title: In vivo inhibition of PC-3 human androgen-independent prostate cancer by a targeted cytotoxic bombesin analogue, AN-215.
abstract: 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 (125)I-[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 PC-3 tumors, displacing the radioligand at an IC(50) 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.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, LA 70146, USA.
authors.forename: A
authors.initials: A
authors.lastname: Plonowski
authors.forename: A
authors.initials: A
authors.lastname: Nagy
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.forename: B
authors.initials: B
authors.lastname: Sun
authors.forename: K
authors.initials: K
authors.lastname: Groot
authors.forename: G
authors.initials: G
authors.lastname: Halmos
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001839:Bombesin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000097:blood; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000627:therapeutic use; D018004:Receptors, Bombesin / Q000032:analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C416531:AN 215; D000903:Antibiotics, Antineoplastic; D011758:Pyrroles; D018004:Receptors, Bombesin; C098751:AN 204; D004317:Doxorubicin; D002265:Carboxylic Ester Hydrolases; D001839:Bombesin