TITLE

PEPTIDE TARGETING OF CCK-2 RECEPTOR IN TUMOUR CELL LINES

AUTHOR(S)
Stubbs, M.; Khan, K.; Watson, S.A.; Grimes, S.; Michaeli, D.; Savage, K.; McStay, M.; Dhillon, A.P.; Caplin, M.E.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA521
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Gastrin binds preferentially to the CCK2 receptor. We have previously demonstrated expression of the CCK2 receptor in a number of hepatopancreaticobilary cancers and uptake of gastrin analogue peptides by CCK2 expressing tumour cell lines. The study also demonstrated dimerization of the peptides in solution. Aim: To compare the uptake of dimer and monomer forms of gastrin analogue peptides in hepatic and pancreatic cancer cell lines. Methods: 4 derivatives of GRTL-1 were labelled using Alexa Fluor 488 dye (Molecular Probes, USA); untreated GRTL-l, GRTL-1 with the cysteine sulfhydryl group protected with N-ethylmaleimide (GRTL-1NEM), a GRTL-1 dimer with a bismaleimidohexane linker ((GRTL-1)[sub 2] BMH) and a GRTL-1 dimer with a bismaleimidotetraethyleneglycol spacer linker ((GRTL-1)[sub 2] BM(PEO)[sub 4]). The labelled peptides were exposed to HepG2 (human hepatocyte carcinoma), AR42J (rat pancreatic adenocarcinoma) and PLC/PRF/5 (human liver hepatoma) cells at a concentration of 20 µg/mJ for 1 hour at 37°C. Cells were fixed with buffered formaldehyde and examined under a fluorescence microscope. Results: (GRTL-1)[sub 2] BMH (AR42J and PLC/PRF/5) and GRTL-1 (HepG2) gave the highest proportion of cells with visible uptake of labelled analogue. High uptake was also seen with (GRTL-1)[sub 2] BM(PEO)[sub 4] but the fluorescence intensity was slightly less intense than for GRTL-1 or (GRTL-1)[sub 2] BMH. The level of GRTL-1-NEM uptake was much lower. Conclusion: Dimeric forms of GRTL-1 show more endocytosis than the monomeric form. GRTL-1 with unsubstituted cysteine undergoes significant dimerization in aqueous solution, so the high uptake seen with this form is probably due to the dimer. Dimeric GRTL-1 therefore shows greater potential for intracellular delivery of potential therapeutic agents to CCK2 positive tumours.
ACCESSION #
9747625

 

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