Efficacy and MRI of rituximab and methotrexate treatment in a nude rat model of CNS lymphoma

¹ Medizinische Klinik m. S. Hämatologie und Onkologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
² Departments of Neurology and Cell and Developmental Biology, Oregon Health and Science University, Portland, OR, USA
³ Department of Neuroradiology, Universitätsklinikum Würzburg, Würzburg, Germany
⁴ Department of Neurology, Oregon Health and Science University, Portland, OR, USA
⁵ Departments of Neurology and Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, USA.; Department of Pharmacy Practice, Oregon State University, Corvallis, OR, USA
⁶ Hématologie, Centre René Huguenin, Saint-Cloud, France
⁷ Departments of Neurology, Neuro-Oncology and Blood-Brain Barrier Program, Oregon Health and Science University, L-603, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA

^* To whom correspondence should be addressed. E-mail: neuwelte{at}ohsu.edu.

	Abstract

Purpose: To determine the efficacy of methotrexate and/or rituximab in a central nervous system lymphoma model, and evaluate magnetic resonance imaging (MRI) modalities for monitoring efficacy. Experimental Design: Female athymic nude rats (rnu/rnu) were inoculated intracerebrally with human MC116 B-lymphoma cells. On day 16–26, rats were randomized to intravenous (IV) treatment with: (1) saline (controls; n = 15); (2) methotrexate 1000 mg/m² (n = 6); (3) rituximab 375 mg/m² (n = 6); and (4) rituximab + methotrexate (n = 6). T2/fluid-attenuated inversion recovery (FLAIR) and gadolinium contrast-enhanced T1 MRI sequences were performed prior to and one week after treatment. Results: Intravenous rituximab gave an objective tumor response in 4 of 6 animals (>50% reduction in tumor volume comparing pre- and post-treatment T2/FLAIR MRI) and resulted in stable disease (50%–125% of baseline) in another animal. The percent change in tumor volume on T2/FLAIR images was significantly different in the control versus rituximab group (p = 0.0051). IV methotrexate slowed tumor growth, compared to controls, but only 1 of 6 animals had an objective response. In untreated controls, tumor histological volumes correlated well with T2/FLAIR or contrast-enhanced T1 images (r = 0.877). In the treatment groups, T2/FLAIR correlation was good, but the gadolinium-enhanced T1 MRI was not significantly correlated with histology (r = 0.19). Conclusions: The MC116 CNS lymphoma model seems valuable for preclinical testing of efficacy and toxicity of treatment regimens. IV rituximab was highly but methotrexate only minimally effective. T2/FLAIR was superior to contrast-enhanced T1 for monitoring efficacy.

Key Words: central nervous system lymphoma, magnetic resonance imaging, methotrexate, rat model, rituximab

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