PT  - JOURNAL ARTICLE
AU  - Bart Cornelissen
AU  - Sonali Darbar
AU  - Jody Mitchell
AU  - Iain Tullis
AU  - Boris Vojnovic
AU  - Katherine Vallis
TI  - Intracellular trafficking of 111In-DTPA-EGF is altered by co-administration of molecularly targeted anticancer agents and influences cell kill by Auger electrons
DP  - 2009 May 01
TA  - Journal of Nuclear Medicine
PG  - 1562--1562
VI  - 50
IP  - supplement 2
4099  - http://jnm.snmjournals.org/content/50/supplement_2/1562.short
4100  - http://jnm.snmjournals.org/content/50/supplement_2/1562.full
SO  - J Nucl Med2009 May 01; 50
AB  - 1562 Objectives The intracellular distribution of Auger-electron emitting radiopharmaceuticals is an important determinant of cytotoxicity. The mechanisms by which these agents are routed through the cell are often ill-understood. For example, it is not known how trafficking of 111In-DTPA-EGF compares to endogenous EGF, or how nuclear localisation, necessary for therapeutic efficacy, may be influenced by co-administration of anticancer agents. Methods Using FRET (Fluorescence Resonance Energy Transfer) confocal microscopy and two-photon FLIM (Fluorescence Lifetime IMaging) we studied the spatio-temporal interaction between EGF-Alexa Fluor 488 and anti-EGFR-Cy3 in MDA-MB-468 and MDA-MB-231HER2 breast cancer cell lines. Using clonogenic assays and 111In internalisation and nuclear localisation assays, we investigated the influence of chloroquine, erlotinib, trastuzumab, farnesyl transferase inhibitor (FTI), and PI3K inhibitors on localisation and cytotoxicity of 111In-DTPA-EGF. Results Using FRET it was shown that EGF continues to interact with EGFR at least 4 hours after internalisation in MDA-MB-468 cells. Nuclear localisation of EGF is enhanced by erlotinib and FTI in MDA-MB-468 cells and by trastuzumab in MDA-MB-231HER2 cells. Erlotinib and FTI sensitized MDA-MB-468 cells, and trastuzumab sensitized MDA-MB-231HER2 cells to 111In-DTPA-EGF. Conclusions 111In-DTPA-EGF interacts physically with EGFR as it traffics through the cell and during nuclear localisation. It is possible to increase the therapeutic efficacy of 111In-DTPA-EGF through co-administration of selected molecularly targeted anticancer drugs.