in vivo inhibition of PC‐3 human androgen‐independent prostate cancer by a targeted cytotoxic bombesin analogue, AN‐215

The effectiveness of chemotherapy targeted to bombesin (BN) receptors was evaluated in nude mice bearing PC‐3 human androgen‐independent prostate cancers. 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 nmol/kg on days 1, 11 and 21. After treatment with AN‐215, tumor volume was 69% (p < 0.01) smaller than that in controls and tumor doubling time was extended from 8.5 ± 0.7 days to 20.3 ± 3.5 days (p < 0.05). Cytotoxic radical 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‐201 group and 16.7% in the group treated with the mixture, but no deaths occurred in mice receiving AN‐215. Because the ester bond linking AN‐201 to the carrier molecule is hydrolyzed much faster in mouse serum than in human serum, in the second experiment we investigated the tolerance to AN‐215 and its effect in nude mice bearing PC‐3 tumors after pharmacological inhibition of serum carboxylesterases. Two applications of AN‐201 at 200 nmol/kg were 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 1, 7, 17 and 26 again produced 69% tumor inhibition. BN receptors on membranes of PC‐3 tumors were detected by 125I‐[Tyr4]BN binding, and expression of mRNA for BRS‐3 and GRP‐R subtypes was also found. AN‐215 showed a high affinity to PC‐3 tumors, displacing the radioligand at an IC50 of 12.95 ± 0.35 nM. Because BN receptors are present on primary and metastatic prostate cancer, targeted chemotherapy with AN‐215 might benefit patients with advanced prostatic carcinoma who relapsed androgen ablation. Int. J. Cancer 88:652–657, 2000. © 2000 Wiley‐Liss, Inc.