RESUMEN
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.
Asunto(s)
Actinio/administración & dosificación , Partículas alfa , Neoplasias de la Mama/radioterapia , Carcinoma Intraductal no Infiltrante/radioterapia , Inmunoconjugados/administración & dosificación , Radioinmunoterapia/métodos , Radioisótopos/administración & dosificación , Radiofármacos/administración & dosificación , Receptor ErbB-2/metabolismo , Trastuzumab/administración & dosificación , Actinio/farmacocinética , Actinio/toxicidad , Partículas alfa/efectos adversos , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/inmunología , Carcinoma Intraductal no Infiltrante/metabolismo , Carcinoma Intraductal no Infiltrante/patología , Femenino , Humanos , Inmunoconjugados/farmacocinética , Células MCF-7 , Ratones Endogámicos NOD , Radioinmunoterapia/efectos adversos , Radioisótopos/farmacocinética , Radioisótopos/toxicidad , Radiofármacos/farmacocinética , Radiofármacos/toxicidad , Receptor ErbB-2/inmunología , Distribución Tisular , Trastuzumab/farmacocinética , Carga Tumoral/efectos de la radiación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Internal irradiation of kidneys as a consequence of radioimmunotherapy, radiation accidents, or nuclear terrorism can result in radiation nephropathy. We attempted to modify pharmacologically, the functional and morphologic changes in mouse kidneys after injection with the actinium ((225)Ac) nanogenerator, an in vivo generator of alpha- and beta-particle emitting elements. METHODS AND MATERIALS: The animals were injected with 0.35 muCi of the (225)Ac nanogenerator, which delivers a dose of 27.6 Gy to the kidneys. Then, they were randomized to receive captopril (angiotensin-converting enzyme inhibitor), L-158,809 (angiotensin II receptor-1 blocker), spironolactone (aldosterone receptor antagonist), or a placebo. RESULTS: Forty weeks after the (225)Ac injection, the placebo-control mice showed a significant increase in blood urea nitrogen (BUN) (87.6 +/- 6.9 mg/dL), dilated Bowman spaces, and tubulolysis with basement membrane thickening. Captopril treatment accentuated the functional (BUN 119.0 +/- 4.0 mg/dL; p <0.01 vs. placebo controls) and histopathologic damage. In contrast, L-158,809 offered moderate protection (BUN 66.6 +/- 3.9 mg/dL; p = 0.02 vs. placebo controls). Spironolactone treatment, however, significantly prevented the development of histopathologic and functional changes (BUN 31.2 +/- 2.5 mg/dL; p <0.001 vs. placebo controls). CONCLUSIONS: Low-dose spironolactone and, to a lesser extent, angiotensin receptor-1 blockade can offer renal protection in a mouse model of internal alpha-particle irradiation.
Asunto(s)
Actinio/toxicidad , Partículas alfa , Riñón/efectos de la radiación , Traumatismos Experimentales por Radiación/prevención & control , Protectores contra Radiación/uso terapéutico , Angiotensina II/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/toxicidad , Animales , Nitrógeno de la Urea Sanguínea , Captopril/toxicidad , Femenino , Imidazoles/uso terapéutico , Riñón/efectos de los fármacos , Riñón/patología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Túbulos Renales/efectos de la radiación , Ratones , Ratones Endogámicos BALB C , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Dosis de Radiación , Traumatismos Experimentales por Radiación/inducido químicamente , Protectores contra Radiación/toxicidad , Distribución Aleatoria , Espironolactona/uso terapéutico , Tetrazoles/uso terapéuticoRESUMEN
The biodistribution and tissue toxicity of intravenously administered 225-actinium (225Ac) complexed with acetate, ethylene diamine tetraacetic acid (EDTA), 1, 4, 7, 10, 13-pentaazacyclopentadecane-N, N', N", N"', N""-pentaacetic acid (PEPA), or the "a" isomer of cyclohexyl diethylenetriamine pentaacetic acid (CHX-DTPA), were examined. The percent of injected dose per organ and per gram of tissue for each chelate complex was determined. 225Ac-CHX-DTPA was evaluated further for radiotoxic effects. Mice receiving > or =185 kBq 225Ac-CHX-DTPA suffered 100% morbidity by 5 days and 100% mortality by 8 days postinjection, and all animals evaluated had significant organ damage. The in vivo instability of the 225Ac-CHX-DTPA complex likely allowed accumulation of free 225Ac in organs, which resulted in tissue pathology.
Asunto(s)
Actinio/farmacocinética , Quelantes/farmacocinética , Isotiocianatos/farmacocinética , Ácido Pentético/análogos & derivados , Actinio/toxicidad , Animales , Quelantes/toxicidad , Relación Dosis-Respuesta en la Radiación , Femenino , Isotiocianatos/síntesis química , Isotiocianatos/toxicidad , Ratones , Ratones Endogámicos BALB C , Ácido Pentético/síntesis química , Ácido Pentético/farmacocinética , Ácido Pentético/toxicidad , Relación Estructura-Actividad , Distribución TisularRESUMEN
This paper describes in vitro cytotoxicity experiments with 213Bi- and 225Ac-immunoconjugates on the human epidermoid tumour cell line A431 using a blood group A-reactive murine IgG (2D11) as the specific antibody and MOPC 21 as the control antibody. With both radionuclides, specific cell-killing was achieved. The observed cytotoxicity of 213Bi (T1/2 - 47 min) indicates that this radionuclide is a useful alternative for the alpha-emitter 212Bi in the treatment of blood-borne malignancies. 225Ac-immunoconjugates (T1/2 of 225Ac is 10 days) may be applicable for the treatment of solid tumours, since the daughter radionuclides of 225Ac contribute to the cytotoxic efficacy by a field effect (i.e. toxicity in an area distal from the antibody-binding site). The lack of an adequate chelator for 225Ac is a major drawback.