CN108853114B - Application of nifurolimus in preparation of medicine for treating cancer-derived brain metastasis tumor - Google Patents
Application of nifurolimus in preparation of medicine for treating cancer-derived brain metastasis tumor Download PDFInfo
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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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The invention provides an application of nifurolimus in preparing a medicament for treating cancer-derived brain metastasis tumor, wherein the cancer is preferably lung cancer, breast cancer or skin cancer, the nifurolimus is a medicament for resisting parasitic diseases, the cancer brain metastasis tumor is a tumor which is generated in other parts of a body and is transferred to the intracranial, the tumor has serious consequences and high lethality rate, but related medicaments for clinically treating the brain metastasis tumor are few, so the invention provides the application of the nifurolimus in preparing the medicament for treating the cancer-derived brain metastasis tumor, and the technical problem is greatly solved.
Description
Technical Field
The invention relates to an application of nifurolimus in preparing a medicament for treating cancer-derived brain metastasis tumor, belonging to the field of medicaments.
Technical Field
Metastatic brain tumors are often the most common hallmarks of cancer, particularly lung, breast or skin cancer.
The proportion of melanoma brain metastases reaches 40%. Brain metastasis is the leading cause of death in patients with advanced non-small cell lung cancer (NSCLC) and breast cancer. Current drug options for treating such patients are limited, especially after brain metastases have occurred.
Primary lung cancer is one of the most common malignant tumors in China, and one of the most common distant metastasis sites of lung cancer is the brain. Of all brain metastases, men ranked lung cancer first, followed by malignant melanoma; women also rank lung cancer first, followed by breast cancer. Brain is one of the common distant metastatic sites of lung cancer, and brain metastasis is the leading cause of treatment failure. With the increase of the incidence of lung cancer, the use of advanced imaging equipment and optimized system treatment prolong the overall life cycle, and the incidence of lung cancer brain metastasis shows a significantly increased trend. The incidence rate of Small Cell Lung Cancer (SCLC) primary brain metastasis is 10%, and can reach 80% after 2 years, the incidence rate of non-small cell lung cancer (non-small cell lung cancer, NSCLC) brain metastasis is about 20%, and the autopsy is 40%.
Breast cancer
Central nervous system metastases are found in 15-25% of breast cancer patients and the incidence is increasing. In addition, the prognosis for these patients is poor, with an annual survival rate of 20%.
Melanoma (MEA)
Brain metastases are a major clinical challenge for melanoma patients, accounting for 60% of patients with metastatic melanoma. This can produce severe clinical symptoms and affect the overall survival prognosis. Brain Metastasis (BM) is a challenge for the treatment of melanoma patients. This life-threatening and quality-of-life-seriously affecting complication occurs in 60% of metastatic melanoma patients during their lesions. The risk of melanoma metastasis to the brain is particularly high compared to other common brain metastases such as lung and breast cancer. Median survival after confirmation of brain metastases is generally in the range of 3.4 to 13.2 months.
Patients with brain metastases have a natural median survival of about 1 month. In this group of patients, only a small fraction of the metastatic lesions are surgically resected. In patients who cannot undergo surgery, median survival for simple hormone therapy is 1-2 months.
Currently, no molecular targeted therapeutic drug is approved specifically for NSCLC brain metastasis.
The difficulty in treating brain tumors is that the drug needs to cross the blood-brain barrier to reach the treatment site. The blood-brain barrier (BBB) is a barrier between blood and nerve cells of brain and spinal cord, and has a structure that capillary vessels in brain and spinal cord are continuous, endothelial cells have no window holes, and the endothelial cells are tightly connected and sealed, so that macromolecular substances can not pass through, but water and certain ions can pass through; intact and continuous basement membrane of capillary blood vessels; the capillary vessel basement membrane is externally provided with a colloidal membrane formed by astrocyte protuberances. The blood brain barrier is a main factor influencing the success of the research and development of central drugs, and almost blocks 100 percent of macromolecular drugs and more than 98 percent of small molecular drugs. Drugs acting on the central nervous system need to overcome the blood brain barrier and can exert therapeutic effects only if sufficient exposure is achieved in the central system.
Clinically, there is a need for a drug for treating cancer-derived brain metastases, which should have a broad-spectrum anti-tumor effect, easily cross the blood-brain barrier, an exact therapeutic effect, and a reasonable cost.
Nifurolimus is currently only approved for the treatment of trypanosomiasis; a clinical trial for treating neuroblastoma (an extracranial tumor) has been carried out, and no study has been made on the role of neuroblastoma in the field of brain metastases caused by cancer, since it has not yet been approved for tumor therapy.
Nifurtimox (Bay 2502) is a nitroheterocyclic compound with a molecular formula of C10H13N3O5S, the trade name is Lampit. The molecular weight is 287.3, the structural formula is shown in formula I,
nifurolimus is now used in the treatment of trypanosomiasis and neuroblastoma.
The use of nifurolimus in the treatment of cancer is disclosed for the first time in patent application CN 200780017695.2. The application relates generally to the use of nifurolimus for the treatment of neuroblastoma. Neuroblastoma (NB) originates in the adrenal medulla or parasympathetic nervous system and is the most common extracranial solid tumor in childhood. However, this application does not disclose any substantial study of the treatment of intracranial tumors with nifurolimus.
In patent application cn201410487143.x, the inventor discloses a nifurolimus dry suspension which is suitable for being administered to children patients and has obviously improved bioavailability, and a preparation method thereof.
In summary, although with the advancement of technology, new tumor treatment drugs are emerging. However, there has been limited progress in brain tumors or brain metastases due to factors such as the blood-brain barrier and lack of sensitivity to chemoradiotherapy. Despite great advances in the treatment of peripheral primary tumors, the efficacy of brain metastases remains questionable. The greater value may be reflected in the inhibition of primary tumors in the periphery, and the reduction or reduction of the occurrence of brain metastases; once brain metastasis occurs, its effect is greatly reduced, and in many cases, its effect on intracranial tumors remains to be further confirmed. In addition, these emerging targeted drugs have a small population of beneficiaries and high treatment costs, such as 300 ten thousand dollars for CAR-T cell therapy newly developed by nova, which is remotely inaccessible to most patients. Therefore, the brain metastasis tumor treatment drug which has broad-spectrum anti-tumor effect, is easy to pass through a blood brain barrier, has definite curative effect and reasonable cost, such as temozolomide and the like, always has huge requirements, and is also the direction of efforts in the pharmaceutical industry.
Disclosure of Invention
In view of the above technical problems, the inventors provide an application of nifurolimus in preparing a medicament for treating cancer-derived brain metastasis.
The inventor gives previous data and data to summarize, finds that the drug against the parasitic disease, namely the nifurolimus, has the effect of treating the cancer in other patents, but no research shows that the nifurolimus has the application in treating and preparing the drug for treating the brain metastasis tumor caused by the cancer based on the difference among various cancers in the field of the brain metastasis tumor caused by the cancer, so the application of the drug in the aspect belongs to the technical blank.
The field of cancer and cancer-induced brain metastases belongs to the field of diseases which are linked with pathogenesis and have characteristics, and only one standard treatment scheme, namely radiotherapy and temozolomide, is approved to be used for treating cancer-derived brain metastases for decades, so that no effective treatment medicine exists clinically.
In view of the above technical problems, the present inventors provide an application of nifurolimus in the preparation of a medicament for treating cancer-derived brain metastasis.
One aspect of the invention provides a method of treating a mammalian (preferably human) subject having a cancer-derived brain metastasis. The method comprises administering to the subject a nifurolimus compound in an amount effective to treat the cancer. In any embodiment, the subject may be free of other indications that require treatment with nifurolimus, i.e., the subject need not additionally have chagas' disease or some other indication, e.g., caused by a microbial infection. The method may additionally comprise treating the subject with chemotherapy, surgery and/or radiation therapy.
The invention further provides a use as described above, wherein the cancer is basal cell carcinoma, skin cancer, breast cancer, bile duct cancer, bladder cancer, bone cancer, brain or CNS cancer, breast cancer, choriocarcinoma, colon and rectal cancer, cancer of connective tissue, cancer of the esophagus, eye cancer, fibroma, head and neck cancer, intraepithelial neoplasia, kidney cancer, larynx cancer, leukemia, liver cancer, lymphoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rhabdomyosarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer or uterine cancer.
Wherein further preferably, the cancer is skin cancer, lung cancer or breast cancer.
Further, the route of administration of the drug is in a form for oral, intrathecal, intracranial, or intramuscular administration.
In a very specific aspect, the composition comprises a pharmaceutical unit dosage form containing an amount of a nitrofuran compound, preferably nifurolimus, effective to treat extended brain metastases of the associated cancer described above.
The therapeutic compositions of the present invention may be administered orally, sublingually, buccally, intranasally, intravenously, intramuscularly, intrathecally, intracranially, peritoneally
Internal, subcutaneous, intradermal, topical, rectal, vaginal, intrasynovial or intravitreal administration.
The medicament can be prepared into tablets, injections, dry suspensions, powder, emulsion or pills.
The route of administration of the drug is for oral, intrathecal, intravenous or intramuscular administration; formulations for oral administration are preferred.
The effective drug dose of the nifurolimus-containing drug is 50-200 mg/Kg.
The invention has the beneficial effects that:
the nifurolimus can be applied to the preparation of the medicine for treating the cancer-derived brain metastasis tumor, the effect can be seen in the biochemical test part of the specific embodiment, the nifurolimus has the growth inhibition effect on human tumor cells, and has a remarkable inhibition effect on human lung cancer brain metastasis tumor, human breast cancer cells and human melanoma, and the medicine can improve the sensitivity of the tumor cells in chemotherapy and is beneficial to further control of tumors.
The invention is further described in the following examples, which are not intended to limit the scope of the invention.
Detailed Description
The nifurolimus compound is administered in a therapeutically effective and physiologically acceptable amount that is necessary or sufficient to achieve a desired beneficial biological effect that the subject is physiologically tolerable, in which case the cancer-derived brain metastasis can be treated. The beneficial biological effect can be measured, for example, by measuring the physiological effect of the treatment after the treatment is administered. The bio-beneficial effect can be an improvement or complete elimination of brain metastases caused by the treated cancer one of ordinary skill in the art can empirically determine the effective amount of a particular nifurolimus compound or combination without undue experimentation. In conjunction with the teachings provided herein, an effective prophylactic or therapeutic treatment regimen that does not cause significant toxicity, yet is fully effective in treating a particular subject, can be planned by selecting among a variety of compounds and weighting factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and preferred mode of administration.
Biochemical example 1
MTT method for determining growth inhibition effect of nifurolimus on human tumor cells
The purpose of the test is to measure the cell survival rate by adopting an MTT method, observe the growth inhibition effect of the nifurolimus on various human tumor cells and normal cells at the cell level, explore whether the nifurolimus has the effect of inhibiting the growth of the tumor cells, the action strength, the sensitivity to different types of tumor cells and the like at the in vitro level, and provide reference information for exploring the action mechanism and the safety evaluation of a tested substance, the administration scheme in clinical tests, the selection of tumor species and the like.
Cell lines: human bone marrow neuroblastoma SH-SY5Y, human neuroblastoma human neuroblast SK-N-SH, human brain glioma cell Hs683, human glioma cell U251, human brain astrocytoma U87MG, human brain tumor cell SF126, human non-small cell lung cancer cell H460, human liver cancer cell Bel7402, human breast cancer cell MCF-7, human stomach cancer cell BGC823, human oral epithelial cancer cell KB, human immortalized keratinocyte strain HaCaT, human liver cancer cell HepG2 and human kidney cancer cell Ketr-3.
The above cells are all commercially available products.
Test protocol: the tumor cells in the logarithmic growth phase are collected and prepared into single-cell suspension with a certain concentration, and the single-cell suspension is generally inoculated into a 96-well plate according to the difference of the growth speed of the cells and 3000 cells per hole, and 100 mu L of the cell suspension is added into each hole. After 24h of culture, nifurolimus or positive control drug (yew intoxication or temozolomide) with different concentrations are respectively added, and the culture is continued. After 48-72 hours, the culture solution containing the liquid medicine is discarded, MTT working solution is added according to the ratio of 0.5mg/ml (0.05 g of thiazole blue MTT is weighed and dissolved in 100ml of Phosphate Buffer Solution (PBS), bacteria in the solution are removed by filtering with a 0.22 mu m filter membrane, and the solution is kept away from light at 4 ℃), 150 mu L of MTT working solution is added in each hole, after incubation is carried out for 4 hours, the MTT working solution is discarded, and 180 mu L of DMSO is added to dissolve formazan (formazan) particles formed by MTT. After gentle shaking, the absorbance OD (545 or 570) was measured with a microplate reader at a reference wavelength of 450nm and the experiment was repeated 3 times.
Detection indexes are as follows: IC of nifurolimus on various tumor cells and normal cells50. The results are shown in Table 1.
TABLE 1 half inhibitory concentrations of nifurolimus against different cell lines
Note: means no such data
The data show that the nifurolimus has growth inhibition effect on different cancer cells, and the growth inhibition effect is in direct proportion to the using concentration.
Biochemical example 2
Therapeutic effect of nifurolimus on nu/nu nude mouse lung cancer human brain metastasis tumor H460
Experimental purpose to evaluate the therapeutic effect of Nifurtimox (Nifurtimox) with different concentrations on nu/nu nude mice with human lung cancer brain metastasis tumor H460.
Experimental material tumor cell line: human lung cancer H460 cell line.
Experimental animals: adult Nu/Nu nude mice (Beijing Wittingle laboratory animal technology Co., Ltd.), 18-20 g, female. The animals were housed in sterile, independently ventilated IVC cages, 5 animals per cage. Is padded by60Co radiation sterilized corncob pad materials have the particle size of 4-6 mm. The mice are fed with the special sterilized feed for the mice, and the purified water is freely drunk. The temperature in the animal laboratory is kept at about 25 ℃, the relative humidity is kept at 40-70%, and the illumination is carried out for 12 hours every day.
The experimental scheme is as follows: cells were cultured, H460 cells (H460-luc2-GFP cells) infected with lentivirus containing pCDH-luc2-GFP plasmid at logarithmic growth phase were trypsinized and collected, and washed with PBS and resuspended, Metrigel (BD Co., U.S. A., Lot: 4335005) was added at a ratio of PBS: Metrigel ═ 2:1 to give a final cell concentration of 2X 107Cells/ml suspension. After the nude mice are anesthetized and fixed, the nude mice are punctured and injected with a micro-syringe slightly to the right side in the lower part of the cranium of the nude mice, and each nude mouse is injected with 20 mul of cell suspension, namely 4 multiplied by 105And (4) cells. And selecting a bioluminescence imaging mode, and detecting a luminous signal in the nude mouse. Three days after the operation modeling, the tumor-bearing mice are subjected to IVIS Spectrum CT in vivo imaging and divided according to softwareThe luminescence intensity in the analysis results was randomly grouped for tumor-bearing mice and administered.
Results of the experiment
Tumor multiplication rate and drug treatment effect are calculated by using tumor bioluminescence intensity. Compared with the tumor luminescence intensity when the experiment is divided into groups (Day 1), after 11 days (Day 11), the tumor luminescence intensity of the nude mice of the control group is increased by about 2125 times; the positive drug temozolomide 30mg/kg treatment group has the tumor luminous intensity increased by 217 times; the tested nifurolimus treatment groups of 50mg/kg, 100mg/kg and 200mg/kg have the tumor luminous intensity increased by 199 times, 98 times and 63 times respectively, and show obvious dose-effect relationship. The tumor doubling rate was significantly reduced in each treatment group compared to the control group (P < 0.001). The tumor inhibition rate is calculated according to the bioluminescence intensity of each tumor-bearing nude mouse group at the end of the experiment (Day 11), the tumor inhibition rate of the positive drug temozolomide 30mg/kg treatment group is 83.1 percent, and the tumor inhibition rates of the test drug nifurolimus 50mg/kg, 100mg/kg and 200mg/kg treatment groups are 84.8 percent, 95.8 percent and 98.0 percent respectively. Therefore, the nifurolimus with different concentrations has strong inhibition effect on nu/nu nude mice with human lung cancer brain metastasis tumor H460. The results are shown in Table 2.
TABLE 2 therapeutic Effect of Nifurolimus on nu/nu nude mice with human Lung cancer brain metastasis H460
P compared to control group<0.05，**P<0.01，***P<0.001; compared with the temozolomide group,＃＃＃P<0.001; compared with the group of nifurolimus 50mg/kg,&&P<0.01(One-way ANOVA and Tukey's test for pairwise comparison)
Biochemical example 3
Growth inhibition of nifurolimus on human breast cancer cell MCF-7 nude mouse brain metastasis
Experiment purpose this experiment selects human breast cancer cell MCF-7 cell strain to establish nude mouse brain metastasis tumor model, observes the growth inhibition effect of nifurolimus, provides reference for clinical application.
Experimental Material
Test article
Name: nifurolimus (English name: Nifurtimox).
Experimental system
1. Strain: Nu/Nu nude mice (Beijing Wittiulihua laboratory animal technology Co., Ltd.).
2. Tumor strain: human breast cancer cell MCF-7.
Tumor model construction and detection method
The experimental design basis is as follows: the following standards were used: the experimental design is carried out according to the guiding principle of non-clinical research technology of cytotoxic antitumor drugs.
Establishing a nude mouse intracranial transplantation tumor model: collecting human breast cancer cells MCF-7 in logarithmic growth phase under sterile condition, and adjusting cell density to 1x 10 with serum-free medium (wisent; 001-8And (4) preparing a cell suspension, and storing the cell suspension in ice water for later use. The nude mice were anesthetized by intraperitoneal injection with 0.5% sodium pentobarbital (50mg/kg), the head skin was sterilized by iodophor in the prone position, the skin was cut about 1.0cm from the center of the top of the mouse head, the skull was exposed, a hole was drilled at a position 0.5mm in front of bregma and 1.5mm to the right of the midline, and a sterile syringe needle (0.7X 30) was used for drilling. The nude mice were fixed in a brain stereotaxic apparatus, the cell suspension was loaded into a microsyringe, and 15 μ L was injected and the skin incision was sutured.
Results of the experiment
After the end of the administration of nifurolimus, the tumor-bearing nude mice were scanned and analyzed using Image J software, and the test results are shown in table 3. The result shows that the growth inhibition rate of the medium and high dose groups (100 and 150mg/kg) of the nifurolimus on MCF-7 cells is more than 50%, and the statistical analysis of SPSS 13.0 shows that compared with a negative control group, the tumor volumes of the medium and high dose groups and the TMZ group of the nifurolimus are significantly different (P < 0.05). The results are shown in Table 3.
TABLE 3 growth inhibition test results of nifurolimus to human breast cancer cell MCF-7 brain metastasis tumor
P <0.05 compared to negative control group
And (4) conclusion: the nifurolimus has obvious growth inhibition effect on the nude mouse brain metastasis of human breast cancer cells MCF-7.
Biochemical example 4
Therapeutic effect of nifurolimus on human melanoma SK-MEL-3 brain metastasis
Experimental purpose the treatment effect of nifurolimus on human melanoma SK-MEL-3 brain metastasis tumor was preliminarily evaluated.
Experimental material tumor cell line: human melanoma SK-MEL-3.
Experimental animals: adult Nu/Nu nude mice (Beijing Wittingle laboratory animal technology Co., Ltd.), 18-20 g, female.
Tumor model construction and detection method
The experimental design basis is as follows: the following standards were used: the experimental design is carried out according to the guiding principle of non-clinical research technology of cytotoxic antitumor drugs.
Establishing a nude mouse intracranial transplantation tumor model: collecting human melanoma SK-MEL-3 in logarithmic growth phase under sterile condition, and adjusting cell density to 1x 10 with serum-free medium (wisent; 001-8And (4) preparing cell suspension, and storing the cell suspension in ice water for later use. The nude mice were anesthetized by intraperitoneal injection with 0.5% sodium pentobarbital (50mg/kg), the head skin was sterilized by iodophor in the prone position, the skin was cut about 1.0cm from the center of the top of the mouse head, the skull was exposed, a hole was drilled at a position 0.5mm in front of bregma and 1.5mm to the right of the midline, and a sterile syringe needle (0.7X 30) was used for drilling. The nude mice were fixed in a brain stereotaxic apparatus, the cell suspension was loaded into a microsyringe, and 15 μ L was injected and the skin incision was sutured.
Results of the experiment
After the end of the administration of nifurolimus, the tumor-bearing nude mice were scanned and analyzed using Image J software, and the test results are shown in table 4. The results show that the growth inhibition rate of the nifurolimus middle and high dose groups (100 and 150mg/kg) on SK-MEL-3 cells is more than 50%, and through statistical analysis of SPSS 13.0, compared with a negative control group, the tumor volumes of the nifurolimus middle and high dose groups and a TMZ group are significantly different (P is less than 0.05). The results are shown in Table 4.
TABLE 4. results of experiment on growth inhibition of Nifurolimus on human melanoma SK-MEL-3 brain metastasis
P <0.05 compared to negative control group
And (4) conclusion: nifurolimus has obvious growth inhibiting effect on nude mouse brain metastasis of human melanoma SK-MEL-3.
Biochemical example 5
Synergistic effect of nifurolimus and radiation therapy
Experimental purpose the synergistic effect of nifurolimus and radiotherapy was evaluated in a human brain glioma model.
Experimental material tumor cell line: human brain glioma cell U87 MG-mCherry-luc.
Experimental animals: adult Nu/Nu nude mice (Beijing Wittingle laboratory animal technology Co., Ltd.), 18-20 g, female.
The experimental design basis is as follows: the experimental design is carried out according to the guiding principle of non-clinical research technology of cytotoxic antitumor drugs.
Tumor model construction and detection method
The experimental scheme is as follows: culturing cells, collecting the logarithmic growth phase of human brain glioma cells U87MG-mCherry-luc (from Yuandy Biotech Co., Ltd., Shanghai) by trypsinization, washing with PBS, resuspending, adding Metrigel (BD Co., U.S. Pat. No.: 4335005) at a ratio of PBS: Metrigel ═ 2:1 to give a final cell concentration of 2X 107Cells/ml suspension. After the nude mice are anesthetized and fixed, the nude mice are punctured and injected with a micro-syringe slightly to the right side in the lower part of the cranium of the nude mice, and each nude mouse is injected with 20 mul of cell suspension, namely 4 multiplied by 105And (4) cells. And selecting a bioluminescence imaging mode, and detecting a luminous signal in the nude mouse. Three days after operation modeling, IVIS Spectrum CT living body imaging is carried out on the tumor-bearing mice, the tumor-bearing mice are randomly grouped according to the luminous intensity in the software analysis result, and the tumor body is administrated or irradiated by X rays (conventional segmentation irradiation))。
The results are shown in Table 5.
Tumor multiplication rate and drug treatment effect are calculated by using tumor bioluminescence intensity. Compared with the tumor luminescence intensity in the experimental grouping, the tumor luminescence intensity of the nude mice of the control group is increased by about 2114 times after 14 days; the positive drug temozolomide 30mg/kg treatment group has 315 times of tumor luminous intensity; the test drug nifurolimus of 50mg/kg treatment group has 411 times of tumor luminous intensity; the luminous intensity of the X-ray irradiation group increased 675 times; and the nifurolimus and X-ray irradiation group only increased the luminous intensity by 85 times. Meanwhile, the combined group has excellent tolerance, basically no animal death and ideal brain weight/body weight index.
The tumor doubling rate was significantly reduced in each treatment group compared to the control group. The tumor inhibition rate was calculated from the bioluminescence intensity of each group of tumor-bearing nude mice at the end of the experiment (day 15), the tumor inhibition rate of the positive drug temozolomide 30mg/kg treatment group was 82.2%, the tumor inhibition rate of the test drug nifurolimus 50mg/kg treatment group was 79.4%, and the strongest tumor inhibition rate of the 50mg/kg nifurolimus + X-ray irradiation group was 94.8%. Therefore, the nifurolimus and the radiotherapy have obvious synergistic effect on the inhibition effect of the human brain glioma cells.
Po is administered orally.
TABLE 5 test results of combination of nifurolimus and radiation therapy
P <0.05, P <0.01, P <0.001, compared to control group
In addition, in other in vivo tumor models including human bone marrow neuroblastoma SH-SY5Y, human lung cancer H460 cell line, human breast cancer MCF-7 and human melanoma SK-MEL-3, a synergistic effect of nifurolimus with radiation therapy was also found to varying degrees. These data show that nifurolimus is a potent radiosensitizer.
Gy is the X-ray radiation dose unit.
The general conclusions for biochemical examples 1-5 are: the nifurolimus has strong growth inhibition effect on various tumor cells, and has obvious inhibition effect on human lung cancer brain metastasis tumor H460, human breast cancer cell MCF-7 and human melanoma SK-MEL-3, which indicates that the nifurolimus has obvious tumor inhibition effect in the field of brain metastasis tumor, can be applied to the preparation of medicines for treating various cancer-derived brain metastasis tumor, and has obvious inhibition effect at 50-200 mg/kg. In addition, nifurolimus can also enhance the sensitivity of tumors to radiation therapy and enhance the effect of other drugs or treatment means.
The above-mentioned embodiments only express a few embodiments of the present invention, and the description is specific and detailed, but it should not be understood as the limitation of the patent scope of the present invention, it should be noted that, for those skilled in the art, many variations and modifications can be made without departing from the concept of the present invention, and these all fall into the protection scope of the present invention, therefore, the protection scope of the present invention is subject to the appended claims.
Claims (1)
1. Application of nifurolimus in preparation of medicine for treating lung cancer, breast cancer or melanoma derived brain metastasis tumor, wherein the nifurolimus is shown in a structure of a formula I, and a molecular formula is C10H13N3O5S or a salt derived therefrom,
the route of administration of the drug is in the form of oral administration.
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