The effect of antibody against vascular endothelial growth factor on tumor growth and metastasis

Vascular endothelial growth factor (VEGF), a very important in the process of tumor angiogenesis, was chosen as a target in a study to determine whether manipulation of angiogenesis with antibody against VEGF may interrupt tumor growth and metastasis. Anti-VEGF antibody was obtained from immunized rabbits, purified on an affinity column, and identified as neutralized antibody by Mile's assay. IVTA₂MA891, a murine spontaneous breast cancer with a high rate of metastasis in lung in TA₂ × 615 F1 mice, was chosen as an animal model in this study, because of the high expression of VEGF in the primary tumor as well as in the lung metastatic tumor. The anti-VEGF antibody could inhibit growth of S180 sarcoma in a dose-dependent manner, and the inhibition rate could reach 41.0% with a dose of 200 μg mouse⁻¹ day⁻¹. Anti-VEGF antibody could inhibit tumor growth by 76.2% in nude mice bearing human gastric cancer (MGC 803). When anti-VEGF antibody was combined with ¹³¹I-3H11, a murine monoclonal antibody conjugated with ¹³¹I, only one of five nude mice developed tumor and 84.0% more inhibition of tumor growth was obtained in comparison with treatment by ¹³¹I-3H11 alone. The growth of the primary tumor was inhibited by 44.0% and the number and size of the metastatic foci in the lungs were reduced by 73.0% and 83.7% respectively in the animal model, with a high rate of metastasis in lung. The anti-VEGF antibody may be potentially useful for clinical treatment of cancer and metastasis. Received: 2 January 1998 / Accepted: 17 March 1998     

Therapeutic angiogenesis with vascular endothelial growth factor in peripheral and coronary artery disease: a review

Therapeutic angiogenesis constitutes an alternative treatment for patients with extensive tissue ischaemia in whom primary vascular reconstruction procedures are not feasible or have previously failed. At present vascular endothelial growth factor (VEGF) has been the most widely used angiogenic factor in experimental and human clinical trials. Early clinical data provide evidence that gene transfer of the VEGF gene can achieve beneficial angiogenesis, with minimal side-effects. Ongoing phase III clinical studies will reveal definitive efficacy.     

Intermittent interferon and polychemotherapy in metastatic melanoma

This study was conducted to evaluate the efficacy and the tolerability of a four-drug chemotherapy regimen combined with interferon (IFN) in metastatic melanoma. Between March 1991 and August 1993, 55 patients with advanced melanoma were enrolled for the present multicentre phase II study. Fortynine patients were eligible and evaluable for toxicity; 48 patients were evaluable for response. The treatment schedule consisted of a 5-day regimen of dacarbazine, vincristine, bleomycin and lomustine, plus 6×10⁶ IU IFN three times weekly subcutaneously for 2 weeks starting on day 8. The cycle was repeated on day 29. Among the 48 assessable patients, 16 objective responses were seen, yielding a response rate of 33% (95% confidence interval 20%–46%). Seven patients achieved a complete response (CR) of a median of 6 + months (range 1 + to 21 + months) and 9 patients achieved a partial response (PR) of a median of 9 months (range 4–13 months). The median overall survival was 12 + months (range 6+ to 23 + months) for the patients with CR and 15 + months (range 8–20 months) for the patients with PR. Even the survival of the 7 patients with stable disease was fairly long (median 12, range 7–17 months), appearing to be significantly longer than the survival of the 25 patients with progressive disease (median 5, range 1–24 + months). The treatment was moderately well tolerated, although all patients experienced some mild form of toxicity, mostly gastrointestinal symptoms, neurotoxicity and haematotoxicity. Grade 3–4 adverse effects were noted in 39% of the patients. No toxic deaths occurred. It can be concluded that the present regimen produces meaningful responses for patients with metastatic melanoma. A randomised study is needed to determine the effect on survival.Abbreviations IFN interferon - DOBC dacarbazine, vincristine, bleomycin, lomustine     

Serum levels of vascular endothelial growth factor and basic fibroblast growth factor in patients with soft-tissue sarcoma

Purpose: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been suggested to be important mediators for tumor-induced angiogenesis. We measured serum VEGF and bFGF levels from patients with soft-tissue sarcomas and correlated serum VEGF and bFGF levels with tumor status at surgery and histological grading. Materials and methods: A group of 18 healthy controls and 85 patients with soft-tissue sarcoma were enrolled in this study. The patients were classified according to tumor status at surgery. Serum levels of VEGF and bFGF were also correlated with histological grading. VEGF and bFGF levels were determined by enzyme-linked immunosorbent assay (Quantikine R&D Systems). Results: Serum VEGF and bFGF levels were significantly elevated in the patient group (VEGF: 580pg/ml, bFbF: 21pg/ml, P = 0.0001). The highest concentrations of serum VEGF and bFGF were found in patients with macroscopic tumor lesions or G3 histology. Serum VEGF levels showed a statistically significant correlation with tumor status and grading (P = 0.006 for tumor status, P = 0.0001 for grading). Conclusions: This study reveals that elevated preoperative serum VEGF and bFGF levels can be detected in the majority of patients with soft-tissue sarcoma. The significant correlation with tumor mass and histological grading suggests that a consecutive monitoring of VEGF and bFGF in the serum of patients with soft-tissue sarcoma might be a valuable marker for tumor follow-up. Received: 26 April 1999 / Accepted: 17 May 1999     

血管内皮细胞生长因子与治疗性血管新生

本文概述了血管内皮细胞生长因子(VEGF)家族及其受体的组成,介绍了调控VEGF表达的因素及VEGF信号传导途径。着重阐述了VEGF促血管新生的作用机制,以及VEGF在治疗性血管新生中的研究与应用现状、存在问题及未来发展前景。还简要介绍了VEGF其他的生物学作用。     

Characterization of a new potent, in vivo neutralizing monoclonal antibody to human vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is an important mediator of tumor-induced angiogenesis and represents a potential target for anticancer therapy. Therefore, we prepared a panel of monoclonal antibodies (mAb) against both the VEGF₁₂₁ and VEGF₁₆₅ isoforms. Three of them completely neutralized the mitogenic stimulation by VEGF of human umbilical vein endothelial cells at mAb concentrations below 0.1 μg/ml. The most potent one, with a dissociation constant (K _d) of 8 pM, inhibited, in a dose-dependent manner, VEGF-induced angiogenesis in a growth factor implant model in mice. A complete inhibition of the angiogenic response was obtained by daily intraperitoneal injections of 10 μg mAb/mouse. Angiogenesis induced by basic fibroblast growth factor was not inhibited by the mAb. Epitope mapping of the mAb, performed by competitive enzyme-linked immunosorbent assay and Western blot analysis, showed that it did not bind to the reduced and denatured monomer of VEGF. Substitutions of three residues (Q87R, G88K, Q89K), located on the major surface loop β5 to β6 of VEGF, resulted in the complete loss of binding (more than 400-fold reduction). The results suggest that the mAb binds primarily to a conformation-dependent epitope on the VEGF dimeric form, encompassing one of the loop regions involved in KDR receptor binding. The mAb with its strong neutralizing properties represents a useful agent for effective blocking of VEGF-mediated tumor neovascularization. Received: 11 November 1998 / Accepted: 16 December 1998     

Therapeutic effect of anti-vascular endothelial growth factor receptor I antibody in the established collagen-induced arthritis mouse model

Synovial angiogenesis plays an important role in the inflammation in rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) is a key molecule in angiogenesis and binds to specific receptors, known as vascular endothelial growth factor receptor I (VEGF RI). In this study, we investigated the therapeutic efficacy of anti-VEGF RI antibody (Ab) on RA using a collagen-induced arthritis (CIA) mouse model. Twelve DBA/1 mice were divided into three groups. All mice except controls were injected with type II collagen. Mice in the anti-VEGF-RI-Ab-treated groups were injected on one posterior paw with 50 μg anti-VEGF RI Ab twice weekly for 3 weeks. Arthritis score and paw thickness were measured and histopathologic assessment of joint sections was performed by hematoxylin–eosin. The infiltration of CD45⁺ inflammatory cells and neovascularization were evaluated by immunohistochemical staining. Anti-VEGF RI Ab significantly attenuated the arthritis severity and histopathologic findings in the CIA mice model. The infiltration of CD45⁺ cells decreased in anti-VEGF-RI-Ab-treated joint tissues. Staining for CD31 revealed reduced synovial neovascularization after anti-VEGF RI Ab treatment. The data showing that in vivo administration of anti-VEGF RI Ab suppressed arthritis in established CIA mice suggest anti-VEGF RI Ab treatment may serve as a new therapeutic modality for RA.     

Hedgehog signaling in the murine melanoma microenvironment

The Hedgehog intercellular signaling pathway regulates cell proliferation and differentiation. This pathway has been implicated to play a role in the pathogenesis of cancer and in embryonic blood vessel development. In the current study, Hedgehog signaling in tumor related vasculature and microenvironment was examined using human umbilical vein endothelial cells and B16F0 (murine melanoma) tumors models. Use of exogenous Sonic hedgehog (Shh) peptide significantly increased BrdU incorporation in endothelial cells in vitro by a factor of 2 (P < 0.001). The Hedgehog pathway antagonist cyclopamine effectively reduced Shh-induced proliferation to control levels. To study Hedgehog signaling in vivo a hind limb tumor model with the B16F0 cell line was used. Treatment with 25 mg/kg cyclopamine significantly attenuated BrdU incorporation in tumor cells threefold (P < 0.001), in tumor related endothelial cells threefold (P = 0.004), and delayed tumor growth by 4 days. Immunohistochemistry revealed that the Hedgehog receptor Patched was localized to the tumor stroma and that B16F0 cells expressed Shh peptide. Furthermore, mouse embryonic fibroblasts required the presence of B16F0 cells to express Patched in a co-culture assay system. These studies indicate that Shh peptide produced by melanoma cells induces Patched expression in fibroblasts. To study tumor related angiogenesis a vascular window model was used to monitor tumor vascularity. Treatment with cyclopamine significantly attenuated vascular formation by a factor of 2.5 (P < 0.001) and altered vascular morphology. Furthermore, cyclopamine reduced tumor blood vessel permeability to FITC labeled dextran while having no effect on normal blood vessels. These studies suggest that Hedgehog signaling regulates melanoma related vascular formation and function. L. Geng and K.C. Cuneo contributed equally to this work.     

类风湿关节炎血管内皮生长因子趋化因子RANTES的研究

目的探讨血管内皮生长因子(VEGF)、调节活化和正常T细胞表达及分泌的趋化因子(RANTES)在类风湿关节炎(RA)发病中的作用,在疾病活动性判断、鉴别诊断中的价值,以及二者是否在RA发病中具有协同作用。方法用酶联免疫吸附试验(ELISA)法测定36例RA患者、20例骨关节炎(OA)患者及20名健康体检人员血清中VEGF和RANTES水平。结果①活动期RA患者血清中VEGF、RANTES水平显著高于缓解期RA组、OA组(P<0.05)及健康对照组(P<0.01),缓解期RA患者血清中VEGF亦显著高于健康对照组(P<0.05),而与OA组相比差异无显著性(P>0.05)。缓解期RA患者血清RANTES水平与OA组及健康对照组之间差异均无显著性(P>0.05)。②RA患者血清VEGF与RANTES之间具有相关性(P<0.05)。结论①活动期RA患者血清VEGF、RANTES水平高于RA缓解期,提示VEGF、RANTES可作为RA活动期判断指标之一。②活动期RA患者血清中VEGF、RANTES水平升高,高于OA组,有助于二者之间的鉴别诊断。③活动期RA患者血清中VEGF、RANTES呈正相关关系,提示VEGF、RANTES在RA的发生、发展中具有相辅相承、互相促进作用。     

Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery

Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can “normalize” their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens.As one of the most prevalent infectious diseases in the world today, Mycobacterium tuberculosis (MTB) infects roughly one-third of the global population, resulting in 2 million deaths annually (1). Although current treatment regimens are largely successful in curing the disease (2), they require 6–8 mo of treatment with up to four agents (3), and multidrug-resistant bacterial strains have emerged and proliferated (4). Resistance to front-line therapies necessitates treatment with up to five or six second-line agents that are poorly tolerated, and treatment success is only achieved in 40–70% of patients (5). Failure to cure drug-resistant disease leads to acquisition of further resistance with a progressively poorer prognosis for these patients, thus fueling an emerging epidemic of drug-resistant disease that threatens to overwhelm fragile health care systems in developing countries (6).When infected with the tuberculosis (TB) bacilli, the body triggers an immune response that walls off the bacteria in dense cellular masses known as granulomas, or tubercular lesions (7). These abnormal tissue structures, which can vary in size within the same host, are surrounded by fibrous cuffs that serve to contain the MTB bacilli (7, 8). Recent studies have demonstrated a wide variation in the spatial distribution of drugs within TB granulomas, with very few agents able to penetrate the central regions (9). This differential ability of drugs to penetrate TB granulomas has been incorporated into modern TB drug development programs as a criterion for optimizing lead molecules and selecting efficacious combinations (10). However, the mechanisms that contribute to this differential penetration of drugs are not fully understood, and novel strategies to improve TB drug delivery and efficacy are urgently needed.Following infection with MTB, pulmonary granulomas form in humans and develop heterogeneous microenvironments, often featuring hypoxia (i.e., low levels of oxygen) and central necrosis, which are recapitulated in nonhuman primate and rabbit models of the disease (11). Large lesions appear to develop their own vasculature, presumably allowing them to continue to grow (7). However, the morphological and functional characteristics of granuloma-associated vessels are largely unknown. In solid tumors, cancer cells can form similar dense tissue masses with abnormal associated vasculature. The physiological abnormalities that characterize tumor vessels have been investigated extensively (12, 13). For example, hypoxia, a common feature in solid tumors, stimulates the overproduction of proangiogenic factors, such as VEGF. Proangiogenic factors enhance the formation of new immature, tortuous, and hyperpermeable vessels (12, 14), often with excess endothelial cells, a lack of associated pericytes (i.e., perivascular cells), and uneven basement membranes (15–17). These atypical features result in an impaired blood flow that further compromises delivery of drugs and oxygen (13). Hypoxia also causes immunosuppression, inflammation, and fibrosis, and it can also confer resistance to many drugs (18). Here, we propose that TB granulomas share many characteristics with solid tumors, namely, that they are associated with abnormal and dysfunctional vasculature that can impair the delivery of small molecules, such as oxygen and antibiotics.Because VEGF is a critical growth factor required for new blood vessel formation (16), anti-VEGF agents were originally developed to block tumor growth by inhibiting blood vessel formation (19). However, bevacizumab, a humanized monoclonal antibody developed to neutralize human VEGF, failed to improve survival benefit as a monotherapy but conferred survival benefit only in combination with chemotherapy or immunotherapy (18). A potential explanation for the success of combined therapies is that bevacizumab “normalizes” the abnormal vasculature of tumors, resulting in improved delivery of concurrently administered anticancer drugs, as well as alleviation of hypoxia (13, 15, 18, 20, 21). However, this strategy has not been tested in a TB disease model. In this study we show, for the first time to our knowledge, in a rabbit model of TB that treatment with bevacizumab normalizes granuloma vasculature, reduces hypoxia, and enhances small molecule delivery during a “window of normalization,” a transient effect observed in tumors (15, 20). Because anti-VEGF drugs have been approved for both malignant and nonmalignant diseases (18), our findings could be rapidly tested in the clinic to enhance TB treatment, shorten treatment duration, and avert the development of treatment resistance.     

Fotemustine and interferon α2b in metastatic malignant melanoma

The efficacy of treatment with fotemustine and interferon (IFN) α was evaluated in metastatic melanoma. A group of 50 patients with metastatic malignant melanoma were treated with a combination of IFNα2b and the nitrosourea fotemustine. The patients received 10 MU IFN three times weekly for 3 weeks and fotemustine at a dose of 100 mg/m² on days 8, 15 and 22. After a 5-week rest period, patients with stabilized or responding disease received a maintenance therapy consisting of 10 MU IFN three times a week for 1 week followed by administration of fotemustine (100 mg/m²) on day 8. This cycle was repeated every 4 weeks until progression occurred. If there was complete remission (CR), treatment was stopped after an additional three cycles. Toxicity and clinical response were scored according to WHO criteria. Objective response was seen in 14 patients (28%; 95% confidence interval 15.6%–40.4%) with four CR and ten partial responses (PR). The median duration of CR was 73 weeks, that of PR 26 weeks. Toxicity was acceptable, enabling treatment on an outpatient basis. The combination of fotemustine with IFNα is effective and well tolerated, but there is no evident advantage over fotemustine monotherapy in the treatment of metastatic melanoma. Received: 11 July 1997 / Accepted: 30 September 1997     

Targeting vascular endothelial growth factor with the monoclonal antibody bevacizumab inhibits human hepatocellular carcinoma cells growing in an orthotopic mouse model

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Liver resection or transplantation is curative for a subset of patients with localized disease, but treatments for advanced disease are generally toxic and ineffective. Aberrant expression of the vascular endothelial growth factor (VEGF) has been implicated in the progression of HCC and represents a valid target for anticancer therapy. Bevacizumab, a humanized anti‐VEGF monoclonal antibody, is currently being evaluated in the treatment of HCC. In addition, other novel anti‐angiogenesis agents are being developed in HCC. Aim: This study examines the effect of bevacizumab in a newly characterized orthotopic model of the disease using the human HCC cell line, Hep 3B, and provides preclinical evidence that an anti‐angiogenic approach holds promise in HCC. Results: Administration of bevacizumab 5 mg/kg intraperitoneal twice a week significantly decreased microvessel density in tumours, decreased human serum α‐fetoprotein measurements and prolonged the time to progression for treatment mice compared with control mice. Conclusions: Our findings suggest that targeting VEGF with bevacizumab may be an effective approach to the treatment of HCC and further study of other novel anti‐angiogenic agents in HCC is warranted.     

Clinical evaluation of in vitro chemosensitivity testing: the example of uveal melanoma

Purpose Results from in vitro chemosensitivity testing recommend treosulfan/gemcitabine chemotherapy for the treatment of stage IV uveal melanoma.Methods Twenty patients received treosulfan 3,500 mg/m² followed by gemcitabine 1,000 mg/m² on day 1 and day 8 repeated on day 29. In cases of prior chemotherapy only 75% of these dosages were used.Results Without any patient achieving an objective response, 25% of patients (95% confidence interval, 8.6–49.1%) had stabilisation of disease. This stabilisation was associated with a prolonged median overall survival of 17 months compared with 7 months for the patients with progressive disease. First-line treatment was not associated with better response or survival although prognostic parameters did not significantly differ from that of other patients.Conclusions The results are disappointing and question the value of individualized chemotherapy based on in vitro assays.     

Serum vascular endothelial growth factor: a prognostic factor in cervical cancer

Purpose  To study pre-treatment serum VEGF of patients with invasive cervical cancer and its possible role as prognostic indicator. Methods  VEGF was measured using ELISA in the largest patient group (n = 167) to date. Reults  Serum VEGF was significantly higher in advanced tumor stage (P = 0.01), large tumor size (tumors larger than 2 cm) (P = 0.03), and the presence of vascular space invasion (P = 0.05). Serum VEGF was associated with disease free and overall survival [DFS: Hazard Ratio (HR) = 2.61; 95% CI 1.32–5.17; P = 0.006; for OS: HR = 2.09; 95% CI 1.54–2.84; P < 0.001, respectively]. In multivariate Cox regression serum VEGF retained its prognostic value for DFS (HR = 2.10, P = 0.03) and OS (HR = 1.92, P = 0.04). Conclusions  Serum VEGF levels correlate with more advanced and more aggressive disease in cervical cancer and may be a useful prognostic factor in patients with cervical cancer.     

Statins differentially regulate vascular endothelial growth factor synthesis in endothelial and vascular smooth muscle cells

Objectives: HMG-CoA reductase inhibitors (statins) can modulate the formation of new blood vessels, but the reports on their contribution to angiogenesis are contradictory. Therefore, we investigated whether the effect of statins is dependent either on the concentration of the drug or on the cell type. Methods and results: Under basal conditions human vascular smooth muscle cells (HVSMC) and microvascular endothelial cells (HMEC-1) constitutively generate and release vascular endothelial growth factor (VEGF). In contrast, primary macrovascular endothelial cells (HUVEC) produce minute amounts of VEGF. Different statins (atorvastatin, simvastatin and lovastatin, 1–10 μmol/l) significantly reduced basal and cytokine-, nitric oxide- or lysophosphatidylcholine (LPC)-induced VEGF synthesis in HMEC-1 and HVSMC. Interestingly, at the same concentrations statins upregulated VEGF generation in HUVEC. Furthermore, statins exerted dual, concentration-dependent influence on angiogenic activities of HUVEC as determined by tube formation assay. At low concentrations (0.03–1 μmol/l) the pro-angiogenic activity of statins is prevalent, whereas at higher concentrations statins inhibit angiogenesis, despite increasing VEGF synthesis. Conclusion: Our data show that statins exert concentration- and cell type-dependent effects on angiogenic activity of endothelial cells and on VEGF synthesis. The data are of relevance for elucidating the differential activity of statins on angiogenesis in cardiovascular diseases and cancer.     

Marked elevation of vascular endothelial growth factor and basic fibroblast growth factor in pericardial fluid of patients with angina pectoris

Although we reported that basic fibroblast growth factor (bFGF) levels in pericardial fluid of patients with unstable angina are apparently increased, it was unclear whether vascular endothelial growth factor (VEGF) is also increased in patients with myocardial ischemia. Using an enzyme-linked immunosorbent assay, we measured the concentrations of VEGF and bFGF in pericardial fluid of 51 patients with open heart surgery. Patients were divided into group A (n=10) with class III unstable angina (Braunwald's classification), group B (n=24) with class I or II unstable angina or stable angina and group C (n=17) with non-ischemic heart disease. The VEGF level in pericardial fluid in group A was 83±7 pg/ml, being significantly (p<0.001) higher than the 27±3 pg/ml in group B and the 28±5 pg/ml in group C. The concentrations of bFGF in pericardial fluid in groups A and B were 1461±579 and 1224±161 pg/ml, respectively, significantly (p<0.05) higher than the 292±97 pg/ml in group C. The level of VEGF in pericardial fluid was increased only in patients with severe rest angina within 2 days before emergency coronary artery bypass graft surgery (CABG), while bFGF was increased in all patients undergoing CABG for coronary artery disease. Thus VEGF and bFGF may play important roles in mediating collateral growth in humans.     

Hepatic failure in a patient treated with dacarbazine (DTIC) for malignant melanoma

Summary A 55-year-old white woman received chemotherapy with DTIC after surgery for malignant melanoma (stage I, SSM IV, depth of invasion 12 mm). She died suddenly during the second treatment cycle. Autopsy revealed massive necrosis of the liver and thrombosis of the hepatic veins. The cause of the fatal outcome is attributed to the adverse toxic effects of DTIC.     

贝伐单克隆抗体对二乙基亚硝胺诱导的原发性肝癌大鼠的防治作用及其对肝癌组织VEGF表达的影响

目的 研究抗血管内皮生长因子（VEGF）单克隆抗体对二乙基亚硝胺（DEN）所致原发性肝癌大鼠的干预作用及其对肝组织VEGF表达的影响。方法 将30只SD 大鼠随机分为正常组、模型组和药物干预组。采用联合应用四氯化碳和DEN法制备原发性肝癌模型,并给予抗VEGF单克隆抗体腹腔注射干预,在正常组和模型组则给予等体积生理盐水注射。连续干预12 w。实验结束,取血和肝组织行相关检查,采用免疫组化法检测肝组织VEGF表达。结果 药物干预组大鼠肝质量、肝表面癌结节数,癌变率和肝脏指数分别为（17.51±2.53）g、（6.86±0.82）个、30%和（4.10±0.79）,均明显低于模型组的【（23.71±3.01）、（21.91±2.75）、100.0%和（5.90±1.01）,P<0.05】;与模型组比,药物干预组大鼠血清AST、ALT和TBIL水平分别为（101.58±19.83） IU/L、（241.52±36.58） IU/L和（62.93±3.03） μmol/L,均明显低于模型组（P<0.05）;病理学检查结果显示,与模型组比,药物干预组动物肝组织损伤明显减轻;免疫组化检测结果则显示,模型组、正常组和药物干预组VEGF相对表达量分别为（35.21±6.92）、（1.00±0.00）和（11.53±3.81）,差异显著（P＜0.05）。结论 抗VEGF单克隆抗体对DEN诱导的原发性肝癌大鼠具有较好的抑瘤作用,而这种作用可能与其抑制了肝组织VEGF表达有关。