Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer.
The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha-emitter 225Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225Ac, however, elicits hematologic toxicity and at high doses free 213Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225Ac-trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225Ac-trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer.
Department of Oncology, Johns Hopkins University School of Medicine, Maryland, USA.
Takahiro
T
Yoshida
Department of Oncology, Johns Hopkins University School of Medicine, Maryland, USA.
Kideok
K
Jin
Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Maryland, USA.
Hong
H
Song
Department of Oncology, Johns Hopkins University School of Medicine, Maryland, USA.
Sunju
S
Park
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Maryland, USA.
David L
DL
Huso
Department of Oncology, Johns Hopkins University School of Medicine, Maryland, USA.
Zhe
Z
Zhang
Department of Oncology, Johns Hopkins University School of Medicine, Maryland, USA.
Han
H
Liangfeng
Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA.
Charles
C
Zhu
European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany.
Frank
F
Bruchertseifer
European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany.
Alfred
A
Morgenstern
Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Maryland, USA.
George
G
Sgouros
Department of Oncology, Johns Hopkins University School of Medicine, Maryland, USA.
Saraswati
S
Sukumar
D000186:Actinium / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D000512:Alpha Particles / Q000009:adverse effects; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011868:Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D014018:Tissue Distribution; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
D000186:Actinium; D018796:Immunoconjugates; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
breast cancer; ductal carcinoma in situ; intraductal; radioimmunotherapy; trastuzumab