Recombinant human endostatin (rh-endostatin), a potential antiangiogenic agent, 
is used in non-small cell lung carcinoma treatment and represses vascular 
endothelial cell growth factor (VEGF) levels in tumor cell. However, precise 
affection of rh-endostatin on the proangiogenic VEGF isoforms (VEGF(165)) or 
antiangiogenic VEGF isoforms (VEGF(165)b) is not clear. We therefore tested the 
hypothesis that rh-endostatin could alter expression of these isoforms to 
regulate tumor growth. A549 cells were exposed to rh-endostatin, and the 
expression of VEGF(165) and VEGF(165)b was detected. The role of SP1 as a 
regulator of isoform expression was investigated. We then examined the 
anticancer and antiangiogenic efficacy of rh-endostatin in combination with 
exogenous VEGF(165)b against A549 cells, EA.HY 926 cells and xenograft model of 
human lung cancer. rh-Endostatin reduced VEGF(165) and induced VEGF(165)b as 
well as inhibited SP1 in A549 cells. SP1 inhibitor (betulinic acid) also 
developed those changes. VEGF(165)b-rh-endostatin combination was highly 
synergistic and inhibited growth, survival, and migration of A549 cells, 
VEGF-mediated VEGFR2 phosphorylation in EA.HY 926 cells, and tumor growth in 
xenograft model of human lung cancer. rh-Endostatin downregulates proangiogenic 
vascular endothelial growth factor A (VEGFA) isoform and upregulates 
antiangiogenic VEGFA isoform, possibly through inhibition of SP1. Furthermore, 
VEGF(165)b sensitizes A549 to rh-endostatin treatment and enhances the 
anticancer effect of rh-endostatin.