| 摘要 |
Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is one of the most frequently expressed angiogenic factors in tumors. Development of VEGF antagonists has become an important approach in cancer therapy. The present invention relates to an anti-VEGF strategy wherein VEGF secretion from tumors cells is prevented. The placenta growth factor-1 (PLGF-1), a member of the VEGF family lacking detectable angiogenic activity, preferentially forms intracellular heterodimers with VEGF in cells co-expressing both factors. A retroviral vector was constructed containing human PLGF-l (SEQ ID NO: 1) or VEGF with a C-terminal KDEL (SEQ ID NO: 7) sequence, which is a signal for endoplasmic reticulum (ER)-retention in mammalian cells. Transduction of murine Lewis lung carcinoma (LLC) cells with the PLGF-1-KDEL retroviral vector almost completely abrogated tumor growth and induced tumor dormancy. Consistent with the dramatic anti-tumor effect, most mouse VEGF molecules remain as intracellular VEGF/PLGF-l heterodimers and only a negligible amount of VEGF homodimers are secreted. As a result, in PLGF-1-KDEL (SEQ ID NO: 3) tumors blood vessels remain at very low numbers and lack branching and capillary networks. Gene transfer of a VEGF-KDEL construct into tumor cells likewise produced a dramatic antitumor effect. Thus, the present invention provides compositions and methods for inhibiting secretion of VEGF from cells. |
