title: Alpha-particle emitting 213Bi-anti-EGFR immunoconjugates eradicate tumor cells independent of oxygenation.
abstract: Hypoxia is a central problem in tumor treatment because hypoxic cells are less sensitive to chemo- and radiotherapy than normoxic cells. Radioresistance of hypoxic tumor cells is due to reduced sensitivity towards low Linear Energy Transfer (LET) radiation. High LET α-emitters are thought to eradicate tumor cells independent of cellular oxygenation. Therefore, the aim of this study was to demonstrate that cell-bound α-particle emitting (213)Bi immunoconjugates kill hypoxic and normoxic CAL33 tumor cells with identical efficiency. For that purpose CAL33 cells were incubated with (213)Bi-anti-EGFR-MAb or irradiated with photons with a nominal energy of 6 MeV both under hypoxic and normoxic conditions. Oxygenation of cells was checked via the hypoxia-associated marker HIF-1α. Survival of cells was analysed using the clonogenic assay. Cell viability was monitored with the WST colorimetric assay. Results were evaluated statistically using a t-test and a Generalized Linear Mixed Model (GLMM). Survival and viability of CAL33 cells decreased both after incubation with increasing (213)Bi-anti-EGFR-MAb activity concentrations (9.25 kBq/ml-1.48 MBq/ml) and irradiation with increasing doses of photons (0.5-12 Gy). Following photon irradiation survival and viability of normoxic cells were significantly lower than those of hypoxic cells at all doses analysed. In contrast, cell death induced by (213)Bi-anti-EGFR-MAb turned out to be independent of cellular oxygenation. These results demonstrate that α-particle emitting (213)Bi-immunoconjugates eradicate hypoxic tumor cells as effective as normoxic cells. Therefore, (213)Bi-radioimmunotherapy seems to be an appropriate strategy for treatment of hypoxic tumors.
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wulbrand
authors.forename: Christof
authors.initials: C
authors.lastname: Seidl
authors.forename: Florian C
authors.initials: FC
authors.lastname: Gaertner
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Markus
authors.initials: M
authors.lastname: Essler
authors.forename: Reingard
authors.initials: R
authors.lastname: Senekowitsch-Schmidtke
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D001729:Bismuth / Q000627:therapeutic use*; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D066246:ErbB Receptors / Q000276:immunology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D018796:Immunoconjugates / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D010100:Oxygen / Q000494:pharmacology*; D010315:Particle Accelerators; D017785:Photons; D011868:Radioisotopes / Q000627:therapeutic use*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018796:Immunoconjugates; D011868:Radioisotopes; D066246:ErbB Receptors; C520777:matuzumab; D010100:Oxygen; D001729:Bismuth