Maintenance Treatment with Bevacizumab Prolongs Survival in anIn vivoOvarian Cancer Model

Abstract

Purpose: Vascular endothelial growth factor (VEGF) plays a central role in tumor angiogenesis and is regarded as a promising therapeutic target.We hypothesized that treatment with bevacizumab, a humanized recombinant anti-VEGF monoclonal antibody, could enhance antitumor response to cisplatin and prolong survival in a murine ovarian cancer model. Experimental Design: We conducted an MTS assay to examine the effect of bevacizumab on proliferation of the VEGF producing human ovarian cancer cell lines in vitro. Next, the antiangiogenic activity of bevacizumab was investigated by in vivo angiogenesis and wound healing assays.We then determined the toxicity and antitumor response of bevacizumab and cisplatin as single agents or in combination in xenograft models of ovarian cancer. Finally, using the same xenograft model, we examined the effect of these regimens, as well as bevacizumab maintenance therapy, on survival. Results: Bevacizumab had no effect on the proliferation of ovarian cancer cells in vitro but significantly inhibited angiogenesis and delayed wound healing in vivo. Bevacizumab inhibited i.p. tumor growth and ascites production in the nu/nu mouse xenograft model and enhanced the therapeutic efficacy of cisplatin. Combination therapy with bevacizumab and cisplatin for 3 weeks was associated with complete disappearance of all macroscopic evidence of disease. Moreover, maintenance treatment with bevacizumab after 3 weeks of induction combination therapy inhibited recurrence and significantly prolonged survival. Conclusions: Bevacizumab has significant antitumor activity not only as a single agent or in combination with cisplatin but may also prolong survival when used as maintenance therapy after a complete response to cisplatin-based chemotherapy.

Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells

“…[3][4][5] Anti-VEGF therapies reduce tumor growth and ascites burden and enhance survival in murine models of EOC, [6][7][8] and treatment with the VEGF antagonist bevacizumab (Avastin) prolonged survival in mice when used as maintenance therapy after a complete response to cisplatin-based chemotherapy. 9 Several human phase II trials showed significant activity in EOC when bevacizumab was used as a single agent, suggesting that the blockade of VEGF signaling may prove effective in clinical disease. However, response rates were variable.…”

VEGF Targeting Agents in Ovarian Cancer

“…In a mouse model of ovarian cancer, treatment with bevacizumab in combination with paclitaxel significantly reduced tumor growth compared with paclitaxel alone (83.3% reduction in the combination arm versus 58.5% reduction in the paclitaxel alone arm) and resulted in the complete inhibition of ascites formation (Hu et al, 2002). Similarly, treatment with bevacizumab in combination with cisplatin significantly reduced tumor growth and ascites formation compared with cisplatin therapy alone (Mabuchi et al, 2008).…”

“…In patients with ovarian cancer, high serum VEGF levels was reported to be an independent risk factor for developing ascites formation (Cooper et al, 2002;Li et al, 2004;Hefler et al, 2006). In an in vivo investigation using an intraperitoneal ovarian cancer model, VEGF inhibition resulted in the complete inhibition of ascites formation (Mesiano et al, 1998;Mabuchi et al, 2008). Since patients with advanced or recurrent ovarian cancer frequently suffer from malignant ascites and require paracentesis for symptomatic relief, the ability of VEGF-targeting agents to inhibit ascites formation makes them attractive candidate treatments for ovarian cancer (Numnum et al, 2006).…”

“…In a preclinical investigation, treatment with bevacizumab significantly inhibited the growth of intraperitoneally inoculated serous ovarian cancer. In addition, bevacizumab treatment significantly inhibited ascites production and prolonged survival of the mice (Mabuchi et al, 2008). The single agent activity of bevacizumab on chemoresistant ovarian cancer has also been evaluated preclinically.…”

“…The effect of VEGF-targeting agent as a maintenance therapy has been investigated in an in vivo ovarian cancer model (Mabuchi et al, 2008). In this investigation, athymic mice were intraperitoneally inoculated with serous ovarian cancer cells.…”