Pharmaceutical composition for inhibiting the metastasis or preventing the recurrence of malignant tumor
A pharmaceutical composition for inhibiting the metastasis or preventing the recurrence of a malignant tumor, which comprises as the active ingredient a polysaccharide derivative comprising a polysaccharide having a carboxyl group bound to an active substance having an anti-tumor activity via an amino acid or a peptide consisting of 2 to 8 amino acids which are the same or different, or a salt thereof.
1 . A method for inhibiting the metastasis or preventing the recurrence of a malignant tumor in a patient in need thereof, said method comprising:
administering to said patient a therapeutically effective amount of a polysaccharide derivative comprising a polysaccharide having a carboxyl group bound to an active substance having an anti-tumor activity via an amino acid or a peptide consisting of 2 to 8 amino acids which are the same or different, or a salt thereof.
2 . The method according to claim 1 , wherein the active substance having an anti-tumor activity is a camptothecin derivative of the formula (I):
wherein R 1 is a substituted or unsubstituted lower alkyl group,
X 1 is a group of the formula: —NHR 2 (R 2 is a hydrogen atom or a lower alkyl group), and
Alk is a straight chain or branched chain C 1-6 alkylene group having optionally an oxygen atom in the chain thereof,
or a compound of the formula (II):
wherein two groups of R 2 to R 6 being adjacent each other combine to form a lower alkylene group, and one of the carbon atoms of said lower alkylene group is substituted by an amino group, and the remaining three groups of R 2 to R 6 are a hydrogen atom, a lower alkyl group or a halogen atom.
3 . The method according to claim 1 or 2 , wherein the polysaccharide having a carboxyl group is a carboxy-C 1-4 alkyldextran or a carboxy-C 1-4 alkyldextran polyalcohol.
4 . The method according to claim 1 or 2 , wherein the polysaccharide having a carboxyl group is a carboxy-C 1-4 alkyldextran.
5 . The method according to claim 1 or 2 , wherein the peptide is a member selected from the group consisting of glycyl-glycyl-L- or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine, L- or D-phenylalanyl-glycine, L- or D-tyrosyl-glycine, L- or D-leucyl-glycine, L- or D-phenylalanyl-citrulline and L- or D-valyl-citrulline.
6 . The method according to claim 1 ,
wherein the polysaccharide having a carboxyl group is a carboxymethyl dextran,
the active substance having an anti-tumor activity is 10-(3′-aminopropyloxy)-7-ethyl-(20S)-camptothecin, and
the peptide is glycyl-glycyl-glycine.
7 . The method according to claim 1 ,
wherein the polysaccharide having a carboxyl group is a carboxy-C 1-4 alkyldextran polyalcohol,
the active substance having an anti-tumor activity is (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolidino[1,2-b]quinoline-10,13(9H,15H)-dione, and
the peptide is glycyl-glycyl-L- or D-phenylalanyl-glycine.
8 . The method according to claim 1 or 2 , which is the method for inhibiting the metastasis of a malignant tumor.
9 . The pharmaceutical composition according to claim 1 or 2 , which is the method for preventing the recurrence of a malignant tumor.
10 . A method for inhibiting the metastasis or preventing the recurrence of a malignant tumor in a patient in need thereof, said method comprising:
administering as the active ingredient a polysaccharide derivative to said patient, wherein said polysaccharide derivative comprises:
a polysaccharide having a carboxyl group bound to an active substance having an anti-tumor activity via an amino acid or a peptide consisting of 2 to 8 amino acids which are the same or different, or a salt thereof;
wherein the polysaccharide having a carboxyl group is a carboxy-C 1-4 alkyldextran or a carboxy-C 1-4 alkyldextran polyalcohol;
wherein said active substance is a camptothecin derivative of the formula (I):
wherein R 1 is a substituted or unsubstituted lower alkyl group,
X 1 is a group of the formula: —NHR 2 (R 2 is a hydrogen atom or a lower alkyl group), and
Alk is a straight chain or branched chain C 1-6 alkylene group having optionally an oxygen atom in the chain thereof,
or a compound of the formula (II):
wherein two groups of R 2 to R 6 in formula (II) being adjacent each other combine to form a lower alkylene group, and one of the carbon atoms of said lower alkylene group is substituted by an amino group, and the remaining three groups of R 2 to R 6 are a hydrogen atom, a lower alkyl group or a halogen atom; and
wherein the peptide is a member selected from the group consisting of glycyl-glycyl-L- or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine, L- or D-phenylalanyl-glycine, L- or D-tyrosyl-glycine, L- or D-leucyl-glycine, L- or D-phenylalanyl-citrulline and L- or D-valyl-citrulline.
11 . The method according to claim 1 , wherein
the polysaccharide having a carboxyl group is a carboxymethyl dextran,
the active substance having an anti-tumor activity is 10-(3′-aminopropyloxy)-7-ethyl-(20S)-camptothecin, and
the peptide is glycyl-glycyl-glycine.
12 . The method according to claim 1 , wherein
the polysaccharide having a carboxyl group is a carboxy-C 1-4 alkyldextran polyalcohol,
the active substance having an anti-tumor activity is (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolidino[1,2-b]quinoline-10,13(9H,15H)-dione, and
the peptide is glycyl-glycyl-L- or D-phenylalanyl-glycine.
13 . The method according to claim 8 , wherein the method inhibits the lymph node metastasis of a malignant tumor.
14 . The method according to claim 8 , wherein the method inhibits the lymph node metastasis from the colon or from the lung.
15 . A method for inhibiting the metastasis or preventing the recurrence of a malignant tumor after a topical therapy in a patient in need thereof, said method comprising:
administering to said patient, after topical therapy, a therapeutically effective amount of a polysaccharide derivative comprising a polysaccharide having a carboxyl group bound to an active substance having an anti-tumor activity via an amino acid or a peptide consisting of 2 to 8 amino acids which are the same or different, or a salt thereof.
16 . The method according to claim 14 , wherein the topical therapy is surgery, radiation therapy, thermotherapy, cryotherapy or laser burning therapy.