Selective enhancer of tumor vascular permeability for optimization of cancer chemotherapy.
Clinical approach using tumor necrosis factor-alpha (TNF-alpha) 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-alpha as a systemic antitumor agent has been limited because of toxic side-effects. To systemically use TNF-alpha as an antitumor agent and the selective enhancer of tumor vascular permeability, we assessed the usefulness of PEGylated TNF-alpha (PEG-TNF-alpha). PEG-TNF-alpha 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-alpha at a dose of 10,000 JRU showed a little hemorrhagic necrosis with severe side-effects. PEG-TNF-alpha induced the enhancement of tumor vascular permeability. The permeability was increased at 1 h, after an i.v. injection of PEG-TNF-alpha 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-alpha didn't affect the permeability of normal tissue and inflammation site. This data suggested that PEG-TNF-alpha was useful agent as selective enhancer of tumor vascular permeability with safe.
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
Yasuo
Y
Yoshioka
Yasuo
Y
Tsutsumi
Haruhiko
H
Kamada
Tetsuya
T
Kihira
Shin-ichi
S
Tsunoda
Yoko
Y
Yamamoto
Takayuki
T
Okamoto
Hiroko
H
Shibata
Yohei
Y
Mukai
Madoka
M
Taniai
Tomoe
T
Shimizu
Maki
M
Kawamura
Yasuhiro
Y
Abe
Shinsaku
S
Nakagawa
Tadanori
T
Mayumi
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry*; D012510:Sarcoma 180 / Q000098:blood supply / Q000188:drug therapy; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols