TY - JOUR T1 - Selective Targeting of <em>E. coli</em> Heat-stable Enterotoxin Analogs to Human Colon Cancer Cells JF - Anticancer Research JO - Anticancer Res SP - 3243 LP - 3251 VL - 26 IS - 5A AU - MICHAEL F. GIBLIN AU - GARY L. SIECKMAN AU - LISA D. WATKINSON AU - SAID DAIBES-FIGUEROA AU - TIMOTHY J. HOFFMAN AU - LEONARD R. FORTE AU - WYNN A. VOLKERT Y1 - 2006/09/01 UR - http://ar.iiarjournals.org/content/26/5A/3243.abstract N2 - Background: Radiolabeled analogs of the E. coli heat-stable enterotoxin (STh) are currently under study as imaging and therapeutic agents for colorectal cancer. The aim of these studies is to compare in vitro and in vivo characteristics of two novel STh analogs with appended DOTA chelating moieties. Materials and Methods: STh analogs were synthesized with pendant N-terminal DOTA moieties and radiolabeled with indium-111. In vitro cell binding was studied using cultured T-84 human colorectal cancer cells, and in vivo biodistribution studies were carried out using T-84 human colorectal tumor xenografts in SCID mice. Results: Competitive radioligand binding assays employing T-84 human colon cancer cells demonstrated similar IC50 values for the F19-STh(2-19) and F9-STh(6-19) analogs. Addition of DOTA to the N-terminus of these peptides elicited distinctly different effects on binding affinities in vitro, effects that were largely unchanged by metallation with nonradioactive natIn. In vivo pharmacokinetic studies in SCID mice bearing T-84 human colon cancer-derived tumor xenografts demonstrated tumor uptake of 0.74±0.1 %ID/g at 4 h post-injection (p.i.) for the 111In-DOTA-F19-STh(2-19) analog, and significantly reduced tumor localization (0.27 + 0.08 %ID/g) for the 111In-DOTA-F9-STh(6-19) analog. Conclusion: These results demonstrate that placement of a DOTA moiety immediately adjacent to Cys 6 in STh significantly inhibits receptor binding in vitro and in vivo, highlighting the need for intervening spacer residues between the pharmacophore and the DOTA chelating moiety in effective STh-based radiopharmaceutical constructs. Copyright© 2006 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved ER -