Aim
To investigate the effects of sorafenib
when co
mbined
with radiofrequency ablation treat
ment in liver tissue, the necrosis volu
me, tissue repair and hepatocellular gro
wth signals
were analyzed in rats. Radiofrequency ablation (RFA) is a
widely applied treat
ment for hepatocellular carcino
ma (HCC). Radiofrequency ablation is co
mbined
with the
multi-tyrosinkinase-inhibitor sorafenib in ongoing clinical trials. Whether this co
mbination treat
ment affects liver tissue repair is unkno
wn.
Materials and methods
Male Sprague Dawley (SD) rats received RFA or sham puncture with concomitant sorafenib (5 mg/kg qd from day 2) or vehicle. Necrosis volume was calculated from resected specimens. Proliferation and micro vessel density were determined by Ki67 and CD31 immunofluorescence, respectively. mRNA expression of hepatocyte growth factor (HGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) was quantified.
Results
While ablation size was identical in all treatment groups at day 1, sorafenib treated animals showed sustained necroses (219 卤 24 vs. 88 卤 52 mm3 in controls; m>Pm> = 0.03), elevated alanine aminotransferase (ALT) and elevated glutamate dehydrogenase (GLDH) (76 卤 37 vs. 47 卤 58 mm3; m>Pm> = 0.50) at day 3. By day 7 necrosis volumes equalized for the treatment groups. Ki67 and CD31 staining showed reduced proliferation and micro vessel density at days 1 and 3 following sorafenib. Growth factors HGF and EGF were significantly overexpressed in liver tissue after sorafenib.
Conclusion
Sorafenib initially promotes necrosis after RFA in liver tissue. The delay in tissue repair is overcome at day 7 presumably by transient compensatory overexpression of growth signals. Based on these data from animal studies further investigation of adjuvant sorafenib in humans is warranted.