CN115068477B - Application of rapamycin derivatives in preparation of antitumor drugs - Google Patents
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- Medicinal Chemistry (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention relates to the field of antitumor drugs, in particular to application of rapamycin derivatives in preparation of antitumor drugs. The rapamycin derivative is 40-O- (3- (4-piperidinecarboxylic acid ethyl ester) -1H-1,2, 3-triazole-1-yl)) ethyl rapamycin. The rapamycin derivative has strong anti-tumor activity through in vitro anti-cancer activity model screening, shows strong inhibition effect on various cancer cell lines, and particularly has obviously improved rapamycin activity compared with a control drug on gastric cancer cell lines. By exploring the in-vivo and in-vitro tumor inhibition activity of the compound, a theoretical basis is provided for the continued deep development of more excellent rapamycin mTOR targeting drugs.
Description
Technical Field
The invention relates to the field of antitumor drugs, in particular to application of rapamycin derivatives in preparation of antitumor drugs.
Background
mTOR is a serine/threonine kinase, a center for cell growth, proliferation and metabolism, which receives information such as hormones, growth factors, trophic factors and cell energy levels, and regulates cell growth, proliferation and metabolism. In cells, mTOR and mTOR C1 composed of accompanying proteins and PI3K and AKT upstream thereof constitute classical PI3K/AKT/mTOR signaling pathways, participate in biological processes such as gene transcription, protein translation, ribosome synthesis, and play an important role in cell growth, apoptosis, metabolism, autophagy, and angiogenesis. In the PI3K/AKT/mTOR signaling pathway, PI3K phosphorylation PIP2 activated by growth factors produces PIP3, which in turn phosphorylates AKT, and activated AKT releases TSC-1/TSC-2 inhibition of mTORC1, allowing mTORC1 to activate and act on downstream substrates. p70S6K1 and 4EBP1 are the most direct and important downstream substrates of mTORC 1. p70S6K1 phosphorylates S6 upon mTOR, driving translation of 5' terminal oligopyrimidine mRNA, promoting translation elongation and ribosome biosynthesis. 4EBP1 is phosphorylated by mTOR and then separated from eIF4E to activate it, which promotes translation of the encoded protein that regulates cell proliferation and metabolism. Thus, excessive activation of mTOR increases synthesis of a variety of proteins associated with tumorigenesis, progression, such as cyclin D1, which promotes cell cycle progression, HIF, which drives expression of the pro-angiogenic factor VEGF, and the like.
The first mTOR inhibitor rapamycin (also known as sirolimus) is a secondary metabolite produced by streptomyces hygroscopicus, which has been used as an immunosuppressant and stent coating drug for rejection reactions of organ transplants and for the treatment of restenosis of the coronary arteries. In the beginning of the 90 s, scientists found 289kDa mTOR in mammalian cells in the study of the mechanism of immunosuppression of rapamycin, and along with the disclosure of mTOR function and mTOR signal transduction pathway, the multifunctional role of rapamycin in anti-tumor and other aspects was recognized. Rapamycin inhibits mTOR activity by binding to mTORC1 after forming a complex with FKBP12, preventing mTOR signaling, leading to apoptosis of tumor cells, promoting autophagy, and the occurrence of cycle arrest. The research of rapamycin for treating cancers such as leukemia, kidney cancer, liver cancer, breast cancer, non-small cell lung cancer, bladder cancer and the like is in clinical trial stage. The antitumor activity of rapamycin attracts attention from pharmaceutical workers in various countries, and the structure of rapamycin is locally modified and altered, from which a series of valuable derivatives are obtained. Temsirimus (trade name: torisel) developed by Hui's pharmaceutical (Wyeth) was approved by the FDA for the treatment of advanced renal cancer, everolimus (trade name: afinitor) developed by Novartis, inc. was approved by the FDA for the treatment of advanced renal cancer, breast cancer, etc. In conclusion, modification and reformation of the rapamycin structure have successfully developed a number of anticancer drugs and achieved more satisfactory clinical effects. Therefore, development of structural modification of rapamycin to obtain rapamycin mTOR-targeted antitumor drugs with stronger antitumor activity has been the effort of drug researchers.
Disclosure of Invention
The invention aims to solve the technical problem of providing an application of rapamycin derivatives in preparing antitumor drugs.
The invention is realized in the following way:
the rapamycin derivative is 40-O- (3- (4-ethyl piperidinecarboxylate) -1H-1,2, 3-triazole-1-yl)) ethyl oxygen rapamycin, and has the following structural formula:
the invention provides application of the rapamycin derivative in preparing an anti-tumor medicament.
Further, the antitumor drug includes a drug that inhibits tumor growth or inhibits proliferation of tumor cells.
Further, the antitumor drug includes a drug that promotes or induces apoptosis of tumor cells.
Further, the tumor includes human non-small cell lung cancer, human gastric cancer, human bladder cancer, human melanoma, human pancreatic cancer, human kidney cancer, human prostate cancer, human neuroblastoma, human colon cancer, breast cancer, human cervical cancer, and human nasopharyngeal cancer.
Further, the tumor cells include human non-small cell lung cancer A549, human gastric cancer AGS, human bladder cancer 5637, human melanoma A375, human pancreatic cancer BXPC-3, human renal cancer cell ACHN, human prostate cancer cell PC-3, human neuroblastoma U251, human colon cancer HCT116, breast cancer cell T47D, cervical cancer CASKI, and nasopharyngeal carcinoma CNE-2.
The invention has the following advantages: according to the invention, through in vitro anti-cancer activity model screening, the rapamycin derivative has strong anti-tumor activity, shows strong inhibition effect on various cancer cell lines, and has obviously improved rapamycin activity compared with a control drug. By exploring the in-vivo and in-vitro tumor inhibition activity of the compound, a theoretical basis is provided for the continued deep development of more excellent rapamycin mTOR targeting drugs.
Drawings
The invention will be further described with reference to examples of embodiments with reference to the accompanying drawings.
Fig. 1 shows the change in tumor volume of each group of nude mice.
FIG. 2 shows CD34 expression (x 400) in transplanted tumor tissue of tumor-bearing nude mice with AGS cells from gastric cancer.
FIG. 3 is a CD34 expression analysis of nude mouse transplanted tumor tissue; * P <0.05 compared with Control group; # to Rapamycin group ratio, P <0.05.
FIG. 4 shows CC3 expression (x 400) of tumor-bearing nude mice transplanted with AGS cells from gastric cancer.
FIG. 5 is a graph showing the analysis of CC3 expression in nude mice transplanted tumor tissue; * P <0.05 compared to Control group.
Detailed Description
The examples are intended to illustrate, but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound prepared in the invention is measured by Bruker ARX-300, and the mass spectrum is measured by Agilent 1100 LC/MSD; the reagents used are analytically pure or chemically pure.
Example 1
1. Preparation of rapamycin derivatives
Step A: preparation of C-40- (2-bromoethyl) oxy rapamycin
12.50g (100 mmol) of bromoethanol was added to 100mL of methylene chloride solution, the mixture was cooled to-30℃after the completion of the addition, 16.10g (150 mmol) of 2, 6-lutidine was added, 33.86g (120 mmol) of trifluoromethanesulfonic anhydride was then added dropwise, and the reaction was magnetically stirred for 2 hours. The reaction was completed by TLC, and after adding 1mL of water, stirring was continued for 10 minutes, the reaction solution was poured into 80mL of water, extracted with dichloromethane, and the extracts were combined and washed with water and dried over anhydrous sodium sulfate. The oily substance was evaporated to dryness and was further subjected to column chromatography to obtain 17.3g (67.58 mmol) of a sulfonate side chain product (compound 2) in 67.5% yield.
Rapamycin 6g (6.60 mmol) was added to 60mL of toluene solution, 5.1g (20 mmol) of sulfonate side chain (compound 2) and 8mL of Diisopropylethylamine (DIPEA) were added, the temperature was raised to 60℃for reaction for 3 hours, after completion of TLC tracking reaction, the reaction solution was poured into 100mL of water, washed with water, extracted with diluted hydrochloric acid, saturated sodium bicarbonate and saturated brine, respectively, and the organic layer was dried over anhydrous sodium sulfate. 4.66g (4.6 mmol) of C-40- (2-bromoethyl) rapamycin (Compound 3) were evaporated to dryness to give 69.3% yield, MS:1044.2 (M+Na).
And (B) step (B): preparation of C-40- (2-azidoethyl) oxy rapamycin
2.04g (2 mmol) of C-40- (2-bromoethyl) oxyrapamycin (Compound 3) was gradually added to 30mL of N, N-dimethylformamide solution, and at room temperature, an aqueous solution of sodium azide (34.4mmol,2.24g,5mL H) 2 O) after the addition was completed, the reaction was carried out at 60℃for 1 hour. After the reaction, the reaction mixture was poured into a large amount of water, extracted with ethyl acetate, and the extracted organic phase was dried and concentrated under reduced pressure, and separated by column chromatography (PE/ac=3:1) to give 1.2g (1.2 mmol) of pale yellow solid, namely C-40- (2-azidoethyl) oxyrapamycin (compound 4), yield: 61.2%, MS:1006.2 (M+Na).
Step C: preparation of 40-O- (3- (4-piperidinecarboxylic acid ethyl ester) -1H-1,2, 3-triazole-1-yl)) ethyl oxygen rapamycin
To a 100mL single port flask were added ethyl 4-piperidinecarboxylate (1.56 g,10 mmol), bromopropyne (1.78 g,15 mmol), sodium carbonate (2.76 g,20 mmol) and 100mL of MF, respectively. The reaction mixture was heated under reflux for 8 hours and then cooled to room temperature, TLC was followed by detection of the end of the reaction, the solvent was distilled off under reduced pressure, extracted with 200mL of ethyl acetate, the organic phase was washed with 30mL of water 3 times, dried over anhydrous sodium sulfate, suction-filtered, the solvent was distilled off under reduced pressure, and then column-chromatographed to give 1.5g (7.7 mmol) of a pale yellow liquid, namely ethyl 1-propynyl-4-piperidinecarboxylate (Compound I), yield 76.92%, MS:218.2 (M+Na).
In a 50mL dry round bottom flask, 0.98g (1 mmo 1), 2mLDMF,2mLH of C-40- (2-azidoethyl) oxy rapamycin (Compound 4) was added 2 0, then 0.30mg (1.5 mmol) of ethyl 1-propynyl-4-piperidinecarboxylate (Compound I) and CuSO4.5H were added in this order 2 O0.8mg (0.032 mmol) and sodium ascorbate 22mg (0.11 mmol) were stirred at room temperature for 1 hour. TLC tracking detection reaction is finished, 100mL of water is added, then 200mL of ethyl acetate is used for extraction, 100mL of water is used for washing an organic phase for 3 times, the organic phase is dried by anhydrous sodium sulfate and then filtered by suction, the solvent is removed by reduced pressure, and then 0.85g (0.73 mmol) of white powder is obtained by column chromatography separation, namely 40-O- (3- (4)-piperidinyl) -1H-1,2, 3-triazol-1-yl) ethyl-oxy-rapamycin (compound I) in 73.4% yield, MS:1187.5 (M+Na).
The column chromatography uses petroleum ether and acetone as eluent.
The conformational features of compound I are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.90(s,1H),6.39(dd,J=14.8,10.8Hz,1H),6.35–6.26(m,1H),6.14(dd,J=15.1,10.2Hz,1H),5.97(d,J=10.6Hz,1H),5.54(dd,J=15.0,8.7Hz,1H),5.41(d,J=9.9Hz,1H),5.28(d,J=5.1Hz,1H),5.16(d,J=4.3Hz,1H),4.52(t,J=4.9Hz,2H),4.18(d,J=5.4Hz,1H),4.13(dt,J=7.0,4.8Hz,3H),3.99–3.92(m,2H),3.87(s,1H),3.84(s,2H),3.76(d,J=5.6Hz,1H),3.66(t,J=7.6Hz,1H),3.59–3.54(m,1H),3.43(d,J=10.7Hz,1H),3.38(s,1H),3.36(s,2H),3.33(s,3H),3.13(d,J=3.0Hz,3H),3.02(dd,J=7.6,3.1Hz,4H),2.75–2.66(m,2H),2.57(dd,J=16.8,6.5Hz,1H),2.34(d,J=12.5Hz,4H),2.05(s,2H),2.02–1.96(m,3H),1.94–1.83(m,5H),1.76(s,4H),1.74(s,1H),1.65(s,4H),1.61(d,J=5.3Hz,3H),1.47(s,5H),1.32(d,J=4.6Hz,2H),1.28(s,1H),1.26(s,3H),1.25(s,2H),1.23(s,1H),1.21(s,1H),1.18(s,1H),1.15(s,2H),1.09(d,J=6.7Hz,3H),1.05(d,J=6.4Hz,3H),0.99(d,J=6.4Hz,3H),0.95(d,J=6.5Hz,3H),0.90(d,J=6.7Hz,3H)。
13 C NMR(125MHz,CDCl 3 )δ215.20,208.21,192.75,174.41,169.26,166.73,140.60,140.00,136.04,135.73,133.53,130.20,130.00,129.43,126.56,126.47,98.47,84.73,84.28,83.13,82.73,77.27,77.16,75.52,68.24,67.17,60.55,60.41,59.28,57.27,55.89,51.25,50.80,46.57,44.21,41.50,40.85,40.53,40.20,38.94,38.27,35.83,35.08,33.79,33.11,32.79,31.49,31.19,29.89,29.69,27.21,27.05,25.27,21.49,21.07,20.66,16.24,15.97,15.85,14.20,13.64,13.25,10.18。
synthetic route to Compound I
2. In vitro experiments:
1. experimental cell
Human non-small cell lung cancer A549, human gastric cancer AGS, human bladder cancer 5637, human melanoma A375, human pancreatic cancer BXPC-3, human renal cancer cell ACHN, human prostate cancer cell PC-3, human neuroblastoma U251, human colon cancer HCT116, human breast cancer cell T47D, human cervical cancer CASKI, and human nasopharyngeal carcinoma CNE-2 were all purchased from Shanghai cell bank of the national academy of sciences.
2. Experimental procedure
2.1 sample preparation
Samples were dissolved in DMSO to a solubility of 10mol/L, and diluted to final concentrations of 0.1, 0.25, 0.5, 1, 2.5, 5, 10, and 20u mol/L, respectively.
2.2 cell culture
Tumor cells in the exponential growth phase were seeded in 96-well plates (cell concentration 10) 5 100 ul/well), for 24hr, adding 100 ul/well of fresh medium with drug, 3 duplicate wells per concentration, and blank control wells (medium only) as negative control, and 3 duplicate wells. Culturing was continued for 72hr, and the culture was terminated.
2.3SRB detection 1
Cells were stopped and 10% TCA 50ul was added to each well and fixed at 4℃for 1hr. Washing with distilled water for 5 times, naturally airing, adding 4mg/ml SRB solution for 50ul per well, dyeing for 30min at room temperature, discarding supernatant, and washing with 1% acetic acid for 5 times to remove non-specifically bound dye. 150ul of 10m mol/L Tris solution is added to each well, shaking is carried out for 5 minutes, OD value is measured by an enzyme label instrument at 540 wavelengths, and inhibition rate is calculated. Calculation of IC by conversion of inhibition Rate Using SPSS software 50 Values.
3. Results and analysis
3. In vivo experiments: experiment for inhibiting AGS (advanced glycemia) transplantation tumor of nude mice and human stomach cancer
In the early experiments, we found that the compound I can effectively inhibit proliferation of gastric cancer cells AGS, SGC7901 and MGC80-3 in vitro, induce apoptosis and block cell cycle in G 0 G 1 And can obviously inhibit the phosphorylation levels of P-mTOR, P-P70S6K1 and P-4EBP in mTOR signaling pathway. Next we explored whether compound I has activity in vivo for the treatment of gastric cancer.
1 Experimental materials
1.1 laboratory animals
Nude mice, male and female, 3-4 weeks old, weighing 15-20g, supplied by Shanghai Laike laboratory animal Co. Animals were kept at constant temperature (25-27 ℃), constant humidity (45% -50%), and all nude mice were kept in an SPF environment. The cages, the padding and the feed are all subjected to high-pressure sterilization treatment. The drinking water, feed and padding after autoclaving were replaced every 3 days.
1.2 gastric cancer cells
Human gastric cancer cell AGS is purchased from Shanghai cell bank of the Chinese sciences.
2 method
2.1 cell culture: in vitro experiments
2.2 preparing a nude mouse tumor-bearing model:
establishing human gastric cancer AGS cell nude mice transplantation tumor model by subcutaneous injection, taking 0.2ml AGS cell suspension (about 3×10) 6 Gastric cancer cells) were injected subcutaneously in the left side rib of nude mice. After inoculation, the feed is fed normally and water is fed daily, and the feed can move freely.
2.3 grouping and drug treatment method:
to treat tumors as long as about 10mm in diameter, 7 female nude mice from tumor-bearing tumors were randomly divided into 3 groups. Group a blank (vehicle) (n=1+1); group B Rapamycin experimental groups (n=3+1); group C FIM X-145 experimental group (n=3+1). The stomach is irrigated once a day for 20 times. Animals were sacrificed after the end of the experiment and the transplanted tumors were isolated intact.
The following treatments were respectively performed:
group A: blank control group (propylene glycol: tween 20: ethanol=18:1:1)
Group B: 10mg/kg Rapamycin (propylene glycol: tween 20: ethanol=18:1:1)
Group C: 10mg/kg of Compound I (propylene glycol: tween 20: ethanol=18:1:1)
2.4 general observations:
observing the general condition of a nude mouse, measuring the tumor volume of the nude mouse transplanted one day before injecting the drug, then measuring the tumor volume every other day in the whole experimental process, measuring the tumor diameter by using a vernier caliper, and respectively measuring in two mutually perpendicular directions, wherein the calculation formula of the tumor volume is as follows: v=0.5ab 2 A represents the long diameter of the tumor, and b represents the wide diameter of the tumor. Tumor growth inhibition was calculated from the tumor growth curves of each group plotted against the change in measured tumor volume. Tumor growth inhibition = (1-change in tumor volume in treated group/change in tumor volume in control group) ×100%.
3 results
3.1 Effect of each treatment group on the volume of human gastric cancer AGS cell tumor-bearing nude mice transplanted tumor
After the human gastric cancer AGS cell tumor-bearing nude mice are treated in a control group, a rapamycin group and a compound I group, the transplanted tumor volumes of the three groups of nude mice are observed to be obviously different by naked eyes, the long diameter and the wide diameter of the transplanted tumor are measured and recorded every other day, and the measured results are substituted into a calculation formula of the transplanted tumor volume. The tumor volume calculation formula is: v=0.5ab 2 A represents the long diameter of the tumor, and b represents the wide diameter of the tumor. As shown in the results of FIG. 1, the control tumors were progressively larger, whereas the compound I group, the Rapamycin group, was significantly smaller than the blank volume (p<0.05 Significant) differences, group I compounds less than group Rapamycin (p<0.01 The difference is significant. The compound I group and the Rapamycin group can obviously inhibit the growth of AGS transplanted tumors, the tumor volume is reduced, and the compound I has stronger tumor growth inhibition effect than the Rapamycin.
3.2 Change in the microvascular Density (CD 34) of tumor-bearing nude mice transplanted with human gastric cancer AGS cells
Microvascular density (microvessel density, MVD) was measured as CD34 positive (FIG. 2), results were analyzed with image pro plus, data were compared using one-way anova and LSD-t test. The results showed that the MVD values of the Rapamycin group, the compound I group and the control group were maximal, the MVD values of the nude mice transplantable tumors of each drug group were significantly reduced, the differences were statistically significant (P < 0.05), and the compound I group was lower than the Rapamycin treated group, the differences were significantly significant (P < 0.05), as shown in fig. 3. It is speculated that compound I, rapamycin may inhibit graft tumor growth by inhibiting angiogenesis.
3.3 expression of human gastric cancer AGS cell tumor-bearing nude mice transplanted tumor tissue cell (CC 3)
Apoptosis of human gastric cancer AGS cell tumor-bearing nude mice transplanted tumor cells was measured by CC3 (clear Caspase-3) positive (FIG. 4), and the results were analyzed by image pro plus to calculate the percentage of CC3 positive cells to total cells, and the data were compared by single factor analysis of variance and LSD-t test. As shown in the results of fig. 5, the compound I group and the Rapamycin group were significantly different in apoptosis (p < 0.05) from the control group in the transplanted tumor cells of each treatment group, and the compound I group was higher in apoptosis ratio than the Rapamycin group (p < 0.05), and the difference was statistically significant.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that the specific embodiments described are illustrative only and not intended to limit the scope of the invention, and that equivalent modifications and variations of the invention in light of the spirit of the invention will be covered by the claims of the present invention.
Claims (5)
1. An application of rapamycin derivatives in preparing antitumor drugs, which is characterized in that: the rapamycin derivative is 40-O- (3- (4-piperidinecarboxylic acid ethyl ester) -1H-1,2, 3-triazole-1-yl)) ethyl rapamycin, and the structural formula is as follows:
the tumor is human non-small cell lung cancer, human gastric cancer, human bladder cancer, human melanoma, human pancreatic cancer, human renal cancer, human prostate cancer, human neuroblastoma, human colon cancer, human breast cancer, human cervical cancer or human nasopharyngeal carcinoma.
2. The use according to claim 1, characterized in that: the antitumor drug comprises a drug for inhibiting tumor growth or inhibiting proliferation of tumor cells.
3. The use according to claim 1, characterized in that: the antitumor drug comprises a drug for promoting or inducing apoptosis of tumor cells.
4. The use according to claim 1, characterized in that: the antitumor drug includes a drug for inhibiting angiogenesis.
5. The use according to claim 1, characterized in that: the antitumor drug comprises a drug for inhibiting the growth of the transplanted tumor.
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