Abstract | UNLABELLED: METHODS: A variety of CCK/ gastrin-related peptides, all bearing the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They were radioiodinated by the lodogen or Bolton-Hunter procedures. The peptides were members of the gastrin or CCK families, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing subcutaneous human MTC xenografts. Diethylenetriamine pentaacetic acid ( DTPA) derivatives of suitable peptides were synthesized successfully, and their preclinical and initial clinical evaluations were performed, labeled with 111In. RESULTS: All members of the CCK or gastrin families were stable in serum (with half-lives of several hours at 37 degrees C); nevertheless, the stability of those peptides bearing N-terminal pGlu residues or D- amino acids was significantly higher. In accordance with their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues. Sulfated CCK derivatives performed significantly better but also displayed a comparably high uptake in normal CCK-A receptor-expressing tissues. This effect was probably due to their similar affinity for both CCK-A and CCK-B receptors. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC-bearing animals showed significant antitumor efficacy compared with untreated controls. DTPA derivatives of minigastrin were successfully developed. In a pilot clinical study, radioiodinated and 111In-labeled derivatives showed excellent targeting of physiological CCK-B receptor-expressing organs, as well as all known tumor sites. CONCLUSION:
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Authors | T M Behr, N Jenner, M Béhé, C Angerstein, S Gratz, F Raue, W Becker |
Journal | Journal of nuclear medicine : official publication, Society of Nuclear Medicine
(J Nucl Med)
Vol. 40
Issue 6
Pg. 1029-44
(Jun 1999)
ISSN: 0161-5505 [Print] United States |
PMID | 10452322
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Gastrins
- Indium Radioisotopes
- Iodine Radioisotopes
- Peptides
- Radioisotopes
- Receptors, Cholecystokinin
- Cholecystokinin
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Topics |
- Adult
- Aged
- Amino Acid Sequence
- Animals
- Carcinoma, Medullary
(diagnostic imaging, metabolism, therapy)
- Carcinoma, Small Cell
(diagnostic imaging, metabolism, therapy)
- Cholecystokinin
(administration & dosage, metabolism)
- Data Interpretation, Statistical
- Female
- Gastrins
(administration & dosage, metabolism)
- Humans
- Indium Radioisotopes
- Iodine Radioisotopes
- Isotope Labeling
- Lung Neoplasms
(diagnostic imaging, metabolism, therapy)
- Lymphatic Metastasis
(diagnostic imaging)
- Male
- Mice
- Mice, Nude
- Middle Aged
- Molecular Sequence Data
- Neoplasm Metastasis
(diagnostic imaging)
- Neoplasms, Experimental
(diagnostic imaging, therapy)
- Peptides
(administration & dosage, genetics)
- Radioisotopes
- Radionuclide Imaging
- Receptors, Cholecystokinin
(analysis, metabolism)
- Thyroid Neoplasms
(diagnostic imaging, metabolism, therapy)
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