CN100431606C - Anti-cancer medicine composition - Google Patents

Anti-cancer medicine composition Download PDF

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CN100431606C
CN100431606C CNB2004100361006A CN200410036100A CN100431606C CN 100431606 C CN100431606 C CN 100431606C CN B2004100361006 A CNB2004100361006 A CN B2004100361006A CN 200410036100 A CN200410036100 A CN 200410036100A CN 100431606 C CN100431606 C CN 100431606C
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benzimidazole
tumor
fluorouracil
carboxamides
anticancer
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CN1634586A (en
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孔庆忠
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Shandong Lanjin Pharmaceuticals Co Ltd
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Shandong Lanjin Pharmaceuticals Co Ltd
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Abstract

The present invention relates to an anticancer medical composition which belongs to the technical field of drugs. The present invention comprises pharmaceutic supplementary materials and anticancer effective components, wherein the anticancer effective components are mainly antimetabolitas and DNA repair enzyme inhibitors, and the DNA repair enzyme inhibitors are selected from poly (ADP-ribose) polymerization enzyme inhibitors and /or DNA-dependent protein kinase inhibitors; the DNA repair enzyme inhibitors can effectively break DNA repair functions in tumor cells, and thereby, the tolerance of the tumor cells for anti metabolism drugs is reduced; the pharmaceutic supplementary materials are mainly high molecular biologic capacitability polymers which can be degraded and absorbed, and in a degradation and absorption process, the DNA repair enzyme inhibitors can be slowly released at part of a tumor; the systemic toxicity reactions of the drugs are reduced obviously, and simultaneously, effective drug concentration can be kept at part of the tumor. The anticancer medical composition is put at part of the tumor, the systemic toxicity reactions of the drugs can be reduced, and the drug concentration of part of the tumor can be enhanced in a selective mode. The treatment effect of non-operative treatments, such as chemotherapeutics, radiotherapy, etc., can be enhanced.

Description

A kind of anticancer pharmaceutical composition
(1) technical field
The present invention relates to a kind of anticancer pharmaceutical composition, belong to technical field of pharmaceuticals.
(2) background technology
The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of antimetabolitas is comparatively obvious, has been widely used in multiple malignant tumor.Yet, discover that further the DNA repair function in many tumor cells obviously increases after treatment.The latter often causes the enhancing of tumor cell to the toleration of antimetabolitas, consequently treatment failure.
Recent findings, deactivation or suppress intracellular dna repair protein can strengthen the part tumor cell to the sensitivity of chemotherapy (referring to " 06-benzyl guanine analog is to the effect of human tumor cells to the cell toxicant sensitivity of alkylating agent " " cancer research " 51 phase 3367-3372 pages or leaves (1991) such as Doran (Dolan et al., Cancer Res., 51,3367-3372,1991)).Yet, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level (referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Qet al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.
Because the principal element of decision therapeutic effect is the drug level of tumor by local and the tumor cell sensitivity to medicine.And the blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, have also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues.Therefore, a concrete theme of the present invention is the local anticancer pharmaceutical composition of placing.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer pharmaceutical composition is provided.
Anticancer pharmaceutical composition of the present invention comprises anticancer effective component and/or pharmaceutic adjuvant, and wherein anticancer effective component is:
(A) one of antimetabolitas and following (B), (C) or its combination
(B) kinases inhibitor of DNA-dependence,
(C) poly-(ADP-ribose) AG14361.
Wherein effective ingredient (B) and (C) be DNA repairase inhibitor is not 0 simultaneously in compositions.The decapacitation of DNA repairase inhibitor suppresses can also increase the sensitivity of tumor cell to (A) outside the tumor growth.Antimetabolitas can stop the synthetic of DNA in different links respectively, suppresses the cell division increment, and cell cycle and DNA are synthetic to play a role by influencing.
Above-mentioned antimetabolitas is selected from, but be not limited to, doxifluridine (Doxifloridine, fortulon), the 5-doxifluridine, floxuridine (fluridine), propylthiouracil, fluorouracil (Fluoracil, Fluracil), the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, sulfur crow purine, tisupurin, Hydrazinium sulfate, dianhydrogalactitol, Aziridinyl Benzoquinone, but sweet smell Luoning, isoeuxanthone, chalone, chlorine is bent phosphoric acid, clastoban, cycloleucine, look into the Chinese holly woods, methyl yellow is looked into the Chinese holly woods sourly, Bai Ruikuaer, oxipurinol, Australia Ma Lite, bromine crust acid (sodium), Brytoslatin-I, bromine urea glycosides, fluorine urea hexylamine, folic acid, methotrexate (methotrexate, MTX), 10-ethyl denitrification aminopterin (deaza-aminopterin), fluoromethotrexate, the dioxy methotrexate, 5, the 10-lonetrexol, N5-Methyltetrahydrohmofotic Acid, buthiopurin, his amide of Dinke, Guang azepine crow glycosides, carmofur (Carmofur), Tegafur-uracil mixt., 6-prenylindole, 6-thioinosine, UFT (Tegafur-Uracil, UFT), coralyne, N-foymylsarcolysin, ammonia (base) pterin (aminopterin), aminopterin sodium (Aminopterin Sodium), 8-azaguanine (8-azaguanine), 6-dimethylamino-8-azaadenosine, (nitro) imuran (azathioprine), uracil, 5-mercaptomethyluracil, azaserine (azaserine), Raltitrexed (Raltitrexed), thunder accounts for for song, nolatrexed dihydrochloride, sophoridine, formyl tetrahydrofolic acid, 5-methyltetrahydrohomofolate, Zoledronate, the temozolomide, bicalutamide, asparaginase (L-Asparaginase, left-handed asparagine), calcium levofolinate, calcium folinate (CalciumLevofolinate, calcium leucovorin), Quinespar, triazinate, trimetrexate, tramadol, the 5-chlorobarbituric acid, 5-diazonium uracil, piracetam, hycamtin, topotecan hydrochloride, cytosine arabinoside (cytosine arabinoside, Cytarabine (Ara-C)), ancitabine (cyclotidine, Cyclocytidine], the hydroxyl guanidine, the 5-fluorouracil nucleoside, the 5-fluorouracil deoxynucleoside claims fluorouracil deoxynucleoside (floxuridine) again, glycerol Citrus chachiensis Hort. alkali, A Lei can loose, isoxazole acetic acid, aminoglutethimide (ethylbenzene amine piperidones, aminoglutethimidium, aminoglutethimide), amonafide, 5-chloro-5-deoxyarabinosylcytosine, atamestane, azacytidine (Azacitidine, 5-azacytidine, the atropic cytidine, AzGR), chloramphenalan (betamerphalan, Betamerphalan), decitabing, dexrazoxane [Dexrazoxane], crisnatol, cristatic acid, carat is sharp flat, the sharp guest of carat, galocitabine [Galocitabine], gemcitabine [Gemcitabine], ibacitabine [Ibacitabine], enocitabine [Enocitabine], ancitabine [Ancitabine], decitabine [Decitabine], flurocitabine (Flurocitabine), capecitabine (Capecitabine), enocitabine, his shore of imidazoles, the non-Shandong of Crane, the OK a karaoke club amide, carzolamide, carbazylquinone, CB-1-252, curcumin, the curcumin diketone, ketotrexate, trimetrexate, Si Poguning, deoxidation Si Poguning, naphthalene urea phosphamide, Ditercalinium Chloride, F-ara AMP-2, fluorine benzyl thiophene ketone, gamlogic acid, goserelin, nitrogen Chinese holly mountain range, Hellebrigenin, inosine dialdehyde, metoprine, mitobronitol (Dibromomannitol, Mitobronitol), mitolactol (Mitolactol), Ke is for ground, Persian, eriolangin, dopan (Chlorethylaminouracil, Dopan), Mei Luogerui, Methyl GAG, GR 30921X, mitotane, fazarabine (Fazarabine), fludarabine (fludarabine), cladribine (cladribine), pentoside (pentostatin), phenaline, benzene comes U.S. special, phosphemide, hair Buddhist nun azoles, Polyprenic Acid, Pteroylaspartic Acid, pteroyltriglutamic acid, fast rice tongue pool, riboprine, simtrazene, Schizophyllan, sodium bromebrate, Solvent Yellow 3, bent fourth sulphur ester, TEM, triaziquone, triciribine, TCN-P NSC-280594, triptolide, triptorelin, nine cloth Lip river azoles, UFT, vitamin B-17, Wei Maining, z-azepine adenosine, prick western cytidine, epipropidine [Epipropidine], the A Monuo phase, adozelesin (Adozelesin), acronine (Acronine), alanosine (Alanosine), ametantrone (Ametantrone), Anastrozole, the A Naxi army, anaxirone (Anaxirone), A Si Yin wakes up, acivicin (Acivicin), atevirdine [Atevirdine], idoxifene (idoxifene), AT-236, hold high and rather study carefully Ji, individual Lu Dabuxin, antineoplaston, antineoplastons, asaphan, Aspargus Granule, AT-346, Bai Ruikuaer (sodium), (hydrochloric acid) Orang Crush, granisetron, tropisetron, dacarbazine, ondansetron, thymosin, tramadol, imatinib mesylate, diclofenac, Thalidomide, the holder fluorine kills star, toremifene, ambroxol, lappaconitine, anti-general etc. because of, thymosin, flutamide, ethyliminum, amine benzene, neoquini oxydum, the N-methylformamide, the jail can reach azoles, NSC-56045, oxisuran, oxylycorine, paphencyl, it is fixed to moor damp Nip, the penberol, prospidine chloride, protoanemonin, good generation born of the same parents, retelliptine, Sensorad, M3, solapalmitine, solaziquonum, stibenemidine, Temozoromide, the many Shillongs of platform, thiaolivacine, the pyridine of nitre ammonia bifurcation, SN-11841,5-fluorouracil (Fluorouracil, 5-FU), mercaptopurine (Mercaptopurine, happy disease is peaceful, 6-MP), thioguanine (thioguanine, 6-TG), ftorafur (Tegafur, tegafur, FT-207) or hydroxyurea (Hydroxycarbamide, hydroxyurea).
Optional wherein one or more of above-mentioned antimetabolitas.
His shore of the preferred Ismipur of above-mentioned antimetabolitas, 5-fluorouracil (5-FU), doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or pentoside.
The content of above-mentioned antimetabolitas in compositions can be from 0.01%-99.99%, with 1%-50% is good, with 2%-40% is best, and kinases inhibitor shared ratio in compositions of gathering (ADP-ribose) AG14361 and DNA-dependence is also decided because of concrete condition, can be from 0.01%-99.99%, with 1%-50% is good, is best with 2%-40%.Below all be weight percentage.
The kinases inhibitor (DNA-dependent protein kinase (DNA-PK) inhibitors) that above-mentioned DNA-relies on is selected from, but be not limited to, wortmannin (wortmannin, WM), .alpha.-5:6-benzopyran (benzochromenone, NU7026), 2-(morphol-4-yl)-.alpha.-5:6-benzopyran-4-base (2-(morpholin-4-yl)-benzo[h] chomen-4-one), 6-aromatic radical-2-morphol-4-base-4H-pyrans-4-base (6-aryl-2-morpholin-4-yl-4H-pyran-4-ones), 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-base (6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones), 2-(4-Lin Ji)-8-phenylchromone (2-(4-morphol inyl)-8-phenylchromone, LY294002), 2-(4-Lin Ji)-8-phenyl-4H-1-.alpha.-5:6-benzopyran-4-1 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, MPB), 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-) (1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone, HMPE), inhibitors of kinases (SU11752), vanillin (vanillin, 3-methoxy-4-hydroxybenzaldehyde), 2-aminopurine (2-Aminopurine, 2-AP), 7-ethyl-10-hydroxycamptothecine (SN-38,7-ethyl-10-hydroxycamptothecin), 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1 (3-cyano-6-hydrazonomethyl-5-(4-pyridyl) pyrid-[1H]-2-one, 0K-1035) or phenylbutyric acid salt (Phenylbutyrate, PB).Above kinases inhibitor can singly select or multiselect, preferred wortmannin .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1 or phenylbutyric acid.
Above-mentioned poly-(ADP-ribose) AG14361 (poly (ADP-ribose) polymerase-1 inhibitor) is selected from: but be not limited to, 3-aminobenzamide (3-aminobenzamide, 3-AB), Benzoylamide (benzamide), 3,4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide (3,4-dihydro-5-methoxyisoquinolin-1 (2H)-one, PD 128763), AG14361 (AG14361), poly polymerase inhibitor (GPI 15427), the amino 2-aromatic radical benzimidazole-4-carboxamides BZ1-6 (2-arylbenzimidazole-4-carboxamide) that replaces, benzimidazole-4-carboxamides BZ1-6 (benzimidazole-4-carboxamides, BZ1-6), tricyclic lactam hydrogen sulfide (tricyclic lactam indoles, TI1-5), three ring benzimidazole carboxylic acid amides (tricyclic benzimidazolecarboxamide, TBC), benzimidazole (benzimidazole), 1H-three ring benzimidazole carboxylic acid amides (1H-Benzimidazole-4-carboxamides, BC), 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6 (2-aryl-1H-benzimidazole-4-carboxamides, ABC), 2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6 (2-phenyl-1H-benzimidazole-4-carboxamide, PBC), 2--(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides BZ1-6 (2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide, HMPBC), 2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6 (2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide, MPBC), 8-hydroxy-2-methyl quinazolinone (NU1025,8-hydroxy-2-methylquinazolin-4-one) or 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6 [NU1085,2-(4-hydroxyphenyl) benzamidazole-4-carboxamide].
Pharmaceutic adjuvant comprises one of following or its combination:
(1) biocompatibility polymer, comprise biodegradable or biological nondegradable polymer and composition thereof or copolymer, (2) water-soluble low-molecular chemical compound is or/and (3) are used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (polyamides), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacicacid), polifeprosan (to the copolymer of carboxy phenyl propane and certain herbaceous plants with big flowers diacid) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin etc.
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description in other United States Patent (USP) that (US 4857311; 4888176; 4789724).
Above-mentioned polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) of mixture, glycolic and the hydroxy carboxylic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid; When PLA and PLGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.The molecular weight of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 1000-100,000, but with 10,000-50000 is preferred; With 10,000-20000 is for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or certain herbaceous plants with big flowers diacid or copolymer for most preferably, as, but be not limited to, molecular weight is that polylactic acid and the molecular weight of 5000-10000 is that the polylactic acid that polylactic acid mixes, molecular weight is 10000-20000 and the molecular weight of 20000-50000 is that the PLGA that the polylactic acid that PLGA mixes, molecular weight is 5000-10000 mixes with the certain herbaceous plants with big flowers diacid, molecular weight is 30000-80000 of 30000-80000 mixes with the certain herbaceous plants with big flowers diacid.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes) and polyphosphazene (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
For regulating other characteristic of drug releasing rate or change anticancer pharmaceutical composition of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar and salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt and sodium salt etc.
The used pharmaceutic adjuvant of anticancer pharmaceutical composition of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of composition for treating solid tumor of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The effective ingredient of anticancer pharmaceutical composition can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.In addition, the effective ingredient of anticancer pharmaceutical composition also can be packaged in the liposome equably, or makes microsphere with art methods.
Characteristics of the present invention are that used pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, inhibitor, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Pharmaceutic adjuvant also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
Anticancer pharmaceutical composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, suspension, ointment, capsule and slow releasing agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, be implanted into agent based on agent for slow releasing in the body or body.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
Because anticancer pharmaceutical composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
When share with above-mentioned non-operative treatment, anticancer pharmaceutical composition of the present invention can be used simultaneously with non-operative treatment, also can use in non-operative treatment is implemented a few days ago, and its purpose is to strengthen as far as possible the sensitivity of tumor.DNA repairase inhibitor (kinases inhibitor that poly-(ADP-ribose) AG14361 and DNA-rely on) has obvious synergistic effect to antimetabolitas, thereby provide a kind of more effective new method for effecting a radical cure former of various human bodies and animal and shifting entity tumor, have very high clinical value and remarkable economical and social benefit.
Route of administration
Anticancer pharmaceutical composition of the present invention can be used through various approach, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant (slow release) implant in slow-releasing pump and slow releasing capsule or the body as selecting for use.
When the effective ingredient of anticancer pharmaceutical composition is antimetabolitas synergist (kinases inhibitor that poly-(ADP-ribose) AG14361 and/or DNA-rely on), this anticancer pharmaceutical composition is based on topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, wherein the tumor body is implanted into agent for most preferably.
Dosage
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.But its principle is to reduce the repair ability of tumor cell to DNA, increases the action effect of therapies such as chemotherapy.The effective dose of the kinases inhibitor that poly-(ADP-ribose) AG14361 or DNA-rely on is 0.01-80 milligram/kg body weight, is ideal with 1-50 milligram/kg body weight, with 2-10 milligram/kg body weight for the most desirable.Kinases inhibitor shared ratio in compositions that poly-(ADP-ribose) AG14361 and/or DNA-rely on decide because of concrete condition, can be good with 1%-50% from 0.01%-99.99%, is the best with 2%-40%.Below all be weight percentage.
When used the part, its blood level maintained reduced levels, and concentration maintains higher level in the tumor.
When kinases inhibitor that gathers (ADP-ribose) AG14361 and/or DNA-dependence and antimetabolitas use in conjunction, the ratio of the two can be arbitrarily, but with 1: 9 to 9: 1 was good, 3: 7 to 7: 3 is good, and the effective dose of antimetabolitas is 0.0l-200 milligram/kg body weight, is ideal with 1-30 milligram/kg body weight, with 2-20 milligram/kg body weight for the most desirable.Below all be weight percentage.
Anticancer pharmaceutical composition of the present invention can be used to prepare the various entity tumors for the treatment of the people, comprises former or the cancer of transfer or the medicine of sarcoma or carcinosarcoma originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Anticancer pharmaceutical composition of the present invention also can be used for the treatment of the various entity tumors of house pet and animal, and when being used for the treatment of the various entity tumor of house pet and animal, the material of species specificity is preferably selected in the active ingredient of anticancer pharmaceutical composition of the present invention for use.
Also can add other medicinal ingredient in the anticancer pharmaceutical composition of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Anticancer pharmaceutical composition of the present invention can be used in the following manner.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can with topical, wherein be released to the best with local slow again as injection in selective arterial injection and the direct tumor body for good through various administrations.When used the part, anticancer pharmaceutical composition of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Anticancer pharmaceutical composition Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.
Anticancer pharmaceutical composition can be made into different shape, and wherein the content of active ingredient is decided because of different needs.Can be good with 1%-50% from 0.1%-99.9%, be best with 2%-40%.This anticancer pharmaceutical composition can be made into various dosage forms, as, but be not limited to injection, suspension, ointment, capsule, and implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and film sample; Can be good with the tremulous pulse approach through various administrations, directly be placed as the best in the tumor body.Most preferred dosage form of the present invention is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and composition for treating solid tumor also can be packed in the liposome.
The characteristics of anticancer pharmaceutical composition technology of preparing of the present invention be kinases inhibitor that poly-(ADP-ribose) AG14361 and/or DNA-are relied on antimetabolitas independent or packaged in combination in pharmaceutic adjuvant, proportionally with active ingredient and pharmaceutic adjuvant dissolving, it is dry afterwards to wait to fill part mixing.Be shaped immediately after to be dried and sterilize packing.
The kinases inhibitor that more than poly-(ADP-ribose) AG14361 and/or DNA-rely on can be in various degree inhibition or reduce the activity of tumor cell DNA repairase, experiment in vivo and vitro of the present invention is found its notable synergistic effect to antimetabolitas.When the two associating topical application, especially local the placement not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
Test one, DNA repairase inhibitor are to the inhibitory action of growth of tumour cell
As mentioned above, in the tumor cell activity of DNA repairase increase be its to the tolerific main cause of antimetabolitas, therefore, DNA repairase inhibitor can strengthen the inhibitory action of antimetabolitas to growth of tumour cell.This experiment is a subjects with pulmonary carcinoma (LH) tumor cell, adding concentration in 24 hours tumor cell of In vitro culture is the DNA repairase inhibitor of 5mM/ml and the 5-fluorouracil (5-FU) of 5mM/ml, continues to cultivate the inhibitory action that detects after 48 hours growth of tumour cell.Suppressing effect (%) is shown in Table 1.
Table 1
DNA repairase inhibitor The inhibitory rate of cell growth (%) that does not add 5-FU The inhibitory rate of cell growth (%) that adds 5-FU
Wortmannin NU7026 6-aromatic radical-2-morphol-4-base-pyrans-4-NU7026 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-NU7026 LY294002 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-) SU11752 40 38 40 44 40 38 50 80 91 80 84 88 90 80
Vanillic aldehyde 2-aminopurine SN-38 OK-1035 PB 3-AB benzamide 3,4-dihydro methoxy isoquinolin-1 (the 2H)-benzamide AG14361 GPI 15427 amino 2-aromatic radical benzimidazole-4-carboxamides benzimidazole-4-carboxamides TI1-5 TBC benzimidazole 1H-Benzimidazole-4-carboxamides 2-aromatic radical that replaces-1H-benzimidazole-4-carboxamides 2-phenyl-1H-benzimidazole-4-carboxamide 2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides 2-(3-anisyl)-1H-benzimidazole-4-carboxamides NU1025 NU1085 51 49 48 50 40 40 34 48 30 40 48 50 40 40 54 50 40 60 40 40 44 48 80 84 80 88 70 71 69 88 92 94 88 90 80 80 84 80 84 80 80 88 90 80
Explain: LY294002, NU7026, SU11752, SN-38, OK-1035, AG14361, GPI 15427, NU1025NU1085 is respectively 2-(4-Lin Ji)-8-phenylchromone, .alpha.-5:6-benzopyran, kinases inhibitor-11752,7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, AG14361-14361, GPI 15427,8-hydroxy-2-methyl quinazolinone and 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
Suppression ratio to the growth of pulmonary carcinoma (LH) cell when 5-FU uses separately is 59%.As can be seen from the above table, the DNA repairase inhibitor that tries all has the notable synergistic effect to 5-FU, wherein the effect of 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6, benzimidazole-4-carboxamides BZ1-6, GPI 15427 and .alpha.-5:6-benzopyran is particularly evident, more than 90%.
According to detecting with quadrat method, with comprising CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.) different tumor cells, after the effect of different DNA repairase inhibitor and other antimetabolitas compared.
Test two, DNA repairase inhibitor are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different DNA repairase inhibitor to methotrexate, and breast carcinoma (BA) inhibitory rate of cell growth (%) is shown in Table 2.
Table 2
DNA repairase inhibitor The inhibitory rate of cell growth (%) that does not add methotrexate The inhibitory rate of cell growth (%) that adds methotrexate
Wortmannin NU7026 6-aromatic radical-2-morphol-4-base-pyrans-4-NU7026 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-NU7026 LY294002 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-) SU11752 vanillic aldehyde 2-aminopurine SN-38 OK-1035 PB 3-AB benzamide 3,4-dihydro methoxy isoquinolin-1 (the 2H)-benzamide AG14361 GPI 15427 amino 2-aromatic radical benzimidazole-4-carboxamides benzimidazole-4-carboxamides TI1-5 TBC benzimidazole 1H-Benzimidazole-4-carboxamides 2-aromatic radical that replaces-1H-benzimidazole-4-carboxamides 2-phenyl-1H-benzimidazole-4-carboxamide 2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides 2-(3-anisyl)-1H-benzimidazole-4-carboxamides NU1025 NU1085 48 50 40 40 34 40 38 40 40 38 50 51 44 49 48 30 40 48 60 40 40 44 48 50 40 40 64 50 56 88 90 88 90 80 80 84 80 69 88 90 90 88 80 84 80 88 70 71 80 80 84 88 90 80 80 84 80 80
LY294002 in the table 2, NU7026, SU11752, SN-38, OK-1035, AG14361, GPI 15427, NU1025, NU1085 is respectively 2-(4-Lin Ji)-8-phenylchromone, .alpha.-5:6-benzopyran, kinases inhibitor-11752,7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, AG14361-14361, GPI 15427,8-hydroxy-2-methyl quinazolinone and 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
Test three, DNA repairase inhibitor are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different DNA repairase inhibitor to ftorafur, and liver cancer cell growth suppression ratio (%) is shown in Table 3.
Table 3
DNA repairase inhibitor The inhibitory rate of cell growth (%) that does not add ftorafur The inhibitory rate of cell growth (%) that adds ftorafur
Wortmannin NU7026 6-aromatic radical-2-morphol-4-base-pyrans-4-NU7026 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-NU7026 LY294002 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-) SU11752 vanillic aldehyde 2-aminopurine SN-38 OK-1035 PB 3-AB benzamide 3,4-dihydro methoxy isoquinolin-1 (the 2H)-benzamide AG14361 GPI 15427 amino 2-aromatic radical benzimidazole-4-carboxamides benzimidazole-4-carboxamides TI1-5 TBC benzimidazole 1H-Benzimidazole-4-carboxamides 2-aromatic radical that replaces-1H-benzimidazole-4-carboxamides 2-phenyl-1H-benzimidazole-4-carboxamide 2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides 2-(3-anisyl)-1H-benzimidazole-4-carboxamides NU1025 NU1085 40 38 50 51 48 50 40 40 34 40 38 48 30 40 48 40 44 49 60 40 40 44 48 50 40 40 64 60 58 88 90 90 88 90 88 90 80 88 70 71 69 80 84 80 88 80 84 80 80 80 84 88 90 80 80 84 80 80
LY294002 in the table 3, NU7026, SU11752, SN-38, OK-1035, AG14361, GPI 15427, NU1025, NU1085 are respectively 2-(4-Lin Ji)-8-phenylchromone .alpha.-5:6-benzopyran, inhibitors of kinases, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, AG14361, poly polymerase inhibitor, 8-hydroxy-2-methyl quinazolinone and 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
Test four, DNA repairase inhibitor are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different DNA repairase inhibitor to gemcitabine, and brain tumor cell growth inhibition ratio (%) is shown in Table 4.
Table 4
DNA repairase inhibitor The inhibitory rate of cell growth (%) that does not add gemcitabine The inhibitory rate of cell growth (%) that adds gemcitabine
Wortmannin NU7026 6-aromatic radical-2-morphol-4-base-pyrans-4-NU7026 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-NU7026 LY294002 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-) SU11752 vanillic aldehyde 2-aminopurine SN-38 OK-1035 PB 3-AB benzamide 3,4-dihydro methoxy isoquinolin-1 (the 2H)-benzamide AG14361 GPI 15427 amino 2-aromatic radical benzimidazole-4-carboxamides benzimidazole-4-carboxamides TI1-5 TBC benzimidazole 1H-Benzimidazole-4-carboxamides 2-aromatic radical that replaces-1H-benzimidazole-4-carboxamides 2-phenyl-1H-benzimidazole-4-carboxamide 2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides 2-(3-anisyl)-1H-benzimidazole-4-carboxamides NU1025 NU1085 50 40 40 34 40 40 44 48 50 40 38 50 51 48 38 40 44 49 60 54 50 48 30 40 48 40 40 40 60 90 90 88 90 88 88 70 71 69 88 90 80 80 84 80 88 80 84 80 80 80 84 88 90 80 80 84 80 80
LY294002 in the table 4, NU7026, SU11752, SN-38, OK-1035, AG14361, GPI 15427, NU1025, NU1085 are respectively 2-(4-Lin Ji)-8-phenylchromone .alpha.-5:6-benzopyran, inhibitors of kinases, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, AG14361, poly polymerase inhibitor, 8-hydroxy-2-methyl quinazolinone and 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
Test five, DNA repairase inhibitor are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different DNA repairase inhibitor to cytosine arabinoside, and pancreatic cancer cell growth inhibition ratio (%) is shown in Table 5.
Table 5
DNA repairase inhibitor The inhibitory rate of cell growth (%) that does not add cytosine arabinoside The inhibitory rate of cell growth (%) that adds cytosine arabinoside
Wortmannin NU7026 6-aromatic radical-2-morphol-4-base-pyrans-4-NU7026 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-NU7026 LY294002 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-) SU11752 vanillic aldehyde 2-aminopurine SN-38 OK-1035 PB 3-AB benzamide 3,4-dihydro methoxy isoquinolin-1 (the 2H)-benzamide AG14361 GPI 15427 amino 2-aromatic radical benzimidazole-4-carboxamides benzimidazole-4-carboxamides TI1-5 TBC benzimidazole 1H-Benzimidazole-4-carboxamides 2-aromatic radical that replaces-1H-benzimidazole-4-carboxamides 2-phenyl-1H-benzimidazole-4-carboxamide 2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides 2-(3-anisyl)-1H-benzimidazole-4-carboxamides NU1025 NU1085 48 50 40 50 40 40 34 30 40 48 44 40 40 54 50 48 40 38 50 51 48 38 40 40 60 44 49 60 40 88 90 88 90 88 90 80 80 84 80 80 84 80 88 80 80 80 88 70 71 69 88 90 90 84 80 80 80 84
LY294002 in the table 5, NU7026, SU11752, SN-38, OK-1035, AG14361, GPI 15427, NU1025, NU1085 are respectively 2-(4-Lin Ji)-8-phenylchromone .alpha.-5:6-benzopyran, inhibitors of kinases, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, AG14361, poly polymerase inhibitor, 8-hydroxy-2-methyl quinazolinone and 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
Test six, DNA repairase inhibitor are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different DNA repairase inhibitor to cladribine, and stomach cancer cell growth inhibition ratio (%) is shown in Table 6.
Table 6
DNA repairase inhibitor The inhibitory rate of cell growth (%) that does not add cladribine The inhibitory rate of cell growth (%) that adds cladribine
Wortmannin NU7026 6-aromatic radical-2-morphol-4-base-pyrans-4-NU7026 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-NU7026 LY294002 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-) SU11752 vanillic aldehyde 2-aminopurine SN-38 0K-1035 PB 3-AB benzamide 3,4-dihydro methoxy isoquinolin-1 (the 2H)-benzamide AG14361 GPI 15427 amino 2-aromatic radical benzimidazole-4-carboxamides benzimidazole-4-carboxamides TI1-5 TBC benzimidazole 1H-Benzimidazole-4-carboxamides 2-aromatic radical that replaces-1H-benzimidazole-4-carboxamides 2-phenyl-1H-benzimidazole-4-carboxamide 2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides 2-(3-anisyl)-1H-benzimidazole-4-carboxamides NU1025 NU1085 34 40 40 50 40 40 30 40 48 44 48 50 40 44 40 48 40 38 50 51 48 38 40 40 60 44 49 60 40 88 70 71 69 88 88 80 80 80 90 90 88 90 80 80 84 88 90 88 90 80 80 84 80 84 80 80 80 84
LY294002 in the table 6, NU7026, SU11752, SN-38, OK-1035, AG14361, GPI 15427, NU1025, NU1085 are respectively 2-(4-Lin Ji)-8-phenylchromone .alpha.-5:6-benzopyran, inhibitors of kinases, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, AG14361, poly polymerase inhibitor, 8-hydroxy-2-methyl quinazolinone and 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
The result of test two to six shows, used DNA repairase inhibitor [kinases inhibitor that poly-(ADP-ribose) AG14361 and DNA-rely on] and various antimetabolitas all have the obvious suppression effect to growth of tumour cell under used concentration, but the two has obvious synergistic effect when share.
Tumor-inhibiting action in the body of test seven, kinases inhibitor and antimetabolitas.
With the rat is subjects, with 2 * 10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 7).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is wortmannin (WM), and the 3rd to 6 group is respectively 5-fluorouracil, methotrexate, carmofur and gemcitabine.The the 7th to 10 group of associating that is respectively MX and 5-fluorouracil, methotrexate, carmofur and gemcitabine.All medicines are all through intratumor injection, and dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 7) on the 30th day.
Table 7
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 78.5±13.3
2(6) WM 62±12.3 ＜0.05
3(6) 5-FU 52±10.5 ＜0.01
4(6) Methotrexate 42±8.6 ＜0.01
5(6) Carmofur 40±7.4 ＜0.01
6(6) Gemcitabine 42±7.6 ＜0.01
7(6) WM+5-FU 22±5.6 ＜0.001
8(6) The WM+ methotrexate 23±5.6 ＜0.001
9(6) The WM+ carmofur 20±4.6 ＜0.001
10(6) The WM+ gemcitabine 18±3.6 ＜0.001
Wortmannin (WM) is a DNA repairase inhibitor, in particular, be kinases inhibitor, and 5-fluorouracil, methotrexate, carmofur and gemcitabine is antimetabolitas.
Tumor-inhibiting action in the body of test eight, poly-(ADP-ribose) AG14361 and antimetabolitas.
With the rat is subjects, with 2 * 10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 8).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is, the 3rd to 6 group is respectively Ismipur, doxifluridine, floxuridine, mercaptopurine.The the 7th to 10 group of associating that is respectively MX and Ismipur, doxifluridine, floxuridine and mercaptopurine.All medicines are all through intratumor injection, and dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 8) on the 30th day.
Table 8
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 88±14
2(6) BD 48±11.3 ＜0.05
3(6) Ismipur 58±10.3 ＜0.01
4(6) Doxifluridine 56±10.4 ＜0.01
5(6) Floxuridine 48±8.0 ＜0.01
6(6) Mercaptopurine 44±6.0 ＜0.01
7(6) The MX+6-purinethol 33±4.3 ＜0.001
8(6) The MX+ doxifluridine 32±3.6 ＜0.001
9(6) The MX+ floxuridine 24±3.2 ＜0.001
10(6) The MX+ mercaptopurine 18±1.6 ＜0.001
Explain: BD: benzimidazole; Its BD is poly-(ADP-ribose) AG14361, and Ismipur, doxifluridine, floxuridine, mercaptopurine are antimetabolitas.
Tumor-inhibiting action in the body of test nine, poly-(ADP-ribose) AG14361 and antimetabolitas.
With the rat is subjects, with 2 * 10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 9).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is Benzoylamide (BM), and the 3rd to 6 group is respectively thioguanine, ftorafur, galocitabine, ibacitabine.The the 7th to 10 group of associating that is respectively HX and thioguanine, ftorafur, galocitabine, ibacitabine.All medicines are all placed in tumor, and dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 9) on the 30th day.
Table 9
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 82.5±15.0
2(6) BM 63.0±14 ＜0.05
3(6) Thioguanine 62±12.3 ＜0.01
4(6) Ftorafur 46±8.4 ＜0.01
5(6) Galocitabine 48±8.0 ＜0.01
6(6) Ibacitabine 40±7.0 ＜0.01
7(6) The BM+ thioguanine 38±6.0 ＜0.001
8(6) The BM+ ftorafur 26±5.6 ＜0.001
9(6) The BM+ galocitabine 24±3.0 ＜0.001
10(6) The BM+ ibacitabine 18±2.6 ＜0.001
Explain: Benzoylamide (BM) is poly-(ADP-ribose) AG14361, and thioguanine, ftorafur, galocitabine, ibacitabine are antimetabolitas.
The result of test seven to nine shows, used DNA repairase inhibitor [kinases inhibitor that poly-(ADP-ribose) AG14361 and DNA-rely on] and various antimetabolitas all have the obvious suppression effect to growth of tumour cell when this concentration, but the two has obvious synergistic effect when share.
The present invention be processed into anticancer pharmaceutical composition preparation method as follows:
1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2. adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and pharmaceutic adjuvant is decided because of specific requirement.
3. removal organic solvent.Vacuum drying or cold drying all can.
4. dried solid composite is made different shape as required.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
In a word, above-mentioned listed various DNA repairase inhibitor comprise that the kinases inhibitor of various poly-(ADP-ribose) AG14361 and DNA-dependence all can suppress the activity of transmethylase.Experimental result shows that also DNA repairase inhibitor among the present invention is to the potentiation of listed antimetabolitas.Therefore, the effective ingredient of anticancer compound of the present invention is the associating of any one (or multiple) DNA repairase inhibitor or any one (or multiple) DNA repairase inhibitor and any one (or multiple) antimetabolitas.Wherein DNA repairase inhibitor comprises the kinases inhibitor that various poly-(ADP-ribose) AG14361 and DNA-rely on.
The anticancer pharmaceutical composition that contains above effective ingredient can be made into any dosage form or shape, but is preferred with the agent for slow releasing, wherein is implanted into agent for most preferably with body.
(4) specific embodiment
The present invention will be further described below by embodiment, but be not limited thereto.
Embodiment 1.
80mg pharmaceutic adjuvant ethylene vinyl acetate copolymer (EVAc) is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 10mg2-(4-Lin Ji)-8-phenylchromone and 10mg 5-fluorouracil, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10%2-(4-Lin Ji)-8-phenylchromone and 10%5-fluorouracil, and body is implanted into agent.The drug release time of this anticancer pharmaceutical composition in external normal saline is 14-24 days, is about 20-35 days at the subcutaneous drug release time of mice.
Embodiment 2. is as described in the embodiment 1, and different is that contained effective ingredient is:
(a) Ismipur of 1-50%, 5-fluorouracil (5-FU), doxifluridine, floxuridine, the wortmannin of mercaptopurine or thioguanine and 1-50%, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-base, 2-(4-Lin Ji)-8-phenylchromone, 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-), inhibitors of kinases, vanillin, 2-aminopurine, 7-ethyl-10-hydroxycamptothecine, the combination of 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1 or phenylbutyric acid salt; Perhaps
(b) 3-aminobenzamide, the Benzoylamide, 3 of the Ismipur of 1-50%, 5-fluorouracil (5-FU), doxifluridine, floxuridine, mercaptopurine or thioguanine and 1-50%, the combination of 4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, poly polymerase inhibitor, the amino 2-aromatic radical benzimidazole-4-carboxamides BZ1-6 that replaces, benzimidazole-4-carboxamides BZ1-6, tricyclic lactam hydrogen sulfide or three ring benzimidazole carboxylic acid amides; Perhaps
(c) Ismipur of 1-50%, 5-fluorouracil (5-FU), doxifluridine, floxuridine, the 2-of mercaptopurine or thioguanine and 1-50% (4-Lin Ji)-8-phenylchromone, benzimidazole, 1H-three ring benzimidazole carboxylic acid amides, 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6,2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6,2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides BZ1-6,2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6, the combination of 8-hydroxy-2-methyl quinazolinone or 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
Below all be weight percentage.
Embodiment 3.
With the 80mg molecular weight is that 10000 PLGA (copolymer of hydroxyacetic acid and glycolic) puts into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg wortmannin and 10mg methotrexate, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% methotrexate and 10% wortmannin, and body is implanted into agent.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is about 30-40 days at the subcutaneous drug release time of mice.Embodiment 4. is as described in the embodiment 3, and different is that contained effective ingredient is:
A) methotrexate of 1-50%, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, 2-(4-Lin Ji)-8-phenylchromone of his shore of enocitabine or imidazoles and 1-50%, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-base, 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-), inhibitors of kinases, vanillin, 2-aminopurine, 7-ethyl-10-hydroxycamptothecine, the combination of 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1 or phenylbutyric acid salt; Perhaps
B) 3-aminobenzamide, the Benzoylamide, 3 of his shore of the methotrexate of 1-50%, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine or imidazoles and 1-50%, the combination of 4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, poly polymerase inhibitor, the amino 2-aromatic radical benzimidazole-4-carboxamides BZ1-6 that replaces, benzimidazole-4-carboxamides BZ1-6, tricyclic lactam hydrogen sulfide or three ring benzimidazole carboxylic acid amides; Perhaps
C) methotrexate of 1-50%, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, the benzimidazole of his shore of enocitabine or imidazoles and 1-50%, 1H-three ring benzimidazole carboxylic acid amides, 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6,2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6,2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides BZ1-6,2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6, the combination of 8-hydroxy-2-methyl quinazolinone or 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
Below all be weight percentage.
Embodiment 5.
With the 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg wortmannin and 10mg methotrexate, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% methotrexate and 10% wortmannin, and body is implanted into agent.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is about 30-40 days at the subcutaneous drug release time of mice.Embodiment 6. is as described in the embodiment 5, and different is that contained effective ingredient is:
A) methotrexate of 2-40%, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, the wortmannin of cladribine or pentoside and 2-40%, 2-(4-Lin Ji)-8-phenylchromone, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-base, 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-), inhibitors of kinases, vanillin, 2-aminopurine, 7-ethyl-10-hydroxycamptothecine, the combination of 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1 or phenylbutyric acid salt; Perhaps
B) the 3-aminobenzamide of the methotrexate of 2-40%, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or pentoside and 2-40%, Benzoylamide, 3, the combination of 4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, poly polymerase inhibitor, the amino 2-aromatic radical benzimidazole-4-carboxamides BZ1-6 that replaces, benzimidazole-4-carboxamides BZ1-6, tricyclic lactam hydrogen sulfide or three ring benzimidazole carboxylic acid amides; Perhaps
C) methotrexate of 2-40%, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, the benzimidazole of cladribine or pentoside and 2-40%, 1H-three ring benzimidazole carboxylic acid amides, 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6,2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6,2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides BZ1-6,2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6, the combination of 8-hydroxy-2-methyl quinazolinone or 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
Below all be weight percentage.
Embodiment 7.
(EVAc) puts into container with the 80mg pharmaceutic adjuvant, add 100 milliliters of dichloromethane dissolving mixings after, add 10mg wortmannin (WM) and 10 milligrams of 5-FU, shake up the dry removal of final vacuum organic solvent again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% wortmannin and percentage by weight 10%5-FU.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-25 days, is about 25-40 days at the subcutaneous drug release time of mice.
Embodiment 8. is as described in the embodiment 7, and the effective ingredient that different is wherein is respectively:
A) .alpha.-5:6-benzopyran of the 5-FU of percentage by weight 5-20% or methotrexate and percentage by weight 5-20%, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 6-aromatic radical-2-morphol-4-base-4H-thiapyran-4-base, 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-), inhibitors of kinases, vanillin, 2-aminopurine, 7-ethyl-10-hydroxycamptothecine, the combination of 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1 or phenylbutyric acid salt; Perhaps
B) the 3-aminobenzamide of the 5-FU of percentage by weight 5-20% or methotrexate and percentage by weight 5-20%, Benzoylamide, 3, the combination of 4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, poly polymerase inhibitor, the amino 2-aromatic radical benzimidazole-4-carboxamides BZ1-6 that replaces, benzimidazole-4-carboxamides BZ1-6, tricyclic lactam hydrogen sulfide or three ring benzimidazole carboxylic acid amides; Perhaps
C) combination of the benzimidazole of the 5-FU of percentage by weight 5-20% or methotrexate and percentage by weight 5-20%, 1H-three ring benzimidazole carboxylic acid amides, 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6,2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6,2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides BZ1-6,2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6,8-hydroxy-2-methyl quinazolinone or 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.
Embodiment 9. is as described in the embodiment 7, and different is that contained effective ingredient is:
A) combination of his shore of 2-30% wortmannin and 2-30%6-purinethol, 5-fluorouracil, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or pentoside; Or
B) 2-30%2-(4-Lin Ji)-8-phenylchromone and 2-30%6-purinethol, 5-fluorouracil, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, the combination of cladribine or pentoside; Or
C) combination of his shore of 2-30% .alpha.-5:6-benzopyran and 2-30%6-purinethol, 5-fluorouracil, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or pentoside.
Below all be weight percentage.
Embodiment 10.
As described in embodiment 1,3 or 7, different is used pharmaceutic adjuvant is following one of a)-d):
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan) polymer, to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
As mentioned above, the preparation method of anticancer pharmaceutical composition of the present invention can be selected as the case may be.Anticancer pharmaceutical composition can be made various dosage forms with existing method, and therefore, above embodiment only is used for explanation, and is not limitation application of the present invention.Said composition except that independent application, also can with many treatment measure use in conjunction: as with use in conjunction such as radiotherapy, high thermal therapeutical, immunization therapy, phototherapy, electrotherapy.When said composition and other treatment measure use in conjunction such as chemotherapy or radiotherapy, the local placement used said composition has uniqueness as synergist advantage and very high clinical value.

Claims (4)

1. an anticancer pharmaceutical composition is made up of anticancer effective component and pharmaceutic adjuvant, it is characterized in that this pharmaceutical composition is the implantation slow release agent;
Pharmaceutic adjuvant is selected from the copolymer, ethylene vinyl acetate copolymer of polylactic acid, hydroxyacetic acid and glycolic, to carboxy phenyl propane/decanedioic acid copolymer and composition thereof or copolymer;
Anticancer effective component is:
(A) one of antimetabolitas and following (B), (C)
(B) kinases inhibitor of DNA-dependence,
(C) poly-(ADP-ribose) AG14361;
Described (A) component antimetabolitas is selected from his shore of Ismipur, 5-fluorouracil, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, galocitabine, gemcitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, capecitabine, imidazoles, GR 30921X, mitotane, fludarabine, cladribine or pentoside;
The kinases inhibitor that described (B) component DNA-relies on is selected from wortmannin .alpha.-5:6-benzopyran or 2-(4-Lin Ji)-8-phenylchromone;
Poly-(ADP-ribose) AG14361 of described (C) component is selected from Benzoylamide or benzimidazole.
2. the anticancer pharmaceutical composition according to claim 1 is characterized in that the anticancer effective component of said composition is:
(a) combination of the .alpha.-5:6-benzopyran of the 5-fluorouracil of 2-30% or methotrexate and 1-20% or 2-(4-Lin Ji)-8-phenylchromone; Perhaps
(b) combination of the Benzoylamide of the 5-fluorouracil of 2-30% or methotrexate and 2-30%;
More than equal weight percentage ratio.
3. the anticancer pharmaceutical composition according to claim 1 is characterized in that the anticancer effective component of said composition is:
(a) combination of his shore of 2-30% wortmannin and 2-30%6-purinethol, 5-fluorouracil, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or pentoside; Or
(b) combination of his shore of 2-30%2-(4-Lin Ji)-8-phenylchromone and 2-30%6-purinethol, 5-fluorouracil, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or pentoside; Or
(c) combination of his shore of 2-30% .alpha.-5:6-benzopyran and 2-30%6-purinethol, 5-fluorouracil, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or pentoside;
More than equal weight percentage ratio.
4. the application of the described anticancer pharmaceutical composition of claim 1 is used to prepare former or the medicine of secondary carcinoma that treatment originates from people and animal brain, central nervous system, kidney, liver, gallbladder, oral cavity, thyroid, skin, mucosa, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, prostate, bladder, colon or rectum.
CNB2004100361006A 2004-11-22 2004-11-22 Anti-cancer medicine composition Expired - Fee Related CN100431606C (en)

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CN101637444B (en) * 2006-03-17 2012-08-15 山东蓝金生物工程有限公司 Anti-cancer drug slow release injection containing gemcitabine
CN105418711A (en) * 2015-11-06 2016-03-23 山东大学 Application of alpha-L-rhamnosidase to preparing hydroxycarbamide and glycoside derivatives
CN109303919B (en) * 2017-07-26 2020-09-04 天津中医药大学 Application of Akt inhibitor in preparation of anti-liver cancer active drug for enhancing lycorine
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1143358A (en) * 1994-03-09 1997-02-19 钮卡斯尔大学风险投资有限公司 Benzamide analogs, useful as parp (ADP-ribosyltransferase, ADRPT) DNA repair enzyme inhibitors
CN1319009A (en) * 1998-09-25 2001-10-24 沃尼尔·朗伯公司 Chemotherapy of cancer with acetyldinaline in combination with gemcitabine, capecitabine or cisplatin
CN1331683A (en) * 1998-11-17 2002-01-16 巴斯福股份公司 2-phenylbenzimidazoles and 2-phenylindoles, and prodn. and use thereof
CN1547471A (en) * 2001-03-15 2004-11-17 ���ĵ�˹ҩ��ɷ����޹�˾ Combination comprising combretastatin and anticancer agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1143358A (en) * 1994-03-09 1997-02-19 钮卡斯尔大学风险投资有限公司 Benzamide analogs, useful as parp (ADP-ribosyltransferase, ADRPT) DNA repair enzyme inhibitors
CN1319009A (en) * 1998-09-25 2001-10-24 沃尼尔·朗伯公司 Chemotherapy of cancer with acetyldinaline in combination with gemcitabine, capecitabine or cisplatin
CN1331683A (en) * 1998-11-17 2002-01-16 巴斯福股份公司 2-phenylbenzimidazoles and 2-phenylindoles, and prodn. and use thereof
CN1547471A (en) * 2001-03-15 2004-11-17 ���ĵ�˹ҩ��ɷ����޹�˾ Combination comprising combretastatin and anticancer agents

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