Biodistribution of humanized anti-VEGF monoclonal antibody/bevacizumab on peritoneal metastatic models with subcutaneous xenograft of gastric cancer in mice
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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.
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 125I-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.
In the analysis of biodistribution, 125I-bevacizumab administrated i.p. indicated low peritoneal clearance. On the other hand, s.c. administration of 125I-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.
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.
KeywordsPeritoneal metastasis Bevacizumab Biodistribution Iodine-125 label Molecular-targeted therapy
The authors declare that there are no conflicts of interest and no support in this study.
- 1.Holm-Nielsen P (1953) Pathogenesis of ascites in peritoneal carcinomatosis. Acta Palhol Microbiol Scand 33:10–21Google Scholar
- 4.Brown HR (1976) Kinetics of angiogenesis in small vessels related to mouse parietal peritoneum. Anal Ree 184:364Google Scholar
- 16.Kakeji Y, Koga T, Sumiyoshi Y et al (2002) Clinical significance of vascular endothelial growth factor expression in gastric cancer. J Exp Clin Cancer Res 16:125–129Google Scholar
- 27.Markman M, Bundy BN, Alberts DS et al (2001) Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19:1001–1007PubMedGoogle Scholar
- 35.Kinuya S, Yokoyama K, Kawashima A et al (2000) Pharmacologic intervention with angiotensin II and kininase inhibitor enhanced efficacy of radioimmunotherapy in human colon cancer xenografts. J Nucl Med. 41:1244–1249Google Scholar
- 43.Browder T, Butterfield CE, Kräling BM et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer 60:1878–1886Google Scholar