Therapy of experimental hepatic cancers with cytotoxic peptide analogs targeted to receptors for luteinizing hormone-releasing hormone, somatostatin or bombesin.
As there is no effective systemic therapy for advanced hepatocellular carcinoma (HCC), we investigated the presence of receptors for somatostatin, bombesin and luteinizing hormone-releasing hormone (LHRH) in SK-Hep-1 human hepatic carcinoma and the effects of cytotoxic analogs of somatostatin (AN-238), bombesin (AN-215) and LHRH (AN-207) on the growth of this tumor. Nude mice bearing SK-Hep-1 HCCs were treated with AN-238, AN-215, AN-207 and their combination, or cytotoxic radical 2-pyrrolinodoxorubicin (AN-201). Tumor growth reduction was determined and cell proliferation characteristics and apoptosis were studied by histologic analysis. The expression of receptors for somatostatin, bombesin and LHRH was investigated by radioreceptor assays and immunohistochemistry. High-affinity binding sites for somatostatin, bombesin and LHRH were detected in SK-Hep-1 cancers. All three cytotoxic peptide analogs inhibited growth of SK-Hep-1 tumors and decreased the cell proliferation rate. Combination therapy with two or three cytotoxic analogs resulted in the strongest tumor inhibition. Receptors for somatostatin, bombesin and LHRH are expressed in SK-Hep-1 human HCC. Cytotoxic peptide analogs targeted to these receptors inhibit growth of this tumor. Targeting to multiple receptors enhances the efficacy of therapy. The results of our study encourage additional experimental investigations to permit the introduction of these cytotoxic analogs into clinical trials.
Szepeshazi
Karoly
K
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, University of Miami Miller School of Medicine, Miami, Florida 33125, USA.
Schally
Andrew V
AV
Treszl
Andrea
A
Seitz
Stephan
S
Halmos
Gabor
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D001839:Bombesin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D011869:Radioligand Assay; D018004:Receptors, Bombesin / Q000378:metabolism*; D011966:Receptors, LHRH / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000378:metabolism*; D014183:Transplantation, Heterologous
C416531:AN 215; C110845:AN 238; D000970:Antineoplastic Agents; D011758:Pyrroles; D018004:Receptors, Bombesin; D011966:Receptors, LHRH; D017481:Receptors, Somatostatin; C098751:AN 204; C104648:AN 207; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin; D001839:Bombesin