In Vivo evaluation of an 111 In-labeled ST-peptide analog for specific-targeting of human colon cancers

Targeting of cholecystokinin-2 receptor (CCK2R) expressing tumors using radiolabeled minigastrin (MG) analogs is hampered by rapid digestion of the linear peptide in vivo. In this study, a new MG analog stabilized against enzymatic degradation was investigated in preclinical studies to characterize the metabolites formed in vivo. The new MG analog DOTA-DGlu-Pro-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2 comprising site-specific amino acid substitutions in position 2, 6 and 8 and different possible metabolites thereof were synthesized. The receptor interaction of the peptide and selected metabolites was evaluated in a CCK2R-expressing cell line. The enzymatic stability of the 177Lu-labeled peptide analog was evaluated in vitro in different media as well as in BALB/c mice up to 1 h after injection and the metabolites were identified based on radio-HPLC analysis. The new radiopeptide showed a highly increased stability in vivo with >56% intact radiopeptide in the blood of BALB/c mice 1 h after injection. High CCK2R affinity and cell uptake was confirmed only for the intact peptide, whereas enzymatic cleavage within the receptor specific C-terminal amino acid sequence resulted in complete loss of affinity and cell uptake. A favorable biodistribution profile was observed in BALB/c mice with low background activity, preferential renal excretion and prolonged uptake in CCK2R-expressing tissues. The novel stabilized MG analog shows high potential for diagnostic and therapeutic use. The radiometabolites characterized give new insights into the enzymatic degradation in vivo.

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In Vitro and In Vivo Evaluation of Two Rational-Designed Nonpeptidic Farnesyltransferase Inhibitors on HT29 Human Colon Cancer Cell Lines

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/000000006783981170 ◽

2006 ◽

Vol 16 (3) ◽

pp. 107-118 ◽

Cited By ~ 5

Author(s):

Nicolas Wlodarczyk ◽

Pauline Gilleron ◽

Régis Millet ◽

Raymond Houssin ◽

Jean-François Goossens ◽

...

Keyword(s):

Colon Cancer ◽

Human Colon ◽

Colon Cancer Cell ◽

Farnesyltransferase Inhibitors ◽

Human Colon Cancer Cell ◽

In Vivo Evaluation ◽

Human Colon Cancer ◽

Colon Cancer Cell Lines

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Ultrastructural Study of a differentiating human colon carcinoma cell line

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100158583 ◽

1990 ◽

Vol 48 (3) ◽

pp. 208-209

Author(s):

Sylvie Polak-Charcon ◽

Mehrdad Hekmati ◽

Yehuda Ben Shaul

Keyword(s):

Cell Line ◽

Morphological Changes ◽

Secretory Granules ◽

Human Colon ◽

Cell Types ◽

Culture Conditions ◽

Morphological Evidence ◽

Human Colon Carcinoma Cell ◽

Colon Cell

The epithelium of normal human colon mucosa “in vivo” exhibits a gradual pattern of differentiation as undifferentiated stem cells from the base of the crypt of “lieberkuhn” rapidly divide, differentiate and migrate toward the free surface. The major differentiated cell type of the intestine observed are: absorptive cells displaying brush border, goblet cells containing mucous granules, Paneth and endocrine cells containing dense secretory granules. These different cell types are also found in the intestine of the 13-14 week old embryo.We present here morphological evidence showing that HT29, an adenocarcinoma of the human colon cell line, can differentiate into various cell types by changing the growth and culture conditions and mimic morphological changes found during development of the intestine in the human embryo.HT29 cells grown in tissue-culture dishes in DMEM and 10% FCS form at late confluence a multilayer of morphologically undifferentiated cell culture covered with irregular microvilli, and devoid of tight junctions (Figs 1-3).

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