title: Fractionated intravesical radioimmunotherapy with (213)Bi-anti-EGFR-MAb is effective without toxic side-effects in a nude mouse model of advanced human bladder carcinoma.
abstract: Gold standard in therapy of superficial, non-muscle invasive urothelial tumors is transurethral resection followed by intravesical instillation therapies. However, relapse is commonly observed and therefore new therapeutic approaches are needed. Application of (213)Bi-immunoconjugates targeting EGFR had shown promising results in early tumor stages. The aim of this study was the evaluation of fractionated application of (213)Bi-anti-EGFR-MAb in advanced tumor stages in a nude mouse model. Luciferase-transfected EJ28 human bladder carcinoma cells were instilled intravesically into nude mice following electrocautery. Tumor development was monitored via bioluminescence imaging. One day after tumor detection mice were treated intravesically either 2 times with 0.93 MBq or 3 times with 0.46 MBq of (213)Bi-anti-EGFR-MAb. Therapeutic efficacy was evaluated via overall survival and toxicity toward normal urothelium by histopathological analysis. Mice without treatment and those treated with the native anti-EGFR-MAb showed mean survivals of 65.4 and 57.6 d, respectively. After fractionated treatment with 0.93 MBq of (213)Bi-anti-EGFR-MAb animals reached a mean survival of 141.5 d and 33% of the animals survived at least 268 d. Fractionated treatment with 0.46 MBq (213)Bi-anti-EGFR-MAb resulted in a mean survival of 131.8 d and 30% of the animals survived longer than 300 d. Significant differences were only observed between the control groups and the group treated twice with 0.93 MBq of (213)Bi-anti-EGFR-MAb. No toxic side-effects on the normal urothelium were observed even after treatment with 3.7 MBq of (213)Bi-anti-EGFR-MAb. The study demonstrates that the fractionated intravesical radioimmunotherapy with (213)Bi-anti-EGFR-MAb is a promising approach in advanced bladder carcinoma.
authors.affiliation: a Department of Nuclear Medicine ; Technische Universität München ; Munich , Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Fazel
authors.affiliation: a Department of Nuclear Medicine ; Technische Universität München ; Munich , Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rötzer
authors.affiliation: a Department of Nuclear Medicine ; Technische Universität München ; Munich , Germany.|b Department of Obstetrics and Gynecology ; Technische Universität München ; Munich , Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Seidl
authors.affiliation: a Department of Nuclear Medicine ; Technische Universität München ; Munich , Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Feuerecker
authors.affiliation: c Department of Urology ; Technische Universität München ; Munich , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Autenrieth
authors.affiliation: d Department of Pathology ; Technische Universität München ; Munich , Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Weirich
authors.affiliation: e European Commission ; Joint Research Center ; Institute for Transuranium Elements ; Karlsruhe , Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: e European Commission ; Joint Research Center ; Institute for Transuranium Elements ; Karlsruhe , Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: a Department of Nuclear Medicine ; Technische Universität München ; Munich , Germany.
authors.forename: Reingard
authors.initials: R
authors.lastname: Senekowitsch-Schmidtke
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D019275:Radiopharmaceuticals
keywords: EJ28 cells; bladder cancer; histopathology; immunotherapy; targeted treatment; toxicity; α-emitter