Research ArticleBasic Science Investigations

In Vitro and In Vivo Application of Radiolabeled Gastrin-Releasing Peptide Receptor Ligands in Breast Cancer

Simone U. Dalm, John W.M. Martens, Anieta M. Sieuwerts, Carolien H.M. van Deurzen, Stuart J. Koelewijn, Erik de Blois, Theodosia Maina, Berthold A. Nock, Luc Brunel, Jean-Alain Fehrentz, Jean Martinez, Marion de Jong and Marleen Melis
Journal of Nuclear Medicine May 2015, 56 (5) 752-757; DOI: https://doi.org/10.2967/jnumed.114.153023

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    (A) Hematoxylin and eosin staining of sections indicating tumor-containing regions, corresponding to autoradiography results in B. (B) Representative examples of 111In-AMBA binding to human BC specimens, without (-block) and with (+block) 10−6 M Tyr4-bombesin. Binding was GRP-R–specific because no binding was observed when the GRP-R was blocked by Tyr4-bombesin. Among GRP-R–positive tumors, a subdivision was made between tumors that were 1%–25%, 26%–50%, 51%–75%, and 76%–100% GRP-R–positive.

  • FIGURE 2.
    FIGURE 2.

    (A) Selective binding and internalization after 1 h of incubation with 10−9 M/0.1 MBq of 111In-AMBA, a GRP-R agonist. Nine human-derived BC cell lines with different molecular properties (18) were screened. Both membrane- and internalized/cell fraction are displayed. Results shown are average of 3 independent experiments, each performed in triplicate (mean ± SD). (B) Significant correlation (P = 0.0108, Rs = 0.8167) between GRP-R messenger RNA (mRNA) expression and level of 111In-AMBA uptake (membrane plus cell fraction).

  • FIGURE 3.
    FIGURE 3.

    (A) Uptake of 111In-AMBA by GRP-R–expressing human-derived BC cell line T47D, at 1, 2, and 4 h after incubation with 10−7 M/10 MBq, 10−8 M/1 MBq, or 10−9 M/0.1 MBq of 111In-AMBA. Results shown are average of 2 independent experiments, each performed in triplicate (mean ± SD). (B) Treatment of T47D cells with 3 different concentrations of AMBA, 177Lu-DTPA, and 177Lu-AMBA for 4 h. Significant reduction of 80% in cell viability was reached when cells were treated with 10−7 M/50 MBq of 177Lu-AMBA, whereas no significant effects were observed when cells were similarly treated with AMBA or 177Lu-DTPA. Results shown are average of 3 independent experiments, each performed in triplicate (mean ± SD).

  • FIGURE 4.
    FIGURE 4.

    SPECT/CT scans indicating orthotopic (green arrows) and subcutaneous (white arrows) tumors of T47D and MCF7 xenograft–bearing mice at 4 h after injection of approximately 35 MBq (200 pmol) of 111In-JMV4168 + 300 μg of phosphoramidon. T47D xenografts were scanned at t1 = 43 d (A) and t2 = 100 d (B). MCF7 xenografts were scanned at t1 = 37 d (C) and t2 = 106 d (D). Bladder uptake is masked. Mice were provided with a chip for identification purposes. T47D xenografts were visualized with higher contrast than MCF7 xenografts.

  • FIGURE 5.
    FIGURE 5.

    Quantification of 111In-JMV4168 uptake in tumors and organs collected after last scan (t2); n = 6 for each mouse model (2 small subcutaneous T47D xenografts were excluded). Significantly (P < 0.0001) higher uptake of 111In-JMV4168 was determined in T47D than in MCF7 xenografts.

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