CN101292980B - Pharmaceutical combination containing rapamycin for treating large intestine cancer - Google Patents
Pharmaceutical combination containing rapamycin for treating large intestine cancer Download PDFInfo
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- CN101292980B CN101292980B CN2007100401740A CN200710040174A CN101292980B CN 101292980 B CN101292980 B CN 101292980B CN 2007100401740 A CN2007100401740 A CN 2007100401740A CN 200710040174 A CN200710040174 A CN 200710040174A CN 101292980 B CN101292980 B CN 101292980B
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Abstract
The invention discloses a drug composite containing rapamycin for curing colorectal cancer. The drug composite is composed of PD98059 (2-amino-4-iso-oxygen flavone) and the rapamycin, the weight proportion of which is 292.4:1-1462:1. The invention can down regulate mTOR of colorectal cancer cells and the protein phosphorylation level of downstream p70s6K and 4E-BP1, so as to inhibit the proliferation activity of the colorectal cancer cells and simultaneously to block the growth cycle of the colorectal cancer cells, and then to inhibit the growth of human colorectal cancer cells and to reduce the incidence rate of the colorectal cancer and the tumor size in rats.
Description
Technical field:
The present invention relates to chemical field, relate in particular to compositions, particularly a kind of pharmaceutical composition that is used for the treatment of colorectal cancer that contains rapamycin.
Background technology:
In the prior art, the effect of pharmaceutical composition that is used for the treatment of colorectal cancer is all undesirable.
Summary of the invention:
The purpose of this invention is to provide a kind of pharmaceutical composition that is used for the treatment of colorectal cancer that contains rapamycin, the described this pharmaceutical composition that is used for the treatment of colorectal cancer that contains rapamycin will solve the unfavorable technical problem of effect of the pharmaceutical composition that is used for the treatment of colorectal cancer in the prior art.
A kind of pharmaceutical composition that is used for the treatment of colorectal cancer that contains rapamycin of the present invention is characterized in that: described pharmaceutical composition is made up of different oxygen flavone of 2-amino-4-and rapamycin.
Further, the mass ratio of different oxygen flavone of described 2-amino-4-and described rapamycin is in 292.4:1 arrives the 1462:1 scope.
Further, in described pharmaceutical composition, also contain pharmaceutically acceptable carrier.
Further, the dosage form of described pharmaceutical composition is pharmaceutically acceptable any dosage form.
Action principle of the present invention: the different oxygen flavone of 2-amino-4-(2 '-amino-3 '-methoxyflavone, the different oxygen flavone of 2-amino-4-, molecular formula C
16H
13NO
3Relative molecular mass 267.3, code name PD98059) is the selective depressant of MEK (mitogen-activated protein/extracellular signal-regulated kinasekinase), act on 217/221 residue of MEK1/2 serine, can suppress its phosphorylation, and then the activation of inhibition Ras/Raf/MEK/ERK signal transduction pathway, thereby suppress the cell increment, regulating cell differentiation and apoptosis.
Rapamycin (rapamycin, RPM, trade name Sirolimus) is the medicine of the anti-transplant rejection reaction of U.S. HOME PRODUCTS company development, and in JIUYUE, 1999 is gone on the market through drugs approved by FDA.RPM is a kind of macrolide antibiotics (the molecular formula C that extracts from water absorption streptomycete (streptomyces hygroscopi cus) fermentation liquid
51H
79NO
13, relative molecular mass 914.2), have lipotropy, be soluble in ethanol, chloroform, acetone and other organic solvent, be slightly soluble in water, be insoluble to ether.Initial RAPA is studied as hypotoxic antifungal drug, found that rapamycin had immunosuppressive action in 1977, beginning in 1989 is tried out rapamycin as the new drug of treatment organ transplant rejection, find again that in recent years it has antitumor action.Effect from present zoopery and clinical practice, rapamycin is the neotype immunosuppressant of a kind of good effect, low toxicity, no nephrotoxicity, the hypertrophy that can suppress various kinds of cell clinically is used for the treatment of immunological rejection after the organ transplantation, and the vascular restenosis of angiocarpy bracket postoperative.The target spot of RPM in mammalian cell is mTOR (mammaliantarget of rapamycin, mammal rapamycin target protein), both signal transduction pathway in conjunction with mTOR mediation capable of blocking.
The present invention is with different oxygen flavone of 2-amino-4-and rapamycin combination, can reduce colorectal cancer cells mTOR and downstream p70s6K thereof, 4E-BP1 protein phosphorylation level, thereby suppressed the colorectal cancer cells proliferation activity, blocked the colorectal cancer cells growth cycle simultaneously, and then play and suppress the growth of human large intestine cancer cell, lower the incidence rate and the effect that reduces gross tumor volume of mice colorectal cancer.
The present invention compares with prior art, and its effect is actively with tangible.The present invention is with different oxygen flavone of 2-amino-4-and rapamycin combination, treating colorectal cancer with independent different oxygen flavone of use 2-amino-4-or rapamycin compares, can obviously suppress the growth of human large intestine cancer cell, can lower the incidence rate of mice colorectal cancer significantly and reduce gross tumor volume.
Description of drawings:
Fig. 1 is that the SW480 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Fig. 2 is that another SW480 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Fig. 3 is that another SW480 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Fig. 4 is that another SW480 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Fig. 5 is that the HCT116 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Fig. 6 is that another HCT116 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Fig. 7 is that another HCT116 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Fig. 8 is that another HCT116 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Fig. 9 is that the HT29 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Figure 10 is that another HT29 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Figure 11 is that another HT29 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Figure 12 is that another HT29 cell cycle in the embodiments of the invention detects collection of illustrative plates.
Figure 13 represents a Western Blot testing result of SW480 cell.
Figure 14 represents another Western Blot testing result of SW480 cell.
Figure 15 represents another Western Blot testing result of SW480 cell.
Figure 16 represents another Western Blot testing result of SW480 cell.
Figure 17 has shown a Western Blot testing result of HCT116 cell.
Figure 18 has shown another Western Blot testing result of HCT116 cell.
Figure 19 has shown another Western Blot testing result of HCT116 cell.
Figure 20 has shown another Western Blot testing result of HCT116 cell.
Figure 21 has shown a Western Blot testing result of HT29 cell.
Figure 22 has shown another Western Blot testing result of HT29 cell.
Figure 23 has shown another Western Blot testing result of HT29 cell.
Figure 24 has shown another Western Blot testing result of HT29 cell.
Figure 25 is that the cardinal principle of mice colorectal cancer in the DMSO effect group is at the body sketch map.
Figure 26 is the sketch map that exsomatizes substantially of mice colorectal cancer in the DMSO effect group.
Figure 27 is adenocarcinoma and part mucinous adenocarcinoma pathology figure (10 * 20) in the DMSO effect group.
Figure 28 is adenocarcinoma and part mucinous adenocarcinoma pathology figure (10 * 40) in the DMSO effect group.
Figure 29 is the sketch map that exsomatizes substantially of mice colorectal cancer in the PD98059 effect group.
Figure 30 is another sketch map that exsomatizes substantially of mice colorectal cancer in the PD98059 effect group.
Figure 31 is height-middle differentiation adenocarcinoma (10 * 20) pathology figure in the PD98059 effect group.
Figure 32 is middle differentiation adenocarcinoma pathology (10 * 20) pathology figure in the PD98059 effect group.
Figure 33 is the sketch map that exsomatizes substantially of mice colorectal cancer in the Rapamycin effect group.
Figure 34 is another sketch map that exsomatizes substantially of mice colorectal cancer in the Rapamycin effect group.
Figure 35 is middle differentiation adenocarcinoma (10 * 20) the pathology figure in the Rapamycin effect group.
Figure 36 is middle differentiation adenocarcinoma (10 * 20) the pathology figure in the Rapamycin effect group.
Figure 37 is the sketch map that exsomatizes substantially of mice colorectal cancer in the 5-aza-dC+RPM effect group.
Figure 38 is another sketch map that exsomatizes substantially of mice colorectal cancer in the 5-aza-dC+RPM effect group.
Figure 39 is LIN (10 * 20) pathology figure in the 5-aza-dC+RPM effect group.
Figure 40 is LIN (10 * 20) pathology figure in the 5-aza-dC+RPM effect group.
The specific embodiment:
The SW480 cell is (available from Shanghai Inst. of Life Science, CAS cell resource center, SIBC) culture medium is RPMI-1640 complete culture solution (10% hyclone, 100U/ml green grass or young crops/streptomycin), HT29 and HCT116 cell are (available from Shanghai Inst. of Life Science, CAS cell resource center, SIBC) culture medium is McCOY ' S5A MEDIUM (Sigma, USA) complete culture solution (10% hyclone, 100U/ml green grass or young crops/streptomycin), three's condition of culture is 95% air, 5%CO
2, 95% humidity, 37 ℃ of constant temperature.
The experiment of embodiment 2MTT colorimetric
Complete culture solution dilution single cell suspension to 3 * 10
4/ ml is seeded to 96 well culture plates with 100 μ l/ holes.After cultivating 24h, when cell is in exponential phase, abandon original fluid, add each group and intervene the medicine working solution, establish following pharmaceutical intervention group respectively:
RPM10nmol/L
PD9805910μmol/L
PD9805910 μ mol/L+RPM10nmol/L (mass ratio of PD98059 and RPM is 292.4:1)
PD9805920μmol/L
PD9805920 μ mol/L+RPM10nmol/L (mass ratio of PD98059 and RPM is 584.8:1)
PD9805940μmol/L
PD9805940 μ mol/L+RPM10nmol/L (mass ratio of PD98059 and RPM is 1169.6:1)
PD9805950μmol/L
PD9805950 μ mol/L+RPM10nmol/L (mass ratio of PD98059 and RPM is 1462:1) matched group adds complete culture solution, and 0.5%PBS, 0.5% dimethyl sulfoxide (DMSO).After continuing cultivation 24,48,72,96h, every hole adds 5mg/ml MTT solution 20 μ l, abandons supernatant behind 37 ℃ of incubation 4h, adds 100 μ l/ hole DMSO, lucifuge room temperature shaking table vibration 20min.Microplate reader dual wavelength (570nm, 630nm) is measured each hole absorbance (A) value and record result.Average behind every group of repetition measurement 5 holes, repeated trials three times (x).The results are shown in Table 1.
Table 1 variable concentrations PD98059 separately and with the influence (x%) of RPM synergy to three kinds of cell viabilities
RPM10nmol/L+PD98059vs.RPM10nmol/L：
◆p<0.05，
*p<0.01
RPM10nmol/L+PD98059vs.PD98059：
▲p<0.01
As seen from the above table, PD98059 and RPM synergy are than using PD98059 and RPM can obviously reduce the vigor of above-mentioned three kinds of colorectal cancer cells separately.
The exponential phase cell is cultivated synchronizing them of 24h with serum-free medium.Change culture fluid for containing different pharmaceutical (RPM10nmol/L, PD9805950 μ mol/L, RPM10nmol/L+PD9805950 μ mol/L, in PD98059 and rapamycin synergy group, the mass ratio of PD98059 and rapamycin is 1462:1) complete culture solution, continue to cultivate 48h.With 0.25% trypsinization collecting cell, the PBS washing after 4 ℃ of dehydrated alcohol are fixing, makes about 10
6The single cell suspension of individual/ml is hatched 10min jointly with the Tris-HCL buffer (pH7.4) that contains the 1%RNA enzyme, after propidium iodide (PI) dyeing, carries out flow cytometer and detects.According to the cell distribution maps of different relatively dna contents, the percentage rate of each cycle cell of match.8 samples of every group of repetition measurement, repeated trials three times, the result represents with x ± SD.The results are shown in Table 2, Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9, Figure 10, Figure 11 and Figure 12.
Table 2 cell cycle testing result (x ± SD)
*p<0.01，
**p<0.001
As shown in Table 2: PD98059 and RPM synergy all have remarkable effect to the growth cycle of SW480, HCT116, three kinds of cells of HT29, SW480 and HT29 cell can be blocked in G1 phase (P＜0.001), the HCT116 cell was blocked in S phase and G1 phase (P＜0.01).
Behind RPM10nmol/L, PD9805950 μ mol/L, the RPM10nmol/L+PD9805950 μ mol/L effect 48h with RIPA cracking process extracting total protein of cell, in PD98059 and rapamycin synergy group, the mass ratio of PD98059 and rapamycin is 1462:1.MTOR, p70s6K use the 7%SDS-PAGE electrophoresis; It is 12% that 4E-BP1 uses SDS-PAGE.Used antibody is as follows: and the anti-people GAPDH of rabbit antibody (1:1000, Sigma), the anti-people mTOR of rabbit antibody (1: 1000, #2972, Cell Signaling, USA), the anti-people's phosphorylation of rabbit mTOR antibody (Ser2448,1: 1000, #2971, Cell Signaling, USA), the anti-people p70s6K of rabbit antibody (1:500, #9202, Cell Signaling, USA), the anti-people's phosphorylation of rabbit p70s6K antibody (Thr421/Ser424,1:1000, #9204S, Cell Signaling, USA), the anti-people 4E-BP1 of rabbit antibody (1:500, #9452, Cell Signaling, USA), the anti-people's phosphorylation of rabbit 4E-BP1 antibody (Thr70,1:500, #9455S, Cell Signaling, USA), and the horseradish peroxidase-labeled goat anti-rabbit igg (1: 2000, #7404, Cell Signaling, USA).Every group of experiment triplicate.Protein band carries out density scan with the biological electrophoresis image analysis software of Smart View, ratio with phosphorylated protein (Pho-4E-BP1, Pho-p70s6K, Pho-mTOR) and corresponding total protein (Pan-4E-BP1, Pan-p70s6K, Pan-mTOR) ribbon density carries out the phosphorylated protein relative quantification, and the result represents with x ± SD.The results are shown in Figure 13 to Figure 24.
By Figure 13 to Figure 24 as can be known, PD98059 and RPM synergy are than using separately PD98059 and RPM can obviously reduce colorectal cancer cells mTOR and downstream p70s6K thereof, 4E-BP1 protein phosphorylation level.
Buy 150 of mices of S-ICR (SCXK (Shanghai) 2003-0003) from laboratory animal base, Chinese Academy of Sciences Songjiang, the cleaning level, female, inbred line, body weight 18～20g.Begin colorectal cancer modeling test after raising a week, give 0.4% Dimethylhydrazine (DMH) 0.05ml/10g, 1 time weekly, subcutaneous injection behind the neck, totally 22 weeks.Intervene medicine in giving each group the 16th week.25 of every treated animals.Administering mode:
1) PD98059 effect group: PD980590.5mg/ml, 0.1ml/, 2 times weekly, lumbar injection;
2) RPM effect group: RPM0.5 μ g/ml, 0.1ml/, 3 times weekly (Monday, Wednesday, Friday), lumbar injection;
3) PD980590.5mg/ml+RPM0.5 μ g/ml synergy group: give Monday, Friday PD980590.5mg/ml, RPM0.5 μ g/ml is dissolved among the DMSO jointly, 0.1ml/ only, lumbar injection; Give RPM0.5 μ g/ml Wednesday, 0.1ml/, lumbar injection; The mass ratio of PD98059 and rapamycin is 666.7:1;
4) DMSO group: DMSO0.1ml/, 3 times weekly (Monday, Wednesday, Friday), lumbar injection.
Wherein DMH is with physiological saline solution, and PD98059, RPM dissolve with DMSO, and each lumbar injection DMSO total amount is no more than 0.1ml.To 24 weeks put to death laboratory animal in batches, dissect the back and observe the large intestine pathological changes, calculate gross tumor volume according to formula [the wide * height of the long * of V=/2].Obviously draw materials at the place from pathological changes, the fixing back of neutral formalin makes paraffin section, and HE dyeing back is observed.The results are shown in Table 3, Figure 25 is to Figure 40.
Table 3.24W respectively organizes mice large intestine mucosa histopathology and changes
Annotate:
1. data are represented with case load (focus number).
(Intraepithelial neoplasia IN) is divided into two-stage, i.e. low level (low grade) and high-level (high grade) 2.WHO the work group is with intraepithelial neoplasia.Low level intraepithelial neoplasia (LIN) refers to that structure and cytological abnormal are limited to the Lower Half of epithelium, is equivalent to slight and moderate dysplasia; High-level intraepithelial neoplasia (HIN) refers to that then structure and cytological abnormal expand to the first half of epithelium, and even holostrome, is equivalent to severe dysplasia and cancer in situ.
3. high, medium and low differentiation infiltrating carcinoma and tumor grade 1,2,3 grade is corresponding.
4. relatively adopt X 2 test between the group,
△Compare P＜0.05 with the DMSO group,
▲Compare P＜0.01 with the DMSO group,
The RPM group is P＜0.05 relatively,
◆Compare P＜0.05 with the PD98059 group.
As known from the above, the pharmaceutical composition of being made up of RPM and PD98059 of the present invention can suppress the growth of human large intestine cancer cell, and the effect of RPM10nmol/L+PD9805950 μ mol/L is better than RPM10nmol/L and the independent medication of PD9805950 μ mol/L.
The present invention can be lowered the incidence rate of mice colorectal cancer, reduces gross tumor volume.
Claims (4)
1. pharmaceutical composition that is used for the treatment of colorectal cancer that contains rapamycin, it is characterized in that: described pharmaceutical composition is made up of different oxygen flavone of 2-amino-4-and rapamycin, and the mass ratio of different oxygen flavone of described 2-amino-4-and rapamycin is in 292.4: 1 to 1462: 1 scope.
2. a kind of pharmaceutical composition that is used for the treatment of colorectal cancer that contains rapamycin as claimed in claim 1 is characterized in that: the dosage form of described pharmaceutical composition is that pharmacy is accepted dosage form.
3. pharmaceutical composition that is used for the treatment of colorectal cancer that contains rapamycin, it is characterized in that: described pharmaceutical composition is made up of the carrier of the different oxygen flavone of 2-amino-4-, rapamycin and pharmaceutically acceptance, and the mass ratio of different oxygen flavone of described 2-amino-4-and rapamycin is in 292.4: 1 to 1462: 1 scope.
4. a kind of pharmaceutical composition that is used for the treatment of colorectal cancer that contains rapamycin as claimed in claim 3 is characterized in that: the dosage form of described pharmaceutical composition is that pharmacy is accepted dosage form.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1551767A (en) * | 2001-02-19 | 2004-12-01 | ��˹��ŵ�� | Cancer treatment |
| US20060094674A1 (en) * | 2002-07-05 | 2006-05-04 | Neel Benjamin G | Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1551767A (en) * | 2001-02-19 | 2004-12-01 | ��˹��ŵ�� | Cancer treatment |
| US20060094674A1 (en) * | 2002-07-05 | 2006-05-04 | Neel Benjamin G | Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms |
Non-Patent Citations (2)
| Title |
|---|
| 陈朝飞等.丝裂原激活蛋白激酶阻断剂与DNA甲基化酶抑制剂对人结肠癌细胞的协同影响.中华消化杂志26 2.2006,26(2),89-90. |
| 陈朝飞等.丝裂原激活蛋白激酶阻断剂与DNA甲基化酶抑制剂对人结肠癌细胞的协同影响.中华消化杂志26 2.2006,26(2),89-90. * |
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