Inhibition of growth of experimental human and hamster pancreatic cancers in vivo by a targeted cytotoxic bombesin analog.

Abstract

OBJECTIVES:

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.

• Authors: Karoly Szepeshazi, Andrew V Schally, Attila Nagy, Gabor Halmos
• Journal: Pancreas (Pancreas) Vol. 31 Issue 3 Pg. 275-82 (Oct 2005) ISSN: 1536-4828 [Electronic] United States
• PMID: 16163060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AN 215
• Antineoplastic Agents
• RNA, Messenger
• Receptors, Bombesin
• Doxorubicin
• Bombesin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Bombesin (analogs & derivatives, pharmacology)
• Carcinoma, Pancreatic Ductal (drug therapy, pathology)
• Cricetinae
• Doxorubicin (analogs & derivatives, pharmacology)
• Humans
• Mice
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, pathology)
• RNA, Messenger (analysis)
• Radioligand Assay
• Receptors, Bombesin (genetics, metabolism)
• Xenograft Model Antitumor Assays