CN107693517B - Application of axitinib and PX-478 in treatment of nasopharyngeal carcinoma - Google Patents
Application of axitinib and PX-478 in treatment of nasopharyngeal carcinoma Download PDFInfo
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- A—HUMAN NECESSITIES
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- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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Abstract
The invention discloses PX-478 and application of combination of axitinib and PX-478 in treating nasopharyngeal carcinoma. The invention discovers for the first time that PX-478 can obviously inhibit the formation of VM of nasopharyngeal carcinoma cells and the growth of transplanted tumor thereof, and has obvious curative effect on nasopharyngeal carcinoma. Meanwhile, researches find that the combination of the axitinib and the PX-478 realizes the synergistic effect and has more obvious treatment effect on nasopharyngeal carcinoma. The invention not only provides new application of the axitinib and the PX-478, but also provides a new treatment medication scheme for treating the nasopharyngeal carcinoma, and has good application prospect in the aspect of preventing and treating the nasopharyngeal carcinoma.
Description
Technical Field
The invention belongs to the technical field of medicines. More particularly, it relates to the use of Axitinib and PX-478 for the treatment of nasopharyngeal carcinoma.
Background
Nasopharyngeal carcinoma is one of the malignant tumors in China, and the incidence rate is the first of the malignant tumors of ear, nose and throat. Nasopharyngeal carcinoma is mostly of moderate sensitivity to radiotherapy, which is the first choice for treatment of nasopharyngeal carcinoma.
However, radiotherapy may cause many complications, (1) systemic reactions including weakness, dizziness, decreased appetite, nausea, vomiting, tastelessness or taste in the mouth, insomnia or somnolence, etc., individual patients may have a change in blood picture, especially a decrease in white cell count, (2) local reactions including skin, mucous membrane and salivary gland reactions, skin reactions including dry dermatitis or even wet dermatitis, and mucosal reactions including congestion, edema, exudation and secretion accumulation of nasopharynx and oropharynx mucous membranes, and a few patients may have parotid swelling after 2Gy irradiation, and when 40Gy irradiation is performed, saliva secretion is significantly decreased, and oral mucous membrane secretion is increased, mucous membrane congestion and redness, and patients have difficulty in dry eating, and ③ radiation therapy withdrawal symptoms including temporomandibular joint dysfunction and soft tissue atrophy fibrosis, radioactive caries, radioactive osteomyelitis and radioactive encephalomyelitis, and at present, there is no reversible and appropriate method.
Moreover, most patients are in the middle and late stage at clinic, and for the cases with low differentiation of cancer, late course of disease and recurrence after radiotherapy, the recurrence and metastasis often occur even after the treatment by normal means of nasopharyngeal carcinoma such as surgery, radiotherapy and chemotherapy.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects of the existing nasopharyngeal carcinoma treatment technology and providing a novel nasopharyngeal carcinoma treatment medicine. The invention discovers for the first time that both the axitinib and the PX-478 can obviously inhibit the growth of nasopharyngeal carcinoma cell transplantable tumors, have obvious curative effect on nasopharyngeal carcinoma, realize the synergistic effect by combining the axitinib and the PX-478, have more obvious curative effect and can be applied to the prevention and treatment of the nasopharyngeal carcinoma.
The invention aims to provide application of PX-478 in preparation of a medicine for treating nasopharyngeal carcinoma.
The invention also aims to provide application of the axitinib and the PX-478 in preparing a medicine for treating nasopharyngeal carcinoma.
The above purpose of the invention is realized by the following technical scheme:
the invention provides application of PX-478 in preparation of a medicine for treating nasopharyngeal carcinoma.
The invention also provides application of the axitinib and the PX-478 in preparation of medicines for treating nasopharyngeal carcinoma.
Particularly preferably, the medicine for treating nasopharyngeal carcinoma refers to a medicine for inhibiting the growth of nasopharyngeal carcinoma.
More specifically, said inhibition of nasopharyngeal carcinoma growth means inhibition of the growth of nasopharyngeal carcinoma cells.
Further, preferably, the nasopharyngeal cancer is EBV-positive nasopharyngeal cancer. Because more than 98% of nasopharyngeal carcinoma patients are EBV positive clinically, the experiment of the invention is carried out by taking EBV positive nasopharyngeal carcinoma as an example.
The invention also provides a medicine for treating nasopharyngeal carcinoma, which contains PX-478.
Further effectively, the medicament also contains axitinib.
Preferably, the medicament is a medicament for treating EBV positive nasopharyngeal carcinoma.
In addition, the medicine can also comprise medically acceptable auxiliary materials or carriers, and can be prepared into different dosage forms or selected to be compounded with other medicines.
In the combined medication scheme of the invention, the axitinib is a tyrosine kinase targeted inhibitor, can resist the traditional neovascularization of tumors by inhibiting Vascular Endothelial Growth Factor Receptors (VEGFR) VEGFR1, VEGFR2 and VEGFR3, and PX-478 is a selective HIF-1 α inhibitor with oral activity.
The invention has the following beneficial effects:
the invention provides application of axitinib and PX-478 in treating nasopharyngeal carcinoma for the first time. The invention discovers for the first time that both the axitinib and the PX-478 can obviously inhibit the growth of nasopharyngeal carcinoma cell transplantation tumor, have obvious curative effect on nasopharyngeal carcinoma and can be applied to the prevention and treatment of the nasopharyngeal carcinoma.
Meanwhile, the invention also proves that the combination of the axitinib and the PX-478 has a synergistic effect for the first time, and has a more obvious treatment effect on nasopharyngeal carcinoma.
The invention not only provides new application of the axitinib and the PX-478, but also provides a new treatment medication scheme for treating the nasopharyngeal carcinoma, and has good application prospect in the aspect of preventing and treating the nasopharyngeal carcinoma.
Drawings
Figure 1 is a graph of the effect of axitinib on vascular endothelial cell vascularization.
FIG. 2 is a graph showing the effect of PX-478 on EBV-positive nasopharyngeal carcinoma cells VM.
FIG. 3 is a graph of the effect of axitinib and PX-478 on EBV-positive nasopharyngeal carcinoma cell transplant tumor size.
FIG. 4 is the immunohistochemical results of the effect of axitinib and PX-478 on EBV-positive nasopharyngeal carcinoma cell transplants.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Years of practical work of an inventor team shows that more than 98% of nasopharyngeal carcinoma patients are EBV positive clinically, so the experiment in the following examples shows that EBV positive nasopharyngeal carcinoma is taken as an example.
Example 1 Effect of Axitinib on vascular endothelial cell vascularization
1. Experimental Material
(1) Medicine preparation: axitinib, having the formula: C22H18N4OS, CAS No.: 319460-85-0
(2) Vascular endothelial cells: human Umbilical Vein Endothelial Cell (HUVEC)
(3) Commercially available matrigel.
2. Experiment grouping
(1) Control group: the blank, HUVEC, was not treated with any drug.
(2) Experimental groups: HUVEC were treated with axitinib.
3. Angiogenesis experiment for detecting influence of axitinib on HUVEC tube formation
(1) Thawing Matrigel at-20 deg.C, spreading 30 μ L in 96-well plate, and placing in 37 deg.C incubator for 30 min;
(2) HUVEC cells in logarithmic growth phase were resuspended in complete medium after trypsinization, and 200. mu.L (containing 5X 10 cells) were taken4Cells) were spread evenly onto Matrigel in 96-well plates;
(3) asitinib was added at a concentration of 1000nM and incubated at 37 ℃ in an incubator for 12 h.
(4) Cell tubulation in the case of inverted microscope.
4. Results of the experiment
The results are shown in fig. 1, which shows that the lumen of HUVEC is significantly reduced after treatment with axitinib, indicating that axitinib is able to resist vascular endothelial cell tubulation.
Example 2 Effect of PX-478 on EBV-Positive nasopharyngeal carcinoma cells VM
1. Experimental Material
(1) Medicine preparation: PX-478 having the formula: C13H20Cl4N2O3, CAS no: 685898-44-6
(2) Cancer cell: EBV-positive nasopharyngeal carcinoma cells (HNE 1-EBV, CNE2-EBV and TWO 3-EBV)
(3) Commercially available matrigel.
2. Experiment grouping
(1) Control group: blank control, i.e. cancer cells were not treated with any drug.
(2) Experimental groups: cancer cells were treated with PX-478.
3. Angiogenesis experiment for detecting influence of PX-478 on EBV positive nasopharyngeal carcinoma cells VM
(1) Thawing Matrigel at-20 deg.C, spreading 30 μ L in 96-well plate, and placing in 37 deg.C incubator for 30 min;
(2) subjecting HNE1-EBV, CNE2-EBV and TWO3-EBV cells in logarithmic growth phase to trypsinization, completely suspending in culture medium, and respectively taking 200μ L (containing 1X 10)5The above three cells) were uniformly plated on Matrigel in a 96-well plate;
(3) adding PX-478 with different concentrations, and incubating at 37 deg.C for 12 h.
(4) Cell tubulation in the case of inverted microscope.
4. Results of the experiment
The results are shown in FIG. 2, and the lumen of EBV-positive nasopharyngeal carcinoma cells was significantly reduced after treatment with PX-478, indicating that PX-478 could resist the formation of EBV-positive nasopharyngeal carcinoma cells VM.
Example 3 Effect of Axitinib in combination with PX-478 on EBV-Positive nasopharyngeal carcinoma cell transplantation tumors
1. Experimental Material
(1) Medicine preparation: axitinib (Axitinib) and PX-478
(2) Cancer cell: EBV positive nasopharyngeal carcinoma cell (CNE 2-EBV)
(3) Commercially available nude mice.
2. Experiment grouping
(1) Control group: blank control, i.e. cancer cells were not treated with any drug.
(2) Group of axitinib: EBV positive nasopharyngeal cancer cells were treated with axitinib.
(3) PX-478 group: EBV positive nasopharyngeal carcinoma cells were treated with PX-478.
(4) Axitinib + PX-478 group: EBV positive nasopharyngeal carcinoma cells were treated concurrently with axitinib and PX-478 PX-478.
3. Nude mouse subcutaneous tumor formation experiment for detecting influence of axitinib or/and PX-478 on EBV positive nasopharyngeal carcinoma cell transplantation tumor
(1) Are respectively 5 × 106Numerical EBV positive nasopharyngeal carcinoma cells (CNE 2-EBV) were implanted subcutaneously in the axilla of 40 3-4 weeks old NOD/SCID mice. Randomized into 4 groups: blank control group, Axitinib group, PX-478 group, and Axitinib + PX-478 group.
(2) When the size of subcutaneous tumor reaches 100-200 mm3The method comprises the following steps: the group of axitinib was given 2 times per mouse 30mg/kg of axitinib per day; PX-478 group administered 5m every other day to each mouseg/kg PX-4781 times; the group of Axitinib + PX-478 each mouse was administered 30mg/kg of Axitinib 2 times daily and 5mg/kg of PX-4781 times every other day.
(3) Tumor size was measured every 2 days and differences in tumor formation were compared between groups.
(4) After 2 weeks, the mice were sacrificed in short necks, tumor tissues were excised, fixed in neutral formalin, paraffin-embedded sections, examined histologically by HE staining, and examined for expression of markers CD31, PAS in immunohistochemical experiments.
4. Results of the experiment
The results are shown in fig. 3, the axitinib and the PX-478 can respectively resist the growth of the EBV positive nasopharyngeal carcinoma cell transplantable tumor, and the combination of the axitinib and the PX-478 has a more remarkable treatment effect on the EBV positive nasopharyngeal carcinoma transplantable tumor, so that the synergistic effect is realized.
In addition, as shown in fig. 4, immunohistochemical results showed that axitinib predominantly inhibited vascularization of CD 31-positive vascular endothelial cells in tumor tissues and PX-478 predominantly reduced vascularization of PAS-positive tumor cells. The combination of the axitinib and the PX-478 reduces the formation of the two blood vessels, and the combination of the axitinib and the PX-478 does not generate negative effects such as mutual inhibition and the like, thereby realizing the synergistic effect.
Claims (7)
1. Application of axitinib and PX-478 in preparation of medicine for treating nasopharyngeal carcinoma, wherein the chemical formula of PX-478 is C13H20Cl4N2O3CAS number 685898-44-6.
2. The use of claim 1, wherein the medicament for treating nasopharyngeal carcinoma is a medicament for inhibiting the growth of nasopharyngeal carcinoma.
3. The use of claim 2, wherein said inhibition of nasopharyngeal carcinoma growth is inhibition of growth of nasopharyngeal carcinoma cells.
4. The use according to any one of claims 1 to 3, wherein the nasopharyngeal carcinoma is EBV-positive nasopharyngeal carcinoma.
5. A medicine for treating nasopharyngeal carcinoma is characterized by comprising axitinib and PX-478, wherein the chemical formula of PX-478 is C13H20Cl4N2O3CAS number 685898-44-6.
6. The medicament of claim 5, wherein the nasopharyngeal cancer is EBV positive nasopharyngeal cancer.
7. The medicament of claim 5, further comprising a pharmaceutically acceptable adjuvant or carrier.
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| CN113893261B (en) * | 2021-06-22 | 2023-01-13 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | Application of circITGB6-ASO and platinum chemotherapeutic drug in preparation of drugs for treating ovarian cancer |
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Non-Patent Citations (3)
| Title |
|---|
| "A Novel Approach to Cancer Therapy using PX-478 as a HIFα Inhibitor";Kyeong Lee等;《Arch Pharm Res》;20111231;第34卷(第10期);第1583-1585页 * |
| "Preclinical activity of axitinib and its associated change of serum biomarkers in nasopharyngeal carcinoma";Hui EP等;《Cancer Res》;20121231;第72卷;第1373页 * |
| "鼻咽癌组织中Survivin 蛋白和HIF - 1α 表达水平及临床意义";明帮春等;《解放军医药杂志》;20170630;第29卷(第6期);第62-64，67页 * |
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