The majority of patients with HCC die within 1 year after the diagnosis. Unfortunately, HCC is often diagnosed at its late stage when potentially curative therapies are least effective. For such patients, medical treatment modalities, including chemotherapy, chemoembolization, ablation, and proton beam therapy, remain disappointing. Most patients show recurrent HCC that rapidly Imatinib purchase progresses to its advanced stage with vascular invasion and multiple intrahepatic metastases and their 5-year survival rate is only 7%. Patients with surgically resectable localized HCC have a better prognosis, but their 5-year survival rate is only 15%-39%, showing that new therapies for this aggressive disease are urgently needed. Angiogenesis plays a critical role in the development of HCC.
Antiangiogenesis therapy, which inhibits blood vessel formation, may be a promising treatment modality for HCC, because HCC depends on a rich blood supply. Tumstatin, a 28-kDa (244 amino acids) peptide fragment derived from the NC1 domain of ��3 chain of type IV collagen, is an endogenous angiogenesis inhibitor, and has two binding sites for av��3 integrin. One is in the N-terminal region of the molecule consisting of amino acids 74-98, which is associated with the anti-angiogenic property. The other is in the C-terminal region consisting of amino acids 185-203, which is associated with the antitumor activity[5�C7]. The peptide fragment of tumstatin consisting of amino acids 74-98 binds to both endothelial and melanoma cells, but only inhibits the proliferation of endothelial cells.
However, the anti-tumor activity of amino acids 185-203 is not realized until this peptide region is exposed by truncation, a requirement not essential for the anti-angiogenic activity of amino acids 74-98. By targeting proliferating tumor cells and endothelial cells in a previous study, we have constructed a fusion gene of the human IgG3 upper hinge region with two tumstatin-derived specific sequences, which exhibit anti-proliferation and anti-angiogenic activities. The human IgG3 upper hinge region is composed of 11 amino acids, and has a good flexibility, thus not affecting the spatial conformations of the connected peptides. The fusion sequence is named vascular basement membrane-derived multifunctional peptide (VBMDMP).
Recombinant VBMDMP (rVBMDMP) can significantly inhibit Brefeldin_A tumor growth and metastasis in a mouse lung carcinoma model. Moreover, rVBMDMP selectively inhibits the proliferation of endothelial and human colon cancer cells, as well as induces apoptosis of endothelial cells in vitro and suppresses the growth of human colon cancer xenografts in Balb/c-nude mice. However, whether rVBMDMP inhibits tumor growth and angiogenesis of human HCC xenografts in a nude mouse model is unknown.