In vivo inhibition of PC-3 human androgen-independent prostate cancer by atargeted cytotoxic bombesin analogue, AN-215

The effectiveness of chemotherapy targeted to bombesin (BN) receptors was e valuated in nude mice bearing PC-3 human androgen-independent prostate canc ers. Cytotoxic BN analogue AN-215, consisting of 2-pyrrolinodoxorubicin (AN -201) linked to BN-like carrier peptide RC-3094, was injected i.v. at 150 n mol/kg on days I, II and 21, After treatment with AN-215, tumor volume was 69% (p < 0.01) smaller than that in controls and tumor doubling time was ex tended from 8.5 +/- 0.7 days to 20.3 +/- 3.5 days (p < 0.05). Cytotoxic rad ical AN-201, carrier RC-3094 and their unconjugated mixture administered at the same dosage were ineffective. The mortality rate was 12.5% in the AN-2 01 group and 16.7% in the group treated with the mixture, but no deaths occ urred in mice receiving AN-215, Because the ester bond linking AN-201 to th e carrier molecule is hydrolyzed much faster in mouse serum than in human s erum, in the second experiment we investigated the tolerance to AN-215 and its effect in nude mice bearing PC-3 tumors after pharmacological inhibitio n of serum carboxylesterases, Two applications of AN-201 at 200 nmol/kg wer e lethal, whereas no mortality was observed after 4 injections of AN-215 at the same dose. Administration of 200 nmol/kg AN-215 on days I, 7, 17 and 2 6 again produced 69% tumor inhibition. BN receptors on membranes of PC-3 tu mors were detected by I-125-[Tyr(4)]BN binding, and expression of mRNA for BRS-3 and GRP-R subtypes was also found, AN-215 showed a high affinity to P C-3 tumors, displacing the radioligand at an IC50 of 12.95 +/- 0.35 nM, Bec ause BN receptors are present on primary and metastatic prostate cancer, ta rgeted chemotherapy with AN-215 might benefit patients with advanced prosta tic carcinoma who relapsed androgen ablation. (C) 2000 Wiley-Liss, Inc.