CN100350975C - Anticarcinogen composition - Google Patents
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- CN100350975C CN100350975C CNB2005100424300A CN200510042430A CN100350975C CN 100350975 C CN100350975 C CN 100350975C CN B2005100424300 A CNB2005100424300 A CN B2005100424300A CN 200510042430 A CN200510042430 A CN 200510042430A CN 100350975 C CN100350975 C CN 100350975C
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Abstract
The present invention relates to an anti-cancer medicinal composition which belongs to the technical field of drugs. The anti-cancer medicinal composition comprises medicinal supplementary materials, tetrazine class drugs packaged in the medicinal supplementary materials, guanine, guanine derivatives or guanine analogs, wherein the guanine, the guanine derivatives or the guanine analogs can suppress the DNA repair function in cells, and can reduce the tolerance of tumor cells for the tetrazine class drugs. The medicinal supplementary materials mainly comprise high molecular biologic capacitability polymers which can be degraded and absorbed, and in the degradation and absorption processes, the anti-cancer drug can be released slowly at part of a tumor, so that the systemic toxicity reactions of human bodies are reduced obviously. Simultaneously, the anti-cancer drug can be applied to part of the tumors for keeping the effective drug concentration. The composition is put on part of the tumor, which can reduce the medicinal systemic toxicity reactions and simultaneously increase the drug concentration of part of the tumor in a selective mode. The treatment effect of non-operative treatment modes, such as chemotherapeutics, radiotherapy, etc., can be enhanced.
Description
(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 tetrazine kind anti-cancer drugs thing 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 nitrosourea cancer therapy drug, consequently treatment failure.
Recent findings, deactivation or suppress intracellular dna repair protein and can strengthen the sensitivity of part tumor cell to chemotherapy, referring to " O6-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 infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA such as carry 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, simple raising dosage is subjected to the restriction of general reaction again, 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 Q et al., J Surg Oncol.1998Oct such as Kong Qingzhongs; 69 (2): 76-82).
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote the growth of its wettability "; referring to beam etc. " increased after the cancer therapy drug pulse screening human lung carcinoma cell Drug tolerance and external invade the profit ability and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (LiangY; et al., Int J Cancer.2004; 111 (4): 484-93).
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.
(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 the anticancer effective component and the pharmaceutic adjuvant of effective anticancer, and anticancer effective component is:
A) tetrazine class medicine and
B) guanine, guanine derivatives or guanine analog.
Tetrazine class medicine is selected from imidazo tetrazine (imidazotetrazine), imidazopyrazine (imidazopyrazine), 1H-imidazo [b] piperazine (1H-imidazo[b] pyrazine), imidazopyridine (imidazopyridine), 1H-imidazo [1,2-a] pyridine (1H-imidazo[1,2-a] pyridinum), procarbazine (procarbazine, PCB), topotecan (topotecan, Topo), Yi Li is for health (irinotecan), mitozolomide (mitozolomide, MTZ), dacarbazine (dacarbazine, DCB), temozolomide (Temozolomide or8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3, and analog or derivant such as 4-carboxyl temozolomide [4--carbonyl] temozolomide 5-tetrazin-4 (3H)-one or NSC 362856)), 3-N-methyl temozolomide [3-N-methyl] temozolomide), the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide (Pyrrolo[2,1-d] [1,2,3,5] tetrazine-4 (3H)-ones), the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o (Pyrrolo[2,1-d] [1,2,3,5] tetrazinones 10a-o), temozolomide's roguing azepine derivatives such as 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides (MTIC, 5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide (8-nitro-3-methyl-benzo-1,2,3,5-tetrazepin-4 (3H)-one, NIME), 3,5-dimethyl-pyrido-1,2,3, and 5-four azatropylidenes-4-temozolomide (3,5-dimethyl-pyrido-1,2,3,5-tetrazepin-4-one, PYRZ), streptozocin (streptozotocin, STZ) and 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides (3-(2-chloroethyl)-N, N-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, CDODTC).
Above-mentioned tetrazine class medicine can singly select or multiselect, is preferred with imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, procarbazine, topotecan, Yi Li for health, mitozolomide, dacarbazine, temozolomide, streptozocin.
Tetrazine kind compound shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-99.99%, is best with 5%-30%.Below all be weight percentage.
Above-mentioned tetrazine class medicine can suppress and destroy the DNA repair function in the tumor cell effectively, and then increases the therapeutic effect of tetrazine kind anti-cancer drugs thing.
Above-mentioned guanine; guanine derivatives or guanine analog are selected from; but be not limited to; 2-amino-6-oxypurine (2-amino-6-oxypurine); guanine (guanine); benzyl guanine (benzylguanine); O6-benzyl guanine (O6-BG); O6-butyl guanine (O6-butylguanines); O6-methyl guanine (O6-MG); O6-alkyl guanine (O6-Alkylguanine); O6-benzyl-2 '-deoxyguanosine (O6-benzyl-2 '-deoxyguanosine); 8-amino-O6-benzyl guanine (8-Amino-O.sup.6-benzylguanine); 8-methyl-O6-benzyl guanine (8-methyl-O.sup.6-benzylguanine); 8-hydroxyl-O6-benzyl guanine (8-hydroxy-O.sup.6-benzylguanine); 8-bromo-O6-benzyl guanine (8-bromo-O.sup.6-benzylguanine); 8-oxygen-O6-benzyl guanine (8-Oxo-O.sup.6-benzylguanine); 8-trifluoromethyl-O6-benzyl guanine (8-trifluoromethyl-O.sup.6-benzylguanine); O6-benzyl uric acid (O.sup.6-Benzyluric acid); O6-benzyl xanthine (O.sup.6-Benzylxanthine); O6-benzyl-2-fluorine hypoxanthine (O.sup.6-Benzyl-2-fluorohypoxanthine); Diacetyl-O.sup.6-benzyl-8-oxoguanine (Diacetyl-O.sup.6-benzyl-8-oxoguanine); O6-benzyl-8-methyl guanine (O.sup.6-Benzyl-8-methylguanine); O6-benzyl-8-oxo guanine (O.sup.6-Benzyl-8-oxoguanine); O6-benzyl-8-bromination guanine (O.sup.6-Benzyl-8-bromoguanine); O6-benzyl-8-trifluoromethyl guanine (O.sup.6-Benzyl-8-trifluoromethylguanine); O6-benzyl-N2-methyl guanine (O.sup.6-benzyl-N.sup.2-methylguanine); O6-benzyl-N2N2-dimethylguanine (O.sup.6-benzyl-N.sup.2; N.sup.2-dimethylguanine); O6-benzyl-8-trifluoromethyl-9-methyl guanine (O.sup.6-benzyl-8-trifluoromethyl-9-methylguanine); O6-benzyl-8-bromo-9-methyl guanine (O.sup.6-benzyl-8-bromo-9-methylguanine); O6-benzyl-8-bromo-9-pivaloyl oxygen methyl guanine (O.sup.6-benzyl-8-bromo-9-(pivaloyloxymethyl) guanine); O6-benzyl-7-pivaloyl oxygen methyl guanine (O.sup.6-benzyl-7-(pivaloyloxymethyl) guanine); O6-benzyl-8-bromo-7-pivaloyl oxygen methyl guanine (O.sup.6-benzyl-8-bromo-7-(pivaloyloxymethyl) guanine); 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine (8-Aza-O.sup.6-benzyl-9-(pivaloyloxymethyl) guanine); 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine (8-Aza-O.sup.6-benzyl-7-(pivaloyloxymethyl) guanine); 8-azepine-O6-benzyl guanine (8-Aza-O.sup.6-benzylguanine); 8-azepine-O6-benzyl-9-methyl guanine (8-Aza-O.sup.6-benzyl-9-methylguanine); N.sup.2-Acetyl-O.sup.6-benzyl-8-oxoguanine (N.sup.2-Acetyl-O.sup.6-benzyl-8-oxoguanine); O6-benzyl-N2-methyl guanine (O.sup.6-Benzyl-N.sup.2-methylguanine); O6-benzyl-N2N2-dimethylguanine (O.sup.6-Benzyl-N.sup.2; N.sup.2-dimethylguanine); 2-amino-6-chloro-8-methyl purine (2-Amino-6-chloro-8-methylpurine); 2; 8-diaminourea-6-chloropurine (2; 8-Diamino-6-chloropurine); O6-benzyl-N2-guanosine (O6-benzyl-N2-acetylguanosine); O6-benzyl-9-cyano group guanine (O6-benzyl-9-cyanomethylguanine (CMBG)); N (7)-methyl guanine (N (7)-methylguanine); O6-benzyl-N2-guanosine (O6-benzylguanosine (BGS)); O6-cycloalkyl guanine (O (6)-cycloalkylguanines); O6-pi-allyl guanine (O (6)-allylguanine); O6-(2-oxyalkyl guanine (O (6)-(2-oxoalkyl) guanine); O6-cycloalkenyl guanine (O (6)-Cycloalkenylguanines; O6-CAG); 1-cyclobutane methyl guanine (1-cyclobutenylmethylguanine; CBMG); 1-cyclopentenyl methyl guanine (1-cyclopentenylmethylguanine; CPMG) and O6-bromothen base guanine (O (6)-(4-bromothenyl) guanine, O6-BTG).
Above-mentioned guanine, guanine derivatives, guanine analog or derivatives thereof also comprise its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Above guanine, guanine derivatives or guanine analog can singly select or multiselect, serve as preferred with O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl-2 '-deoxyguanosine, 8-amino-O6-benzyl guanine, 8-methyl-O6-benzyl guanine, 8-hydroxyl-O6-benzyl guanine, 8-bromo-O6-benzyl guanine and 8-oxygen-O6-benzyl guanine.
Guanine, guanine derivatives or the guanine analog content in compositions can be good with 1%-50% from 0.01%-99.99%, is best with 5%-30%.
Guanine and derivant thereof, analog decapacitation suppress can also increase the sensitivity of tumor cell to tetrazine kind anti-cancer drugs thing outside the tumor growth.
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) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin, Fibrinogen and agarose 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.Its representative 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 5000 to 10000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 20000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 5000 to 10000 polylactic acid mixes with the certain herbaceous plants with big flowers diacid, molecular weight is that 30000 to 80000 PLGA mixes with the certain herbaceous plants with big flowers diacid.The indication molecular weight is the molecular weight peak value scope for being recorded by GPC all.
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 anti-cancer 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 anti-cancer 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 anticancer pharmaceutical composition 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, muddy suspension, ointment, capsule, slow releasing agent, implant, implantation slow release 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, based on agent for slow releasing in the body or implant.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.Guanine derivatives and guanine analog have potentiation significantly to act on to tetrazine kind anti-cancer drugs thing, 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.Whether route of administration depends on multiple factor, as position, tumor place, perform the operation or transfer, gross tumor volume size, tumor classification, patient age, health, bearing status and requirement etc.For obtain active drug concentration in position, tumor place, arterial perfusion optionally, intra-bladder instillation (intracavitary), (intraspinal) administration in abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and the canalis spinalis, but also place in the internal organs or in the tumor body, as in the enteric cavity, in the intravesical, uterine cavity, in intravaginal, gastric and the esophagus etc.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-releasing pump, slow releasing capsule, implant, slow releasing agent or sustained release profile in vivo test implant as selecting for use.
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 tetrazine class medicine 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.
When guanine derivatives or guanine analog and tetrazine kind anti-cancer drugs thing use in conjunction, the weight ratio of the two is 1-9: 1 to 1: 1-9, the effective dose of tetrazine class medicine is 0.01-80 milligram/kg body weight, with 1-50 milligram/kg body weight is ideal, with 2-10 milligram/kg body weight for the most desirable.And the effective dose of guanine derivatives or guanine analog is 0.01-500 milligram/kg body weight, is ideal with 1-100 milligram/kg body weight, with 5-50 milligram/kg body weight for the most desirable.
Anticancer pharmaceutical composition of the present invention can be used to prepare the medicine of the entity tumors such as various cancers, sarcoma or carcinosarcoma for the treatment of people, house pet and various animals, comprises former or cancer or sarcoma or the carcinosarcoma that shifts 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, Folium Nicotianae preparatum portion, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Also can add other medicinal ingredient in this anticancer pharmaceutical composition, 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.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can be through various administrations, with topical, as selective arterial injection and directly injection or be placed as goodly in the tumor body, wherein are released to the best with local slow again.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 5%-30%.This anticancer pharmaceutical composition can be made into various dosage forms, as, but be not limited to injection, muddy suspension, ointment, capsule, implant, slow releasing agent and implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous; 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; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and anticancer pharmaceutical composition also can be packed in the liposome.
The characteristics of anticancer pharmaceutical composition technology of preparing of the present invention be with guanine derivatives or guanine analog and tetrazine class medicine separately or packaged in combination in pharmaceutic adjuvant, with active ingredient and pharmaceutic adjuvant dissolving, the universe is dry afterwards to wait to fill part mixing according to a certain percentage.Treat that the universe is shaped immediately after dry and sterilizes packing.
Above guanine derivatives or guanine analog 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 tetrazine class medicine.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.
The external tumor-inhibiting action of test one, tetrazine class medicine and guanine derivatives.
Used tumor cell comprises CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Following tetrazine class medicine and guanine derivatives are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 1.
Table 1
| Oncocyte | TMZ | O6-BG | TMZ+ O6-BG | O6-bG | TMZ+ O6-bG | O6-MG | TMZ+ O6-MG | O6-AG | TMZ+ O6-AG |
| CNS | 68％ | 64％ | 90％ | 66％ | 98％ | 64％ | 90％ | 66％ | 98％ |
| C6 | 62％ | 64％ | 96％ | 60％ | 98％ | 64％ | 96％ | 60％ | 98％ |
| SA | 58％ | 60％ | 86％ | 56％ | 92％ | 60％ | 86％ | 60％ | 92％ |
| BC | 54％ | 64％ | 94％ | 54％ | 84％ | 54％ | 94％ | 64％ | 84％ |
| BA | 54％ | 62％ | 98％ | 62％ | 82％ | 52％ | 98％ | 62％ | 82％ |
| LH | 60％ | 58％ | 90％ | 62％ | 92％ | 68％ | 90％ | 62％ | 92％ |
| PAT | 54％ | 56％ | 94％ | 66％ | 98％ | 66％ | 94％ | 56％ | 98％ |
Annotate: TMZ: the temozolomide belongs to tetrazine class medicine; O6-BG:O6-benzyl guanine, O6-bG:O6-butyl guanine, O6-MG:O6-methyl guanine (O6-MG), O6-AG:O6-alkyl guanine all belong to guanine derivatives.
The external tumor-inhibiting action of test two, tetrazine class medicine and guanine derivatives.
With used tumor cell in the test one, following tetrazine class medicine and guanine derivatives are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 2.
Table 2
| Oncocyte | MTZ | O6-BG | O6-BG +MTZ | O6-bG | O6-bG +MTZ | O6-MG | O6-MG +MTZ | O6-AG | O6-AG +MTZ |
| CNS | 67％ | 64％ | 92％ | 67％ | 96％ | 65％ | 94％ | 64％ | 96％ |
| C6 | 62％ | 66％ | 96％ | 60％ | 98％ | 64％ | 96％ | 60％ | 94％ |
| SA | 56％ | 60％ | 88％ | 58％ | 90％ | 68％ | 86％ | 58％ | 92％ |
| BC | 54％ | 56％ | 94％ | 54％ | 84％ | 64％ | 90％ | 64％ | 86％ |
| BA | 57％ | 52％ | 96％ | 62％ | 80％ | 68％ | 98％ | 56％ | 82％ |
| LH | 62％ | 66％ | 90％ | 68％ | 90％ | 50％ | 92％ | 60％ | 90％ |
| PAT | 54％ | 66％ | 96％ | 66％ | 98％ | 56％ | 94％ | 56％ | 98％ |
Annotate: MTZ: mitozolomide belongs to tetrazine class medicine; O6-BG:O6-benzyl guanine, O6-bG:O6-butyl guanine, O6-MG:O6-methyl guanine, O6-AG:O6-alkyl guanine all belong to guanine derivatives.
The external tumor-inhibiting action of test three, tetrazine class medicine and guanine derivatives.
With used tumor cell in the test one, following tetrazine class medicine and guanine derivatives are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 3.
Table 3
| Oncocyte | IRT | O6-BG | IRT+ O6-BG | O6-bG | IRT+ O6-bG | O6-MG | IRT+ O6-MG | O6-AG | IRT+ O6-AG |
| CNS | 67％ | 64％ | 92％ | 67％ | 96％ | 65％ | 94％ | 64％ | 96％ |
| C6 | 62％ | 66％ | 96％ | 60％ | 98％ | 64％ | 89％ | 60％ | 94％ |
| SA | 56％ | 60％ | 88％ | 58％ | 90％ | 68％ | 88％ | 58％ | 92％ |
| BC | 54％ | 56％ | 94％ | 54％ | 84％ | 64％ | 90％ | 64％ | 86％ |
| BA | 57％ | 52％ | 96％ | 62％ | 80％ | 68％ | 88％ | 66％ | 82％ |
| LH | 62％ | 66％ | 90％ | 68％ | 90％ | 50％ | 92％ | 60％ | 90％ |
| PAT | 54％ | 66％ | 96％ | 66％ | 98％ | 56％ | 89％ | 66％ | 98％ |
Annotate: IRT: Yi Li belongs to tetrazine class medicine for health; O6-BG:O6-benzyl guanine, O6-bG:O6-butyl guanine, the O6-MG:O6-methyl guanine, O6-AG:O6-alkyl guanine all belongs to guanine derivatives.
The external tumor-inhibiting action of test four, tetrazine class medicine and guanine derivatives.
With used tumor cell in the test one, following tetrazine class medicine and guanine derivatives are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 4.
Table 4
| Oncocyte | PCB | O6-BG | O6-BG +PCB | O6-bG | O6-bG +PCB | O6-MG | O6-MG +PCB | O6-AG | O6-AG +PCB |
| CNS | 57％ | 68％ | 98％ | 68％ | 98％ | 68％ | 88％ | 59％ | 94％ |
| C6 | 52％ | 76％ | 96％ | 62％ | 98％ | 64％ | 90％ | 60％ | 90％ |
| SA | 46％ | 60％ | 88％ | 58％ | 90％ | 68％ | 90％ | 88％ | 95％ |
| BC | 58％ | 66％ | 94％ | 54％ | 84％ | 60％ | 89％ | 64％ | 88％ |
| BA | 57％ | 58％ | 96％ | 68％ | 88％ | 68％ | 88％ | 56％ | 82％ |
| LH | 60％ | 68％ | 98％ | 68％ | 90％ | 50％ | 89％ | 60％ | 92％ |
| PAT | 55％ | 66％ | 96％ | 68％ | 98％ | 58％ | 94％ | 56％ | 96％ |
Annotate: PCB: procarbazine is tetrazine class medicine; O6-BG:O6-benzyl guanine, O6-bG:O6-butyl guanine, the O6-MG:O6-methyl guanine, O6-AG:O6-alkyl guanine all belongs to guanine derivatives.
The external tumor-inhibiting action of test five, tetrazine class medicine and guanine derivatives.
With used tumor cell in the test one, following tetrazine class medicine and guanine derivatives are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 5.
Table 5
| Oncocyte | Top | O6-BG | Top+ O6-BG | ，O6-bG | Top+ O6-bG | O6-MG | Top+ O6-MG | O6-AG | Top+ O6-AG |
| CNS | 67％ | 64％ | 92％ | 67％ | 96％ | 65％ | 94％ | 64％ | 96％ |
| C6 | 62％ | 66％ | 96％ | 60％ | 98％ | 64％ | 96％ | 56％ | 94％ |
| SA | 56％ | 60％ | 88％ | 58％ | 90％ | 68％ | 86％ | 58％ | 92％ |
| BC | 54％ | 56％ | 94％ | 54％ | 84％ | 64％ | 90％ | 54％ | 86％ |
| BA | 57％ | 52％ | 96％ | 62％ | 80％ | 68％ | 98％ | 66％ | 82％ |
| LH | 62％ | 66％ | 90％ | 68％ | 90％ | 50％ | 92％ | 60％ | 90％ |
| PAT | 54％ | 66％ | 96％ | 66％ | 98％ | 56％ | 94％ | 56％ | 98％ |
Annotate: Top: topotecan is tetrazine class medicine; O6-BG:O6-benzyl guanine, O6-bG:O6-butyl guanine, the O6-MG:O6-methyl guanine, O6-AG:O6-alkyl guanine all belongs to guanine derivatives.
The external tumor-inhibiting action of test six, tetrazine class medicine and guanine derivatives.
With used tumor cell in the test one, following tetrazine class medicine and guanine derivatives are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 6.
Table 6
| Oncocyte | DCB | O6-BG | DCB+ O6-BG | O6-bG | DCB+ O6-bG | O6-MG | DCB+ O6-MG | O6-AG | DCB+ O6-AG |
| CNS | 67％ | 64％ | 92％ | 67％ | 96％ | 65％ | 94％ | 64％ | 96％ |
| C6 | 62％ | 66％ | 96％ | 60％ | 98％ | 64％ | 89％ | 60％ | 94％ |
| SA | 56％ | 60％ | 88％ | 58％ | 90％ | 68％ | 86％ | 58％ | 92％ |
| BC | 54％ | 56％ | 94％ | 54％ | 84％ | 64％ | 90％ | 64％ | 86％ |
| BA | 57％ | 52％ | 96％ | 62％ | 80％ | 68％ | 88％ | 66％ | 82％ |
| LH | 62％ | 66％ | 90％ | 68％ | 90％ | 50％ | 92％ | 60％ | 90％ |
| PAT | 54％ | 66％ | 96％ | 66％ | 98％ | 56％ | 94％ | 66％ | 98％ |
Annotate: DCB: dacarbazine is tetrazine class medicine; O6-BG:O6-benzyl guanine, O6-bG:O6-butyl guanine, the O6-MG:O6-methyl guanine, O6-AG:O6-alkyl guanine all belongs to guanine derivatives.
Test one to six result shows that used tetrazine class medicine and various guanine derivatives all have the obvious suppression effect to growth of tumour cell when this concentration, but the two has obvious synergistic effect when share.
Test seven, guanine analog are to the inhibitory action of O6-methyl guanine-DNA-transmethylase
As mentioned above, DNA repairase such as increasing of O6-methyl guanine-DNA-transmethylase are that it is to the tolerific main cause of tetrazine class medicine in the tumor cell, therefore, detection compound can be used for screening tetrazine class medicament synergistic agent to the influence of this enzyme activity.This experiment is subjects with the lung carcinoma cell, with the transmethylase Sickledex guanine analog and derivant thereof is screened.Adding concentration in 24 hours the various tumor cells of In vitro culture is the medicine of 5mM/ml, continues to cultivate the inhibitory action that detects after 48 hours the Methyl transporters enzyme activity.Suppressing effect (%) is shown in Table 7.
Table 7
| Methyltransferase inhibitors | Methyl transporters enzyme inhibition rate (%) |
| O6-BG guanine benzyl guanine O6-BuG O6-MG O6-alkyl guanine 2-amino-6-oxypurine O6-benzyl 2 '-deoxyguanosine 8-Amino-O.sup.6-benzylguanine 8-methyl-O.sup.6-benzylguanine 8-hydroxy-O.sup.6-benzylguanine 8-bromo-O.sup.6-benzylguanine 8-Oxo-O.sup.6-benzylguanine 8-trifluoromethyl-O.sup.6-benzylguanine O.sup.6-Benzyluric acid O.sup.6-Benzylxanthine | 88 60 66 80 80 84 80 80 88 78 78 78 90 86 48 46 |
| O6--2- -O6--8- O6--8- O6--8- O6--8- O6--8- O6--N2- O6--N2N2- O6--8--9- O6--8--9- O6--8--9- O6--7- O6--8--7- 8--O6--7- 8--O6--7- 8--O6- 8--O6--9- -O6--8- O6--N2- O6--N2 N2- 2--6--8- 2,8--6- O6--N2- O6--9- O6--N2- N ( 7 )- O6- 1- 1- O6- | 48 48 86 88 88 90 68 68 70 80 86 82 80 84 86 90 80 82 82 60 68 62 78 80 80 86 88 86 86 89 |
As can be seen from the above table, institute's reagent thing all has obvious inhibitory action to transmethylase, O6-benzyl guanine wherein, O6-alkyl guanine, 8-amino-O6-benzyl guanine, 8-oxygen-O6-benzyl guanine, O6-benzyl-8-methyl guanine, O6-benzyl-8-oxo guanine, O6-benzyl-8-bromination guanine, O6-benzyl-8-trifluoromethyl guanine, O6-benzyl-8-bromo-9-methyl guanine, O6-benzyl-8-bromo-9-pivaloyl oxygen first guanine, 8-azepine-O6-benzyl guanine, O6-cycloalkenyl guanine, 1-cyclobutane methyl guanine, the effect of 1-cyclopentenyl methyl guanine and O6-bromothen base guanine etc. is particularly evident, all more than 80%.
With multiple other tumor cell (comprising the cerebral tumor (CNS-1, C6,9L), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma, cancer of pancreas, renal carcinoma and the esophageal carcinoma etc.) is that subjects draws similar results.
In a word, above-mentioned listed various guanines and derivant thereof the activity that all can suppress transmethylase.Experimental result also shows the potentiation to listed tetrazine class medicine of guanine among the present invention and derivant thereof.Therefore, the effective ingredient of anticancer compound of the present invention is the associating of guanine and derivant thereof and any one or multiple tetrazine class medicine or packing separately.The entity-tumor-resistant medicine composition that contains above effective ingredient can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing type.
Because used guanine and the derivant thereof of anticancer pharmaceutical composition of the present invention is of universal significance to tetrazine class medicine enhanced sensitivity, and the inside and outside discharges comparatively slowly and is steady, so, the selection of guanine and derivant thereof is very extensive in the anticancer pharmaceutical composition of the present invention, and the associating of same guanine and derivant and tetrazine class medicine also can be chosen wantonly.Anticancer pharmaceutical composition can be made various dosage forms and shape with existing method, but is preferred with the agent for slow releasing.
With multiple other tumor cell (comprising the cerebral tumor (CNS-1, C6,9L), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma, cancer of pancreas, renal carcinoma and the esophageal carcinoma etc.) is that the explanation of table as a result tetrazine class medicine, especially procarbazine, topotecan, the Yi Li that subjects draws replaces the action effect of health, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine, imidazopyrazine and 1H-imidazo [b] piperazine, imidazopyridine etc. all to be subjected to the influence of methyl transferase activity.It acts on will have among following animal experiment and the embodiment more fully to tumor treatment and describes.
The preparation method of anticancer pharmaceutical composition of the present invention is 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 medicine 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.
(4) specific embodiment
Anticancer pharmaceutical composition of the present invention further is illustrated by following examples, but is not limited thereto.
Embodiment one:
With the 80mg molecular weight is that 20000 polylactic acid (PLA) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add 5mg temozolomide and 15mg O6-benzyl guanine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the anticancer pharmaceutical composition of 5% temozolomide and 15%O6-benzyl guanine.It is subcutaneous that the pastille complex is put in white mice, regularly takes out and survey medicament contg, according to the residual drug amount, and calculates accumulative total and discharge percent (%).Found that medicine evenly discharged 80-95% in 30 days.Below all be weight percentage.
Embodiment two:
As described in embodiment one, different is that anticancer effective component is:
The imidazo tetrazine of 1-50%; imidazopyrazine; 1H-imidazo [b] piperazine; imidazopyridine; 1H-imidazo [1; 2-a] pyridine; 4-carboxyl temozolomide; 3-N-methyl temozolomide; the pyrroles [2; 1-d] [1; 2; 3; 5] tetrazine-4 (3H)-temozolomide; the pyrroles [2; 1-d] [1; 2; 3; 5] tetrazine 10a-o; 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides; 8-nitro-3-methyl-phendioxin; 2; 3; 5-four azatropylidenes-4-temozolomide; 3; 5-dimethyl-pyrido-1; 2; 3; 5-four azatropylidenes-4-temozolomide; 3-(2-ethyl chloride)-N; N dimethyl-4-oxygen-3; 4-glyoxalidine [5; 1-d]-1; 2; 3; 5-tetrazine-8-carboxylic acid amides or 5-(triazenyl) imidazoles-4-carboxylic acid amides; procarbazine; topotecan; Yi Li is for health; mitozolomide; dacarbazine; the temozolomide; the O6-benzyl guanine of 3-aminobenzene amide or 6-aminonicotinamide and 1-50%; guanine; the benzyl guanine; O6-butyl guanine; the O6-methyl guanine; O6-alkyl guanine; 2-amino-6-oxypurine; O6-benzyl 2 '-deoxyguanosine; 8-amino-O6-benzyl guanine; 8-methyl-O6-benzyl guanine; 8-hydroxyl-O6-benzyl guanine; 8-bromo-O6-benzyl guanine; 8-oxygen-O6-benzyl guanine; 8-trifluoromethyl-O6-benzyl guanine; O6-benzyl uric acid; O6-benzyl xanthine; O6-benzyl-2-fluorine hypoxanthine; Diacetyl-O.sup.6-benzyl-8-oxoguanine; O6-benzyl-8-methyl guanine; O6-benzyl-8-oxo guanine; O6-benzyl-8-bromination guanine; O6-benzyl-8-trifluoromethyl guanine; O6-benzyl-N2-methyl guanine; O6-benzyl-N2N2-dimethylguanine; O6-benzyl-8-trifluoromethyl-9-methyl guanine; O6-benzyl-8-bromo-9-methyl guanine; O6-benzyl-8-bromo-9-pivaloyl oxygen first guanine; O6-benzyl-7-pivaloyl oxygen methyl guanine; O6-benzyl-8-bromo-7-pivaloyl oxygen first guanine; 8-azepine-O6-benzyl-7-pivaloyl oxygen first guanine; 8-azepine-O6-benzyl-7-pivaloyl oxygen first guanine; 8-azepine-O6-benzyl guanine; 8-azepine-O6-benzyl-9-methyl guanine; N.sup.2-Acetyl-O.sup.6-benzyl-8-oxoguanine; O6-benzyl-N2-methyl guanine; O6-benzyl-N2N2-dimethylguanine; 2-amino-6-chloro-8-methyl purine; 2,8-diaminourea-6-chloropurine; O6-benzyl-N2-guanosine; O6-benzyl-9-cyano group guanine; O6-benzyl-N2-guanosine; N (7)-methyl guanine; O6-cycloalkenyl guanine; 1-cyclobutane methyl guanine; the combination of 1-cyclopentenyl methyl guanine or O6-bromothen base guanine.Below all be weight percentage.
Embodiment three:
With the 80mg molecular weight is that 10000 polylactic acid (PLGA) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add 10mg imidazopyrazine and 10mg O6-butyl guanine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains anticancer pharmaceutical composition and contains 10% imidazopyrazine and 10%O6-butyl guanine.The pastille complex is prevented in white mice subcutaneous, regularly taken out and survey medicament contg,, and calculate accumulative total and discharge percent (%) according to the residual drug amount.Found that medicine evenly discharged 90-95% in 30 days.Below all be weight percentage.
Embodiment four:
As described in embodiment one, different is that anticancer effective component is:
The O6-benzyl guanine of 1-50%, guanine, the benzyl guanine, O6-butyl guanine, the imidazo tetrazine of O6-methyl guanine or O6-alkyl guanine and 1-50%, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide, 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides or 5-(triazenyl) imidazoles-4-carboxylic acid amides, procarbazine, topotecan, Yi Li is for health, mitozolomide, dacarbazine, the temozolomide, the combination of 3-aminobenzene amide or 6-aminonicotinamide.Below all be weight percentage.
Embodiment five:
(EVAc) puts into container with the 80m ethylene vinyl acetate copolymer, add 100 milliliters of dichloromethane dissolving mixings after, add 10mg mitozolomide and 10mg O6-methyl guanine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains anticancer pharmaceutical composition and contains 10% mitozolomide and 10%O6-methyl guanine.The pastille complex is prevented in white mice subcutaneous, regularly taken out and survey medicament contg,, and calculate accumulative total and discharge percent (%) according to the residual drug amount.Found that medicine evenly discharged 90-95% in 30 days.Below all be weight percentage.
Embodiment six:
80m polifeprosan (to carboxy phenyl propane (p-CPP): the percentage by weight of certain herbaceous plants with big flowers diacid (SA) is 20: 80) is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 10mg procarbazine and 10mg O6-alkyl guanine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains anticancer pharmaceutical composition and contains 10% procarbazine and 10% O6-alkyl guanine.The pastille complex is prevented in white mice subcutaneous, regularly taken out and survey medicament contg,, and calculate accumulative total and discharge percent (%) according to the residual drug amount.Found that medicine evenly discharged 90-95% in 30 days.Below all be weight percentage.
Embodiment seven:
As described in embodiment one, three, five or six, used pharmaceutic adjuvant is respectively one of following or its combination that different is:
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) polifeprosan (to carboxy phenyl propane (p-CPP): the copolymer of certain herbaceous plants with big flowers diacid (SA), to carboxy phenyl propane (p-CPP): the weight ratio of certain herbaceous plants with big flowers diacid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.。
Embodiment eight:
As described in embodiment six, different is that anticancer effective component is one of (a)～(d):
(a) 10% O6-benzyl guanine and 10% imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide, 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides or 5-(triazenyl) imidazoles-4-carboxylic acid amides, procarbazine, topotecan, Yi Li is for health, mitozolomide, dacarbazine, the temozolomide, the combination of 3-aminobenzene amide or 6-aminonicotinamide;
(b) 10% O6-butyl guanine and 10% imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide, 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides or 5-(triazenyl) imidazoles-4-carboxylic acid amides, procarbazine, topotecan, Yi Li is for health, mitozolomide, dacarbazine, the temozolomide, the combination of 3-aminobenzene amide or 6-aminonicotinamide;
(c) 10% O6-methyl guanine and 10% imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide, 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides or 5-(triazenyl) imidazoles-4-carboxylic acid amides, procarbazine, topotecan, Yi Li is for health, mitozolomide, dacarbazine, the temozolomide, the combination of 3-aminobenzene amide or 6-aminonicotinamide;
(d) 10% O6-alkyl guanine and 10% imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide, 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides or 5-(triazenyl) imidazoles-4-carboxylic acid amides, procarbazine, topotecan, Yi Li is for health, mitozolomide, dacarbazine, the temozolomide, the combination of 3-aminobenzene amide or 6-aminonicotinamide.
Below all be weight percentage.
Embodiment nine: tumor-inhibiting action in the body of tetrazine class medicine and guanine derivatives.
With the rat is subjects, with 2 * 10
5Individual tumor cell (hepatocarcinoma) subcutaneous injection treats that in its hypochondrium tumor growth was divided into following 10 groups (seeing Table 8) with it after 14 days, treated with the local anticancer pharmaceutical composition of placing.The 1st group is matched group, the the 2nd to 6 group is the single therapy group, is respectively 10% temozolomide (the 2nd group), 10%O6-benzyl guanine (O6-BG) (the 3rd group), 10%O6-butyl guanine (the 4th group), 10%O6-methyl guanine (the 5th group) or 10%O6-alkyl guanine (O6-AG) (the 6th group); The the 7th to 10 group is the therapeutic alliance group.Anticancer pharmaceutical composition is selected from embodiment 8.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 8) on the 10th day.
Table 8
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 82±21cm 3 | |
| 2(6) | TMZ | 61±15cm 3 | ＜0.05 |
| 3(6) | O6-BG | 50±12.5cm 3 | ＜0.01 |
| 4(6) | O6-bG | 45±12cm 3 | ＜0.01 |
| 5(6) | O6-MG | 46±13cm 3 | ＜0.01 |
| 6(6) | O6-AG | 40±13cm 3 | ＜0.01 |
| 7(6) | TMZ+O6-BG | 31±12cm 3 | ＜0.001 |
| 8(6) | TMZ+O6-bG | 30±13cm 3 | ＜0.001 |
| 9(6) | TMZ+O6-MG | 20±12cm 3 | ＜0.001 |
| 10(6) | TMZ+O6-AG | 21±8cm 3 | ＜0.001 |
Annotate: TMZ: the temozolomide is a tetrazine class medicine; And O6-BG:O6-benzyl guanine, O6-bG:O6-butyl guanine, the O6-MG:O6-methyl guanine, O6-AG:O6-alkyl guanine all belongs to guanine derivatives.
Embodiment ten: tumor-inhibiting action in the body of tetrazine class medicine and guanine derivatives.
With the rat is subjects, with 2 * 10
5Individual tumor cell (hepatocarcinoma) subcutaneous injection treats that in its hypochondrium tumor growth was divided into following 10 groups (seeing Table 9) with it after 14 days, treated with the local anticancer pharmaceutical composition of placing.The 1st group is matched group, the the 2nd to 6 group is the single therapy group, is respectively 10% mitozolomide (MTZ) (the 2nd group), 10%O6-benzyl guanine (O6-BG) (the 3rd group), 10%O6-butyl guanine (the 4th group), 10%O6-methyl guanine (the 5th group) or 10%O6-alkyl guanine (O6-AG) (the 6th group); The the 7th to 10 group is the therapeutic alliance group.Anticancer pharmaceutical composition is selected from embodiment 8.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 9) on the 10th day.
Table 9
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 82±21cm 3 | |
| 2(6) | MTZ | 61±15cm 3 | ＜0.05 |
| 3(6) | O6-BG | 50±12.5cm 3 | ＜0.01 |
| 4(6) | O6-bG | 45±12cm 3 | ＜0.01 |
| 5(6) | O6-MG | 46±13cm 3 | ＜0.01 |
| 6(6) | O6-AG | 40±13cm 3 | ＜0.01 |
| 7(6) | MTZ+O6-BG | 31±12cm 3 | ＜0.001 |
| 8(6) | MTZ+O6-bG | 30±13cm 3 | ＜0.001 |
| 9(6) | MTZ+O6-MG | 20±12cm 3 | ＜0.001 |
| 10(6) | MTZ+O6-AG | 21±8cm 3 | ＜0.001 |
Annotate: MTZ: mitozolomide is a tetrazine class medicine; And O6-BG:O6-benzyl guanine, O6-bG:O6-butyl guanine, the O6-MG:O6-methyl guanine, O6-AG:O6-alkyl guanine all belongs to guanine derivatives.
Embodiment 11: tumor-inhibiting action in the body of tetrazine class medicine and guanine derivatives.
With the rat is subjects, with 2 * 10
5Individual tumor cell (hepatocarcinoma) subcutaneous injection treats that in its hypochondrium tumor growth was divided into following 10 groups (seeing Table 9) with it after 14 days, treated with the local anticancer pharmaceutical composition of placing.The 1st group is matched group, the the 2nd to 6 group is the single therapy group, is respectively 10% procarbazine (PCB) (the 2nd group), 10%O6-benzyl guanine (O6-BG) (the 3rd group), 10%O6-butyl guanine (the 4th group), 10%O6-methyl guanine (the 5th group) or 10%O6-alkyl guanine (O6-AG) (the 6th group); The the 7th to 10 group is the therapeutic alliance group.Anticancer pharmaceutical composition is selected from embodiment 10.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 10) on the 10th day.
Table 10
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6) | Contrast PCB ACNU BCNU CCNU Estramustine PCB+ACNU PCB+BCNU PCB+CCNU PCB+ Estramustine | 89.5 23cm 3 68 5.3cm 3 40 2.3cm 3 33 3.6cm 3 34 3.4cm 3 32 3.8cm 3 22 3.6cm 3 20 3.6cm 3 18 3.6cm 3 16 3.6cm 3 | ＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001 |
Annotate: PCB: procarbazine is a tetrazine class medicine; And O6-BG:O6-benzyl guanine, O6-bG:O6-butyl guanine, the O6-MG:O6-methyl guanine, O6-AG:O6-alkyl guanine all belongs to guanine derivatives.
The result of embodiment nine to 11 shows, compares with matched group, and the independent application of tetrazine kind anti-cancer drugs thing and guanine derivatives all has certain tumor-inhibiting action (P＜0.05).Yet use in conjunction has obvious synergistic effect (P＜0.001).Similar potentiation also sees the associating of other tetrazine class medicine and other guanine derivatives.
Because the used guanine derivatives of anticancer pharmaceutical composition of the present invention is of universal significance to tetrazine class medicine enhanced sensitivity, and the inside and outside discharges comparatively slowly and is steady, so, the selection of tetrazine class medicine is very extensive in the anticancer pharmaceutical composition of the present invention, and the associating of same tetrazine class medicine and guanine derivatives also can be chosen wantonly.Anticancer pharmaceutical composition can be made various dosage forms and shape with existing method, but is preferred with the agent for slow releasing.Above embodiment only is used for explanation, and is not limitation application of the present invention.
Claims (2)
1. an anticancer pharmaceutical composition comprises anticancer effective component and pharmaceutic adjuvant, it is characterized in that this pharmaceutical composition is the implantation slow release agent, and wherein anticancer effective component is composed of the following components:
10% mitozolomide and
10%O6-benzyl guanine, O6-butyl guanine or O6-methyl guanine;
Described pharmaceutic adjuvant is a slow-release auxiliary material, and pharmaceutic adjuvant is selected from one of following or its combination:
A) molecular weight is the polylactic acid 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;
C) ethylene vinyl acetate copolymer;
D) to the copolymer of carboxy phenyl propane and decanedioic acid, to carboxy phenyl propane: the weight ratio of decanedioic acid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
2. the application of the described anticancer pharmaceutical composition of claim 1 in the preparation inhibiting tumor medicine.
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| CN1145622A (en) * | 1993-06-08 | 1997-03-19 | 癌症研究运动技术有限公司 | 06-substituted guanine derivatives, a process for their prepn. and their use |
| CN1244123A (en) * | 1997-01-28 | 2000-02-09 | 普罗克特和甘保尔公司 | Kit for inhibiting the growth of cancers, comprising a chemotherapeutic agent and a benzimdazole, and optionally a protentiator |
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2005
- 2005-02-03 CN CNB2005100424300A patent/CN100350975C/en not_active Expired - Fee Related
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| US5352669A (en) * | 1990-03-13 | 1994-10-04 | The Of The United States Of America As Represented By The Department Of Health And Human Services | O6 -benzylated guanine, guanosine and 2'-deoxyguanosine compounds possessing O6 -alkylguanine-DNA alkyltransferase depleting activity |
| CN1117711A (en) * | 1993-01-14 | 1996-02-28 | 癌症研究行动技术有限公司 | potentiation of temozolomide in human tumour cells |
| CN1145622A (en) * | 1993-06-08 | 1997-03-19 | 癌症研究运动技术有限公司 | 06-substituted guanine derivatives, a process for their prepn. and their use |
| CN1244123A (en) * | 1997-01-28 | 2000-02-09 | 普罗克特和甘保尔公司 | Kit for inhibiting the growth of cancers, comprising a chemotherapeutic agent and a benzimdazole, and optionally a protentiator |
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