Preclinical and initial clinical evaluation of 111In-labeled nonsulfated CCK8 analog: a peptide for CCK-B receptor-targeted scintigraphy and radionuclide therapy.

The presence of cholecystokinin (CCK)-B (gastrin) receptors has been shown in more than 90% of medullary thyroid cancers (MTCs) and in a high percentage of small cell lung cancers, stromal ovarium cancers and several other tumor types.
The aim of this study was to evaluate in vitro and in vivo whether 111In-labeled CCK-B receptor-specific CCK8 analog [D-Asp26,Nle28,31]CCK26-33 (D-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2) is suitable for CCK-B receptor scintigraphy based on the finding that unlabeled nonsulfated diethylenetriamine pentaacidic acid [DTPA0]CCK8 and tetraazacyclododecanetetraacetic acid [DOTA0]CCK8 analogs show high and specific binding for CCK-B receptors in human tumors. Fifty percent inhibitory concentrations were in the low nanomolar range.
In vitro, [111In-DOTA0]CCK8 showed specific internalization in CCK-B receptor-positive rat pancreatic tumor cells AR42J. Internalization of the analog appeared to be time and temperature dependent and receptor specific. From the data obtained with [111In-DOTA0]CCK8 and (125I)I-gastrin, the latter being a specific ligand for the CCK-B receptor, the rat pancreatic cell line CA20948 also appeared to be CCK-B receptor positive. This provides an in vitro and in vivo rat tumor model because this cell line can be grown to solid tumors in Lewis rats. In vivo biodistribution experiments in CA20948 tumor-bearing Lewis rats showed rapid clearance of [111In-DOTA0]CCK8, and specific uptake was found in the CCK-B receptor-expressing stomach and tumor. Furthermore, comparing [111In-DOTA0]CCK8 with the radioiodinated nonsulfated CCK10 analog (D-Tyr-Gly-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2), both ligands having high affinity for the CCK-B receptor, tumor-to-blood ratios were significantly higher for [111In-DOTA0]CCK8 than for 125I-CCK10, analogous to the findings with radioiodinated and 111In-labeled octreotide. The study in humans with [111In-DTPA0]CCK8 showed receptor-specific uptake in the CCK-B receptor-positive stomach and in metastases in the neck region up to 48 h after injection.
[111In-DOTA0]CCK8 is most promising for scintigraphy and, after coupling to therapeutic radionuclides, for radionuclide therapy of human CCK-B receptor-positive tumors such as MTC and small cell lung cancer.
AuthorsM de Jong, W H Bakker, B F Bernard, R Valkema, D J Kwekkeboom, J C Reubi, A Srinivasan, M Schmidt, E P Krenning
JournalJournal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 40 Issue 12 Pg. 2081-7 (Dec 1999) ISSN: 0161-5505 [Print] UNITED STATES
PMID10616889 (Publication Type: Journal Article)
Chemical References
  • Indium Radioisotopes
  • Peptide Fragments
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin
  • cholecystokinin (26-33), indium-DOTA(0)-Asp(26)-Nle(28,31)-
  • Cholecystokinin
  • Animals
  • Cholecystokinin (pharmacokinetics, therapeutic use, toxicity)
  • Drug Evaluation
  • Female
  • Humans
  • Indium Radioisotopes
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Pancreatic Neoplasms (chemistry, radionuclide imaging)
  • Peptide Fragments (pharmacokinetics, therapeutic use, toxicity)
  • Rats
  • Rats, Inbred Lew
  • Rats, Wistar
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin (analysis)
  • Thyroid Neoplasms (chemistry, radionuclide imaging)
  • Tissue Distribution
  • Tumor Cells, Cultured

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: