CN1660434A - Combination of medication for anti malignant tumours and application - Google Patents
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Abstract
An anticancer medicinal composition with low poison for treating more cancers is composed of the adenylate cyclase activator Forskolin, phosphodiesterase inhibitor (theocin), or IBMX, which can increase the concentration of cAMP in cells, and the carboxyaminotriazole or its derivative or its intermediate.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of anti-malignant tumor medicine, the particularly drug synergism of cAMP concentration level and a series of anti-malignant tumor medicines combinations of obtaining in the high cell of carboxylic amine triazole
Background technology
The human malignant tumor of finding is existing historical more than 3000.Malignant tumor is a kind of uncontrolled unordered paraplasm phenomenon of cell.Malignant cell is compared with normal cell, and structure, function and metabolic unusual are arranged, and they have paranormal hypertrophy ability, and this hypertrophy and body are not in tune.The generating process of malignant tumor is called canceration.Canceration is a complexity, multistage process.The most of malignant tumor may develop from individual cells.The characteristic of malignant cell comprise cell ceaselessly with unordered division, and aggressive (tissue infiltration towards periphery) and transitivity are arranged.
Malignant tumor is generally also according to its tissue-derived name.What derive from epithelial tissue is referred to as cancer (carcinoma), adds " cancer " word during name after its source organization name, as the malignant tumor that derives from squamous epithelial cancer is called squamous cell carcinoma.The malignant tumor that takes place from mesenchymal tissue (comprising fibrous connective tissue, fat, muscle, vascular, bone, cartilaginous tissue etc.) is referred to as sarcoma (sarcoma), and its naming method is to add " sarcoma " after the organization name of source, for example fibrosarcoma etc.As the structure of existing cancer in the tumor structure of sarcoma is arranged again, then be called carcinosarcoma (carcinosarcoma).On pathology, cancer is meant the malignant tumor in epithelial tissue source, but " cancer " (cancer) often makes a general reference all malignant tumor traditionally.
In various diseases, cancer is one of principal disease of causing death.According to World Health Organization's report, have in the world every year to surpass 1,000 ten thousand new cases of cancers generations.In 2000,5,300,000 routine male and 4,700,000 routine women's generation malignant tumor are arranged, add up to 6,200,000 examples and die from this disease, the whole world because of accounting for of malignant tumor death total death toll 12%.Although advanced medical skill is arranged, because the prolongation of average life, reasons such as the change of life style and smoking if there is not further to suppress the measure of cancer, expects the year two thousand twenty whole world cancer morbidity and will rise 50%, and number of the infected will reach 15,000,000.Point out also in the report that the same with developed country in developing country, cancer has become a main hygienic issues.Pulmonary carcinoma, breast carcinoma, colorectal carcinoma, gastric cancer, hepatocarcinoma and cervical cancer are the highest several cancers of sickness rate.The cancer front three cause of the death and front three common cancer are different, and the cancer front three cause of the death is: pulmonary carcinoma accounts for 17.8% of all cancer mortalities, gastric cancer 10.4%, hepatocarcinoma 8.8%.
The main method of treatment malignant tumor comprises at present: the chemotherapy of operative treatment, cancer therapy drug, radiotherapy and biological response modifier and other treatment.Wherein chemotherapy is occupied irreplaceable status in leukemia in the advanced malignant tumor treatment.But because the poor selectivity of anti-malignant tumor medicine, toxic and side effects is big, causes the malignant tumor patient immunologic hypofunction, and quality of life reduces, and this makes the use of chemotherapeutics be subjected to certain restriction.In addition, the generation of multidrug resistance has also limited the use of chemotherapeutics.Therefore, medicine that low toxicity high selectivity, the drug resistance of research a new generation are low and improvement Therapeutic Method become the utmost point when affair for the treatment of malignant tumor.Wherein, strengthening the anti-malignant tumor activity of medicine and reduce drug toxicity by drug combination is a kind of development trend.
The innovation and creation content
The purpose of this invention is to provide a kind of can anti-malignant tumor activity and the low inhibition malignant-tumor agent compositions of toxicity.
Another object of the present invention provides with the inhibition malignant tumor medicine preparation of this pharmaceutical composition as active component.
A further object of the present invention provides the application of this pharmaceutical composition as the medicine in the treating malignant tumor.
Anti-malignant tumor medicine compositions proposed by the invention is made up of medicine and carboxylic amine triazole or derivatives thereof or its intermediate of cAMP concentration level in the cell that can raise.
Above-mentioned anti-malignant tumor medicine compositions, the described medicine of cAMP concentration level in the cell of raising is the agonist IBMX of adenylate cyclase activating agent Forskolin and derivant, Pimobendane theophylline and derivant thereof, Gs G-protein linked receptor and in the derivant one or more thereof, and the medicine of cAMP concentration level and the mass ratio of carboxylic amine triazole or derivatives thereof or its intermediate are 10～10000: 100 in the described cell that can raise.
Concrete, the mass ratio of described Forskolin and carboxylic amine triazole or derivatives thereof or the combination of its intermediate is 20～100: 100; The mass ratio of described theophylline and carboxylic amine triazole or derivatives thereof or the combination of its intermediate is 500～2000: 100; The mass ratio of described IBMX and carboxylic amine triazole or derivatives thereof or the combination of its intermediate is 500～2000: 100.
Above-mentioned anti-malignant tumor medicine compositions, both can be the medicine of cAMP level in one or more described rising born of the same parents and the combination of carboxylic amine triazole and intermediate or derivant, also can be the medicaments derivative of cAMP level in one or more risings born of the same parents and the combination of carboxylic amine triazole and intermediate or derivant.
Anti-malignant tumor medicine preparation provided by the invention, be with above-mentioned anti-malignant tumor medicine compositions as active component, and be aided with acceptable pharmaceutical carrier.Described preparation is tablet, capsule or oral liquid.
Above-mentioned anti-malignant tumor medicine compositions and preparation directly can be used as the medicine in the oncotherapy.
Generally speaking, the present invention relates to patient is bestowed a kind of pharmaceutical composition of treatment effective dose, of said composition itself, by medicine and the carboxylic amine triazole of cAMP concentration level in the cell that can raise of effective ratio of treatment and amount, or derivatives thereof or intermediate composition.This component can be worked in coordination with the growth that carboxylic amine triazole suppresses malignant tumor, reduces the effective dose of carboxylic amine triazole, and then increases the curative effect of carboxylic amine triazole and the toxic and side effects of reduction carboxylic amine triazole.Pharmaceutical composition of the present invention and preparation can be used as the medicine of multiple treating malignant tumor (as lung cancer in non-cellule type and carcinoma of prostate etc.).
Description of drawings
Fig. 1 describes is SH-SY5Y cell administration after 48 hours, and the Forskolin that cell counting observation post gets, theophylline and IBMX suppress the result of the test of SH-SY5Y cell proliferation cooperative effect to carboxylic amine triazole.
Fig. 2 describes is HeLa cell administration after 48 hours, and the Forskolin that cell counting observation post gets, theophylline and IBMX suppress the result of the test of HeLa cell proliferation cooperative effect to carboxylic amine triazole.
Fig. 3 describes is Bel-7402 cell administration after 48 hours, and the Forskolin that cell counting observation post gets, theophylline and IBMX suppress the result of the test of Bel-7402 cell proliferation cooperative effect to carboxylic amine triazole.
Fig. 4 describes is the mice administration of transplantability Lewis ' LC tumor after 8 days, and Forskolin, theophylline and the IBMX of weighing tumor tissues weight gained suppresses the result of the test of mice transplantability Lewis ' LC tumor growth cooperative effect to carboxylic amine triazole.
The specific embodiment
Pharmaceutical composition of the present invention is made up of with carboxylic amine triazole or derivatives thereof or intermediate the medicine of cAMP concentration level in the cell that can raise.
Knownly can raise that 1. the medicine of cAMP level has the directly material of activated adenyl cyclase in the born of the same parents, for example Forskolin etc.; 2. the material that suppresses the cAMP phosphodiesterase, for example theophylline (theophylline), 3-isobutyl-1-methylxanthine (3-isobutyl-1-methylxanthine, IBMX) and their derivant etc.These medicines can inducing apoptosis of tumour cell, suppresses tumor cell proliferation (Lingzhi Zhang, 2004; SN Kim, 2001), its possible mechanism of action is the level by cAMP in the rising cell, so activated protein kinase A (proteinkinase A, PKA), again by modulin phosphorylation or gene transcription or express propagation and the apoptosis that influences cell.
Wherein, Forskolin (structural formula is as follows) is the diterpene-kind compound that at first extracts from India's Labiatae Coleus plant Coleus forskohlii Briq. (coleus forskohlii) root the external seventies in 20th century, has heart tonifying, blood pressure lowering, relievings asthma, effect such as antiinflammatory, antiplatelet aggregation, reduction intraocular pressure.Research thinks that Forskolin passes through direct exciting adenyl cyclase, improves cyclic adenosine monophosphate (cAMP) concentration in the multiple histiocyte, regulates thereby participate in the various kinds of cell function, plays regulating action widely in vivo.Abroad the crude extract of forskolin as a kind of health product, be used for the fat-reducing.In the human trial that India Shri C.B.Patel research center is done, there are 60 obese patients to participate in the research.These patients every day, taking medicine before meal took for 12 weeks continuously with the Forslean (including 10%forskolin) of 500mg at twice.When research finished, these patients' body weight obtained significantly to descend, and has on average descended 2.3%.Under study for action, any toxic and side effects do not occur, this shows that forskolin is very little to the toxicity of human body.U.S. Sabinsa company has developed a kind of stable forskolin eye drop now at the Sami of research institution of India laboratory, be used for the treatment of glaucoma and reduce intraocular pressure, before clinical, obtain gratifying result in the animal experiment, now just planned to carry out a polycentric clinical trial.
Theophylline is a kind of Pimobendane, by suppressing the cAMP phosphodiesterase, reduces the degraded of cAMP, the level of the intracellular cAMP that raises.Theophylline and derivant thereof (as aminophylline, diprophylline) have been widely used in clinical treatment now, are mainly used in treatment bronchial asthma, asthmatic bronchitis, obstructive emphysema and cardiac edema, angina pectoris etc.Theophylline energy relaxing smooth muscle, excited cardiac muscle, excited maincenter, and diuresis is arranged.The effect of its relaxing smooth muscle is more outstanding to the bronchus that is in spasticity.To acute and chronic asthma, no matter oral, injection or rectally are all effective in cure.To asthmatic chronic bronchitis, because the excited skeletal muscle of its energy can strengthen respiratory muscle contractility and the sensation that alleviates the patient respiratory muscle fatigue.
IBMX (3-isobutyl-1-methylxanthine, structural formula is as follows) is one of xanthic derivant.Because it can suppress the cAMP phosphodiesterase more specifically, reduce the degraded of cAMP, so be widely used in changing with the cAMP level that prevents to cause in the various relevant experimental studies of cAMP owing to the di-phosphate ester enzymatic degradation.Have not yet to see it and be used for clinical medical report as medicine.
Carboxylic amine triazole (Carboxyamidotriazole, chemical name CAI) they are 5-amido-1-[3,5-two chloro-4-(4-chlorobenzene formacyl) benzyl]-1H-1,2,3-triazole-4-Benzoylamide; (1H-1,2,3-Triazole-4-carboxamide, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl) phenyl] methyl]-) (US Patent 4590201).Its intermediate is 4-(4-chlorobenzene formacyl)-3,5-dichloro benzyl nitrine.Can be divided into 4 families according to its replacement and its derivant of modification position: (I) substituent on triazole ring; (II) remove derivant behind the benzophenone group; (III) halogen atom or the part of removing on the benzophenone group removed the product of benzophenone group; (IV) remove triazole or change the product of the substituent group on the benzophenone group.
Discover that CAI has anti-malignant tumor hyperplasia and metastasis effect.And compare with general cell toxicity medicament, its toxic and side effects is very low, may be a kind of novel anti malignant tumor medicine likely.Other has bibliographical information (Kohn EC, et al, Cancer Res.54:935 ~ 942), and the said derivative of CAI also has antitumor action, but intensity is lower than CAI.
Preclinical study finds that CAI can suppress the blood vessel endothelium hypertrophy, generates thereby suppress tumor neogenetic blood vessels.Its mechanism of action is still unclear.There are some researches show, CAI may be by suppressing the non-activated form calcium channel on the cell membrane, influence VEGF (vascular endothelial growth factor A, VEGF-A) activate information transfering path behind its receptor (VEGFR-2), thereby suppressed the blood vessel endothelium hypertrophy that causes thus, suppressed tumor neovasculature generation.(Faehling?M.，Kroll?J.et?al.??Essential?role?of?calciumin?vascular?endothelial?growth?factor?A-induced?signalling：mechanicsm?of?theantiangiogenic?effect?of?carboxyamidotriazole.FESEB?J.16：1805(2002))。
Experimental results show that CAI has inhibitory action to multiple malignant cell cording, comprising spongioblast oncocyte (Jacobs, W; Mikkelsen T, Kohn EC et al.Inhibitory effects of CAI in glioblastoma growthand invasion.J Neurooncol.32 (2): 93-101,1997), head and neck squamous cell cancerous cell (Wu Y, PaladAJ, Kohn EC et al.Inhibition of head and neck squamous cell carcinoma growth andinvasion by the calcium influx inhibitor carboxyamido-triazole.Clin Cancer Res.3 (11): 1915-21,1997), breast cancer cell (Lambert PA, Somers KD, Kohn EC et al.Antiproliferativeand antiinvasive effects of carboxyamido-triazole on breast cancer cell lines.Surgery.122 (2): 372-8; Discussion 378-9,1997; Yeh YA, Weber G, Quercetin:synergistic actionwith carboxyamidotriazole in human breast carcinoma cells.Life Sci.57 (13): 1285-92,1995; Kohn EC, Liotta LA L651582:a novel antiproliferative and antimetastasis agent.JNatl Cancer Inst.82 (1): 54-60,1990), transitional cell bladder carcinoma cell line (Kohn EC, Liotta LA L651582:anovel antiproliferative and antimetastasis agent.J Natl Cancer Inst.82 (1): 54-60,1990), neurogliocytoma (Kohn EC, Liotta LA L651582:a novel antiproliferative andantimetastasis agent.J Natl Cancer Inst.82 (1): 54-60,1990), pancreatic cancer cell, prostate gland cancer cell (Wasilenko WJ, Palad AJ, Kohn EC et al.Effects of the calcium influx inhibitorcarboxyamido-triazole on the proliferation and invasiveness of human prostate tumor celllines.Int J Cancer.68 (2): 259-64,1996), melanoma cell (Fink-Puches R, Helige C, Kerl H et al.Inhibition of melanoma cell directional migration in vitro via different cellulartargets.Exp Dermatol.2 (1): 17-24,1993) and ovarian cancer cell (Kohn EC; Liotta, LA L651582:a novel antiproliferative and antimetastasis agent.J Natl Cancer Inst.82 (1): 54-60,1990) hypertrophy of tens of kinds of tumor cells such as.Former and the growth and the transfer of metastatic tumor simultaneously also suppressing to form in the nude mice.
Confirmed also that with ongoing some clinical experiments CAI can suppress growth of tumor, invasion and attack and transfer in wide spectrum ground both at home and abroad, and toxic action is less.
External clinical I phase and the II phase experimental study of having finished has following 7:
1.CAI treat unmanageable tumor I clinical trial phase research (NCI-92-C-0054P, NCI-MB-281)
2.CAI study with the I clinical trial phase of ketoconazole therapeutic alliance late malignant tumour (UCCRC-9019, CI-T97-0086)
Every day oral CAI treat the research of intractable solid tumor and lymphadenomatous I/II clinical trial phase (WCCC-CO-9397, NCI-T93-0193C)
4.CAI the II phase randomized clinical trial research (CLB-69901) of treatment metastatic renal cell cancer
5.CAI the treatment immunotherapy invalid late period the renal cell carcinoma patient II clinical trial phase research (E-4896)
6.CAI with X-ray therapy be used for jointly act last glioblastoma the II clinical trial phase (JHOC-NABTT-9904, NABTT-9904)
The II clinical trial phase research of 7. oral CAI treatment androgen dependent/non-dependent carcinoma of prostate (NCI-97-C-0059C, NCI-T96-0053)
The clinical experimental study of well afoot has following 3:
1.CAI treatment parenchyma in late period or intractable lymphadenomatous I clinical trial phase research (NCI-95-C-0015F, NCI-CPB-334, NCI-T94-0006N)
2.CAI treat intractable or recurrent epithelial ovarian cancer, carcinoma of fallopian tube or constitutional peritoneal cancer II clinical trial phase research (NCI-98-C-0012, NCI-T97-0112)
The III clinical trial phase research of 3. oral CAI treatment III phase lung cancer in non-cellule type (NCCTG-972451, CTSU)
Can find from above-mentioned material, some I, II clinical trial phase result are verified safety and the preliminary effectiveness of CAI, and obtain on a series of bases about clinical dosage and drug metabolism data, begin to carry out the III clinical trial phase at concrete tumor.
Through state food and drug administration approval, the I clinical trial phase of presiding over the CAI anticarcinogenesis that carries out by Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences is well afoot also.
The inventor suppresses the experimentation that the effect of growth of tumour cell carries out to carboxylic amine triazole and shows in external, body: carboxylic amine triazole all demonstrates in various degree antitumor activity to 11 kinds of human cancer cell strains in cultivating, especially with to U251, A549, MCF-7 is the most responsive, IC50＜1 μ g/ml, Bel-7402, PAA are also had stronger inhibitory action, and the IC50 value is 1.056 and 3.753 μ g/ml.To HCT-8, EJ, BGC-803,431 and the IC50 value of A2780 at 4.079-6.851 μ g/ml, the IC50 of CaEs-17 cell＜10 μ g/ml.
The efficacy of medicine observing of carboxylic amine triazole to 7 strain animal transplanting tumors and the transplanting of 2 strain human cancer cell nude mices finished in experiment in the body.Carboxylic amine triazole oral medication dosage is 40mg/kg, 20mg/kg and 10mg/kg, after the administration 8 times, to S180, ESC, Lewis LC, the suppression ratio of EMT6 and the strain of five animal tumors of B16, high dose is 45～66%, middle dosage is 30～40%, the low dosage majority is lower than 30%, but H22 and L1210 are not shown tumor-inhibiting action.To people's cancer BTEP-Sml and OS732, the high dose tumour inhibiting rate is respectively 59.42 and 66.31% after the administration 14 times, and The above results statistics t test P value is all less than 0.001.Show that carboxylic amine triazole demonstrates clear and definite dose-effect relationship to the effect of most tumor strains.
Carboxylic amine triazole suppresses in the experiment that the mice transplanted tumor lung shifts, the lung of Ma891 and U14 is shifted no obvious inhibitory action, but can alleviate the lesion degree due to the transfer.Under 40mg/kg dosage, the lung metastasis obviously reduces to LA795, and suppression ratio reaches 58.8% (P＜0.01).
Carboxylic amine triazole does not have the prolongation effect to the time-to-live of L1210, but to ESC, the increase in life span of three dosage reaches 99.11%, 78.13% and 58.04% respectively.Show the life span that carboxylic amine triazole can significant prolongation ESC mice.
Above-mentioned experimental result shows that with traditional cell toxicant anti-malignant tumor medicine comparison, the most tangible advantage of CAI is that its untoward reaction is slight, and incidence rate is lower.On inhibition effect, relatively poor to the direct repression of malignant cell to malignant tumor.Though CAI also has the effect that suppresses the malignant tumor new vessels except directly suppressing the proliferative effect of malignant cell, its overall clinical tumor-inhibiting action still is lower than cell toxicity medicament.Therefore, how to keep the advantage of CAI low toxicity and increase its antitumaous effect, just become a very important problem.
Characteristics of the present invention have been to find a kind of advantage that can keep CAI can strengthen the drug regimen of its anticarcinogenesis again.
The present invention is on the basis of research and experiment, and behind the medicine of discovery carboxylic amine triazole cAMP level in the above-mentioned arbitrary born of the same parents that can raise of combination, compositions is more obvious to the inhibition effect of tumor, and the combination medical instrument has synergistic function.
Pharmaceutical composition of the present invention is the pharmaceutical preparation combination with cAMP level in the increase born of the same parents of the carboxylic amine triazole or derivatives thereof of 100 quality or intermediate and 10～10000 quality.Some concrete compositionss have been exemplified in the embodiment of the invention, be the carboxylic amine triazole or derivatives thereof of 100 quality or the theophylline compositions of intermediate and 500 to 2000 quality, perhaps being the compositions of the Forskolin of the carboxylic amine triazole or derivatives thereof of 100 quality or intermediate and 20 to 100 quality, perhaps is the compositions of the IBMX of the carboxylic amine triazole or derivatives thereof of 100 quality or intermediate and 500 to 2000 quality.
Among the present invention, above-mentioned composition all has obvious suppression to SH-SY5Y, Bel-7402 and HeLa cell line proliferation.
Below effect by specific embodiment and experimental verification above-mentioned composition.
Embodiment 1
The compositions of this example checking Forskolin, theophylline, IBMX and carboxylic amine triazole suppresses the cooperative effect of SH-SY5Y cell proliferation.
Experiment material:
People's neuroblastoma SH-SY5Y cell line
Forskolin, theophylline and IBMX are available from Sigma.
DMSO is available from Beijing chemical reagents corporation
Experimental technique: the SH-SY5Y tumor cell that the collection body outgrowth is good is mixed with 5 * 10 with the RPMI1640 culture medium that contains 10% calf serum
4/ ml cell suspension is inoculated in 12 well culture plates, and every hole 1ml (contains 5 * 10
4Individual oncocyte), put 37 ℃, 5%CO
2Cultivate after 24 hours in the incubator and discard former culture medium, add the RPMI1640 complete medium 1ml that contains the respective concentration medicine, three porocyte quantity cell quantity during administration is to start with counted in every group three hole simultaneously.Continue cultivation and discard culture medium after 48 hours, 0.05 pancreatin-0.02EDTA Digestive system digestion collecting cell is used blood cell counting plate counting cells quantity down in inverted microscope.The suppression ratio computing formula is as follows:
100% * (solvent control group cell quantity-administration group cell quantity)/when beginning administration (solvent control group cell quantity-cell quantity)
Experimental result: the results are shown in Table 1 and Fig. 1.
Table 1: different pharmaceutical is to the inhibition result of SH-SY5Y cell proliferation
| Grouping | Cell counting (* 10 4Cell) (Mean ± SD) | Suppression ratio (%) |
| Solvent control | ????71.3±11.7 | ????- |
| 5 μ mol/L carboxylic amine triazoles | ????46.5±7.9 | ????46.5 |
| 1μmol/L?Forskolin | ????61.8±8.6 | ????17.8 |
| 5 μ mol/L carboxylic amine triazole+1 μ mol/L Forskolin | ????31.5±7.0 | ????74.6 |
| 100 μ mol/L theophylline | ????63.9±11.5 | ????13.8 |
| 5 μ mol/L carboxylic amine triazole+100 μ mol/L theophylline | ????36.4±6.2 | ????65.5 |
| 100μmol/L?IBMX | ????58.1±9.0 | ????24.6 |
| 5 μ mol/L carboxylic amine triazole+100 μ mol/L IBMX | ????33.9±7.8 | ????70.2 |
The result shows, the carboxylic amine triazole of using 5 μ mol/L separately is 46.5% to the suppression ratio of SH-SY5Y cell line proliferation; Application 1 μ mol/L Forskolin only is 17.8% to the suppression ratio of SH-SY5Y cell line proliferation separately, using separately 100 μ mol/L theophylline only is 13.8% to the suppression ratio of SH-SY5Y cell line proliferation, and using 100 μ mol/L IBMX separately only is 24.6% to the suppression ratio of SH-SY5Y cell line proliferation; When same dose carboxylic amine triazole and Forskolin use in conjunction, pair cell is that the inhibition of proliferation rate is 74.6%, uses carboxylic amine triazole to rise 28.1% more separately, uses Forskolin to rise 56.8% more separately; When same dose carboxylic amine triazole and 100 μ mol/L theophylline use in conjunction, pair cell is that the inhibition of proliferation rate is 65.5%, uses carboxylic amine triazole to rise 19% more separately, uses theophylline to rise 51.7% more separately; When same dose carboxylic amine triazole and 100umol/L IBMX use in conjunction, pair cell is that the inhibition of proliferation rate is 70.2%, uses carboxylic amine triazole to rise 23.7% more separately, uses IBMX to rise 45.6% more separately; Provable thus Forskolin, theophylline and IBMX suppress the cooperative effect of SH-SY5Y cell proliferation to carboxylic amine triazole.
Embodiment 2
This example checking Forskolin, theophylline and IBMX suppress the cooperative effect of HeLa cell proliferation to carboxylic amine triazole.
Experiment material is that human cervical carcinoma cell is HeLa, and other reagent and experimental technique are with embodiment 1.
Experimental result sees Table 2 and Fig. 2.
Table 2: different pharmaceutical is to the inhibition result of HeLa cell proliferation
| Grouping | Cell counting (* 10 4Cell) (Mean ± SD) | Suppression ratio (%) |
| Solvent control | ????38.9±7.1 | ????- |
| 10 μ mol/L carboxylic amine triazoles | ????26.7±7.9 | ????42.2 |
| 10μmol/L?Forskolin | ????34.5±3.9 | ????15.2 |
| 10 μ mol/L carboxylic amine triazole+10 μ mol/L Forskolin | ????14.4±4.0 | ????84.8 |
| 100 μ mol/L theophylline | ????33.9±8.3 | ????17.1 |
| 100 μ mol/L theophylline+10 μ mol/L carboxylic amine triazoles | ????20.0±7.6 | ????65.2 |
| 100μmol/L?IBMX | ????30.3±7.4 | ????29.9 |
| 100 μ mol/L IBMX+10 μ mol/L carboxylic amine triazoles | ????20.4±4.5 | ????63.9 |
The result shows, the carboxylic amine triazole of using 10 μ mol/L separately is 42.2% to the suppression ratio of HeLa cell line proliferation; Application 10 μ mol/L Forskolin only are 15.2% to the suppression ratio of HeLa cell line proliferation separately, using separately 100 μ mol/L theophylline only is 17.1% to the suppression ratio of HeLa cell line proliferation, and using 100 μ mol/L IBMX separately only is 29.9% to the suppression ratio of HeLa cell line proliferation; When same dose carboxylic amine triazole and Forskolin use in conjunction, pair cell is that the inhibition of proliferation rate is 84.8%, uses carboxylic amine triazole to rise 42.6% more separately, uses Forskolin to rise 69.6% more separately; When same dose carboxylic amine triazole and 100umol/L theophylline use in conjunction, pair cell is that the inhibition of proliferation rate is 65.2%, uses carboxylic amine triazole to rise 23% more separately, uses theophylline to rise 48.1% more separately; When same dose carboxylic amine triazole and 100umol/LIBMX use in conjunction, pair cell is that the inhibition of proliferation rate is 63.9%, uses carboxylic amine triazole to rise 21.7% more separately, uses theophylline to rise 34.0% more separately; The provable thus cooperative effect that carboxylic amine triazole is suppressed the HeLa cell proliferation to Forskolin, theophylline and IBMX.
Embodiment 3
This example checking Forskolin, theophylline and IBMX suppress the cooperative effect of Bel-7402 cell proliferation to carboxylic amine triazole.
Experiment material is Bel7402 Bel-7402, and other reagent and experimental technique are with embodiment 1.
Experimental result sees Table 3 and Fig. 3.
Table 3: different pharmaceutical is to the inhibition result of Bel-7402 cell proliferation
| Grouping | Cell counting (* 10 4Cell) (Mean ± SD) | Suppression ratio (%) |
| Solvent control | ????77.5±11.0 | ????- |
| 10 μ mol/L carboxylic amine triazoles | ????48.3±7.7 | ????50.9 |
| 10μmol/L?Forskolin | ????59.5±7.8 | ????31.3 |
| 10 μ mol/L Forskolin+10 μ mol/L carboxylic amine triazoles | ????34.2±5.0 | ????75.3 |
| 100 μ mol/L theophylline | ????75.2±10.1 | ????4.1 |
| 100 μ mol/L theophylline+10 μ mol/L carboxylic amine triazoles | ????46.1±7.7 | ????54.6 |
| 100μmol/L?IBMX | ????73.0±11.7 | ????5.8 |
| 100 μ mol/L IBMX+10 μ mol/L carboxylic amine triazoles | ????39.6±10.3 | ????65.9 |
The result shows, the carboxylic amine triazole of using 10 μ mol/L separately is 50.9% to the suppression ratio of Bel-7402 cell line proliferation; Application 10 μ mol/L Forskolin are 31.3% to the suppression ratio of Bel-7402 cell line proliferation separately, using separately 100 μ mol/L theophylline only is 4.1% to the suppression ratio of Bel-7402 cell line proliferation, and using 100 μ mol/L IBMX separately only is 5.8% to the suppression ratio of Bel-7402 cell line proliferation; When same dose carboxylic amine triazole and Forskolin use in conjunction, pair cell is that the inhibition of proliferation rate is 75.3%, uses carboxylic amine triazole to rise 24.4% more separately, uses Forskolin to rise 44% more separately; When same dose carboxylic amine triazole and 100umol/L theophylline use in conjunction, pair cell is that the inhibition of proliferation rate is 54.6%, uses carboxylic amine triazole to rise 3.7% more separately, uses theophylline to rise 50.5% more separately; When same dose carboxylic amine triazole and 100umol/L IBMX use in conjunction, pair cell is that the inhibition of proliferation rate is 65.9%, uses carboxylic amine triazole to rise 15.0% more separately, uses IBMX to rise 60.1% more separately; The provable thus cooperative effect that carboxylic amine triazole is suppressed the Bel-7402 cell proliferation to Forskolin, theophylline and IBMX.
Embodiment 4
This example checking Forskolin, theophylline and IBMX suppress the cooperative effect of mice transplantability Lewis ' LC tumor growth to carboxylic amine triazole.
Experiment material: BALB/C strain mice is II level laboratory animal, SCXK11-00-0006 number of issuing on May 25th, 2000 for Ministry of Science ﹠ Technique of PRC of the quality certification number.Body weight 18-22g, each 20 of male and female are available from Chinese Academy of Medical Sciences's Experimental Animal Center.
Experimental technique: under the sterile working, get Lewis ' the LC tumor tumor knot that well-grown does not have ulceration, select the healthy downright bad tumor tissues that do not have, put into dismembyator after shredding, add an amount of normal saline (NS), grind to form the unicellular homogenate of tumor, under mirror, behind the counting, transfer to 1 * 10 with NS
7The concentration of/ml cell, in the right axil subcutaneous vaccination of mice, every is injected oncocyte liquid 2 * 10
6/ 0.2ml.Administration after 8 days weighing tumor tissues weight observe various medicines and compositions inhibitory action to mice transplantability Lewis ' LC tumor growth.The inhibition rate of tumor growth computing formula is as follows:
(it is heavy that the average tumor of average tumor weight/matched group is organized in the 1-treatment) * 100%
Experimental result: the results are shown in Table 4 and Fig. 4.
Table 4:
| Grouping | The tumor weight (Mean ± SD, g) | Tumour inhibiting rate (%) |
| Negative control | ????1.36±0.39 | ????0.0 |
| 20mg/kg carboxylic amine triazole | ????0.96±0.40 | ????29.4 |
| 10mg/kgForskolin | ????1.22±0.29 | ????10.6 |
| 10mg/kgForskolin+20mg/kg carboxylic amine triazole | ????0.39±0.17 | ????71.6 |
| The 100mg/kg theophylline | ????1.26±0.32 | ????7.5 |
| 100mg/kg theophylline+20mg/kg carboxylic amine triazole | ????0.62±0.21 | ????54.4 |
| 100mg/kg?IBMX | ????1.24±0.37 | ????8.8 |
| 100mg/kg IBMX+20mg/kg carboxylic amine triazole | ????0.72±0.26 | ????47.1 |
Animal vivo test is the result show, the tumour inhibiting rate of irritating stomach to give dosage be 20mg/kg carboxylic amine triazole mice transplantability Lewis ' LC tumor is 29.4%.When with 10mg/kgforskolin together during gastric infusion, the tumour inhibiting rate of mice transplantability Lewis ' LC tumor is risen to 71.6%, risen 41.2%, shown the obvious synergistic effect.When with 100mg/kg theophylline together during gastric infusion, the tumour inhibiting rate of mice transplantability Lewis ' LC tumor is risen to 54.4%, risen 25%, shown the obvious synergistic effect.When with 100mg/kg IBMX together during gastric infusion, the tumour inhibiting rate of mice transplantability Lewis ' LC tumor is risen to 47.1%, risen 17.7%, shown the obvious synergistic effect.
Above embodiment and experimental result show that adenylate cyclase activating agent Forskolin, Pimobendane theophylline, the IBMX that can increase cAMP level in the born of the same parents can work in coordination with increases the depression effect of carboxylic amine triazole to SH-SY5Y, Bel-7402 and HeLa cell line proliferation; Can work in coordination with increases carboxylic amine triazole to mice transplantability Lewis ' LC tumor growth pressed down the tumor effect.In fact, compositions of the present invention can be used as the broad spectrum activity medicine for the treatment of malignant tumor.
Below specifically enumerate compositions of the present invention, the medicine of the interior cAMP level of born of the same parents that wherein raises and two kinds of components of carboxylic amine triazole are for bringing into play the medicinal ingredient of synergistic function, those skilled in the art all understand, actual compositions, also should comprise the medicine of cAMP level in one or more risings born of the same parents and the combination of carboxylic amine triazole and intermediate or derivant, the medicaments derivative of cAMP level and the combination of carboxylic amine triazole and intermediate or derivant in one or more risings born of the same parents, the derivant of these chemical compounds comprises pharmaceutically acceptable salt class example hydrochloric acid salt, chloride, chelate and metabolite; Pharmaceutical composition of the present invention also can comprise those pharmaceutical carriers, especially for the pharmaceutically acceptable system carrier of oral administration.The present invention also comprises the combination of the metabolite of two class medicinal ingredients.The present composition also can comprise the form that one or more medicinal active ingredients are slowly discharged.
Pharmaceutical composition of the present invention can be made into solid or liquid preparation form, is based solutions as the granule suspension or with PEG.But the form of preferred oral, but also can parenteral mode administration.
Impose sufficient dosage to tumor patient with compositions of the present invention and preparation, can alleviate and treat multiple corresponding tumor.
Among the present invention, relate to the pharmaceutical dosage unit forms that is used for systematic administration (medicine controlled releasing of oral, topical, percutaneous), it is effective to treat mammal, comprises the mankind." dosage unit form " refers to physically dispersive unit, be suitable for to taking be not as one as animal, each unit contains enough active component of scheduled volume, by adjusting the method for pharmacy of described composition for reaching systemic administration, can calculate required effect.
The enforcement of dosage unit forms of the present invention is tablet, capsule, be present in the oral liquid in the liquid-carrier.The solid diluent of Peroral solid dosage form pharmaceutical units form or carrier are selected from lipid, carbohydrate, protein, solid mineral matter: as starch, sucrose, Kaolin, dicalcium phosphate, gelatin, arabic gum, Semen Maydis pulp, corn starch, Pulvis Talci or the like.Capsule, no matter hard is still soft, can use diluent commonly used and excipient to make, as edible oil, calcium carbonate, calcium stearate, magnesium stearate or the like.Be used for oral liquid pharmaceutical formulation and can be made into aqueous solution or aqueous solution, preferably contain suspending agent.As sodium carboxymethyl cellulose, methylcellulose, arabic gum, polyvinylpyrrolidone, polyvinyl alcohol or the like.
Above-mentioned preparation must keep stable when making and store, also contain antiseptic with antibacterial and antifungal character such as oxybenzene alkyl esters, chlorobutanol, benzyl alcohol, phenol, thiomersalate or the like usually outside basic solvent or suspension.Under many circumstances, preferably contain isotonic agent, as saccharide or sodium chloride.Carrier and excipient comprise vegetable oil, water, ethanol and polyhydric alcohol such as glycerol, propylene glycol, liquid polyethylene glycol or the like.
The preparation of dosage unit form pharmaceutically is the general description according to the front, is accompanied by the method that adaptive system forms administration, and the effective dose of the active component of necessity in each dosage unit form is provided.Usually, unit dosage form will contain the necessary active component of 3-73% (weight).
Be used for and the corresponding mammiferous treatment of the inventive method, a kind of effective dosage that constitutes by the exact dose of necessary active substance, it if can impose the form of medication that adapts with it and definite preparation according to characteristic, the order of severity of the patient's condition, mammiferous kind, age, body weight and the situation of implementing clinical treatment, will have very good effect.Give when needs under the situation of exact dose, can give a test dose in advance, observe clinical response then to determine required exact dose.Generally speaking, the effective dose of administration to every kilogram of person's body weight about every day of about 1mg that is subjected to the medicine between every kilogram of the 50mg.Preferably every day, 0.5mg/kg was to about 25mg/kg.
Obviously, content of medicines and the composition that uses clinically should be adjusted the carrying capacity of single ingredient according to the degree and the patient of disease.Further, the metabolite of the medicine of cAMP level or carboxylic amine triazole should use with suitable form in the rising born of the same parents.
Claims (10)
1, a kind of anti-malignant tumor medicine compositions is made up of medicine and carboxylic amine triazole or derivatives thereof or its intermediate of cAMP concentration level in the cell that can raise.
2, anti-malignant tumor medicine compositions according to claim 1, it is characterized in that, the described medicine of cAMP concentration level in the cell of raising is the agonist IBMX of adenylate cyclase activating agent Forskolin and derivant, Pimobendane theophylline and derivant thereof, Gs G-protein linked receptor and in the derivant one or more thereof, and the medicine of cAMP concentration level and the mass ratio of carboxylic amine triazole or derivatives thereof or its intermediate are 10～10000: 100 in the described cell that can raise.
3, anti-malignant tumor medicine compositions according to claim 1 and 2 is characterized in that, the mass ratio of described Forskolin and carboxylic amine triazole or derivatives thereof or the combination of its intermediate is 20～100: 100.
4, anti-malignant tumor medicine compositions according to claim 1 and 2 is characterized in that, the mass ratio of described theophylline and carboxylic amine triazole or derivatives thereof or the combination of its intermediate is 500～2000: 100.
5, anti-malignant tumor medicine compositions according to claim 1 and 2 is characterized in that, the mass ratio of described IBMX and carboxylic amine triazole or derivatives thereof or the combination of its intermediate is 500～2000: 100.
6, anti-malignant tumor medicine compositions according to claim 1 and 2, it is characterized in that, be the medicine of cAMP level in one or more described rising born of the same parents and the combination of carboxylic amine triazole and intermediate or derivant, or the medicaments derivative of the interior cAMP level of one or more risings born of the same parents and the combination of carboxylic amine triazole and intermediate or derivant.
7, the pharmaceutical preparation of anti-malignant tumor as active component, and is aided with acceptable pharmaceutical carrier with the arbitrary described anti-malignant tumor medicine compositions of claim 1 to 6.
According to the pharmaceutical preparation of the described anti-malignant tumor of claim 7, it is characterized in that 8, described preparation is tablet, capsule or oral liquid.
9, the pharmaceutical composition of the arbitrary described anti-malignant tumor of claim 1-6 is as the application of the medicine in the oncotherapy.
10, the pharmaceutical preparation of claim 7 or 8 arbitrary described anti-malignant tumors is as the application of the medicine in the oncotherapy.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100023875A CN100493609C (en) | 2005-01-19 | 2005-01-19 | Medicine composition for treating malignant tumours and application |
| PCT/CN2006/000030 WO2006076854A1 (en) | 2005-01-19 | 2006-01-10 | Combination medication for malignant tumors and application |
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| CNB2005100023875A CN100493609C (en) | 2005-01-19 | 2005-01-19 | Medicine composition for treating malignant tumours and application |
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| CN100493609C CN100493609C (en) | 2009-06-03 |
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| WO (1) | WO2006076854A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101553225B (en) * | 2006-10-16 | 2012-06-06 | 中国医学科学院基础医学研究所 | The uses of the carboxy-amido-triazole compounds |
| CN107308172A (en) * | 2017-07-04 | 2017-11-03 | 深圳瑞科生物科技有限公司 | A kind of antineoplastic containing aryl ketones phosphate compound and its application |
| CN109674789A (en) * | 2019-01-23 | 2019-04-26 | 中国医学科学院基础医学研究所 | The purposes of carboxyltriazole and glutamate uptake and metabolic poison in antitumor |
| CN112083109A (en) * | 2019-07-08 | 2020-12-15 | 广东银珠医药科技有限公司 | Carboxyaminotriazole impurity and preparation method and detection method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4590201A (en) * | 1984-02-02 | 1986-05-20 | Merck & Co., Inc. | 5-amino or substituted amino 1,2,3-triazoles |
| FR2849055A1 (en) * | 2002-12-18 | 2004-06-25 | Exonhit Therapeutics Sa | Using inhibitors of protein FKBP65 for treating cancer and other diseases where angiogenesis is involved, also new isoforms of FKBP65, related nucleic acids and diagnostic uses |
-
2005
- 2005-01-19 CN CNB2005100023875A patent/CN100493609C/en active Active
-
2006
- 2006-01-10 WO PCT/CN2006/000030 patent/WO2006076854A1/en not_active Application Discontinuation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101553225B (en) * | 2006-10-16 | 2012-06-06 | 中国医学科学院基础医学研究所 | The uses of the carboxy-amido-triazole compounds |
| CN107308172A (en) * | 2017-07-04 | 2017-11-03 | 深圳瑞科生物科技有限公司 | A kind of antineoplastic containing aryl ketones phosphate compound and its application |
| CN109674789A (en) * | 2019-01-23 | 2019-04-26 | 中国医学科学院基础医学研究所 | The purposes of carboxyltriazole and glutamate uptake and metabolic poison in antitumor |
| CN109674789B (en) * | 2019-01-23 | 2021-10-26 | 广东银珠医药科技有限公司 | Application of carboxyamidotriazole and glutamic acid uptake and metabolism inhibitor in resisting tumors |
| CN112083109A (en) * | 2019-07-08 | 2020-12-15 | 广东银珠医药科技有限公司 | Carboxyaminotriazole impurity and preparation method and detection method thereof |
Also Published As
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| CN100493609C (en) | 2009-06-03 |
| WO2006076854A1 (en) | 2006-07-27 |
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