RESUMEN
PURPOSE: Met, an oncogene product and receptor tyrosine kinase, is a keystone molecule for malignant progression in solid human tumors. We are developing Met-directed imaging and therapeutic agents, including anti-Met monoclonal antibodies (MetSeek). In this study, we compared two antibodies, Met5 and Met3, for nuclear imaging of human and canine Met-expressing tumor xenografts in nude mice. EXPERIMENTAL DESIGN: Xenografts representing cancers of three different human tissue origins and metastatic canine prostate cancer were raised s.c. in host athymic nude mice. Animals were injected i.v. with I-125-Met5 or I-125-Met3, posterior total body gamma camera images were acquired for several days postinjection, and quantitative region-of-interest activity analysis was done. RESULTS: PC-3, SK-LMS-1/HGF, and CNE-2 xenografts imaged with I-125-Met5 were compared with PC-3, SK-LMS-1/HGF, and DU145 xenografts imaged with I-125-Met3. Nuclear imaging contrast was qualitatively similar for I-125-Met5 and I-125-Met3 in PC-3 and SK-LMS-1/HGF host mice. However, by region-of-interest analysis, the set of human tumors imaged with I-125-Met3 exhibited a pattern of rapid initial tumor uptake followed by a continuous decline in activity, whereas the set of human tumors imaged with I-125-Met5 showed slow initial uptake, peak tumor-associated activity at 1 day postinjection, and persistence of activity in xenografts for at least 5 days. GN4 canine prostate cancer xenografts were readily imaged with I-125-Met5. CONCLUSIONS: We conclude that radioiodinated Met3 and Met5 offer qualitatively similar nuclear images in xenograft-bearing mice, but quantitative considerations indicate that Met5 might be more useful for radioimmunotherapy. Moreover, canine prostate cancer seems to be a suitable model for second-stage preclinical evaluation of Met5.
Asunto(s)
Anticuerpos Monoclonales/química , Neoplasias/diagnóstico , Neoplasias/patología , Proteínas Proto-Oncogénicas c-met/biosíntesis , Animales , Perros , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Ratones , Ratones Desnudos , Neoplasias Nasofaríngeas/patología , Trasplante de Neoplasias , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-met/fisiología , ARN Interferente Pequeño/metabolismo , Radioinmunoterapia/métodos , Cintigrafía , Factores de TiempoRESUMEN
PURPOSE: Inappropriate expression of the receptor tyrosine kinase Met and its ligand is associated with an aggressive phenotype and poor clinical prognosis for a wide variety of solid human tumors. We are developing imaging and therapeutic agents that target this receptor-ligand complex. In this study, we evaluated the ability of radioiodinated anti-Met monoclonal antibodies from a single hybridoma clone to image human Met-expressing tumor xenografts. EXPERIMENTAL DESIGN: Xenografts of four different tissue origins were raised s.c. in host athymic nude mice. Animals received i.v. injections of I-125-Met3, posterior total body gamma camera images were acquired for several days after injection, and quantitative region-of-interest activity analysis was performed. RESULTS: The autocrine Met-expressing tumors S-114 and SK-LMS-1/HGF and the paracrine Met-expressing human prostate carcinoma PC-3 were satisfactorily imaged with I-125-Met3. By region-of-interest analysis, mean initial tumor-associated activities in S-114, SK-LMS-1/HGF, and PC-3 were 18.6 +/- 2.1, 7.2 +/- 2.2, and 5.4 +/- 2.6% estimated injected activity, and the mean ratios of tumor:total body activity at 3 days after injection were 0.32 +/- 0.13, 0.15 +/- 0.06, and 0.10 +/- 0.04, respectively. Human melanoma xenografts, however, accounted for < or =3% of injected or total body activity. We observed a direct rank order correlation between relative levels of Met3-derived radioactivity in xenografts and relative quantities of Met expressed by the respective cultured tumor cell lines. CONCLUSIONS: We conclude that I-125-Met3 is effective for imaging human Met-expressing xenografts of different tissue origins, and we infer that I-125-Met3 distinguishes human tumor xenografts according to their levels of Met expression.