Targeting Vascular Endothelial Growth Factor Blockade: Ascites and Pleural Effusion Formation

Abstract

Primary Purpose. Formation of ascites and pleural effusion (PE) is a common problem for patients with advanced-stage cancer. These fluid accumulations cause severe symptoms such as abdominal distention, shortness of breath, cachexia, anorexia, and fatigue. Preclinical models have demonstrated that vascular endothelial growth factor (VEGF) plays a pivotal role in the accumulation of malignant PE or ascites. This study investigated whether blockade of VEGF activity would reduce biological activity of PE and ascites on endothelial cells of cancer patients.Patients and Methods. The activity of VEGF in PE and ascites of 58 patients (39 with PE and 19 with ascites) was measured. An endothelial cell proliferation assay with human umbilical vein endothelial cells was used to determine the biological activity of ascites and PE.Results. VEGF concentrations ranged from 67-6,245 pg/ml. A significantly higher concentration of VEGF was detected in the ascites and PE of patients with cancer (median, 1,290 pg/ml) than in patients with nonmalignant disease (median, 250 pg/ml; p = 0.02). Of the 58 PE and ascites samples, 41 were biologically active, based on a two-to fourfold stimulation of endothelial cell proliferation in 72 hours. VEGF concentrations were significantly higher in the biologically active samples compared with the 17 nonactive samples (2,056 pg/ml versus 771 pg/ml; p = 0.02). Coincubation of the samples with either a neutralizing polyclonal antibody against VEGF or SU5416, a small molecule inhibitor of the VEGF receptor Flk-1/KDR, inhibited endothelial cell proliferation by 66% and 100%, respectively. The inhibition caused by the antibody and that caused by SU5416 correlated significantly (r = 0.8, p < 0.001).Conclusion. We conclude that malignant ascites and PE contain high levels of biologically active VEGF. This study strongly supports the hypothesis that blockade of VEGF, such as that afforded by SU5416, may benefit cancer patients with recurrent ascites or PE formation.

Vascular endothelial growth factor and soluble intercellular adhesion molecule-1 in lung adenocarcinoma with malignant pleural effusion: Correlations with patient survival and pleural effusion control

“…Several lines of studies agreed with our results demonstrating that VEGF levels are higher in malignant effusions from various cancers (including lung carcinomas, breast and mesotheliomas [22]) than that in benign diseases [23][24][25][26]. These results demonstrated that VEGF expression was associated with MPE.…”

Treatment of Malignant Ascites

“…• One study showed that 19 cancer patients with malignant ascites of varying tumor types, including gastrointestinal tumors, had a significantly higher concentration of VEGF in aspirated fluid compared to patients with nonmalignant disease (P = 0.020). SU5416, an anti-VEGF receptor 2 small molecule inhibitor, is hypothesized to have activity Treatment of Malignant Ascites Chung and Kozuch in malignant ascites accumulation and is under testing [70]. The anti-VEGF antibody has not yet reached clinical applications in the reduction of GI-associated malignant ascites.…”

The diagnostic significance and the assessment of the value of vascular endothelial growth factor as a marker for success of chemical pleurodesis in malignant pleural effusion

“…A new experimental study for the treatment of PE includes VEGF receptor (receptor tyrosine kinase) blockage model for human tumors [23,24]. VEGF receptor blockage model may also provide a new therapeutic approach for pleural malignancies.…”