodium chloride, mannitol, glucose, etc.) for injection in distilled water. And vegetable oils such as sesame oil and corn oil. The dispersed intravascular embolic agent is administered using a catheter inserted from the appropriate artery into the tumor dominant artery while monitoring with an angiographic agent.
For example, in the case of liver cancer, administration is performed as selectively as possible to a tumor site through a catheter inserted into the hepatic artery from the gastroduodenal artery. The amount varies depending on the type, amount, particle size, and degradability of the intravascular embolic substance, the type, site, and size of the tumor, and the type and amount of the angiogenesis inhibitor.
More preferably, it is selected from 5 mg to 5 g. For example,
6-O- (N-chloroacetylcarbamoyl) fumagillol and 4- (N'-chloroacetylureido) -2
-Fumagillol derivatives such as-(1,2-epoxy-1,5-dimethtyl-4-hexenyl) -1- (1,3-dihydrobenzo [c] thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride In the case of microspheres of a lactic acid-glycolic acid copolymer containing (1), the dose per dose is selected from 10 mg to 2 g. In the case of the microspheres described above, a sufficient effect can be obtained by administering 2 g once a month to an adult.

Since the intravascular embolizing agent containing the angiogenesis inhibitor of the present invention is administered into the artery of the tumor, it is necessary to satisfy the conditions of an ordinary injection. Depending on the stability of the components, these embolic agents may be oily preparations containing angiogenesis inhibitors, or oily preparations that dissolve or disperse at the time of use, or solid or powdery preparations using the above-mentioned materials, and furthermore, raw materials may be used. Preparations which dissolve and disperse at the time of use using biodegradable materials are preferred. In addition, preservatives, stabilizers, isotonic agents, solubilizers, dispersants, excipients and the like usually used in injections may be added to this embolic agent. The tumor to which the intravascular embolizing agent containing the angiogenesis inhibitor of the present invention can be applied is not particularly limited, as long as it can selectively insert a catheter into its artery, regardless of primary or metastatic nature. Currently, the tumor most commonly treated with chemoembolization is unresectable liver cancer, followed by kidney cancer. However, it is now possible with advanced medical technology to selectively insert catheters into the arteries of most organs. (“Arterial infusion cancer chemotherapy”, supervised by Yoshinobu Nakamura, Tetsuo Taguchi, Cancer And chemotherapy
(1986)), and the application of this therapy will be further expanded in the future. Therefore, the intravascular embolizing agent of the present invention is used for tumors such as liver cancer, kidney cancer, renal pelvis cancer, pancreatic cancer, bladder cancer, prostate cancer, breast cancer, gastric cancer, colon cancer, and colon cancer currently undergoing arterial infusion chemotherapy. Is effective for Further, the intravascular embolizing agent of the present invention is effective for various tumors of warm-blooded animals such as humans, monkeys, horses, cows, pigs, dogs, rabbits, sheep, rats and mice.

[0053]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which do not limit the present invention.

Example 1 45 mg of 6-O- (N-chloroacetylcarbamoyl) fumagillol (hereinafter abbreviated as compound a) and a lactic acid-glycolic acid copolymer (hereinafter abbreviated as PLGA, lactic acid / glycolic acid = 75/25) Molar ratio, weight average molecular weight 1050
2) was dissolved in a mixture of 2 g of dichloromethane and 0.7 g of chloroform. This solution was poured into 400 ml of a 0.1% aqueous solution of polyvinyl alcohol, and an emulsion was prepared using a small homogenizer. The organic solvent in this emulsion was volatilized under stirring, and the obtained microspheres (hereinafter abbreviated as msp) were collected by a centrifuge. After dispersing the msp in distilled water again and centrifuging to remove free drug, the collected msp was lyophilized to complete solvent removal and dehydration.

Example 2 Male Kbl: VX ₂ was subcutaneously subcutaneously in the lower right knee of a JW rabbit.
Carcinoma cell suspensions were implanted. Two weeks after transplantation, the rabbits were divided into four groups, and 50 mg was added to a solution containing 1 mg of compound a.
Polystyrene (hereinafter abbreviated as PS) (average particle size 50 μ
m), only PSmsp dispersed in a dispersion medium, or a solution of compound a was administered from the upper side of the femoral artery (ia) on the same side, and the tumor volume 5 days after administration
(Major axis × minor axis × height) was measured. Relative values (V5 / V0,%) with the volume of each group before administration as 100% and the volume ratio (T / C,%) with the untreated control group were determined and are shown in Table 1.

[0056]

[Table 1] 置 Treatment (ia) Number of cases V5 / V0 (%) T / C (%) ────────────────────────────── No treatment 10 227 100 Compound a 3 175 77 PS 4 134 59 Compound a + PS 281 36 で は Intra-arterial administration of drug-free PSmsp or Compound a solution to tumor volume Was reduced to 59% and 77% of the untreated group, but increased to 134% and 175% before administration, respectively. On the other hand, in the embolization of the artery due to simultaneous administration of the angiogenesis inhibitor compound a and the msp of PS, it was reduced to 81% before administration and suppressed to 36% of the untreated group.

Example 3 50 mg of PLGAmsp (msp-1) containing 1 mg of compound a prepared in Example 1 and 50 mg of PL containing no drug
The anti-cancer effect after intra-arterial administration of GA msp (msp-p) or 1 mg of the compound a aqueous solution was examined in the same manner as in Example 2. Table 2 shows the percentage (V7 / V0,%) of the volume of the tumor 7 days after administration to the volume of each group before administration and the volume ratio (T / C,%) to the untreated control group. The auricular vein (iv)
Solutions containing more 1 mg of compound a were added on days 0, 2, and 5
The anti-cancer effect in the group administered multiple times was similarly evaluated. Note that ms
The particle size of both p-1 and msp-p is 25 to 125 μm
It is.

[0058]

[Table 2] 処 Number of treatment cases V7 / V0 (%) T / C (%) ─ ──────────────────────────── No treatment 10 358 100 Aqueous solution (ia) 3 247 69 msp-p (ia) 4 225 63 msp-1 (ia) 5 41 11 aqueous solution (iv) 2 294 82 ───────────────────────────── msp-p or aqueous solution Intra-arterial administration increased the tumor volume to 225% and 247% before administration, which was 63% and 69%, respectively, in the untreated group, whereas the msp containing the angiogenesis inhibitor compound a Embolization with -1 reduced to 41% before administration and 11% in the untreated group.
The T / C value obtained here is about 1/8 of that obtained by intravenous administration of compound a, which is three times the total dose of the embolic agent, and its anticancer effect is remarkable. Reduction of side effects can be expected. In a further long-term observation, the dose of Compound a was increased to 5 mg 5 times every 2 to 3 days (total dose 2
5 mg) subcutaneously and the T / C after 12 days is 45%
In the case of msp-1 according to the present invention, a single (1 mg) administration resulted in a further lower T / C of 32% on day 12, which was at least 1/25 dose stronger than the conventional multiple administration. The effect was obtained. That is, the dosage of the preparation of the present invention can be reduced.

Example 4 50 mg of PLGA containing 1.5 mg of 6α- (N′-chloroacetylureido) -6-desoxyfumagillol (hereinafter abbreviated as compound b) prepared according to Example 1 msp
(Msp-2) and PLGA msp containing no compound b
For (msp-p), the anticancer effect after intra-arterial administration was examined in the same manner as in Example 2. Table 3 shows the results 7 days after the administration. The particle diameters of msp-2 and msp-p were 25 to 25.
125 μm.

[0060]

[Table 3] 処置 Treatment (ia) Number of subjects V7 / V0 (%) T / C (% ) {No treatment 10 358 100 msp-p 4 225 63 msp-2 2319} ───────────────────────────

In the case of embolization with msp-p, the volume of the tumor increased to 225% before embolization after 7 days, which was 63% of the untreated group, while containing the compound b which is an angiogenesis inhibitor. Embolization with msp-2 reduced to 31% before administration,
A remarkable effect was obtained, which was 9% of the untreated group.

Example 5 50 mg of msp-1 or 1.23 mg of 4- (N'-chloroacetylureido) -prepared according to Example 1
2- (1,2-epoxy-1,5-dimethyl-4-hexenyl) -1- (1,3-dihydrobenzo [c] thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride (hereinafter compound c) ) Containing 50 mg of PLGAmsp (msp-3) dispersed in an aqueous solution of 1 mg of doxorubicin hydrochloride (hereinafter abbreviated as DOX), 50 mg of msp-p dispersed in the same aqueous solution of DOX, or The above DOX aqueous solution alone was administered intraarterially, and the anticancer effect was examined in the same manner as in Example 2. Table 4 shows the percentage of the volume of the tumor at 5, 7, and 9 days after administration with respect to the volume of each group before administration. The particle size of msp-3 is 2
5 to 125 μm.

[0063]

[Table 4] 処置 Treatment (ia) Number of cases 5 days 7 days 9 days ──── ────────────────────────── No treatment 10 227 358 468 DOX 4 162 324 377 msp-p + DOX 470 89 182 msp-1 + DOX 5 24 19 23 msp-3 + DOX 2 27 20 28 無 In the group of single injection of DOX solution, none The tumor growth was slightly suppressed but not shrunk compared to the treatment group. msp−p
In the embolization by co-administration of DOX and DOX, the tumor volume was reduced to 70 and 89% before embolization after 5 and 7 days, but increased again after 9 days and increased to 182% before embolization. In contrast, the simultaneous administration of DOX with msp-1 and msp-3 containing the compounds a and c, which are angiogenesis inhibitors, is about 23% and 28% before administration even after 9 days.
Respectively, and the remarkable anticancer effect continued.

Example 6 70 mg of compound c and 2.9 g of bovine serum albumin (BS
A) was dissolved in 4.5 ml of water, and this solution was added to 80 ml of sesame oil containing 1 ml of sorbitan sesquioleate to form a water / oil emulsion using a stirrer. After 10 minutes, 20 ml of sesame oil in which glutaraldehyde was dissolved in saturation was added to this emulsion, and the mixture was stirred at room temperature for 5 hours to carry out a crosslinking reaction. Thereafter, this emulsion was centrifuged, and a washing operation was performed in which the supernatant was replaced with the same volume of isopropyl alcohol for three times.
After repeating this step, the mixture is dried under reduced pressure to obtain BS containing compound c.
A msp (msp-BSA) was obtained.

Example 7 In the same manner as in Example 2, 50 mg of each of msp-3 containing compound c used in Example 5 and msp-BSA obtained in Example 6 were intraarterially administered in the same manner as in Example 2 to evaluate the anticancer effect. investigated. Table 5 shows the results 7 days after the administration. The msp in the dry state
-The particle size of BSA is 25 to 75 m.

[0066]

Table 5 処置 Treatment (ia) Number of subjects V7 / V0 (%) T / C (% ) {No treatment 16 350 100 msp-3 359 17 msp-BSA 350 14}で は In the untreated group, the tumor volume increased to 350% after 7 days, whereas msp-3 In the embolization group with msp-BSA and msp-BSA, the reduction was 59% and 50%, respectively, and the remarkable effect of reducing the tumor volume in the untreated group to 17% and 14% was obtained.

Example 8 1 ml of iodized poppy oil (hereinafter abbreviated as LPD) or LP in which 1 mg of compound a or compound c was dissolved and dispersed
The anticancer effect after intra-arterial administration of 1 ml of D alone was examined in the same manner as in Example 2. Table 6 shows the results 5 days after the administration.

[0068]

[Table 6] ──────────────────────────────── Treatment (ia) Number of subjects V5 / V0 (%) T / C (%) ──────────────────────────────── No treatment 16 219 100 LPD 3 178 81 LPD + compound a 4 86 39 LPD + compound c 3 111 51 腫 瘍 Tumors in untreated group and LPD alone administration group After 5 days, the volume increased to 219% and 178%, whereas the embolization group with compound a and LPD and the embolization group with compound c and LPD were 86% and 111%, respectively. Significant effects were obtained, reducing to 39% and 51% of the volume.

[0069]

The intravascular embolizing agent containing the angiogenesis inhibitor and the intravascular embolus of the present invention enhances the anticancer effect of the angiogenesis inhibitor and reduces the dose of the conventional angiogenesis inhibitor. Side effects can be reduced. In addition, it shows a stronger and sustained anticancer effect when used in combination with an anticancer drug, and is extremely useful as a chemoembolizer for malignant tumors.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/715 A61K 31/715 31/728 31/728 31/74 31/74 33/00 33/00 33/44 33/44 38/00 A61P 35/00 38/17 43/00 121 A61P 35/00 A61K 37/02 43/00 121 37/12 (56) Reference European Patent Application Publication 357061 (EP, A1) Cancer (Philadelphia) , Vol. 50, No. 1, (1982) p. 1-5 Cancer Res. Vol. 5, (1984) p. 2115-2121 Cancer Res. Vol. 9, (1988) p. 2446−2450 (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 45/00 A61K 9/08 A61K 9/107 A61K 31/335 A61K 31/38 A61K 31/715 A61K 31/728 A61K 31 / 74 A61K 33/00 A61K 33/44 A61K 38/00 A61K 38/17 A61P 35/00 A61P 43/00 CA (STN) EMBASE (STN) MEDLINE (STN)

Claims (17)

(57) [Claims] Claims: 1. An embolization therapy for cancer using an intravascular embolic substance.
Anti-cancer action enhancer of fumagillol derivative . 2. A carcinostatic effect enhancer is oil solution, carcinostatic effect enhancer <br/> agent according to claim 1 which is an emulsion or suspension. 3. The anticancer action enhancer has a particle size of 10 to 1000 μm.
2. The anticancer-enhancing agent according to claim 1, which is an emulsion or suspension containing m particles. 4. The fumagillol derivative is 6-O- (N-chloroacetylcarbamoyl) fumagillol.
The anticancer effect enhancer according to the above. 5. A fumagillol derivative is 6 [alpha] (N'chloroacetyl ureido) -6-de carcinostatic effect enhancer of claim 1 which is Sokishi fumagillol. 6. A method according to claim 1, wherein the fumagillol derivative is 4- ( N'- chloroacetylureido) -2- (1,2-epoxy-1,5-
The anticancer effect enhancer according to claim 1, which is dimethyl-4-hexenyl) -1- (1,3-dihydrobenzo [c] thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride. 7. A control according to claim 1, wherein the fumagillol derivative is characterized in that it is contained within the intravascular embolizing substance
Cancer action enhancer . 8. The control of claim 1, wherein the fumagillol derivative is characterized by being adsorbed on the surface of the intravascular embolizing substance
Cancer action enhancer . 9. The method according to claim 1, wherein the embolic substance is an oil, a metal, an insoluble salt of a metal, a ceramic, a wax, an activated carbon, a polypeptide, a polysaccharide, a polyfatty acid ester, a polyamino acid, a polyaldehyde, a polyvinyl polymer or a maleic anhydride. The anticancer action enhancer according to claim 1, which is an acid polymer. 10. intravascular embolizing substance, anticancer effect increase in claim 1, wherein the slowly soluble or decomposing polymer in vivo
Strong agent. 11. The method according to claim 1, wherein the intravascular embolic material is gelatin, albumin, collagen, starch, hyaluronic acid, polylactic acid or lactic acid-glycolic acid copolymer.
Anticancer action enhancer . 12. An intravascular embolic material having a lactic acid / glycolic acid molar ratio of 100/0 to 30/70 and a molecular weight of 1,000.
The anticancer effect enhancer according to claim 1, which is a polylactic acid or a lactic acid-glycolic acid copolymer having 0 to 100,000. Carcinostatic effect enhancer of claim 1 wherein the glycolic acid copolymer - 13. intravascular embolizing substance is lactic acid. 14. fumagillol derivative is 6-O- (N- chloroacetylcarbamoyl) intravascular embolizing substance is lactic acid fumagillol - carcinostatic effect enhancer of claim 1 is a glycolic acid copolymer. In 15. fumagillol derivative is 6 [alpha] (N'chloroacetyl ureido) -6-desoxyephedrine fumagillol, intravascular embolizing substance is lactic acid - anticancer action of claim 1 wherein the glycolic acid copolymer Enhancer . 16. The method of claim 1, wherein the fumagillol derivative is 4- ( N'- chloroacetylureido) -2- (1,2-epoxy-1,5).
-Dimethyl-4-hexenyl) -1- (1,3-dihydrobenzo [c] thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride, wherein the intravascular embolizing substance is a lactic acid-glycolic acid copolymer. Claim 1
Anticancer action enhancer . 17. The anticancer- enhancing agent according to claim 1, further comprising an anticancer agent.