Development of a novel recombinant disintegrin, contortrostatin, as an effective anti-tumor and anti-angiogenic agent.
Contortrostatin (CN) (Mr 13,500 Da) is a novel homodimeric disintegrin isolated from the venom of Agkistrodon contortrix contortrix (Southern Copperhead) snake and displays two RGD motifs (one on each chain), which modulate its interaction with integrins on tumor cells and angiogenic vascular endothelial cells. In previous studies, we have shown that native CN administered in a liposomal formulation exhibits potent anti-angiogenic and tumor growth inhibitory activities. Current isolation of the protein from crude venom is difficult and prohibitively expensive for translation into the clinic. In this report, we describe a method amenable to large-scale production of a soluble monomeric form of recombinant CN with biologic activity; the protein is expressed directly in the cytoplasm of an engineered bacterial system with an expression yield of approximately 20 mg/l of culture. We present here the in vitro assays as well as the anti-tumor and anti-angiogenic evaluation of liposomal recombinant CN in an orthotopic, xenograft model of human breast cancer.
Minea
Radu
R
Pivotal BioSciences, Inc., Keck School of Medicine, Los Angeles, Calif. 90033, USA.
Swenson
Stephen
S
Costa
Fritz
F
Chen
Thomas C
TC
Markland
Francis S
FS
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000096:biosynthesis* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D003001:Cloning, Molecular / Q000379:methods*; D019483:Disintegrins / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D008081:Liposomes / Q000627:therapeutic use; D011994:Recombinant Proteins; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D019483:Disintegrins; D008081:Liposomes; D011994:Recombinant Proteins; C403494:contortrostatin