Inhibition of growth of experimental human and hamster pancreatic cancers in vivo by a targeted cytotoxic bombesin analog.
OBJECTIVE
Targeting anticancer agents to receptors for peptide hormones such as bombesin/gastrin-releasing peptide (GRP) on tumor cells increases the efficacy and lowers the toxicity of cancer therapy. We studied the expression of bombesin/GRP receptors in 6 experimental pancreatic cancers and evaluated tumor inhibition in vivo produced by targeted chemotherapy with the cytotoxic bombesin analog AN-215.


METHODS
Nude mice with xenografts of Panc-1, CFPAC-1, Capan-1, Capan-2, MiaPaCa-2, and SW-1990 human ductal pancreatic cancers, as well as hamsters with nitrosamine-induced pancreatic cancers, were treated with AN-215 or its cytotoxic radical 2-pyrrolinodoxorubicin (AN-201) for 7 to 12 weeks. Tumor growth reduction and survival were analyzed, and cell proliferation rate and apoptosis were examined by histologic methods. Bombesin/GRP receptors on the tumors were studied by ligand-binding assays and their mRNA expression was studied by reverse transcriptase-polymerase chain reaction.


RESULTS
All tumors expressed mRNA for subtype 1 bombesin/GRP receptor, but MiaPaCa-2, and in one experiment, SW-1990 tumors did not show binding sites for bombesin. AN-215 powerfully inhibited the growth of all pancreatic cancers that expressed functional receptors for bombesin/GRP. AN-201 was less effective on most tumors and somewhat more toxic than AN-215.


CONCLUSIONS
Bombesin/GRP receptors are expressed on most ductal pancreatic carcinoma cell lines and can be used for targeted chemotherapy with the cytotoxic bombesin analog AN-215.
Szepeshazi
Karoly
K
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, and Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Schally
Andrew V
AV
Nagy
Attila
A
Halmos
Gabor
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001839:Bombesin / Q000031:analogs & derivatives* / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D006224:Cricetinae; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D011869:Radioligand Assay; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C416531:AN 215; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D004317:Doxorubicin; D001839:Bombesin