Effective prevention of sorafenib-related vascular damage induced adverse events and maintenance of hepatic function by dried bonito broth and histidine

Abstract

Background: Sorafenib (SOR) is an anti-angiogenic chemotherapeutic that prolongs the survival rates of patients with hepatocellular carcinoma. However, SOR also damages normal vasculature and causes associated adverse events, including hand-foot syndrome and hypertension (HT). We previously reported in an animal study that vascular damage resulted in the narrowing of the normal vascular dimension area in medaka fish (Oryzias), and histidine (HIS), a major amino acid contained in dried bonito broth (DBB), prevented these changes. Therefore, in the study, we analyzed the effects of DBB and HIS on SOR-related vascular damages and associated adverse events in patients. Materials and methods: Three-dimensional (3D) vascular images of abdominal regions reconstituted from computed tomography were assessed to compare vascular diameter prior to and following SOR administration in groups receiving SOR monotherapy, DBB+SOR, and HIS+SOR. The clinical courses of hand-foot syndrome and HT and the toxicities of SOR in biochemical assays were monitored and compared between the groups. Correlations between hepatic function and SOR-related changes in the portal venous area dimension were also assessed. Results: SOR-related vascular damage revealed narrowing of the normal abdominal vasculature in the human body, which was monitored using 3D images. The damage was ameliorated by DBB and HIS, however, HIS had a more marked effect, particularly on the renal arteries and portal vein (PV). Maintenance of blood flow contributed to the maintenance of total cholesterol, prothrombin time, albumin (ALB), and renal functions. Changes in the 3D vascular area dimension of the PV and level of serum ALB were significantly correlated. The occurrences of the clinical symptoms of hand-foot syndrome and HT were lower in the DBB- and HIS-treated groups. Conclusion: Our results clearly demonstrate that DBB and HIS prevented SOR-related abdominal vascular damage and effectively maintained hepatic function, and prevented clinical symptoms and toxicity. Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000025937 and UMIN000026898).

Keywords: albumin; dried bonito broth; hepatocellular carcinoma; histidine; sorafenib; vascular area dimension.

Figure 1

Study design. The control group (n=6) was treated with SOR without DBB or HIS. The DBB+SOR group (n=6) and the HIS +S OR group (n=6) were treated with SOR with DBB and SOR with HIS. Abbreviations: SOR, sorafenib; DBB, dried bonito broth; HIS, histidine; CT, computed tomography.

Figure 2

Impact of SOR on normal blood vessels. DSA images of a representative case. (A) before SOR administration and (B) 3 months after SOR administration. 3D images of the vascular structure reconstructed from CT images (C) before SOR administration and (D) 3 months after SOR administration. Abbreviations: DSA, digital subtraction angiography; SOR, sorafenib; CT, computed tomography; CHA, common hepatic artery; RHA, right hepatic artery; LHA, left hepatic artery; SPA, splenic artery; CA, celiac artery.

Figure 3

Representative 3D images of vasculature in the SOR, DBB+SOR, and HIS+SOR groups. 3D images of the LHA in the SOR monotherapy group before SOR administration (A) and approximately 1 month after initiation of SOR (B). DBB+SOR group (C and D). HIS+SOR group (E and F). Abbreviations: LHA, left hepatic artery; SOR, sorafenib; DBB, dried bonito broth; HIS, histidine.

Figure 4

Effect of DBB and HIS on the changes in vascular area dimension caused by SOR. The ratio of vascular area dimension from after to before SOR administration was compared between groups treated with or without DBB or HIS. The values represent means ± SD (n=6 for each group). *P<0.05; **P<0.01; NS, not significant. Kruskal–Wallis test followed by Dunn’s multiple comparison tests. Abbreviations: CHA, common hepatic artery; RHA, right hepatic artery; LHA, left hepatic artery; SPA, splenic artery; CA, celiac artery; SMA, superior mesenteric artery; RRA, right renal artery; LRA, left renal artery; PV, portal vein; SOR, sorafenib; DBB, dried bonito broth; HIS, histidine.

Figure 5

Effect of DBB and HIS on the changes in serum biochemical factors caused by SOR. Notes: (A–I) Changes in serum biochemical factors from before to after SOR administration were compared between the groups treated with or without DBB or HIS. The values represent means ± SD (n=6 for each group). N.S., not significant, Kruskal–Wallis test followed by Dunn’s multiple comparison tests. Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; TBIL, total bilirubin; TC, total cholesterol; TG, triglycerides; PT, prothrombin time; BUN, blood urea nitrogen; CRE, creatinine; PLT, platelets; SOR, sorafenib; DBB, dried bonito broth; HIS, histidine

Figure 6

Effect of DBB and HIS on serum ALB level and PV area dimension. Notes: (A) Changes in serum ALB from the levels before SOR administration were compared between the groups treated with or without DBB or HIS. The values represent means ± SD (n=6 for each group). *P<0.05. Kruskal–Wallis test followed by Dunn’s multiple comparison test. (B) Changes in serum ALB and PV area dimension. The bold black line shows the trend line, and analysis of the correlation between changes in serum ALB and PV area dimension was performed. *P<0.05, Pearson’s correlation test. Abbreviations: ALB, albumin; PV, portal vein; SOR, sorafenib; DBB, dried bonito broth; HIS, histidine.