| According to the latest global statistics, the incidence of ovarian cancer ingynecologic malignancies has risen to second place, the mortality rate at the top. Thecombination of chemotherapy based on the platinum and cytoreductive surgery for ovariancancer is recognized as the best initial treatment plan,However the relapse proportion ofpatients after condition improved up to70%-80%. The reason is that surgery for recurrenthigh, easily transferred to distant spread of ovarian cancer treatment less effective, but youneed to face the chemotherapy drug resistance in ovarian cancer and other issues.Therefore, invasion, metastasis and resistance to chemotherapy in ovarian cancertreatments are always two difficultiesis,also become the research hot spot.Platinum-resistant ovarian cancer patients are treatment options are: surgery, radiotherapy,chemotherapy, immunotherapy, hormonal therapy and so on, hormonal therapy is one ofthe most focus of treatments, of which the most widely studied with GnRH analogues.Artificial GnRH analogues are50-100times the natural biological effects of GnRH.GnRH analogues can compete for binding with the pituitary GnRH receptors, inhibitingLH, FSH secretion, causing functional gonadotropin inhibitory effect,80%of GnRHanalogues with GnRH-Ⅰ receptor binding.Ovarian cancer is a hormone-dependenttumor, about80%of human epithelial ovarian cancer tissue expression of GnRH-Ⅰreceptor. Angiogenesis and invasion and metastasis of tumor cells is an important aspect oftumor distant metastasis. Vascular endothelial growth factor (VEGF) is known most active,the most exclusive angiogenic factors, as is often the most important molecularangiogenesis. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes,which can effectively degrade extracellular matrix, is believed to play an important role intumor invasion and metastasis; Tissue inhibitor of metalloproteinase (TIMPs) capable ofspecifically binding MMPs, reducing the activity of MMPs, the imbalance between the twoas the most important direction of research cell invasion and metastasis.EGFR is animportant factor in cancer signal transduction pathway, a large number of studies haveconfirmed EGFR is highly correlated with angiogenesis, can stimulate the expression ofVEGF to induce angiogenesis. EGFR can induce increased activity of MMPs, therebypromoting tumor cell invasion and metastasis. GnRH analogues can be combined withGnRH-1receptor which expressed on ovarian cancer cell surface, the activity of EGFRdown,,platinum-resistant ovarian cancer cells abnormally high EGFR expression. Earlyexperiments demonstrated that drug-resistant ovarian cancer cells abnormally high EGFR expression, invasion and metastasis and invasion capacity enhancement,GnRH analoguesmay decrease the expression of EGFR of OVCAR-3/CDDP cells, inhibition of cellinvasion and metastasis. So if you can cut EGFR high expressed in platinum-resistantovarian cancer cell by GnRH analogues to inhibit tumor invasion and metastasis andangiogenesis?This research will study the effects of triptorelin in combination withcisplatin for platinum-resistant ovarian cell invasion, metastasis and angiogenesis,makingmore in-depth study.Objective: To observe the GnRH analogues triptorelin in combination with cisplatin forplatinum-resistant human ovarian cancer cell OVCAR-3/CDDP invasion and metastasis,angiogenesis, and study the possible molecular mechanisms.Methods: According to gradually increase the use of CDDP concentrations in vitro effectof inducing intermittent resistance, is currently moderate resistance. Experimentsaccording to different treatment methods are divided into:(1) control group:(2) cisplatingroup;(3) triptorelin treatment groups;(4) combined with cisplatin triptorelin group.Detection of different drug treatment groups of,EGFR,VEGF, MMP-2, MMP-9, TIMP-1,mRNA TIMP-2expression levels relative impact of using Real-time PCR; Western blotprotein immunoblot assay VEGF protein expression; Plan marks and transwell chamberinvasion experiments compare the changes of platinum-resistant ovarian cancer invasionand metastasis ability; Chorioallantoic membrane assay combined effects of the drugs ontumor tissue angiogenesis.Results:(1) triptorelin combinat with cisplatinion decreases the mRNA expression ofEGFR in OVCAR-3/CDDP cells, while lower VEGF, MMP-2, MMP-9mRNA expression,TIMP-1and TIMP-2mRNA expression increased, the difference was statisticallysignificant (P <0.05) the two drugs combined make MMP-2/TIMP-2, MMP-9/TIMP-1ratio decreased.(2) triptorelin,cisplatin treatment groups compared with the control group,the protein expression of VEGF in OVCAR-3/CDDP cells reduced. The expression of thetwo drugs in combination reduces more obviouly.(3) The different treatment groupscompared with control cells in scratch experiments of OVCAR-3/CDDP cells,scratcheshealing rates decreased, while Transwell chamber cell-penetrating cells also reduced (P<0.05), the difference there was statistically significant; compared with the control group,the two-drug combination treatment group decreased more significantly, the difference wasstatistically significant (P <0.05)(4) The CAM experiment indicated that the vascularinhibitory rates of OVCAR-3/CDDP-implanted tumors in the combination treatment group was36.50%, being significantly higher than that in the triptorelin group20.76%andcisplatin group16.66%.Conclusion: In vitro induction of acquired resistance to cisplatin in ovarian cancer celllines OVCAR-3, and combination of triptorelin and cisplatin inhibit resistant ovariancancer invasion,metastasis and angiogenesis, and the inhibitory effect compared withmonotherapy significantly. GnRH analogues for the treatment of platinum-resistantrecurrent ovarian clinical emergence may have great... |
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