Title: Targeting EGFR and HER2 with 211At-Labeled Molecules: Unexpected and Expected Dose-Effect Relations in Cultured Tumor Cells
Volume: 1
Issue: 3
Author(s): J. Carlsson, A. C. Steffen, A. L. Sundberg, M. Vikstrom, A. Orlova, L. Gedda, B. Stenerlow, H. Lundqvist and V. Tolmachev
Affiliation:
Keywords:
211At, A431, affibody, ammonium chloride, antibody, astatine, BT474, EGF, EGFR, iressa
Abstract: This article is based on results from four published experimental studies. I: Three HER2 overexpressing cell lines were exposed to α-particles from the HER2 binding affibody molecule 211At- (ZHER2:4)2. The sensitivity differed; SKOV3 was resistant, SKBR3 intermediate and BT474 sensitive. The differences were unexpected since it is assumed that different types of cells should have a similar sensitivity to high-LET radiation. II: Effects of 211At-EGF in combination with the lysosomotropic base ammonium chloride were studied in A431 cells. The therapy effects of 211At-EGF increased by co-treatment with ammonium chloride, which was expected. III: Therapy effects of combined 211At-EGF and gefitinib treatment were studied using gefitinib sensitive A431 and resistant U343MG cells. The combined treatment reduced the survival of the resistant cells but in the gefitinib sensitive cells, the combined treatment increased survival, which was highly unexpected. IV: SKBR3 cells were exposed to the antibody trastuzumab that was labeled with 211At. A limited number of astatine decays per cell gave low survival, which was expected. Conclusion: The well-known high effectiveness of alpha particles to kill tumor cells was confirmed in all four studies. However, the dose-effect relations were complicated and more research is needed to evaluate factors of importance, such as internalization rate of the targeting agent, subcellular distribution and retention time of 211At.
