Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models

Abstract

Background:Bevacizumab is being incorporated as first-line therapy with standard-of-care chemotherapy on epithelial ovarian carcinoma (EOC). We investigated bevacizumab combined with chemotherapy on tumour progression and mouse survival in EOC xenograft models.Methods:Bevacizumab was administered concomitantly with cisplatin plus paclitaxel (DDP+PTX), continued after induction (maintenance) or started after chemotherapy. The effect on tumour progression was monitored by bioluminescence imaging (BLI) (1A9-luc xenograft). Tumour dissemination into the peritoneal organs and ascites formation (HOC22 xenograft) was evaluated by histological analysis at the end of treatment (interim) and at euthanasia (survival). The effects on overall survival (OS) were investigated in both EOC models.Results:Bevacizumab with PTX+DDP delayed tumour progression in mice bearing EOC xenografts. OS was significantly extended, with complete responses, by bevacizumab continued after stopping chemotherapy in the HOC22 xenograft. Bevacizumab alone inhibited ascites formation, with only limited effect on tumour burden, but combined with PTX+DDP reduced ascites and metastases. Bevacizumab started after induction with PTX+DDP and maintained was equally effective on tumour progression and survival on 1A9-luc xenograft.Conclusion:Bevacizumab combined with chemotherapy not only affected tumour progression, but when administered as maintenance regimen significantly prolonged survival, reducing ascites, and tumour dissemination. We believe our findings are consistent with the clinical results and shed light on the potential effects of this kind of treatment on tumour progression.

Chemotherapy Counteracts Metastatic Dissemination Induced by Antiangiogenic Treatment in Mice

“…However, the overall survival benefits of those antiangiogenic drugs have been modest: often the response to therapy is short lasting, and patients become refractory or escape treatment (8,36). Recent preclinical studies have even shown increased invasion and metastasis in mouse tumor models treated with certain angiogenesis inhibitors (16)(17)(18)(19)(20)(21)(22). Less clear is whether the resistance/escape to therapy using angiogenesis inhibitors, with accelerated disease progression or increased mortality, also happens in patients.…”

“…In some studies, antiangiogenic therapy was extremely effective on the primary tumor and metastasis, improving survival (13)(14)(15). However, surprisingly, recent studies reported that treatment of tumor-bearing mice, mainly with anti-VEGF/VEGFR-related compounds, increased tumor invasiveness and metastasis (16)(17)(18)(19)(20)(21)(22). Clinical data on the effect of antiangiogenesis in general, or anti-VEGF therapy, on malignant progression are lacking and widely debated.…”

“…Artificial metastases were obtained by injecting Renca-luc cells (1 Â 10 5 ) into the tail vein (30). In vivo bioluminescence imaging (BLI) was used to confirm the presence of tumors, to randomize mice to start therapy or for nephrectomy, and to follow tumor growth and metastatic progression (22). Results are plotted as photon count (PC).…”

“…Effect of sunitinib on survival ( ÃÃÃÃ , P < 0.0001; right). B, animals (10 per group) were killed with a median primary tumor of 2 Â 10 5 PC (tumor weight $1 g) on different days (median vehicle 19 (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26); sunitinib 32 (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), and lung metastases were assessed by BLI (mean AE SEM). Primary tumor (PC; left); lung metastatic burden (PC; right) at scheduled death (mean AE SEM; Ã , P < 0.05).…”

“…22). Tumor cells were maintained in RPMI-1640 (Voden Medical Instrument), supplemented with 10% fetal calf serum, 0.1 mmol/L nonessential amino acids, 1 mmol/L sodium pyruvate, and 2 mmol/L L-glutamine (Lonza Sales).…”