Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide in vitro and in vivo

Based on the fact that somatostatin (SST) analogs have given promising resu lts fur treatment of hepatocellular cancer, we performed both in vitro and in vivo investigations to define the role of a depot formulation of the lon g acting SST-analog lanreotide (LAN). A decrease of cells in the S-phase as compared to controls (p<0.03) followed by a significant, dose-dependent in duction of apoptosis could be demonstrated in Hep G2 cells along with a dos e-dependent influence of the peptide on cellular proliferation. Northern bl otting demonstrated the presence of mRNA for SSTR subtypes 2, 3 and 4 in He p G2 cells, but only slight SSTR expression in normal liver tissue. In addi tion, 21 untreated patients with advanced HCC not amenable to surgery were administered 30 mg of LAN by deep intramuscular injection every 14 days unt il documented disease progression. Fifteen of these patients also underwent scanning with commercially available In-111-DTPA-D-Phe(1)-Octreotide (In-1 11-OCT) to define the in vivo expression of SSTR. No positive In-111-OCT sc ans were obtained, indicating the absence of relevant amounts of functional SSTR2 in HCC. One patient (5%) showed a partial response to treatment, 8 p atients had stable disease (38%), while the remaining patients progressed d uring treatment. The median survival was 4.2 months (range 1.2-13+), and th e median time to progression was 2.5 months (range, 1.5-7+). However, 4 pat ients (19%) had an increase in WHO performance status lasting between 2.5 a nd 6 months, 5 patients (24%) had an increase in body weight, while pain ma rkedly improved in 1 additional patient (5%). In total, 5 patients (24%) ha d a decrease in serum-AFP levels by at least 30%. Our results clearly indic ate the ability of LAN to decrease the S-phase fraction along with inductio n of apoptosis in Hep G2 cells in a dose-dependent manner. Our data suggest clinical potential of SST-analogs in HCC and indicate that suboptimal dose s of the peptide might have been administered in our series.