title: Stimulation of proliferation in the colorectal mucosa by gastrin precursors is blocked by desferrioxamine.
abstract: Precursors of the peptide hormone gastrin stimulate proliferation in the colorectal mucosa and promote the development of colorectal carcinoma. Gastrins bind two ferric ions selectively and with high affinity, and the biological activity of glycine-extended gastrin (Ggly) in vitro is dependent on the presence of ferric ions. The aim of the present study was to determine whether or not iron is required for biological activity of progastrin and Ggly in vivo. Rats that had undergone a colostomy were infused with Ggly, and proliferation was measured in the defunctioned rectal mucosa. Proliferation was also measured in the colonic mucosa of hGAS and MTI-Ggly mice, which, by definition, overexpress progastrin and Ggly, respectively. The requirement for iron was assessed by thrice-weekly injection of the chelating agent desferrioxamine (DFO). The proliferation index in the defunctioned rectal mucosa was significantly increased in the Ggly-infused rats, and the increase was significantly reduced after treatment with DFO. Treatment with DFO significantly reduced the crypt height and proliferation index in the colonic mucosa of hGAS and MTI-Ggly mice but had no effect on the same variables in wild-type mice. These observations are consistent with the hypothesis that the biological activity of progastrin and Ggly in vivo is dependent on the presence of ferric ions and further suggest that chelating agents may block the stimulatory effects of gastrin precursors in the development of colorectal carcinoma.
authors.affiliation: University of Melbourne Department of Surgery, Austin Health, Heidelberg 3084, Victoria, Australia.
authors.forename: Audrey
authors.initials: A
authors.lastname: Ferrand
authors.forename: Shamilah
authors.initials: S
authors.lastname: Lachal
authors.forename: Gianni
authors.initials: G
authors.lastname: Bramante
authors.forename: Suzana
authors.initials: S
authors.lastname: Kovac
authors.forename: Arthur
authors.initials: A
authors.lastname: Shulkes
authors.forename: Graham S
authors.initials: GS
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003125:Colostomy; D003676:Deferoxamine / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005755:Gastrins / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015918:Infusion Pumps, Implantable; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011498:Protein Precursors / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017262:Siderophores / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D005755:Gastrins; D011498:Protein Precursors; D017262:Siderophores; C013706:big gastrin; D007501:Iron; D003676:Deferoxamine
references.citation: Cancer Res. 1987 Apr 1;47(7):1749-50
references.pmid: 3815370
references.citation: J Natl Cancer Inst. 2003 Jan 15;95(2):154-9
references.pmid: 12529348
references.citation: Biochim Biophys Acta. 2002 Oct 2;1603(1):31-46
references.pmid: 12242109
references.citation: Gynecol Oncol. 2003 Jul;90(1):91-5
references.pmid: 12821347
references.citation: FEBS Lett. 2006 Nov 13;580(26):6195-8
references.pmid: 17064691
references.citation: Gut. 2006 Oct;55(10):1449-60
references.pmid: 16641131
references.citation: Nutr Rev. 2001 May;59(5):140-8
references.pmid: 11396694
references.citation: Gastroenterology. 1998 Aug;115(2):275-80
references.pmid: 9679032
references.citation: Clin Cancer Res. 2006 Dec 1;12(23):6876-83
references.pmid: 17145804
references.citation: Gynecol Oncol. 2002 Apr;85(1):95-102
references.pmid: 11925126
references.citation: Am J Physiol. 1999 Aug;277(2):R572-81
references.pmid: 10444566
references.citation: Nutr Cancer. 2004;49(2):162-9
references.pmid: 15489209
references.citation: Protein J. 2004 Jan;23(1):65-70
references.pmid: 15115183
references.citation: Cancer. 2004 Mar 15;100(6):1311-23
references.pmid: 15022301
references.citation: Biochemistry. 2001 Sep 11;40(36):10741-6
references.pmid: 11535048
references.citation: Int J Cancer. 2001 Nov 1;94(3):307-13
references.pmid: 11745407
references.citation: Gastroenterology. 2000 Jul;119(1):162-71
references.pmid: 10889165
references.citation: Gastroenterology. 1993 Apr;104(4):1099-107
references.pmid: 8462798
references.citation: J Clin Endocrinol Metab. 1999 Jan;84(1):233-9
references.pmid: 9920090
references.citation: J Biol Chem. 2004 Jan 23;279(4):2453-60
references.pmid: 14530269
references.citation: Cancer Res. 1990 Aug 15;50(16):4929-30
references.pmid: 2379156
references.citation: Clin Cancer Res. 2000 Dec;6(12):4719-24
references.pmid: 11156225
references.citation: Gut. 1994 Apr;35(4):530-5
references.pmid: 7909785
references.citation: Anticancer Res. 1994 Sep-Oct;14(5B):2109-12
references.pmid: 7840508
references.citation: J Endocrinol. 2004 May;181(2):315-25
references.pmid: 15128280
references.citation: N Engl J Med. 2008 Jan 17;358(3):221-30
references.pmid: 18199861
references.citation: J Clin Invest. 1996 Oct 15;98(8):1918-29
references.pmid: 8878444
references.citation: Int J Cancer. 2002 Jul 10;100(2):140-3
references.pmid: 12115561
references.citation: Gastroenterology. 1995 Oct;109(4):1142-53
references.pmid: 7557079
references.citation: Drug Metab Rev. 1990;22(5):531-79
references.pmid: 2078994
references.citation: Cancer Res. 1998 Feb 1;58(3):473-8
references.pmid: 9458092
references.citation: Gastroenterology. 1997 Nov;113(5):1576-88
references.pmid: 9352860
references.citation: Cancer Res. 1988 Dec 15;48(24 Pt 1):7189-92
references.pmid: 3191493
references.citation: J Biol Chem. 2002 Dec 13;277(50):48602-9
references.pmid: 12270941
references.citation: Cancer Lett. 2006 Jul 18;238(2):188-96
references.pmid: 16111806
references.citation: Gut. 2001 Jan;48(1):47-52
references.pmid: 11115822
references.citation: Dig Dis Sci. 1999 Mar;44(3):560-9
references.pmid: 10080151
references.citation: J Clin Invest. 1999 Apr;103(8):1119-26
references.pmid: 10207163