Selective Enhancer of Tumor Vascular Permeability for Optimization of Cancer Chemotherapy

抄録

Clinical approach using tumor necrosis factor-alpha (TNF-α) as selective destruction against tumor endothelial cells and selective enhancer of tumor vascular permeability for effective accumulation of antitumor chemotherapeutic agents has attracted attention. However, the clinical application of TNF-α as a systemic antitumor agent has been limited because of toxic side-effects. To systemically use TNF-α as an antitumor agent and the selective enhancer of tumor vascular permeability, we assessed the usefulness of PEGylated TNF-α (PEG-TNF-α). PEG-TNF-α at a dose of 1000 JRU showed marked hemorrhagic necrosis in S-180 tumors without side-effects due to selective destruction of tumor vasculature, whereas wild-type TNF-α at a dose of 10000 JRU showed a little hemorrhagic necrosis with severe side-effects. PEG-TNF-α induced the enhancement of tumor vascular permeability. The permeability was increased at 1 h, after an i.v. injection of PEG-TNF-α and returned to the basal level at 2 h. In addition, high molecular weight of PEG (molecular weight; 500K) accumulated in tumor tissue as well as low molecular weight of PEG (molecular weight; 12K). On the other hand, PEG-TNF-α didn't affect the permeability of normal tissue and inflammation site. This data suggested that PEG-TNF-α was useful agent as selective enhancer of tumor vascular permeability with safe.