The sequence of drug administration influences the antitumor effects of bevacizumab and cyclophosphamide in a neuroblastoma model

Currently, the prognosis of neuroblastoma is poor, and new therapeutic strategies are needed. This study aimed at evaluating whether the administration sequence of bevacizumab and cyclophosphamide influenced the antitumor effects in a neuroblastoma model. Bevacizumab was administered at 5 mg/kg body weight weekly, alone or combined with cyclophosphamide, to treat a neuroblastoma xenograft in nude mice, and the tumor inhibition rates were compared. The functions of tumor vessels at different time points after bevacizumab administration were detected by Hoechst 33342 labeling. The antitumor effects of cyclophosphamide, administered concomitantly with bevacizumab or when vessel function was most improved post-bevacizumab administration, were compared. The tumor inhibition rates of the neuroblastoma xenograft treated with bevacizumab, cyclophosphamide, or both were 38.1, 44.0, and 56.0%, respectively (P < 0.05). Bevacizumab reduced 64% of angiogenesis. Tumor vessel function was most improved 6 days after bevacizumab administration. The tumor inhibition rates in mice treated with cyclophosphamide, concomitantly with bevacizumab or 6 days after bevacizumab administration, were 55.9 and 66.8%, respectively (P < 0.05). Bevacizumab can reduce neuroblastoma growth and has a synergistic effect when combined with cyclophosphamide in vivo. This synergistic effect is further enhanced when cyclophosphamide is administered after bevacizumab, when tumor vessel function is most improved.