ecallantide and Neoplasms

Recent advances in combinatorial protein engineering have made it possible to develop non-Ig protein scaffolds that can potentially substitute for most whole antibody-associated properties. These protein scaffolds display most of the binding properties associated with the variable domain of antibodies. In theory, many different natural human protein backbones are suitable to be used as recombinant templates for engineering ; in practice however, only a few have yielded the necessary properties to be translated into << druggable biologicals >>. Amongst these properties, potential broad specificities towards any kind of target, ease of production, small size, good tolerability and low immunogenicity are essential. Intellectual property is another key issue. In this review, a particular emphasis will be given to the most validated non-Ig scaffolds that have reached the clinical development phase.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies; Antineoplastic Agents; Biopolymers; Clinical Trials as Topic; Drug Design; Drug Screening Assays, Antitumor; Fibronectins; Humans; Inflammation; Mice; Mice, Nude; Models, Molecular; Neoplasms; Neovascularization, Pathologic; Peptide Fragments; Peptides; Protein Conformation; Protein Engineering; Protein Structure, Tertiary; Receptors, LDL; Staphylococcal Protein A; Structure-Activity Relationship

Topics: Animals; Biomarkers, Tumor; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus; Female; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Male; Mice; Neoplasms; Peptide Hydrolases; Plasma Kallikrein; Risk; Thrombosis; Tissue Kallikreins

In cancer tumors, growth, invasion, and formation of metastasis at a secondary site play a pivotal role, participating in diverse processes in the development of the pathology, such as degradation of extracellular matrix. Bauhinia seeds contain relatively large quantities of peptidase inhibitors, and two Bauhinia inhibitors were obtained in a recombinant form from the Bauhinia bauhinioides species, B. bauhinoides cruzipain inhibitor, which is a cysteine and serine peptidase inhibitor, and B. bauhinioides kallikrein inhibitor, which is a serine peptidase inhibitor. While recombinant B. bauhinoides cruzipain inhibitor inhibits human neutrophil elastase cathepsin G and the cysteine proteinase cathepsin L, recombinant B. bauhinioides kallikrein inhibitor inhibits plasma kallikrein and plasmin. The effects of recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor on the viability of tumor cell lines with a distinct potential of growth from the same tissue were compared to those of the clinical cytotoxic drug 5-fluorouracil. At 12.5 µM concentration, recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor were more efficient than 5-fluorouracil in inhibiting MKN-28 and Hs746T (gastric), HCT116 and HT29 (colorectal), SkBr-3 and MCF-7 (breast), and THP-1 and K562 (leukemia) cell lines. Additionally, recombinant B. bauhinoides cruzipain inhibitor inhibited 40 % of the migration of Hs746T, the most invasive gastric cell line, while recombinant B. bauhinioides kallikrein inhibitor did not affect cell migration. Recombinant B. bauhinioides kallikrein inhibitor and recombinant B. bauhinoides cruzipain inhibitor, even at high doses, did not affect hMSC proliferation while 5-fluorouracil greatly reduced the proliferation rates of hMSCs. Therefore, both recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor might be considered for further studies to block peptidase activities in order to target specific peptidase-mediated growth and invasion characteristics of individual tumors, mainly in patients resistant to 5-fluorouracil chemotherapy.

Topics: Antineoplastic Agents, Phytogenic; Bauhinia; Cathepsin G; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cysteine Endopeptidases; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fluorouracil; Humans; Neoplasms; Plasma Kallikrein; Protease Inhibitors; Protozoan Proteins; Recombinant Proteins; Seeds