Mechanistic insights of snake venom disintegrins in cancer treatment.

Snake venoms are a potential source of various enzymatic and non-enzymatic compounds with a defensive role for the host. Various peptides with significant medicinal properties have been isolated and characterized from these venoms. Few of these are FDA approved. They inhibit tumor cells adhesion, migration, angiogenesis and metastasis by inhibiting integrins on transmembrane cellular surfaces. This plays important role in delaying tumor growth, neovascularization and development. Tumor targeting and smaller size make them ideal candidates as novel therapeutic agents for cancer treatment. This review is based on sources of these disintegrins, their targeting modality, classification and underlying anti-cancer potential.

Improved antithrombotic activity and diminished bleeding side effect of a PEGylated αIIbß3 antagonist, disintegrin.

INTRODUCTION: The applicability of protein drugs is confined by protein degradation and rapid elimination. PEGylation of polypeptides improves protein stability by sterically obstructing the degradation by serum proteases and reduces renal clearance by the increased mass. EXPERIMENTAL APPROACH: We compared the antithrombotic activities of intact rhodostomin (Rn) and PEGylated rhodostomin (PRn) both in vitro and in vivo systems. In addition, the functional half-life in inhibiting platelet aggregation and the tendency in causing bleeding side effect were investigated. RESULTS: Rn and PRn both potently inhibited human and mouse platelet aggregation induced by collagen, thrombin or ADP in vitro with a similar IC50 around 60-100nM. Rotational thromboelastometry assay indicated that PRn was more effective than Rn in preventing clot formation in human whole blood. In platelet-rich plasma from mice injected with Rn or PRn, the inhibitory effects on collagen-induced platelet aggregation were also comparable, but Rn caused higher bleeding tendency. In ferric chloride-induced arterial thrombosis, Rn and PRn significantly prolonged occlusion time at high dosage (0.2µg/g). However, PRn obviously prolonged the occlusion time even given at a lower dosage (0.06µg/g). The functional half-life assay revealed that PEGylation prolonged the in vivo half-life of Rn. CONCLUSIONS: PRn exhibits higher antithrombotic potency and longer half-life in vivo as compared with native Rn on a molar basis. In addition, PRn exhibits a better safety profile at an efficacious antithrombotic dose in vivo. Therefore, PEGylation may be one of the ideal options in modifying disintegrin derivatives as the safe therapeutic agents for integrin-related diseases.