Intravesical alpha-radioimmunotherapy with 213Bi-anti-EGFR-mAb defeats human bladder carcinoma in xenografted nude mice.
Transurethral resection of urothelial carcinoma often results in tumor recurrence due to disseminated tumor cells. Therefore, new therapeutic strategies are urgently needed. The aim of this study was to establish an orthotopic human bladder carcinoma mouse model using the epidermal growth factor receptor (EGFR)-overexpressing bladder carcinoma cell line EJ28 and to compare therapeutic efficacy of intravesically instilled alpha-particle-emitting (213)Bi-anti-EGFR-monoclonal antibody (mAb) with mitomycin C.


METHODS
Female Swiss nu/nu mice were intravesically inoculated with luciferase-transfected EJ28 human bladder carcinoma cells after the induction of urothelial lesions by electrocautery. At different time points after cell inoculation, mice were treated intravesically with (213)Bi-anti-EGFR-mAb, mitomycin C, or unlabeled anti-EGFR-mAb. Tumor development and therapeutic response were evaluated via bioluminescence imaging.


RESULTS
Mice without therapy and those treated with unlabeled anti-EGFR-mAb reached a median survival of 41 d and 89 d, respectively. Mice that underwent therapy with 0.925 MBq of (213)Bi-anti-EGFR-mAb 1 h, 7 d, or 14 d after cell instillation survived more than 300 d in 90%, 80%, and 40% of the cases, respectively. Therapy with 0.37 MBq 1 h or 7 d after tumor cell inoculation resulted in survival of more than 300 d in 90% and 50% of mice, respectively. Mitomycin C treatment after 1 h and 7 d prolonged survival to more than 300 d in 40% and 50%, respectively; however, treatment turned out to be nephrotoxic. In contrast, no signs of nephrotoxicity could be observed after (213)Bi-anti-EGFR-mAb treatment.


CONCLUSIONS
The study suggests that radioimmunotherapy using intravesically instilled (213)Bi-anti-EGFR-mAb is a promising option for treatment of bladder cancer in patients.
Department of Nuclear Medicine, Technische Universität München, Munich, Germany.
Birgit
B
Pfost
Christof
C
Seidl
Michael
M
Autenrieth
Dieter
D
Saur
Frank
F
Bruchertseifer
Alfred
A
Morgenstern
Markus
M
Schwaiger
Reingard
R
Senekowitsch-Schmidtke
D000283:Administration, Intravesical; D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001729:Bismuth / Q000737:chemistry*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D049409:Luciferases, Firefly / Q000235:genetics; D008163:Luminescent Measurements; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000627:therapeutic use; D016499:Radioimmunotherapy; D011868:Radioisotopes; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D011868:Radioisotopes; D016685:Mitomycin; D049409:Luciferases, Firefly; D066246:ErbB Receptors; D001729:Bismuth