Biodistribution of humanized anti-VEGF monoclonal antibody/bevacizumab on peritoneal metastatic models with subcutaneous xenograft of gastric cancer in mice.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is correlated with peritoneal metastasis of gastric cancer, increasing vascular permeability accompanied by accumulation of ascites. The aim of the current study is to investigate the biodistribution of bevacizumab in a peritoneal metastatic model of gastric cancer and to clarify which is more suited to treatment of peritoneal metastasis, systemic or regional therapy.


METHODS
A highly peritoneal-seeding cell line of gastric cancer, OCUM-2MD3, which exhibited high production and release of VEGF was used in this study. The biodistribution of bevacizumab was investigated using peritoneal metastatic models together with subcutaneous xenografts, and (125)I-radiolabelled bevacizumab was administrated to these models subcutaneously (s.c.) or intraperitoneally (i.p.), respectively. In addition, the anti-tumor response of bevacizumab and paclitaxel was assessed as single agents or in combination using peritoneal metastatic models.


RESULTS
In the analysis of biodistribution, (125)I-bevacizumab administrated i.p. indicated low peritoneal clearance. On the other hand, s.c. administration of (125)I-bevacizumab showed preferential accumulation in subcutaneous tumors and peritoneal nodules, with a high blood concentration. In peritoneal metastatic models, the effects of bevacizumab were found for both the growth inhibition of peritoneal nodules (P < 0.01) and the reduction of ascites (P < 0.05). These effects were more prominent by s.c. administration compared with i.p. administration and were increased in combination with i.p. paclitaxel.


CONCLUSIONS
Bevacizumab should be administrated systemically compared to regionally, and the combination with i.p. paclitaxel has a potential to be useful for patients with peritoneal metastasis of gastric cancer.
Yagi
Yasumichi
Y
Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, Japan. y-yagi@live.jp
Fushida
Sachio
S
Harada
Shinichi
S
Tsukada
Tomoya
T
Kinoshita
Jun
J
Oyama
Katsunobu
K
Fujita
Hideto
H
Ninomiya
Itasu
I
Fujimura
Takashi
T
Kayahara
Masato
M
Kinuya
Seigo
S
Yashiro
Masakazu
M
Hirakawa
Kousei
K
Ohta
Tetsuo
T
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D000068258:Bevacizumab; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004396:Coloring Agents; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007457:Iodine Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000627:therapeutic use; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D007457:Iodine Radioisotopes; D013778:Tetrazolium Salts; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C022616:thiazolyl blue; D017239:Paclitaxel