CN101332301A - Antineoplastic composition and use thereof - Google Patents
Antineoplastic composition and use thereof Download PDFInfo
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- CN101332301A CN101332301A CNA2007101414235A CN200710141423A CN101332301A CN 101332301 A CN101332301 A CN 101332301A CN A2007101414235 A CNA2007101414235 A CN A2007101414235A CN 200710141423 A CN200710141423 A CN 200710141423A CN 101332301 A CN101332301 A CN 101332301A
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Abstract
The invention discloses an anti-tumor combination and the application thereof; the anti-tumor combination which includes effective dose of platinum-based chemotherapy and AKT inhibitor and / or p70S6K1 inhibitor has the function of inhibiting the drug resistance of the tumor to the platinum-based chemotherapy, improves the effects of anti-tumor drugs, and can be used for preparing drugs that can resist various tumors, such as lung cancer, ovarian cancer, prostate cancer, breast cancer, stomach cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck squamous cell carcinoma, thyroid cancer, osteosarcoma, etc.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of anti-tumor compositions and application thereof.
Background technology
Since [1] such as nineteen sixty-five Rosenberg found platinum family chemical compound tool active anticancer, the research and the application of platinum group metal cancer therapy drug were developed rapidly.Cisplatin (cisplatin, the Cis-DDP, Cisplatin, Cis-Diaminodichloroplatin Platinol, CDDP) be wherein act on the strongest a kind of.CDDP has that anticancer spectrum is wide, effect is strong, with multiple antineoplastic agent characteristics such as synergism are arranged, be one of medicine the most frequently used in the current combined chemotherapy, all can show curative effect multiple entity tumors such as ovarian cancer, carcinoma of prostate, carcinoma of testis, pulmonary carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, malignant lymphoma, breast carcinoma, incidence scale cancer, thyroid carcinoma and osteogenic sarcomas.[2]。According to statistics, China based on CDDP or have the chemotherapy regimen of the compatibility that CDDP participates in to account for 70%～80%[2 of all chemotherapy regimens].CDDP from the seventies begin to be used for clinical since, medicine is treated in a linearize that has become the multiple malignant tumor of treatment.CDDP belongs to cell cycle nonspecific agent (CCNSA), and cisplatin can form the 26S Proteasome Structure and Function that cross link destroys DNA with urine purine, adenine, the cytosine on the DNA.By forming in the chain with dna molecular or interchain cross-join or stop the effect of approach such as the RNA molecule duplicates again performance antitumor pharmacology.Carboplatin be first by the clinical second filial generation platinum kind anti-cancer drugs of accepting extensively because its digestive tract reaction and nephrotoxicity are little, need not aquation during application, and have the anticancer spectrum similar to cisplatin.Great mass of data shows that the anticancer mechanism of action of cisplatin and carboplatin is identical, and main action target spot is DNA[4].In addition, some new platinum medicines also are applied to clinical gradually in recent years.For example, (Le Shading Oxaliplatin) belongs to new platinum kind anti-cancer drugs to oxaliplatin, and wherein pt atom and 1,2 diamino cyclohexane extraction (DACH) and the combination of an oxalic acid base are single enantiomorphs.
Oxaliplatin has been applied to clinical, with 5-fluorouracil and folinic acid (formyl tetrahydrofolic acid) associating one line application of treatment transitivity colorectal cancer.Obtain the approval Initial Public Offering of korean foods medicine State Security Department according to platinum (eptaplatin) in July, 1999, be used for the treatment of small cell lung cancer, gastric cancer, cervical cancer and colorectal carcinoma.
But, owing to comprise that the platinum medicine of CDDP has toxic and side effects, can occur anemia, albuminuria during heavy dose of the application, feel sick, vomiting, abnormal liver function, nervous system abnormality, hematopoietic cell reduce regulating liver-QI, renal function injury etc.Cytotoxicity is that the high nucleophilic sites of platinum class complex and DNA forms the result who receives in the covalency.On the other hand, after platinum medicine acted on tumor cell, cell can produce acquired drug-resistance, had influenced such medicine using dosage and curative effect clinically.Be known that at present, tumor cell produces drug resistance and P glycoprotein (P-gp) and the overexpression of mdr-1 gene to platinum medicine, glutathion S-transferase activity increases, and the topoisomerase enzymatic activity reduces, and it is relevant to reach the decline of p53 expression, the rising of bc1-2 expression etc.Existing studies show that, tumor cell can be reduced platinum medicine gathering in vivo by the permeability that changes cell membrane, thereby the efficacy of a drug is alleviated; Strengthen the repair ability of the DNA of self cell, and can block number of mechanisms such as apoptosis pathway, thereby show resistance, make the curative effect of platinum medicine treatment tumor reduce [5-7] platinum medicine.But tumor cell produces drug-fast mechanism to platinum medicine and awaits to further investigate.Also effectively do not overcome at present the medicine that tumor develops immunity to drugs to platinum medicine clinically.
List of references:
1.Rosenberg?B，Van?Camp，Krgas?T.Inhibition?of?cell?division?in?Escherichia?coli?byelectrolysis?products?from?a?platinum?eletrode.Nature，1965；205：698-699.
2.Siddik?ZH.Cisplatin：mode?of?cytotoxic?action?and?molecular?basis?of?resistance.Oncogene?2003；22：7265-79.
3. Li Jun, Pei Renmo, Shu Liang, Chen Bo, Fan Shunwu. cisplatin combined carboplatin is to the experimentation of osteosarcoma cell toxic action. People's Armed Police's medical college journal .2002; 12:106-108.
4.Smith?IE，Evans?BD.Carboplatin(JM8)as?a?single?agent?and?in?combination?in?thetreatment?of?small?cell?lung?cancer.Cancer?Treat?Rev.1985；12?suppl?A：73-75.
5.Cvijic?ME，Yang?WL，Chin?KV.Cisplatin?sensitivity?in?cAMP-dependent?proteinkinase?mutants?of?Saccharomyces?cerevisiae.Anticancer?Res?1998；18：3187-92.
6.Krishan?A，Fitz?CM，Andritsch?I.Drug?retention，efflux，and?resistance?in?tumor?cells.Cytometry?1997；29：279-85.
7.Ohmichi?M，Hayakawa?J，Tasaka?K，Kurachi?H，Murata?Y.Mechanisms?of?platinumdrug?resistance.Trends?Pharmacol?Sci?2005；26：113-16.
Summary of the invention
The objective of the invention is at above-mentioned technical problem, provide a kind of and can effectively overcome the anti-tumor compositions that tumor develops immunity to drugs to platinum medicine.
Another object of the present invention provides the application of above-mentioned anti-tumor compositions.
The inventor with cisplatin as the representative of platinum medicine as object of study, find the AKT amplification and cross the target molecule p70S6K1 that expresses by its downstream effects and regulate pulmonary carcinoma, carcinoma of prostate and ovarian cancer cell and produce drug resistance.Therefore, we think that the activation of AKT/p70S6K1 signal path is tumor cell produces acquired drug-resistance to platinum medicine an important molecule mechanism.We are verified, because the inhibitor of AKT and p70S6K1 can strengthen the effect of CDDP to tumor cell, therefore, inhibitor and the platinum medicine of using AKT and p70S6K1 share, not only may reduce the consumption of platinum medicine, and can delay drug resistance generation and reversing tumor cell acquired drug-resistance.
The objective of the invention is to realize by following technical measures:
A kind of anti-tumor compositions, this medicine contain platinum medicine and the AKT inhibitor and/or the p70S6K1 inhibitor for the treatment of effective dose.
Described anti-tumor compositions, this medicine contains following components in weight percentage: platinum medicine 50-90% and AKT inhibitor 10-50% form compound recipe, or platinum medicine 50-90% and p70S6K1 inhibitor 10-50% composition compound recipe.
Described anti-tumor compositions, wherein platinum medicine is cisplatin, carboplatin, oxaliplatin or JM216.
Described anti-tumor compositions, it is characterized in that the platinum medicine of effective therapeutic dose is as follows respectively by the clinical administration amount that the surface integrating reaches blood drug level: cisplatin is 20-300mg/m
2, carboplatin is 100-900mg/m
2, oxaliplatin is 30-300mg/m
2, JM216[full name cis-two chloro-is trans-acetic acid (ammonia cyclohexylamine) closes platinum (Shi Guibao company)] be 100-120mg/m
2
Described anti-tumor compositions, wherein the AKT inhibitor is chemical micromolecule, chemicals, micromolecule polypeptide, the biomolecule inhibitor that can suppress the vigor of AKT by chemistry or molecular biology method.(Triciribine VQD-002) has been applied to clinical, nearest this medicine of discovering and can have suppressed AKT as antineoplastic agent, can be used as the inhibitor of AKT, and the clinical administration amount that reaches blood drug level by the surface integrating is 10-100mg/m as triciribine
2Perhaps use RX-0201 (Archexin), be a kind of and micromolecule polypeptides complementary 20 oligonucleotides of AKT1mRNA, can directly act on AKT, suppress its generation (Rexahn pharmaceutical factory), the clinical administration amount that reaches blood drug level by the surface integrating is 100-300mg/m
2
Described anti-tumor compositions, wherein the p70S6K1 inhibitor is chemical micromolecule, chemicals, micromolecule polypeptide, the biomolecule inhibitor that can suppress the vigor of p70S6K1 by chemistry or molecular biology method.As use the synthetic siRNA of little RNA perturbation technique (siRNA) at p70S6K1, the clinical administration amount that reaches blood drug level by the surface integrating is 50-700mg/m
2
Described anti-tumor compositions is made appropriate dosage forms with the adjuvant that pharmaceutically allows.These dosage forms can be tablet, granule, capsule, injection etc.
The application of described anti-tumor compositions in the anti-pulmonary carcinoma of preparation, ovarian cancer, carcinoma of prostate, breast carcinoma, gastric cancer, nasopharyngeal carcinoma, esophageal carcinoma, malignant lymphoma, incidence scale cancer, thyroid carcinoma, osteogenic sarcoma medicine.
Beneficial effect of the present invention:
We discover by the inside and outside, and the amplification of AKT expresses that CDDP is produced acquired drug-resistance is closely related with lung carcinoma cell with crossing; The vigor of AKT is that pulmonary carcinoma, carcinoma of prostate and ovarian cancer cell are necessary to CDDP generation drug resistance; Clinical data has also confirmed our cell in vitro result of experiment, and promptly cell is relevant with the activity of AKT to the drug resistance of CDDP; The inhibitor of using AKT can strengthen the effect that CDDP suppresses tumor in vivo and in vitro; AKT promotes that by p70S6K1 tumor cell produces drug resistance to CDDP, and the inhibitor of p70S6K1 also can strengthen the inhibitory action of CDDP to tumor.Therefore, the activation of AKT is that kinds of tumors produces the reason of tolerance to CDDP, and AKT and p70S6K1 inhibitor have synergism to CDDP, can prevent from the reversing tumor cell CDDP to be produced drug resistance.The present invention adopts and to contain the anti-tumor compositions that the platinum medicine of treat effective dose and AKT inhibitor and/or p70S6K1 inhibitor are prepared from, and has and suppresses the drug resistance of tumor to platinum medicine, the effect of raising antitumor drug.Anti-tumor compositions provided by the invention can be used for preparing the medicine of kinds of tumors such as anti-pulmonary carcinoma, ovarian cancer, carcinoma of prostate, breast carcinoma, gastric cancer, nasopharyngeal carcinoma, esophageal carcinoma, malignant lymphoma, incidence scale cancer, thyroid carcinoma, osteogenic sarcoma.
Description of drawings
Fig. 1 is that A549/CDDP cell AKT expresses and AKT1 gene amplification.Wherein A is the cell proliferation curve, IC
50Represent 50% suppression ratio, B is protein immunoblotting figure, and C is reverse-transcription polymerase chain reaction (RT-PCR) sepharose electrophoresis figure, and D is genome PCR sepharose electrophoresis figure and statistical result figure, and * represents that statistical significance is arranged, p＜0.05.
Fig. 2 is the cell proliferation curve.After wherein A carries the adenovirus of crt gene fragment and AKT1 for the A549 cell infection, cell proliferation curve after the CDDP effect, B is after Human Prostate Cancer Cells DU145 cell infection carries the adenovirus of crt gene fragment and AKT1, cell proliferation curve after the CDDP effect, C is that A549/CDDP cell infection cell infection carries crt gene fragment and Akt-DN (AKT dominant negative, it is the AKT mutant, have the structure similar to wild type AKT, can suppress its vigor with wild type AKT competition, can not be with signal transduction to the downstream) adenovirus after, cell proliferation curve after the CDDP effect, D is after Proliferation of Human Ovarian Cell A2780 cell infection cell infection carries the adenovirus of crt gene fragment and AKT-DN, the cell proliferation curve after the CDDP effect.
Fig. 3 is the immunohistochemical optical microscope photograph of phosphorylation AKT.Wherein A, B, C, D are prognosis of squamous cell lung cancer, and E, F, G, H are the adenocarcinoma of lung clinical samples, phosphorylation AKT is divided into-(A and E) ,+(B and F), ++ (C and G) and ++ 4 grades of+(D and H).
Fig. 4 is A549/CDDP and A549 cell proliferation and a tumor growth in vivo curve chart behind the inhibition AKT vigor.Wherein A is the A549/CDDP cell, adopt CDDP or CDDP to share the growth curve that LY294002 (suppressing the Akt vigor) obtains, figure B is that A549 adopts CDDP or CDDP to share the growth curve that LY294002 obtains, C is that 2 kinds of cells adopt CDDP or CDDP to share the western blot figure that phosphorylation AKT expresses behind the LY294002, D is a tumor growth curve behind the A549/CDDP inoculation nude mice, and E is a tumor growth curve behind the A549 inoculation nude mice.
Fig. 5 is western blot figure and the tumor cell proliferation curve of phosphorylation p70S6K1 behind the inhibition p70S6K1.Wherein A is the western blot figure of rapamycin effect back phosphorylation p70S6K1, B is an immunoblotting density semi-quantitative results cartogram, * expression has statistical significance, p＜0.05, C share the growth curve that rapamycin obtains for the A549/CDDP cell adopts CDDP or CDDP, and D share the growth curve that rapamycin obtains for the A549 cell adopts CDDP or CDDP.
The specific embodiment
The present invention is further illustrated by the following examples.
Preparation embodiment 1
Get CDDP 100-300mg, RX-0201 (AKT inhibitor) 300mg adds an amount of injection adjuvant commonly used, adopts the injection common process to make injection.
Get CDDP 100-300mg, triciribine 10-200mg adds an amount of injection adjuvant commonly used, adopts the injection common process to make injection.
Preparation embodiment 3
Get CDDP 100-300mg,, add an amount of injection adjuvant commonly used, adopt the injection common process to make injection at siRNA (siAKT) 100-900mg of AKT.We also intend making compound injection with the AKT inhibitor of other biological and chemical with similar method and cisplatin.
Card taking platinum 100-1000mg, RX-0201 (AKT inhibitor) 300mg adds an amount of injection adjuvant commonly used, adopts the injection common process to make injection.
Card taking platinum 100-1000mg, triciribine 10-200mg adds an amount of injection adjuvant commonly used, adopts the injection common process to make injection.
Preparation embodiment 6
Card taking platinum 100-1000mg at siRNA (siAKT) 100-900mg of AKT, adds an amount of injection adjuvant commonly used, adopts the injection common process to make injection.We also intend making compound injection with the AKT inhibitor of other biological and chemical with similar method and carboplatin.
Preparation embodiment 7
CDDP 100-300mg or carboplatin 100-1000mg at siRNA (siP70S6K1) 100-900mg of p70S6K1, add an amount of injection adjuvant commonly used, adopt the injection common process to make injection.We also intend making compound injection with the p70S6K1 inhibitor of other biological and chemical with similar method and CDDP or carboplatin.
Get CDDP 100-300mg, RX-0201 (AKT inhibitor) 300mg at siRNA (siP70S6K1) 200mg of p70S6K1, adds an amount of injection adjuvant commonly used, adopts the injection common process to make injection.
Among the above-mentioned preparation embodiment:
siAKT：GAAGGAAGTCATCGTGGCC(SEQ?ID?No.1)
Synthetic primer: positive-sense strand: GAAGGAAGTCATCGTGGCC
Antisense strand: GGCCACGATGACTTCCTTC
siP70S6K1：GTTCAAGCTCATCCATTCT(SEQ?ID?No.2)
Synthetic primer: positive-sense strand: GTTCAAGCTCATCCATTCT
Antisense strand: AGAATGGATGAGCTTGAAC
Synthetic method system well known to a person skilled in the art method.
The condition that experimentizes among the following effect embodiment:
(1) experiment medicine:
The inhibitor LY294002 of CDDP, AKT upstream target molecule, rapamycin (rapamycin) are bought the company in Sigma.
(2) laboratory animal:
Nude mouse, 18-22g, the Shanghai Experimental Animal Center provides.
(3) tumor strain source:
People's nonsmall-cell lung cancer adenocarcinoma cell strain A549, prostate gland cancer cell strain DU145, ovarian cancer cell strain A2780 are provided by Chinese Academy of Sciences's Shanghai cell.The CDDP mdr cell (A549/CDDP) of A549 when the concentration of CDDP in culture fluid reaches 5 μ g/ml, was cultivated 6 months with the culture fluid of the CDDP that contains this concentration at least.For getting rid of CDDP, be object of study with 1 month A549/CDDP of drug withdrawal to genome and chromosomal direct effect.
Effect embodiment 1:
(CDDP) dosage is induced 549 CDDP mdr cell (A549/CDDP) as mentioned above for Cisplatin, Cis-Diaminodichloroplatin Platinol progressively to increase cisplatin.With 1 month A549/CDDP cell of drug withdrawal and parental cell A549 as object of study, the CDDP effect that adds variable concentrations is after 48 hours, use tetrazole indigo plant (MTT) method and measure the absorbance of 570nm, obtain the quantity of living cells, draw the cell proliferation curve under the CDDP effect, obtain the CDDP concentration (IC that 50% tumor cell is suppressed
50).People's non-small cell lung cancer cell strain A549/CDDP of CDDP acquired drug-resistance compares the IC of CDDP with its parental cell
50Increase to about 4 times (Figure 1A), illustrate that we have successfully induced the A549/CDDP mdr cell.Cracking A549 and A549/CDDP cell, measure the AKT (representing activatory AKT) of phosphorylation by Western blot (immunoblotting) method, find that the expression of the total AKT of mdr cell then is respectively parental cell 1.84 and 2.34 times (Figure 1B), the prompting mdr cell has the activation of AKT and crosses and express.Express the mechanism that increases for further clear and definite AKT protein level, use the results suggest of RT-polymerase chain reaction (RT-PCR) and genome PCR, mdr cell AKT1mRNA level and genome AKT1 examine the shellfish number than the obvious increase of parental cell (Fig. 1 C and D).Human AKT comprises 3 kinds of hypotype: AKT1, AKT2 and AKT3, and our result of study explanation, the AKT protein expression increases and activation is the result of AKT1 gene amplification.
Effect embodiment 2:
For clear and definite AKT is expressed in tumor cell to the mechanism of action in the CDDP generation acquired drug-resistance, we infect A549 and Human Prostate Cancer Cells DU145 respectively with the adenovirus that carries AKT1, green fluorescent protein (GFP is carried in infection, adenovirus in contrast) carries out cell proliferation experiment with method as hereinbefore in contrast.The result shows that the expression that increases AKT1 makes the IC of A549 cell CDDP
50Increase to 18.77 μ mol/L (Fig. 2 A) from 7.65 μ mol/L, then be increased to 12.16 μ mol/L (Fig. 2 B), illustrate that the expression of exogenous increase AKT1 is enough to increase the drug resistance of cell to CDDP from 6.97 μ mol/L at the DU145 cell.For verifying further whether AKT1 is that cell is necessary to CDDP generation drug resistance, we are with carrying AKT-DN (AKT dominant negative, it is the AKT mutant, have the structure similar to wild type AKT, can suppress its vigor with wild type AKT competition, can not be with signal transduction to the downstream) adenovirus infect A549/CDDP and Proliferation of Human Ovarian Cell A2780 respectively, the adenovirus that GFP is carried in infection in contrast, carry out cell proliferation experiment, the result shows that the expression that suppresses AKT makes the IC of A549/CDDP cell CDDP
50Be reduced to 16.74 μ mol/L (Fig. 2 C) from 32.05 μ mol/L, then drop to 8.65 μ mol/L (Fig. 2 D) at the A2780 cell from 15.63 μ mol/L, illustrate that the expression that suppresses AKT can increase the sensitivity of cell to CDDP, AKT is that tumor cell is necessary to CDDP generation drug resistance.
Effect embodiment 3:
Be the relation of judging that clinical pulmonary carcinoma patient tumors cell is expressed phosphorylation in CDDP drug resistance and the tumor tissues-AKT, we use the former nutrient of being commissioned to train of tumor cell from lung carcinoma cell, and detect the sensitivity of cell to CDDP with the MTT method, obtain IC
50Numerical value.Use immunohistochemistry same patient's tumor tissue is dyeed, detect the expression of phosphorylation-AKT.The expression classification of phosphorylation-AKT is as follows :-, feminine gender, cell non-coloring; +, faint cytoplasm is painted and dye without nucleus; ++,＜20% the strong cytoplasm nuclear staining of tumor cell performance; The strong cytoplasm nuclear staining of tumor cell performance of +++,＞20%.Through statistical analysis, find IC
50Numerical value and p-AKT express classification obviously relevant (table 1).
Table 1. non parametric tests (Kruskal Wallis Test)
Annotate: AC: adenocarcinoma; SC: scale cancer; BC: bronchovesicular cancer; LC: maxicell pulmonary carcinoma
Effect embodiment 4:
Whether relevant for studying the AKT mediated cell with the vigor of its upstream target molecule PI3K to the drug resistance of CDDP, we are with three phosphatidyl inositol kinase (PI3K, it is the upstream regulation molecule of AKT, its inhibitor can suppress the vigor of AKT) inhibitor LY294002 (5 and 10 μ mol/L) and CDDP share, detect the IC of CDDP
50, single group in contrast with cisplatin.LY294002 and CDDP share the IC that can obviously reduce mdr cell CDDP
50(Fig. 4 A), and the IC of parental cell
50Reduce and not obvious (Fig. 4 B).After the medication 2 hours, Western blot result shows, phosphorylation-AKT of A549/CDDP and total AKT expression ratio parental cell obviously strengthen, the LY294002 that uses 10 μ mol/L can significantly suppress the expression of mdr cell and parental cell phosphorylation-AKT, the repressed degree of mdr cell obviously is better than parental cell, the two only has faint expression at LY294002 effect back phosphorylation-AKT, the result consistent (Fig. 4 C) of this protein expression result and our drug sensitive experiment, this experiment in vitro explanation suppresses the antitumor action that AKT can significantly increase CDDP, and can make mdr cell to CDDP sensitivity, reversing drug resistance.
Effect embodiment 5:
For further verifying the interior curative effect that LY294002 and CDDP share, we use nude mice and carry out following zoopery:
Nude mice is equally divided into 4 groups: A549 solvent (DMSO) processed group; A549 uses the LY294002 group; A549/CDDP solvent processing group; A549/CDDP uses the LY294002 group.Beginning in the 3rd day behind the tumor cell inoculation, LY294002 group gives the LY294002 that lumbar injection 25mg/kg is dissolved in PBS, or equal volume, (DMSO is the solvent of LY294002, in contrast) 2 times/week of administration to be dissolved in the dimethyl sulfoxide of PBS.When diameter of tumor during greater than 5mm, the CDDP of 4 processed group lumbar injection 4mg/kg.Altogether 3 weeks of administration, measure the tumor size 3 times weekly, gross tumor volume calculates with formula (wide by 2 * long)/2.Found that, the A549/CDDP group is used the antitumor action that LY294002 can obviously strengthen CDDP, gross tumor volume does not rise appreciably, since the 11st day, LY294002 is significantly less than in conjunction with the volume of CDDP treatment group and singly organizes with CDDP, and CDDP is not obvious to the inhibitory action of mdr cell tumor, and gross tumor volume obviously increases (Fig. 4 D).And A549 group LY294002 also can strengthen the antitumor action of CDDP, but effect is obvious not as mdr cell.List is better than late period to the inhibitory action of tumor in early days with CDDP, adds with the LY294002 group to organize (Fig. 4 E) less than single with CDDP at the 16th and the 18th day gross tumor volume.Because PI3K is the upstream effect molecule of AKT, LY294002 suppresses the activation of AKT by the activity that suppresses PI3K, this results suggest, LY294002 is obvious to the drug-fast non-small cell lung cancer cell effect of acquired CDDP, can strengthen the cytotoxicity of CDDP, suppress growth of tumor in the animal body, therefore, prove also that by other experiment the vigor that suppresses AKT can strengthen effect, the reversing drug resistance of CDDP.
Effect embodiment 6:
For judging the AKT downstream signaling molecule relevant with the CDDP drug resistance, we handle cell after 2 hours with rapamycin (rapamycin) and CDDP, measure the expression of phosphorylation-p70S6K1 (representing the activation of p70S6K1) and total p70S6K1.Western blot result shows that rapamycin can obviously suppress the expression of mdr cell and parental cell p-p70S6K1, proves that the vigor of p70S6K1 reduces (Fig. 5 A), to the inhibition of mdr cell more obvious (Fig. 5 B).Use rapamycin and act on A549/CDDP and A549 cell, measure IC in conjunction with CDDP
50Similar with LY294002, use rapamycin and can significantly strengthen the cytotoxicity of CDDP to mdr cell, the IC of CDDP
50Drop to 11.25 μ mol/L (Fig. 5 C) from 30.74 μ mol/L.And it is also not obvious to the potentiation of CDDP that parental cell is used rapamycin, IC
50Drop to 5.97 μ mol/L (Fig. 5 D) from 8.11 μ mol/L.Above results suggest, it is closely related that the vigor of p70S6K1 and A549/CDDP produce the CDDP drug resistance, and the vigor that suppresses p70S6K1 also can obviously strengthen the effect of CDDP to mdr cell, by making mdr cell to the CDDP sensitivity and reversing drug resistance.
＜110〉Nanjing Medical University
＜120〉a kind of anti-tumor compositions and application thereof
<160>2
<210>1
<211>19
<212>DNA
＜213〉artificial sequence
<400>1
gaaggaagtc?atcgtggcc?19
<210>2
<211>19
<212>DNA
＜213〉artificial sequence
<400>2
gttcaagctc?atccattct?19
Claims (10)
1, a kind of anti-tumor compositions is characterized in that this medicine contains platinum medicine and the AKT inhibitor and/or the p70S6K1 inhibitor for the treatment of effective dose.
2, anti-tumor compositions according to claim 1, it is characterized in that this medicine contains following components in weight percentage: platinum medicine 50-90% and AKT inhibitor 10-50% form compound recipe, or platinum medicine 50-90% and p70S6K1 inhibitor 10-50% composition compound recipe.
3, anti-tumor compositions according to claim 1 and 2 is characterized in that platinum medicine is cisplatin, carboplatin, oxaliplatin or JM216.
4, anti-tumor compositions according to claim 1, it is characterized in that the platinum medicine of effective therapeutic dose is as follows respectively by the clinical administration amount that the surface integrating reaches blood drug level: cisplatin is 20-300mg/m
2, carboplatin is 100-900mg/m
2, oxaliplatin is 30-300mg/m
2, JM216 is 100-120mg/m
2
5, anti-tumor compositions according to claim 1 is characterized in that the AKT inhibitor is for suppressing chemical micromolecule, chemicals, micromolecule polypeptide, the biomolecule inhibitor of the vigor of AKT by chemistry or molecular biology method.
6, anti-tumor compositions according to claim 1 is characterized in that the AKT inhibitor is triciribine or RX-0201.
7, anti-tumor compositions according to claim 6, it is characterized in that AKT inhibitor consumption is: triciribine is 10-100mg/m by the clinical administration amount that the surface integrating reaches blood drug level
2, perhaps RX-0201 is 100-300mg/m by the clinical administration amount that the surface integrating reaches blood drug level
2
8, anti-tumor compositions according to claim 1 is characterized in that the p70S6K1 inhibitor is for suppressing chemical micromolecule, chemicals, micromolecule polypeptide, the biomolecule inhibitor of the vigor of p70S6K1 by chemistry or molecular biology method; Preferred p70S6K1 inhibitor is for using the synthetic siRNA at p70S6K1 of little RNA perturbation technique, and the clinical administration amount that reaches blood drug level by the surface integrating is 50-700mg/m
2
9, anti-tumor compositions according to claim 1 is characterized in that the adjuvant of said composition and pharmaceutically permission is made appropriate dosage forms.
10, the application of the described anti-tumor compositions of claim 1 in the anti-pulmonary carcinoma of preparation, ovarian cancer, carcinoma of prostate, breast carcinoma, gastric cancer, nasopharyngeal carcinoma, esophageal carcinoma, malignant lymphoma, incidence scale cancer, thyroid carcinoma, osteogenic sarcoma medicine.
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| CN105561314A (en) * | 2016-01-25 | 2016-05-11 | 江苏省人民医院 | P70s6k1 and application of interference sequence of P70s6k1 in preparation of medicine for reversing resistance of non-small cell lung cancer to gefitinib |
| US20160271072A1 (en) * | 2013-10-22 | 2016-09-22 | The University Of North Carolina At Chapel Hill | Polymer nanoparticles containing multiple agents and methods thereof |
| JP2016222711A (en) * | 2008-05-12 | 2016-12-28 | ユニヴァーシティ オブ サウス フロリダ | Compositions including triciribine, and methods of use thereof |
| CN108892700A (en) * | 2018-05-27 | 2018-11-27 | 杭州星鳌生物科技有限公司 | A kind of new antitumoral compounds and its application in preparation of anti-tumor drugs |
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