Expression of angiogenic factors and their clinical significances in acute myeloid leukemia
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To explore the effects of thalidomide on the expressions of vasc ular growth factors in parental and cisplatin_resistant human lung adenocarcinom a cell line A549 and A549 .Methods:RT_PCR and Immunohistochemistry were used to detect mRNA and protein expression of VEGF in A549 and A549 .Results:From t he 1st to 5 th day after treatment with physiological concentration of thalidomi de(6 mg/L),VEGF mRNA expression levels in A549 were significant higher than that before treatment.VEGF mRNA expression levels in A549 were significant lower. There were significant differences in A549 and A549 among different concentra tion of thalidomide on the 5 th day.The protein expressions were significant coi ncided with the relative VEGF mRNA expression levels in A549 and A549 .Conclus ion:Physiological concentration of thalidomide up_regulated VEGF mRNA expression significantly in A549.But large dose of thalidomide inhibits VEGF expression si gnificantly.Moreover,thalidomide down_regulated VEGF mRNA expression significant ly in A549 .It is dose_independent.The protein expression is significantly coi ncided with the relative VEGF mRNA.
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Aim To observe the regulatory effect of LZBZY on the growth of H22 tumor and the expression of vascular endothelial growth factor(VEGF) in transplanted H22 tumor of mice,and explore whether the inhibition of tumor is related to the inhibition of vascular growth.Methods The mice were vaccinated with H22 cells suspension(1×107/ml) 0.2 ml each one.The observation was made on the weight of the transplanted tumor of the mice,then the inhibitory rate was calculated.The expression of VEGF was determined by the immunohistochemical method.Results The LZBZY group had significant effect on inhibiting the tumor growth(P0.05,P0.01),when compared with the model group,the pathological detective results showed that the positive rate of expression of VEGF was 100% in each group with the degree difference.Moreover,the expression of VEGF was decreased obviously in LZBZY group(P0.05,P0.01).Conclusion The LZBZY can inhibit the growth of the transplanted H22 tumor of mice and decrease the expression of the VEGF.
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To observe the effect of drug-containing serum of Chinese traditional herbal decoction Weikangning (WKN) on growth of gastric cancer cell, expression of vascular endothelial growth factor (VEGF) and its receptors including KDR and Flt-1.A total of 120 male Wistar rats were given high, medium and low-dose WKN. After the drug-containing serum was prepared, the gastric cancer cells MGC-803 of different dose groups were cultured with the drug-containing serum, respectively. The gastric cell growth was observed by using light microscope and flow cytometer,the expression of VEGF and its receptor Flt-1 was detected with SABC immunohistochemistry method and the mRNA expression levels of VEGF and its receptors including KDR and Flt-1 of different groups were detected with reverse transcription-polymerase chain reaction (RT-PCR), respectively.The gastric cancer cell growth and cell cycle of the three medicated groups were significantly improved as compared with those of the control group (P <0. 01) ,the proportion of cells in G0 - G1 phase was increased,while the cells in S phase were decreased. It was shown that the apoptotic rates were increased in the medicated groups in a dose-dependent manner. The gray scales ( microm(2) ) of VEGF and Flt-1 in high, medium and low dose groups was 182. 44 +/-0. 54,178. 65 +/-0. 56,174. 80 +/-0. 81 and 168. 51 +/- 0. 81,162. 01 +/-0. 52,148. 20 +/-0. 69, respectively vs 147.82 +/-0. 15(P <0.01) and 144.31 +/-0.71 (P <0.01) in the control group. The mRNA expression of VEGF and its receptors significantly decreased in gastric cancer cells after cultured with WKN contained serum (P < 0. 01 ).WKN has inhibitory effects on gastric cancer cell growth and mRNA expression of VEGF as well as its receptors KDR and Flt-1.
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AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA
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Introduction
Vascular Endothelial Growth Factor (VEGF-A) is a key contributor to growth of colorectal carcinoma (CRC). Consequently, several anti-VEGF-A drugs have been developed to target this pathway, the most notable of which is bevacizumab, licensed for treatment of metastatic CRC. The phase III clinical trial demonstrating its efficacy achieved an overall 30% increase in median survival, but to date there have been no markers identified that can predict the subgroup of responders (~20%).
We have previously shown that CRC tumours produce variable ratios of both pro-angiogenic VEGF-A165 and anti-angiogenic VEGF-A165b and that the latter can inhibit tumour growth in vivo (Varey et al., 2006b). We have also shown that bevacizumab has a similar affinity for both VEGF-A165 and VEGF-A165b (Varey et al., 2006a). Therefore we sought to evaluate whether CRC tumours producing principally anti-angiogenic VEGF-A (VEGF-A165b) would respond differently to bevacizumab therapy compared to those producing predominantly VEGF-A165.
Methods
The human colon carcinoma cell line LS174t (expresses 5.7±0.3% VEGF165b) was transfected to over-express VEGF-A165b (expresses 109±16% VEGF165b). We then subcutaneously injected 2x106 cells/ nude mouse of either the parent cell line (n=12) or the VEGF-A165b derivative (n=14). The following day treatment with twice weekly intra-peritoneal injections of either 50µg bevacizumab or saline commenced in each cell line group and tumour growth monitored.
Results
The parent cell line, expressing principally VEGF-A165 grew much faster than VEGF-A165b over-expressing cells, with or without treatment with bevacizumab. However, whereas the VEGF-A165 cells grew much slower when treated with bevacizumab compared to saline (p=0.0026), there was no difference in the growth of the VEGF-A165b tumours when treated with bevacizumab or saline (p=0.79).
Conclusions
We have previously shown that a significant minority of patients with CRC have a predominance of VEGF-A165b expression in their tumours. The results here demonstrate that inhibition by bevacizumab of VEGF-A works effectively in those tumours that express a predominance of pro-angiogenic VEGF-A165, but not those producing predominantly anti-angiogenic VEGF-A165b. We therefore suggest that measuring the ratio of VEGF-A165b to VEGF-A165 in tumours from CRC patients may enable more accurate selection of patients most likely to benefit from Avastin treatment.
Varey, A. H. R., et al. (2006a). Microcirculation 13, 511-34.
Varey, A. H. R., et al. (2006b). Colorectal Dis 8, 99-102.
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Objective: to evaluate the levels of VEGF, COX-2, PGE-2 in comparison with the effectiveness of radiation therapy with or without a COX-2 inhibitor.
Materials and methods. The study involved 38 patients with non-small cell lung cancer (NSCLC) aged 32 to 80 years (median — 66 years), stage III of the process (50 %) prevailed, histological studies revealed squamous cell cancer in 74 %. To evaluate the results of the study, patients were divided into 2 subgroups: 1 — a subgroup (20 patients who received radiation therapy (RT) in combination with a COX-2 inhibitor — ranselex), 2 — a subgroup (18 patients who received RT). Radiation therapy was performed on linear accelerators Clinac 600C. During RT, patients received a COX-2 inhibitor — ranselex 100 mg per day. To determine the content of angiogenesis factors VEGF, COX-2, and PGE-2, blood sampling was performed in patients before irradiation and after a course of radiotherapy. The content of VEGF, COX-2, and PGE-2 was determined in blood serum by ELISA using standard reagent kits: of Vector-Best CJSC (Russia) for VEGF, commercial reagent kits of Invitrogen COX-2 ELISA Kit (Great Britain) and Prostaglandin T2 ELISA Kit (Germany).
Results. An elevated level of VEGF, COX-2, PGE-2 in the blood serum of patients with NSCLC before radiation treatment was revealed, which indicates the activity of neoangiogenesis processes in the tumor. It was found that in patients with NSCLC after RT in combination with the COX-2 inhibitor ranselex, a 1.9-fold decrease in VEGF was observed against a 2.4-fold decrease in the COX-2 content and 1.7-fold PGE-2. In RT without ranselex, VEGF decreased by 1.4 times and the levels of COX-2 and PGE-2 did not change, which indicates inhibition of the COX-2 inhibitor of angiogenesis. The relationship between the concentration of the pro-angiogenic factor VEGF and the levels of COX-2, PGE-2 and the objective response with which the direct effect of RT was evaluated was established. With regression of the tumor process, a decrease in the level of VEGF was observed, more pronounced in RT with ranselex, which indicates the effectiveness of RT. With progression, a consistently high level of VEGF was observed, which is an unfavorable sign and is possibly associated with the tumor resistance to the therapy and the further unfavorable course of the disease.
Conclusions. The relationship between the concentration of pro-angiogenic factors — VEGF, COX-2, PGE-2 and the objective response was determined, for which the direct effect of radiation therapy with or without a COX-2 inhibitor of ranselex (regression, stabilization, progression) was evaluated. It was shown that a more pronounced decrease in VEGF content is observed after radiation therapy (RT) with ranselex compared with RT without ranselex, which indicates inhibition of COX-2 inhibitor angiogenesis, and thereby leads to an increase in the effectiveness of RT.
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Objective: To explore the expression of VEGF and P~(53) in acute leukemia(AL) cells,and its value for therapy and prognosis.Method: The VEGF and P~(53) expression was assayed by immunohistochemical staining.Result:The expression rates of VEGF and P~(53) were 69.39% and 55.10%,respectively in 49 AL patients,and were significantly higher than those in the control group.The expression of both VEGF and P~(53) was positive and the complete remission rate was apparently reduced.Conclusion: The high expression of VEGF and P~(53) in AL cells may predict the disease development,chemotherapeutical effect and prognosis.
Clinical Significance
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Objective To study the therapeutic effect of AdH1-siRNA/VEGF(vascular endothelial growth factor)combined with chemotherapy in mice with Lewis lung cancer.Methods A replication-defective recombinant adenovirus AdH1-siRNA/VEGF targeting mouse VEGF was constructed using the homologous recombination technique.After established Lewis lung carcinoma models,40C57BL/6mice were randomly and egually divided into 5groups of A(chemotherapy),B(treated with AdH1-siRNA/VEGF),C(treated with AdCMV/GFP),D(chemotherapy plus AdH1-siRNA/VEGF)and E(normal saline control).The tumor volume was measured.The expressions of VEGF in cell culture medium and serum after infection of the indicated adenovirus were detected by indirect ELISA and the microvessel density(MVD)of tumor was counted under the microscopy after immunohistochemical examination.Results AdH1-siRNA/VEGF could specifically decrease the secretion of VEGF in tumor cells.The tumor volume was smaller in groups of A,B and D than that in groups of E and C(P0.05).Serum level of VEGF was lower in group B than that in groups of C and E(P0.05).The number of MVD was less in groups of B and D than that in groups of C and E(P0.01).Conclusion The recombinant adenovirus-mediated siRNA can obviously downregulate VEGF expression in vitro and in vivo,which reduces the angiogenesis and growth of tumors.RNAi combined with chemotherapy has a synergistic inhibition effect on tumors.
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To investigate the effect of vascular endothelial growth factor (VEGF) on tumor angiogenesis in gallbladder carcinoma.Fifty one patients with gallbladder carcinoma were enrolled as observation group. Thirty healthy people were included as control group. Chemically synthesized siRNA sequences targeting VEGF was transfected with VEGF-siRNA. A blank group (group B), a negative control group (transfected with independent sequence, group C), and an inhibition group (transfected with VEGF siRNA, group D) were established. Physiological saline was set as group A. The expression of VEGF was detected by qRT-PCR. The expression of VEGF protein was detected by Western blot. MVD was used to measure microvessel density. CCK-8, Transwell and flow cytometry were used to detect cell proliferation, invasion and apoptosis.The tumor volume of nude mice and VEGF mRNA expression in group D was significantly smaller than that in group B and C (P<0.05). The MVD density in group B and C was significantly higher than that in group D (P<0.01). The proliferation of cells was detected from the 3rd day, and the proliferation of cells in the blank and negative control groups was faster than that of the inhibition group (P<0.05). The apoptosis rate of the blank group and the negative control group was lower than that of the inhibition group (P<0.001).VEGF is highly expressed in serum of patients with cholangiocarcinoma, it promotes angiogenesis, proliferation and invasion of gallbladder cancer cells, and inhibits apoptosis of tumor cells.
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Mechanism of IFN- α combinedwith ATRA in liver cancer therapy in perioperative phase of intervention
：Objective To study aadjunctive treatment that has a better curative effect and fewer side effects inperioperative phase of interventional therapy.Method An animal model of HCC CBRH7919 wasestablished by implanting 22 Wistar rats with tumor tissue.The hepatic artery was tied offon week 3 after formation of tumor.The rats were divided into 2 groups:(1)control group(n= 12): peritoneal injection with normal saline;(2)interferon-α(IFN-α)+all-transretinoic acid(ATRA)large dose group(n= 10): peritoneal injection with IFN-α(1million U/Kg qod)andATRA(10 mg/Kg qd).After the hepatic artery being tied off,the ratswere treated on the 1st day and sacrificed on 9th day.The levels of expression of tumormetastasis associated gene,protein,tumor mirovessel density,and tumor cells apoptosis weredetermined.Results The mRNA of tumor metastasis associated gene VEGF and bFGF weredetected by RT-PCR.bFGF and VEGF gene in tumor tissue of IFN-α+RA group reducedsignificantly as compared with control group(P＜0.05).The result of bF-GF andVEGF protein in tumor tissue analyzed by immunohistochemistry was accordant with theRT-PCR.The levels of bFGF and VEGF in IFN-α+RA group decreasedsignificantly: a few bFGF and little VEGF.The expression of VEGF in serum was detected byELISA.The level of VEGF was different significantly between control group and IFN-α+RAgroups(92.5 ±13.9 pg/ml vs 69.8 ±20.4 pg/ml,P＜0.05).Mirovesseldensity(MVD)was detected by immunohistochemistry.More new vessels were found in tumortissue of the control group.However,new vessels in the IFN-α+RA groups reducedsignificantly.The level of MVD in control group was 114 ± 18/HP vs 66 ± 5/HP in IFN-α+RAgroups(P＜0.05).In the detection of tumor cells apoptosis,more necrotic areawas found in tumor tissue of IFN-α+RA group.An significant increase inthe necrosis cells(Annexin V-Pi+)was analyzed by flow cytometer.Cell nucleus was dyed toindigo through TUNEL method,and unevenly distributional chromatin was observed bymicroscopy.Apoptotic index was(3.715 ±1.57)in control groups vs(12.34±4.78)% in IFN-α+RAgroup(P＜0.05).Conclusion Inhibition of tumor angiogenesis through IFN-α combined with RA therapy can stop growth and metastasize of livercancer.The early and combined treatment with two anti-tumor angiogenesis drugs inperioperative phase of intervention plays an important role in prevention of recurrenceand metastasis of liver cancer after surgery.
Liver Cancer
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