CN110694070A - Application of cytotoxic antitumor drug in preparation of tumor-related tissues - Google Patents
Application of cytotoxic antitumor drug in preparation of tumor-related tissues Download PDFInfo
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Abstract
The invention provides application of cytotoxic antitumor drugs in preparation of tumor-related tissues, and researches show that the drugs can obviously promote tumor growth under the administration condition of a certain concentration or dose lower than the conventional maximum tolerated dose, and the application of the drug can be used for establishing a tumor growth model, producing and culturing in vivo and in vitro tumor tissues and tumor cells, culturing tissue cells closely related to the growth of the tumor tissues in a tumor microenvironment, separating and extracting specific tissue components and the like.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to application of a cytotoxic antitumor drug in preparation of tumor-related tissues.
Background
Malignant tumors are one of the most major diseases causing human death. Tumor tissues have heterogeneity and consist of tumor cells, tumor stem cells, fibroblasts, endothelial cells, pericytes, lymphocytes, macrophages and other types of bone marrow-derived cells and local tissue-derived cells, and the tissue cells interact and influence through direct action or indirect ways such as secreting cytokines and the like to jointly form a tumor microenvironment. The tumor microenvironment contains cells, cytokines and compound components which can promote the growth of the tumor and also contains cells, cytokines and compound components which can inhibit the growth of the tumor. This complex heterogeneous nature of tumor tissue is one of the important causes that make tumors difficult to heal. However, some components in the above-mentioned cells, cytokines and compounds in tumor tissues also have the effect of inhibiting or promoting the growth of tumor or other cells, and some components in the above-mentioned cells, cytokines and compounds are obtained by the processes of culturing, separating, extracting and the like in vivo, in vitro or in combination, so that the tumor or other diseases has potential application prospects for treatment and research. In recent years, there is a cellular immunotherapy method in which immune cells are extracted from autologous or allogeneic tumor tissues, processed in vitro, and then returned to a patient for therapy.
However, the preparation of tumor-associated models, tissues, cells and related components is currently limited.
Disclosure of Invention
The invention provides an application of a cytotoxic antitumor drug in preparation of a tumor-related histiocyte material.
The invention is realized by the following technical scheme:
application of cytotoxic antitumor drug in preparing tumor-related tissue is provided.
Preferably, the cytotoxic antitumor drug is a drug acting on a DNA chemical structure, a drug interfering nucleic acid synthesis, a drug acting on nucleic acid transcription, a topoisomerase inhibitor acting on DNA replication, a drug interfering mitosis, methylisoindin, procarbazine, dacarbazine, sodium cantharidate, norcantharidin, tretinoin, arsenous acid or elemene.
Furthermore, the medicine acting on the chemical structure of the DNA is alkylating agent medicine, platinum medicine, anthracycline medicine or antibiotic for destroying the DNA; the medicine for interfering the nucleic acid synthesis is a dihydrofolate reductase inhibitor, a thymidylate synthase inhibitor, a purine nucleotide tautomerism inhibitor, a ribonucleotide reductase inhibitor, a DNA polymerase inhibitor or a DNA repair inhibitor; the drug acting on nucleic acid transcription is actinomycin D, aclacinomycin or praamycin; the topoisomerase inhibitor acting on DNA replication is a topoisomerase I inhibitor or a topoisomerase II inhibitor; the drug that interferes with mitosis is a drug that affects tubulin assembly, a drug that interferes with ribosome function to block protein synthesis, or a drug that affects amino acid supply to prevent protein synthesis.
Further, the alkylating agent is nitrogen mustard, cyclophosphamide, thiotepa, cyclophosphamide, ifosfamide, melphalan, carmustine, lomustine, semustine, nimustine, fotemustine, estramustine, azomethine, nitramustine, mechlorethamine phthalate, chlorambucil, hexamethylmelamine, busulfan or temozolomide; the platinum drug is carboplatin, cisplatin, oxaliplatin, sulplatin, lobaplatin or nedaplatin; the anthracycline is daunorubicin, doxorubicin, epirubicin, pirarubicin, idarubicin, mitoxantrone or aclarubicin; the antibiotic for destroying DNA is mitomycin, bleomycin or pingyangmycin.
Further, the dihydrofolate reductase inhibiting drug is methotrexate, pemetrexed or raltitrexed; the thymidylate synthase inhibitor is fluorouracil, tegafur, difurofluorouracil, deoxyfluoroguanosine, carmofur, capecitabine, methylisoindole, tegafur or eufordine; the purine nucleotide tautomerism inhibitor is mercaptopurine or thioguanine; the ribonucleotide reductase inhibitor is hydroxyurea; the DNA polymerase inhibitor is cytarabine, azacytidine, gemcitabine, decitabine, ancitabine or fludarabine; the DNA repair inhibitor is cladribine.
Further, the topoisomerase I inhibitor is irinotecan, topotecan, camptothecin or hydroxycamptothecin; the topoisomerase II inhibitor is podophyllotoxin, etoposide, teniposide or amsacrine.
Further, the tubulin assembly affecting drug is vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, taxotere or docetaxel; the protein synthesis medicine for interfering with the function retardation of the ribosome is harringtonine or homoharringtonine; the drug that affects the supply of amino acids to prevent protein synthesis is asparaginase.
Preferably, the tumor-associated tissue is a solid benign or malignant tumor characterized by a solid mass.
Preferably, the tumor-associated tissue is sarcoma, lung cancer, melanoma, breast cancer, liver cancer, lymph cancer, pancreatic cancer, bone cancer, myeloma, and tumors occurring in the digestive system, genitourinary system, nervous system, circulatory system, endocrine system, skin, or skeletal tissue.
Preferably, the tumor-related tissue is tumor-bearing animal, tumor tissue, tumor cell, tumor stem cell or tumor microenvironment tissue cell, or a substance component produced by tumor tissue, tumor cell, tumor stem cell or tumor microenvironment tissue cell.
Compared with the prior art, the invention has the following beneficial technical effects:
the invention discovers that the low-dose cytotoxic chemotherapy medicament shows abnormal effect of promoting the growth of the tumor in certain dose range occasionally in the research. Through further research, the pharmacological effect of promoting the tumor growth is not only observed on a certain cytotoxic drug or a certain tumor strain, but also observed on other tested cytotoxic drugs of other classes, and similar responses are shown when different tumor strains are selected for testing. Therefore, this phenomenon is common among cytotoxic chemotherapeutic drugs.
The invention selects various cytotoxic antitumor drugs with different action mechanisms, such as cyclophosphamide, 5-fluorouracil, methotrexate, cisplatin and the like, and systematically observes the influence of the drugs on the growth of different solid tumors of mice by single or multiple times of drug administration within a larger administration dose range lower than the conventional treatment dose. The research results show that under certain concentration or dosage conditions lower than the conventional maximum tolerated dosage, the medicine shows the effect of obviously promoting the growth of tumors or the proliferation of tumor cells. The phenomenon can be used for accelerating the growth of tumors and preparing tumor-bearing animals; the medicine can be used for producing and culturing in vivo or in vitro tumor tissues and tumor microenvironment cells by utilizing the tumor growth promoting effect of the medicine, and further can be used for separating and extracting the tumor tissues, the tumor cells and substance components contained in the tumor tissues and the tumor cells, and finally is applied to research, development or treatment. Therefore, tumor-bearing animals, tumor tissues, tumor cells, tissue cells related to tumor microenvironment, tumor cell factors and substance components can be obtained by using the medicine, and the potential value of the medicine for commercial application is realized. The growth of the tumor tissue cells or the generation of related substance components is promoted by a drug stimulation method, which is beneficial to the acquisition of related materials and has potential application of further research, popularization and commercialization.
Drawings
FIG. 1 is a graph of the growth of S180 tumors in mice promoted by low doses of cyclophosphamide; A. tumor growth status, b. tumor weight of different dosing groups, injections: p <0.01vs NS; NS is normal saline.
Figure 2 is a graph of the growth of S180 tumors in mice promoted by low dose methotrexate; A. tumor growth status, b. tumor weight of different dosing groups, injections: p <0.05, P <0.01vs Control.
FIG. 3 is a graph of the growth of S180 tumors in mice promoted by low doses of 5-fluorouracil; A. tumor growth status, b. tumor weight of different dosing groups, injections: p <0.01vs NS; NS is normal saline.
FIG. 4 is a graph showing that low doses of cisplatin promote growth of S180 tumors in mice; A. tumor growth status, b. tumor weight of different dosing groups, injections: p <0.05vs NS; NS is normal saline.
FIG. 5 is a graph of the growth of tumors in low dose cyclophosphamide promoted in S180 mice; A. tumor growth status b. tumor weight of different dosing groups, injections: p <0.05vs NS; NS is normal saline.
FIG. 6 is a graph of the growth of mouse B16 tumor promoted by low dose cyclophosphamide; A. tumor growth status, b. tumor weight of different dosing groups, injections: p <0.05vs NS; NS is normal saline.
Figure 7 is a graph of low dose methotrexate promoting growth of mouse B16 tumors; A. tumor growth status b. tumor weight of different dosing groups, injections: p <0.05vs NS; NS is normal saline.
FIG. 8 is a graph of the growth of mouse B16 tumor promoted by low dose 5-fluorouracil; A. tumor growth status b. tumor weight of different dosing groups, injections: p <0.05vs NS; NS is normal saline.
FIG. 9 is a graph of the growth of mouse B16 tumor promoted by low dose cisplatin; A. tumor growth status, b. tumor weight of different dosing groups, injections: p <0.05vs NS; NS is normal saline.
FIG. 10 shows that low doses of cyclophosphamide promote the growth of Lewis lung carcinoma in mice; A. tumor growth status b. tumor weight of different dosing groups, injections: p <0.01vs NS; NS is normal saline.
FIG. 11 is a graph of tumor microvascular density promoted by low dose cyclophosphamide or 5-fluorouracil; note: p <0.001 vsNS; NS is normal saline.
Figure 12 is the effect of low concentration of 5-FU on tumor cell proliferation, migration and invasiveness a. cell proliferation b. cell migration c. cell migration d. cell invasion, note: p <0.05, P <0.01vs Control.
FIG. 13 is a graph of conditioned medium stimulation of myeloid-derived cells with 5-FU to promote proliferation of B16 tumor cells or umbilical vein endothelial cells, injected with: p <0.05vs Control.
Detailed Description
In order to further understand the technical features of the present invention, the present invention is described in detail below with reference to the specific drawings and embodiments. The embodiments are only specific descriptions of the technical solutions of the present invention, and do not limit the present invention, and the protection scope of the present invention is not limited to these embodiments. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
The research result of the invention shows that the low-dose single or multiple administration of the cytotoxic antitumor drug has the pharmacological effect of promoting the growth of the tumor, and the related cytotoxic antitumor drug comprises the following drugs which are used independently or in combination: (1) alkylating agents acting on the chemical structure of DNA, such as nitrogen mustard, cyclophosphamide, thiotepa, cyclophosphamide, ifosfamide, carmustine, lomustine, semustine, nimustine, fotemustine, estramustine, azomethine, nitramustine, mechlorethamine phthalate, hexamethylmelamine, busulfan, temozolomide, etc.; (2) platinum drugs such as carboplatin, cisplatin, oxaliplatin, lobaplatin, nedaplatin, and the like; anthracyclines, such as daunorubicin, doxorubicin, epirubicin, pirarubicin, mitoxantrone, aclarubicin, and the like; (3) DNA damaging antibiotics such as mitomycin, bleomycin, pingyangmycin and the like; (4) dihydrofolate reductase inhibitors which interfere with the synthesis of nucleic acids, such as methotrexate, pemetrexed and the like; (5) thymidylate synthase inhibitors such as fluorouracil, tegafur, deoxyfluoroguanosine, carmofur, capecitabine, tegafur, and idoxuridine; (6) purine nucleotide tautomerism inhibitors such as mercaptopurine, thioguanine, and the like; (7) ribonucleotide reductase inhibitors such as hydroxyurea and the like; (8) DNA polymerase inhibitors such as cytarabine, gemcitabine, fludarabine, etc.; (9) drugs acting on nucleic acid transcription, such as actinomycin D, aclacinomycin, praramycin and the like; (10) topoisomerase I inhibitors acting on DNA replication, such as irinotecan, topotecan or hydroxycamptothecin, etc.; (11) topoisomerase II inhibitors such as etoposide, teniposide, amsacrine, and the like; (12) drugs that interfere with mitosis and affect tubulin assembly, such as vinblastine, vincristine, vindesine, vinorelbine, paclitaxel or docetaxel, and the like; (13) protein synthesis-retarding agents that interfere with the function of the ribosome, such as homoharringtonine; (14) drugs that affect the supply of amino acids and prevent protein synthesis, such as asparaginase and the like; (15) other classes of antineoplastic drugs with tumor cytotoxicity, such as methylisoindin, procarbazine, dacarbazine, norcantharidin, tretinoin, asparaginase, arsenous acid, elemene, etc.
The cytotoxic antitumor drug also comprises a pharmaceutically acceptable salt, a pharmaceutically acceptable modified structure and/or a mixture containing other auxiliary components. Can be made into oral preparation, injection, inhalation preparation, topical preparation or external preparation, and the preparation comprises quick release preparation, sustained release preparation or controlled release preparation.
The low dose single or multiple administration of the cytotoxic antineoplastic agent is administered at a single dose that is any dose below the single maximum tolerated dose of the agent. The frequency of administration is from a single administration to multiple divided doses per day or continuous daily administration. The drug may be administered at regular time, fixed frequency, or at irregular time, fixed or non-fixed frequency.
The cytotoxic antitumor drug can promote tumor growth on various animals such as mice, animal tissues and cells thereof, and also can promote tumor growth on human and human tissues and cells.
The tumor types include, but are not limited to, sarcomas, lung cancers, melanomas, breast cancers, liver cancers, lymphatic cancers, pancreatic cancers, bone cancers, as well as tumors occurring in the digestive system, tumors occurring in the urogenital system, tumors occurring in the nervous system, tumors occurring in the circulatory system, tumors occurring in the endocrine system, and other types of solid tumors.
The cytotoxic antitumor drug has the effect of promoting tumor growth through but not limited to direct effect on tumor cells or/and indirect effect on bone marrow-derived cells, endothelial cells and other tumor microenvironment cells.
The preparation of the tumor-related tissue comprises in-vivo or in-vitro preparation methods or processes, the preparation range comprises but is not limited to in-vivo tumor-bearing animals or tumor tissues, in-vitro tumor tissues or tumor tissue components, in-vitro tumor cells, tumor stem cells or tumor microenvironment tissue cells, and various cytokines or compound products are obtained by using the medicine and the tumor tissues, the tumor cells, the tumor stem cells or the tumor microenvironment tissue cells. Tumor microenvironment tissue cells include, but are not limited to, fibroblasts, pericytes, endothelial cells, immune cells, bone marrow derived cells in tumor tissue.
The invention researches the influence of low dose of cytotoxic antitumor drugs on tumor growth under the condition of single or multiple administration. Specific examples are as follows.
Example 1
Effect of Low dose cytotoxic antitumor drugs on the growth of sarcoma tumor in S180 mice
(1) Effect of Low dose Cyclophosphamide (CTX) on S180 tumor growth
Kunming mice vaccinated S180 tumors subcutaneously were randomly divided into 6 groups: control group, 10mg/kg CTX group, 20mg/kg CTX group, 40mg/kg CTX group, 60mg/kg CTX group, and 80mg/kg CTX group. The CTX low-dose abdominal cavity is administrated at intervals for multiple times, and the medicine has two-way effect on S180 tumor growth: at lower doses, tumor growth increased with increasing drug dose, showing a significant promoting effect; when the dosage of cyclophosphamide reaches a certain action dosage, the effect of inhibiting the growth of the tumor is also shown. (as shown in FIG. 1)
(2) Effect of Low dose Methotrexate (MTX) on S180 tumor growth
Kunming mice inoculated S180 tumors subcutaneously were randomly divided into 5 groups: control group, 0.625mg/kg MTX group, 1.25mg/kg MTX group, 2.5mg/kg MTX group and 5mg/kg MTX group, were administered intraperitoneally at low dose intervals. The results show that the low-dose MTX shows obvious promotion effect on S180 tumor growth under the dosage of 0.625mg/kg, 1.25mg/kg and 0.25 mg/kg. (as shown in FIG. 2)
(3) Effect of Low dose 5-Fluorouracil (5-FU) on S180 tumor growth
50 Kunming mice subcutaneously inoculated with S180 were randomly divided into 5 groups: a control group, a 1mg/kg5-FU group, a 3mg/kg5-FU group, a 10mg/kg 5-FU group and a 30mg/kg 5-FU group, and a low dose was administered intraperitoneally at intervals of multiple times. As a result, the low dose of 5-FU has a significant effect on the promotion of S180 tumor growth. (as shown in FIG. 3)
(4) Effect of Low dose Cisplatin (CDDP) on S180 tumor growth
40 Kunming mice were inoculated S180 tumor cells by subcutaneous injection, and randomly divided into 5 groups: saline group, 0.375mg/kg CDDP group, 0.75mg/kg CDDP group, 1.5mg/kg CDDP group, and 3mg/kg CDDP group. 24h after inoculation, the corresponding dose of CDDP was given intraperitoneally as described above in groups, followed by administration intraperitoneally once every 48 h. Mice were sacrificed after day 11, tumor tissue was isolated and weighed. The results indicate that therapeutic doses of cisplatin reduced S180 tumor growth, and below this dose, showed tumor growth promoting effects. (as shown in FIG. 4)
(5) Effect of Low dose Cyclophosphamide (CTX) on tumor growth in S180 tumor-bearing mice
When the average tumor volume of tumor-bearing mice is about 100mm3At time, mice were randomly divided into 5 groups: control group, 10mg/kg CTX group, 20mg/kg CTX group, 40mg/kg CTX group and 80mg/kg CTX group, 7 of each group. When the tumor volume of S180 reaches 100mm3The latter low dose was administered every other day by intraperitoneal injection, and the control group was given physiological saline. The results show that the low-dose medicament obviously promotes the growth of the tumorPerforming the action; when a certain action dosage is reached, the promotion effect of the medicine on the growth of the tumor is weakened or disappears. (as shown in FIG. 5)
Example 2
Effect of Low dose cytotoxic antitumor drugs on melanoma tumor growth in B16 mice
(1) Effect of Low dose Cyclophosphamide (CTX) on B16 tumor growth
36C 57BL/6 mice vaccinated subcutaneously with B16 were randomly divided into 6 groups: control group, 2.5mg/kg CTX group, 5mg/kg CTX group, 10mg/kg CTX group, 20mg/kg CTX group and 40mg/kg CTX group, were administered intraperitoneally at low dose intervals. The results indicate that the CTX low dose interval also exhibits some bilateral effects on B16 tumor growth: at a lower dose, the tumor growth is increased along with the increase of the drug dose, and the drug has obvious promotion effect on the tumor growth; when the dosage of cyclophosphamide reaches a certain action dosage, the effect of inhibiting the growth of the tumor is also shown. (as shown in FIG. 6)
(2) Effect of Low dose Methotrexate (MTX) on B16 tumor growth
30 female C57BL/6 mice vaccinated with B16 melanoma cells were randomly divided into 5 groups: control group, 0.625mg/kg MTX group, 1.25mg/kg MTX group, 2.5mg/kg MTX group and 5mg/kg MTX group, were administered intraperitoneally at low dose intervals. The results show that multiple MTX doses have a bidirectional effect on the growth of B16 melanoma; at lower doses, the growth of B16 tumors increased with increasing MTX dose, MTX promoting the growth of B16 tumors; as the dose of MTX continued to increase, MTX showed an inhibitory effect on the growth of B16 tumors. (as shown in FIG. 7)
(3) Effect of Low dose 5-Fluorouracil (5-FU) on B16 tumor growth
36C 57BL/6 mice vaccinated subcutaneously with B16 were randomly divided into 6 groups: the control group, the 1mg/kg5-FU group, the 3mg/kg5-FU group, the 10mg/kg 5-FU group, the 30mg/kg 5-FU group and the 60mg/kg5-FU group were administered intraperitoneally at low dose intervals. The result shows that the low dose of 5-FU has obvious promotion effect on the growth of B16 tumor. (as shown in FIG. 8)
(4) Effect of Low dose Cisplatin (CDDP) on B16 tumor growth
The inoculated C57BL/6 mice 40 were randomly divided into 5 groups: saline group, 0.05mg/kg group, 0.19mg/kg group, 0.75mg/kg group, and 3mg/kg group. 24h after inoculation, the corresponding dose of cisplatin was given as a group intraperitoneal injection, followed by intraperitoneal administration once every 48 h. The results show that therapeutic doses of cisplatin significantly reduced tumor growth, and below this dose, an increased tumor growth effect was exhibited. (as shown in FIG. 9)
Example 3
Effect of Low dose Cyclophosphamide (CTX) on tumor growth in Lewis Lung cancer mice
18C 57BL/6 mice vaccinated subcutaneously with Lewis lung carcinoma were randomly divided into 3 groups: control, 20mg/kg CTX and 40mg/kg CTX groups, were administered intraperitoneally at low doses several times at intervals, and animals were sacrificed after 28 days. The results show that low dose of CTX significantly promotes the growth of Lewis lung cancer. (as shown in FIG. 10)
Example 4
Effect of Low dose cytotoxic antitumor drugs on tumor angiogenesis
Mice were inoculated with B16 melanoma and administered intraperitoneally every other day, animals were sacrificed 7 times after administration, tumor tissues were dissected, and paraffin embedding and sectioning of tumor tissues were performed. Staining of CD31 on tumor tissue sections using immunohistochemical methods labeled blood vessels. The result shows that the low-dose Cyclophosphamide (CTX) or 5-fluorouracil (5-FU) has obvious promotion effect on the B16 tumor angiogenesis, and the promotion of the tumor angiogenesis is an important way for promoting the tumor growth by the low-dose CTX and 5-FU. (as shown in FIG. 11)
Example 5
Effect of Low dose cytotoxic antitumor drugs on tumor cell function
The influence of cytotoxic drugs on the proliferation, migration and invasion capabilities of B16 tumor cells is determined by taking low-dose 5-fluorouracil (5-FU) as a representative. The influence of 5-FU concentrations of 0. mu.M, 0.4. mu.M, 2. mu.M, 10. mu.M and 50. mu.M on the proliferation, migration and invasion number of B16 tumor cells was observed in vitro by using a cell proliferation experiment, a scratch experiment, a Transwell migration experiment and a Transwell invasion experiment, respectively. The results show that 5-FU reduced the proliferation potency of B16 tumor cells after 48h in vitro culture, with statistical differences between 5-FU concentrations of 2. mu.M, 10. mu.M and 50. mu.M. However, the scratch results show that the mean migration distance of B16 cells in the 0.4. mu.M, 2. mu.M, 10. mu.M and 50. mu.M groups was significantly greater than that in the control group after the group-fed culture for 12h and 24 h. The Transwell migration results showed that the number of B16 cell migrations was increased in the 0.4 μ M group, the 2 μ M group, the 10 μ M group, and the 50 μ M group compared to the control group, and they were all statistically different. The Transwell invasion results show that the numbers of B16-invaded cells of the 0.4. mu.M group, the 2. mu.M group, the 10. mu.M group and the 50. mu.M group are increased compared with the control group, and the differences are significant. From the above results, it is clear that low concentration of 5-FU can significantly promote the migration and invasion ability of B16 melanoma cells. (as shown in FIG. 12)
Example 6
Effect of 5-FU-stimulated bone marrow-derived cell (BMDCs) conditioned Medium on proliferation of B16 tumor cells or umbilical vein endothelial cells (HUVECs)
BMDCs were stimulated with 5-FU at various concentrations for 48h to obtain conditioned medium, which was added to a 96-well plate containing 3X 103B 16 cells per well for culture, and after 48h proliferation of B16 was analyzed. The results show that the BMDCs conditioned medium without drug stimulation had no significant effect on proliferation of B16 cells compared to the control group without BMDCs; the 0.4. mu.M, 2. mu.M, 10. mu.M and 50. mu.M 5-FU-stimulated BMDCs conditioned medium promoted tumor cell proliferation compared to the 0. mu.M 5-FU group without drug stimulation, and the difference was statistically significant at concentrations of 2. mu.M and 10. mu.M. Similar to tumor cells, conditioned medium with 0 μ M5-FU stimulating BMDCs had no significant effect on HUVECs proliferation; conditioned media from BMDCs stimulated with 0.4. mu.M, 2. mu.M and 10. mu.M 5-FU promoted cell proliferation of HUVECs compared to 0. mu.M 5-FU, with statistical differences between the 10. mu.M 5-FU group and inhibition of HUVECs proliferation in the 50. mu.M group. The result shows that the 5-FU can indirectly play the roles of promoting the proliferation of tumor cells and promoting the angiogenesis through the ways of BMDCs and the like. (as shown in FIG. 13)
The foregoing is merely a preferred embodiment of the present invention, which is described in some detail and with reference to specific details, but is not to be construed as limiting the scope of the invention. The examples of the combination of more than one of the drugs are not listed here. The spirit and scope of the present invention is broadly defined in the appended claims, and any other technical entity or method implemented by another person without departing from the spirit of the invention is intended to be covered by the claims if it is identical to or equivalent to the claims.
Claims (10)
1. Application of cytotoxic antitumor drug in preparing tumor-related tissue is provided.
2. The use according to claim 1, wherein said cytotoxic antineoplastic agent is a drug acting on DNA chemical structure, a drug interfering with nucleic acid synthesis, a drug acting on nucleic acid transcription, a topoisomerase inhibitor acting on DNA replication, a drug interfering with mitosis, methylisoindoline, procarbazine, dacarbazine, sodium cantharidine, norcantharidin, tretinoin, arsenous acid or elemene.
3. The use according to claim 2, wherein the drug acting on the chemical structure of DNA is an alkylating drug, a platinum drug, an anthracycline drug or a DNA-damaging antibiotic; the medicine for interfering the nucleic acid synthesis is a dihydrofolate reductase inhibitor, a thymidylate synthase inhibitor, a purine nucleotide tautomerism inhibitor, a ribonucleotide reductase inhibitor, a DNA polymerase inhibitor or a DNA repair inhibitor; the drug acting on nucleic acid transcription is actinomycin D, aclacinomycin or praamycin; the topoisomerase inhibitor acting on DNA replication is a topoisomerase I inhibitor or a topoisomerase II inhibitor; the drug that interferes with mitosis is a drug that affects tubulin assembly, a drug that interferes with ribosome function to block protein synthesis, or a drug that affects amino acid supply to prevent protein synthesis.
4. The use according to claim 3, wherein the alkylating agent is nitrogen mustard, cyclophosphamide, thiotepa, cyclophosphamide, ifosfamide, melphalan, carmustine, lomustine, semustine, nimustine, fotemustine, estramustine, mechlorethamine, nitramustine, chlorambucil, mechlorethamine phthalate, hexamethylmelamine, busulfan or temozolomide; the platinum drug is carboplatin, cisplatin, oxaliplatin, lobaplatin, sulplatin or nedaplatin; the anthracycline is daunorubicin, doxorubicin, epirubicin, pirarubicin, idarubicin, mitoxantrone or aclarubicin; the antibiotic for destroying DNA is mitomycin, bleomycin or pingyangmycin.
5. The use according to claim 3, wherein the dihydrofolate reductase inhibitor is methotrexate, pemetrexed or raltitrexed; the thymidylate synthase inhibitor is fluorouracil, tegafur, difurofluorouracil, deoxyfluoroguanosine, carmofur, capecitabine, methylisoindole, tegafur or eufordine; the purine nucleotide tautomerism inhibitor is mercaptopurine or thioguanine; the ribonucleotide reductase inhibitor is hydroxyurea; the DNA polymerase inhibitor is cytarabine, azacytidine, gemcitabine, decitabine, ancitabine or fludarabine; the DNA repair inhibitor is cladribine.
6. The use according to claim 3, wherein the topoisomerase I inhibitor is irinotecan, topotecan, camptothecin or hydroxycamptothecin; the topoisomerase II inhibitor is podophyllotoxin, etoposide, teniposide or amsacrine.
7. The use according to claim 3, wherein the drug affecting tubulin assembly is vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, taxotere or docetaxel; the protein synthesis medicine for interfering with the function retardation of the ribosome is harringtonine or homoharringtonine; the drug that affects the supply of amino acids to prevent protein synthesis is asparaginase.
8. The use of claim 1, wherein the tumor-associated tissue is a solid benign or malignant tumor characterized by a solid mass.
9. The use of claim 1, wherein the tumor-associated tissue is sarcoma, lung cancer, melanoma, breast cancer, liver cancer, lymph cancer, pancreatic cancer, bone cancer, myeloma, and tumors occurring in the digestive system, genitourinary system, nervous system, circulatory system, endocrine system, skin, or skeletal tissue.
10. The use of claim 1, wherein the tumor-associated tissue is a tumor-bearing animal, a tumor tissue, a tumor cell, a tumor stem cell or a tumor microenvironment tissue cell, or a composition of matter produced by a tumor tissue, a tumor cell, a tumor stem cell or a tumor microenvironment tissue cell.
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| CN112048475A (en) * | 2020-08-25 | 2020-12-08 | 北京科途医学科技有限公司 | Method for culturing chordoma organoid, transplant and culture medium |
| CN114377067A (en) * | 2020-10-22 | 2022-04-22 | 中国科学院上海营养与健康研究所 | Application of grape seed extract in preparation of drugs for targeted removal of tumor microenvironment senescent cells and inhibition of tumors |
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| WO2017062751A1 (en) * | 2015-10-08 | 2017-04-13 | The Regents Of The University Of California | Compounds and methods for promoting stress resistance |
| CN108403690A (en) * | 2018-05-15 | 2018-08-17 | 泰山医学院 | It is a kind of inhibit melanoma cells proliferation drug and its application |
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| WO2017062751A1 (en) * | 2015-10-08 | 2017-04-13 | The Regents Of The University Of California | Compounds and methods for promoting stress resistance |
| CN108403690A (en) * | 2018-05-15 | 2018-08-17 | 泰山医学院 | It is a kind of inhibit melanoma cells proliferation drug and its application |
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| CN112048475A (en) * | 2020-08-25 | 2020-12-08 | 北京科途医学科技有限公司 | Method for culturing chordoma organoid, transplant and culture medium |
| CN114377067A (en) * | 2020-10-22 | 2022-04-22 | 中国科学院上海营养与健康研究所 | Application of grape seed extract in preparation of drugs for targeted removal of tumor microenvironment senescent cells and inhibition of tumors |
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