人骨肉瘤细胞多药耐药机制及其逆转剂的研究
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摘要
骨肉瘤作为一种常见的骨源性恶性肿瘤,其化疗后的多药耐药现象严重影响患者的治疗效果和预后,其耐药机制和逆转剂的研究一直是研究的热点。在体外建立多药耐药的细胞模型已逐渐成为研究骨肉瘤多药耐药性的有利工具。氨甲蝶呤作为骨肉瘤化疗的基础药物,其在临床初始化疗缓解后常会产生耐药性。
目前临床上己证实与肿瘤多药耐药有关的耐药基因主要有MDRl、MRP、LRP、GST-π、TOPOⅡa等。因此,检测U-2 OS/MTXr中这5个耐药基因及其表达产物表达水平的变化,基本能反映出骨肉瘤组织产生耐药时耐药基因表达水平的变化情况。放疗作为骨肉瘤化疗的辅助手段,也可以收到不错的治疗效果,但骨肉瘤放疗与其多药耐药的关系尚无人研究。骨肉瘤多药耐药逆转的研究也不是很多,这和以往的逆转剂效果不理想有关。
本实验采用氨甲蝶呤大剂量冲击间歇诱导的方法建立了骨肉瘤多药耐药细胞模型,通过对耐药细胞的基本特征、交叉耐药、细胞生长曲线、细胞周期及凋亡以及5个耐药基因的表达变化情况、放疗与骨肉瘤多药耐药的关系、新的逆转剂的尝试等进行了研究。为进一步研究人骨肉瘤耐药机制和耐药逆转剂提供一定的帮助。
Objective: Osteosarcomas are the most frequent malignant bone tumors. Further studies have shown that multidrug resistance (MDR) to chemotherapeutic agents is a major barrier to the successful treatment of Osteosarcomas. As the basic drug of chemotherapy, methotrexate will create drug resistance after chemotherapy has become effective. To establish a multidrug resistance cell model anti-methotrexate of human osteosarcoma from the U-2 OS cell line is very necessary for testing its attributes, crossing-drug resistance, cell growth curve, cell periodicity and apoptosis through laboratory methods and providing some assistance for studying and researching mechanism of multidrug resistance and reversal agent of drug resistance about human osteosarcoma.
At present drug resistance genes about multidrug resistance clinically include MDRl, MRP, LRP, GST-π, TOPOⅡa, et al. Accordingly, detecting to the expression of five genes in osteosarcoma multidrug resistance cells can react the change of the expression of drug resistance genes in human osteosarcoma tissue. constantly MDR1 gene is the target gene for reversing osteosarcoma MDR. But mechanism of osteosarcoma acquired MDR incriminate the participate of multiple genes. The interception to MDR1 only can’t raise the sensibility of all chemotherapeutics. Our experiment researched the expression of five genes in Osteosarcoma multidrug resistance cells and sensitive cells for finding of other mechanisms of Osteosarcoma acquired MDR and reversing target.
Now clinically lots of doctors deal with osteosarcoma patients by the means of the combination chemo and radiotherapy. And the means receive satisfied curative effect. Because the tumor cells create multidrug resistance after chemo, radiotherapy will be applicated at the same time or after chemo, its premise is that tumor cells are sensitive to radioactive rays. This viewpoint needs be confirmed. Records about osteosarcoma chemo are much more than about osteosarcoma radiotherapy, its reason is possibly that osteosarcoma tissues aren’t sensitive at radioactive rays. Our research will prove the change of the expression of osteosarcoma drug resistance genes AP:PA of radiotherapy, this research can offer reference for clinical practice.
Lots of specialists think highly of the research of reversal agent of drug resistance domestic at abroad and domestic. The reports about reversal agent of osteosarcoma drug resistance are less, it concerned with the effect of formerly reversal agents. Our research will investigate reversal densities and reversal spectrums of verapamil and the shen-mai injection, it can provide experiment and theory foundation for the osteosarcoma chemotherapeutic effect. Methods: The human osteosarcoma U-2 OS cells were exposed to high dose of methotrexate to introduce it’s multidrug resistance (U-2 OS/MTXr). The morphology and ultramicrostructure of the cells were observed using light microscope and transmission electron microscopy. The sensitivity of the multidrug resistance was measured by MTT assay. The proliferation ability of the cells was measured by growth curve. The cell cycle and apoptosis are detected by flow cytometer(FCM). The change of the expression of MDR1, MRP, LRP, GST-π, TOPOⅡa are detected by RT-PCR. The change of the expression of P-gp is detected by westenblot. The Osteosarcoma multidrug resistance cells and sensitive cells are exposed to 5,10,15,20,25 Gy rays. Survival curve under rays is measured by MTT assay.
The changes of the expression of MDR1, MRP, TOPOⅡa are detected by RT-PCR. The reversal densities of verapamil and the shen-mai injection are measured by MTT assay, reversal spectrums of verapamil and the shen-mai injection are detected by this way.
Results: The human osteosarcoma U-2 OS/MTXr cell line that it can grow under 5μg/ml methotrexate is established. Disordered structure of the U-2 OS/MTXr cells was observed through microscopy. The increase of granular endoplasmic reticulums and apophyses was observed throught transmission electron microscopy. The resistance index of the U-2 OS/MTXr cells to methotrexate in was 63.The cells also had resistance to other anticancer drug.
The proliferation ability of U-2 OS/MTXr increased significantly by the drawing of growth curve. The cell G1 period and G2 period reduce and S period increase. The cell proliferation index of the U-2 OS/MTXr cells increased, but apoptotic index degraded. The expression of bcl-2 increased, but the expression of p53 degraded. The U-2 OS/MTXr cell displayed multidrug resistance molecule alteration. The result of RT-PCR manifested that in the U-2 OS/MTXr cells, the expression of MDR1 and MRP increased, and the expression of TOPOⅡa reduced. The result of westenblot displayed that the expression of P-gp increased in the U-2 OS/MTXr cells. The 50% inhibitory dose of the U-2 OS/MTXr cells was (24.2±0.24) Gy, and the 50% inhibitory dose of the U-2 OS cells was (19.45±0.32) Gy. It was increased 1.24 times. The result of RT-PCR increased unobviouslly after radiotherapy manifested the expression of drug resistance genes. Uninhibitory dose verapamil can raise the depressant effect on the U-2 OS/MTXr cell to MTX, ADM, VCR and MIT, the depressant effect to CDDP is ambiguous, the depressant effect to cyclophosphamide is between the former; and uninhibitory dose shen-mai injection can raise the depressant effect on the U-2 OS/MTXr cell to MTX, ADM, VCR and CDDP, the depressant effect to CDDP and MIT is ambiguous.
Conclusion:
1. A multidrug resistance cell line (U-2 OS/MTXr)of human osteosarcoma is established, which will benefit to further studies as a new experimental model.
2. The mechanism of osteosarcoma acquired MDR furthermore is concerned with MRP and TOPOⅡa besides MDR1 and P-gp.
3. The radiotherapy of osteosarcoma can’t raise multidrug resistance. But the toleration to radioactive of osteosarcoma drug resistance cell ray is higher than that of osteosarcoma sensitive cell.
4. Verapamil and the shen-mai injection can partly reverse the U-2 OS/MTXr cell MDR.
目前临床上己证实与肿瘤多药耐药有关的耐药基因主要有MDRl、MRP、LRP、GST-π、TOPOⅡa等。因此,检测U-2 OS/MTXr中这5个耐药基因及其表达产物表达水平的变化,基本能反映出骨肉瘤组织产生耐药时耐药基因表达水平的变化情况。放疗作为骨肉瘤化疗的辅助手段,也可以收到不错的治疗效果,但骨肉瘤放疗与其多药耐药的关系尚无人研究。骨肉瘤多药耐药逆转的研究也不是很多,这和以往的逆转剂效果不理想有关。
本实验采用氨甲蝶呤大剂量冲击间歇诱导的方法建立了骨肉瘤多药耐药细胞模型,通过对耐药细胞的基本特征、交叉耐药、细胞生长曲线、细胞周期及凋亡以及5个耐药基因的表达变化情况、放疗与骨肉瘤多药耐药的关系、新的逆转剂的尝试等进行了研究。为进一步研究人骨肉瘤耐药机制和耐药逆转剂提供一定的帮助。
Objective: Osteosarcomas are the most frequent malignant bone tumors. Further studies have shown that multidrug resistance (MDR) to chemotherapeutic agents is a major barrier to the successful treatment of Osteosarcomas. As the basic drug of chemotherapy, methotrexate will create drug resistance after chemotherapy has become effective. To establish a multidrug resistance cell model anti-methotrexate of human osteosarcoma from the U-2 OS cell line is very necessary for testing its attributes, crossing-drug resistance, cell growth curve, cell periodicity and apoptosis through laboratory methods and providing some assistance for studying and researching mechanism of multidrug resistance and reversal agent of drug resistance about human osteosarcoma.
At present drug resistance genes about multidrug resistance clinically include MDRl, MRP, LRP, GST-π, TOPOⅡa, et al. Accordingly, detecting to the expression of five genes in osteosarcoma multidrug resistance cells can react the change of the expression of drug resistance genes in human osteosarcoma tissue. constantly MDR1 gene is the target gene for reversing osteosarcoma MDR. But mechanism of osteosarcoma acquired MDR incriminate the participate of multiple genes. The interception to MDR1 only can’t raise the sensibility of all chemotherapeutics. Our experiment researched the expression of five genes in Osteosarcoma multidrug resistance cells and sensitive cells for finding of other mechanisms of Osteosarcoma acquired MDR and reversing target.
Now clinically lots of doctors deal with osteosarcoma patients by the means of the combination chemo and radiotherapy. And the means receive satisfied curative effect. Because the tumor cells create multidrug resistance after chemo, radiotherapy will be applicated at the same time or after chemo, its premise is that tumor cells are sensitive to radioactive rays. This viewpoint needs be confirmed. Records about osteosarcoma chemo are much more than about osteosarcoma radiotherapy, its reason is possibly that osteosarcoma tissues aren’t sensitive at radioactive rays. Our research will prove the change of the expression of osteosarcoma drug resistance genes AP:PA of radiotherapy, this research can offer reference for clinical practice.
Lots of specialists think highly of the research of reversal agent of drug resistance domestic at abroad and domestic. The reports about reversal agent of osteosarcoma drug resistance are less, it concerned with the effect of formerly reversal agents. Our research will investigate reversal densities and reversal spectrums of verapamil and the shen-mai injection, it can provide experiment and theory foundation for the osteosarcoma chemotherapeutic effect. Methods: The human osteosarcoma U-2 OS cells were exposed to high dose of methotrexate to introduce it’s multidrug resistance (U-2 OS/MTXr). The morphology and ultramicrostructure of the cells were observed using light microscope and transmission electron microscopy. The sensitivity of the multidrug resistance was measured by MTT assay. The proliferation ability of the cells was measured by growth curve. The cell cycle and apoptosis are detected by flow cytometer(FCM). The change of the expression of MDR1, MRP, LRP, GST-π, TOPOⅡa are detected by RT-PCR. The change of the expression of P-gp is detected by westenblot. The Osteosarcoma multidrug resistance cells and sensitive cells are exposed to 5,10,15,20,25 Gy rays. Survival curve under rays is measured by MTT assay.
The changes of the expression of MDR1, MRP, TOPOⅡa are detected by RT-PCR. The reversal densities of verapamil and the shen-mai injection are measured by MTT assay, reversal spectrums of verapamil and the shen-mai injection are detected by this way.
Results: The human osteosarcoma U-2 OS/MTXr cell line that it can grow under 5μg/ml methotrexate is established. Disordered structure of the U-2 OS/MTXr cells was observed through microscopy. The increase of granular endoplasmic reticulums and apophyses was observed throught transmission electron microscopy. The resistance index of the U-2 OS/MTXr cells to methotrexate in was 63.The cells also had resistance to other anticancer drug.
The proliferation ability of U-2 OS/MTXr increased significantly by the drawing of growth curve. The cell G1 period and G2 period reduce and S period increase. The cell proliferation index of the U-2 OS/MTXr cells increased, but apoptotic index degraded. The expression of bcl-2 increased, but the expression of p53 degraded. The U-2 OS/MTXr cell displayed multidrug resistance molecule alteration. The result of RT-PCR manifested that in the U-2 OS/MTXr cells, the expression of MDR1 and MRP increased, and the expression of TOPOⅡa reduced. The result of westenblot displayed that the expression of P-gp increased in the U-2 OS/MTXr cells. The 50% inhibitory dose of the U-2 OS/MTXr cells was (24.2±0.24) Gy, and the 50% inhibitory dose of the U-2 OS cells was (19.45±0.32) Gy. It was increased 1.24 times. The result of RT-PCR increased unobviouslly after radiotherapy manifested the expression of drug resistance genes. Uninhibitory dose verapamil can raise the depressant effect on the U-2 OS/MTXr cell to MTX, ADM, VCR and MIT, the depressant effect to CDDP is ambiguous, the depressant effect to cyclophosphamide is between the former; and uninhibitory dose shen-mai injection can raise the depressant effect on the U-2 OS/MTXr cell to MTX, ADM, VCR and CDDP, the depressant effect to CDDP and MIT is ambiguous.
Conclusion:
1. A multidrug resistance cell line (U-2 OS/MTXr)of human osteosarcoma is established, which will benefit to further studies as a new experimental model.
2. The mechanism of osteosarcoma acquired MDR furthermore is concerned with MRP and TOPOⅡa besides MDR1 and P-gp.
3. The radiotherapy of osteosarcoma can’t raise multidrug resistance. But the toleration to radioactive of osteosarcoma drug resistance cell ray is higher than that of osteosarcoma sensitive cell.
4. Verapamil and the shen-mai injection can partly reverse the U-2 OS/MTXr cell MDR.
引文
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