Experimental therapy of PC-3 and DU-145 human androgen-independent prostate cancers with targeted cytotoxic analog of somatostatin AN-162.

Abstract

236 Background: Management of castration-resistant prostate cancer (CRPC) is challenging because of limitations in efficacy of current therapies. Somatostatin receptors are expressed in human CRPC. Here we tested targeted somatostatin AN-162 analog consisting of doxorubicin (DOX) conjugated to octapeptide RC-121, acting as a carrier, in human androgen-independent prostate cancer cell lines in vitro and in vivo. Methods: Expression of mRNA for the five subtypes of the somatostatin receptor in PC-3 and DU-145 human prostate cancer cell lines was evaluated by RT-PCR. Somatostatin receptor binding was measured with radioligand assays. The effect of AN-162 and DOX on the viability of PC-3 and DU-145 cells was assessed by MTS assay. Nude mice bearing PC-3 and DU-145 tumors were randomized to 5 groups (control, AN-162, DOX, somatostatin analog RC-160 as a control, and DOX + RC-160). Treatment consisted i.v. injections of AN-162, DOX, RC-160, DOX + RC-160, or vehicle once a week for 4 weeks. Tumor volume was measured every week; the study lasted 28 days. The doses of AN-162 were equivalent to 1.45 mg/kg DOX (2.5 μmol/kg). Results: The PC-3 and DU-145 cell lines were positive for the five subtypes of the somatostatin receptor. AN-162 and DOX (0.10–10 µM) inhibited the proliferation of PC-3 and DU-145 prostate cancer cells in a dose-dependent manner. AN-162 exerted a stronger inhibition of proliferation than DOX alone, but in vitro the difference was not significant. In vivo, AN-162 significantly inhibited growth of both tumor models’ compared with the controls and the groups given equimolar doses of doxorubicin, RC-160, or doxorubicin unconjugated to RC-160. Conclusions: Our work demonstrates potent inhibitory effects of AN-162 on somatostatin receptor positive androgen-independent prostate cancers, which were greater than any of the components of AN-162. The mechanisms of action of targeted cytotoxic analog of somatostatin AN-162 in CRPC should be explored. Our findings suggest the possible use of AN-162 in patients with CRPC.