VIP receptor antagonists inhibit mammary carcinogenesis in C3(1)SV40T antigen mice.
The effects of a vasoactive intestinal peptide (VIP) receptor antagonist on mammary carcinogenesis were investigated using the C3(1)SV40T antigen (ag) mice. Ten microg/day VIPhybrid (VIPhyb) administered daily subcutaneously increased significantly the survival of C3(1)SV40Tag mice. At 5.2 months, VIPhyb significantly reduced the mammary tumor burden in C3(1)SV40Tag mice relative to control animals. 125I-VIP bound with high affinity to mouse mammary tumor homogenate. Because (Lys15, Arg16, Leu27)VIP1-7GRF8-27 (VPAC1 selective) but not Ro25-1553 (VPAC2 selective) inhibited specific 125I-VIP binding to mammary tumor membranes with high affinity, VPAC1 receptors predominate. By RT-PCR, VPAC1 receptor mRNA was detected in mammary tumors. By Western blot, a major 60 Kdalton band was detected in mammary tumor extracts using VPAC1 receptor antisera. By immunocytochemistry, VPAC1-R immunostaining was detected in the cytosol and plasma membrane but not the nucleus of fixed mammary tumor tissue. Using laser capture microdissected tumor cells and surface enhanced laser desorption/ionization (SELDI) techniques on mammary tumor cells, the proteomic profile was altered in mice treated with VIPhyb. Because VPAC1 receptor antagonists increase the survival and reduce the tumor burden in C3(1)SV40Tag mice, they may function as chemopreventive agents in mammary cancer.
Moody
Terry W
TW
Department of Health and Human Services, National Institutes of Health, NCI Office of the Director, Center for Cancer Research, NCI, Bethesda, MD 20892, USA. moodyt@mail.nih.gov
Dudek
James
J
Zakowicz
Halina
H
Walters
James
J
Jensen
Robert T
RT
Petricoin
Emmanual
E
Couldrey
Chris
C
Green
Jeff E
JE
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D015153:Blotting, Western; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D008838:Microcomputers; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D040901:Proteomics; D018005:Receptors, Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives* / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D000952:Antigens, Polyomavirus Transforming; D009363:Neoplasm Proteins; C110307:PG 97-269; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D018005:Receptors, Vasoactive Intestinal Peptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C089777:Ro 25-1553; D014660:Vasoactive Intestinal Peptide