α-particle-emitting radionuclides are highly cytotoxic and are thus promising candidates for use in targeted radioimmunotherapy of cancer. Due to their high linear energy transfer (LET) combined with a short path length in tissue, α-particles cause severe DNA double-strand breaks that are repaired inaccurately and finally trigger cell death. For radioimmunotherapy, α-emitters such as (225)Ac, (211)At, (212)Bi/(212)Pb, (213)Bi and (227)Th are coupled to antibodies via appropriate chelating agents. The α-emitter immunoconjugates preferably target proteins that are overexpressed or exclusively expressed on cancer cells. Application of α-emitter immunoconjugates seems particularly promising in treatment of disseminated cancer cells and small tumor cell clusters that are released during the resection of a primary tumor. α-emitter immunoconjugates have been successfully administered in numerous experimental studies for therapy of ovarian, colon, gastric, blood, breast and bladder cancer. Initial clinical trials evaluating α-emitter immunoconjugates in terms of toxicity and therapeutic efficacy have also shown positive results in patients with melanoma, ovarian cancer, acute myeloid lymphoma and glioma. The present problems in terms of availability of therapeutically effiective α-emitters will presumably be solved by use of alternative production routes and installation of additional production facilities in the near future. Therefore, clinical establishment of targeted α-emitter radioimmunotherapy as one part of a multimodal concept for therapy of cancer is a promising, middle-term concept.
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 a-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. Conclusion: The study suggests that radioimmunotherapy using intravesically instilled 213 Bi-anti-EGFR-mAb is a promising option for treatment of bladder cancer in patients.
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