Angiostatin gene transfer: Inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest

Abstract

The antitumoral effects that follow the local delivery of the N-terminal fragment of human plasminogen (angiostatin K3) have been studied in two xenograft murine models. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molecule from the cytomegalovirus promoter (AdK3). In in vitro studies, AdK3 selectively inhibited endothelial cell proliferation and disrupted the G 2 ͞M transition induced by M-phasepromoting factors. AdK3-infected endothelial cells showed a marked mitosis arrest that correlated with the downregulation of the M-phase phosphoproteins. A single intratumoral injection of AdK3 into preestablished rat C6 glioma or human MDA-MB-231 breast carcinoma grown in athymic mice was followed by a significant arrest of tumor growth, which was associated with a suppression of neovascularization within and at the vicinity of the tumors. AdK3 therapy also induced a 10-fold increase in apoptotic tumor cells as compared with a control adenovirus. Furthermore, we showed that systemic injection of AdK3 delayed C6 tumor establishment and growth, confirming that angiostatin can function in a paracrin manner. Our data support the concept that targeted antiangiogenesis, using adenovirus-mediated gene transfer, represents a promising alternative strategy for delivering antiangiogenic factors as their bolus injections present unsolved pharmacological problems.

Viral vector-mediated transduction of a modified thrombospondin-2 cDNA inhibits tumor growth and angiogenesis

“…Similarly, tumor treatment with other antiangiogenic gene transfer such as angiostatin, endostatin, and platelet factor-4 also led to reduced tumor size with inhibiting tumorassociated vascularization. [17][18][19] Together with other reports, our data suggested that the delivery of the antiangiogenic genes could constitute an attractive solution to problems that resulted from the usage of recombinant proteins. [17][18][19] The present data provide the first demonstration that viral vector-based delivery of the cDNA for NfTSP2 can be used to modulate the tumor growth in the in vivo mouse tumor model.…”

Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation

“…27 Cell cycle regulatory proteins that are critical to endothelial cell proliferation such as M-phase phosphoproteins have recently been shown to be downregulated by angiosatin. 28 Furthermore, an angiostatin-endostatin fusion gene showed significantly greater inhibition of human umbilical vein endothelial cell tube formation in vitro and potent antitumor effects in a melanoma model in vivo, than angiostatin, endostatin, or a combination of the two genes. 20 In our experiments, transfection with angiostatin gene first and endostatin gene later was inefficient, whereas reverse order induced a significant antitumor effect.…”

A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer

“…7 Angiostatin has been described to exert potent antiangiogenic and antitumor activities in a variety of murine tumor models. [7][8][9][10] Similarly, a 20-kDa (184 amino acid (aa)) C-terminal fragment of collagen XVIII, termed endostatin (ES), is reported to be a potent inhibitor of tumor angiogenesis and micrometastases development. 5,11 The urokinase plasminogen activator (uPA) binds to its receptor uPAR via its light chain fragments, 12 known as amino-terminal fragment ATF (residues .…”