Copyright 2009 by the Society for Neuro-Oncology
Efficacy and MRI of rituximab and methotrexate treatment in a nude rat model of CNS lymphoma
Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité-Universitätsmedizin Berlin, Berlin, Germany (K.J.); Departments of Neurology (L.L.M., S.J.L., R.D.B., D.F.K., E.A.N.), Cell and Developmental Biology (L.L.M.), Medical Informatics and Clinical Epidemiology (D.F.K.), Public Health and Preventive Medicine (D.F.K.), and Neurosurgery (E.A.N.), Oregon Health and Science University, Portland, OR, USA; Department of Neuroradiology, Universitätsklinikum Würzburg, Würzburg, Germany (C.G.V.); Department of Pharmacy Practice, Oregon State University, Corvallis, OR, USA (D.F.K.); Hématologie, Centre René Huguenin, Saint-Cloud, France (C.S.); Veterans Administration Medical Center, Portland, OR, USA (E.A.N.)
Address correspondence to Edward A. Neuwelt, Department of Neurology, Neuro-Oncology, and Blood-Brain Barrier Program, Oregon Health and Science University, L-603, 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA (neuwelte{at}ohsu.edu).
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Abstract |
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To determine the efficacy of methotrexate and/or rituximab in a CNS lymphoma model and to evaluate MRI modalities for monitoring efficacy, we inoculated female athymic nude rats (rnu/rnu) intracerebrally with human MC116 B-lymphoma cells. Between days 16 and 26, rats were randomized to receive intravenous (IV) treatment with (1) saline (controls, n = 15), (2) methotrexate 1,000 mg/m2 (n = 6), (3) rituximab 375 mg/m2 (n = 6), or (4) rituximab plus methotrexate (n = 6). T2/fluid-attenuated inversion recovery (FLAIR) and gadolinium contrast-enhanced T1 MRI sequences were performed prior to and 1 week after treatment. IV rituximab gave an objective tumor response in four of six animals (>50% reduction in tumor volume comparing pre- and posttreatment 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 one of six 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). The MC116 CNS lymphoma model seems valuable for preclinical testing of efficacy and toxicity of treatment regimens. IV rituximab was highly effective, but methotrexate was only minimally effective. T2/FLAIR was superior to contrast-enhanced T1 for monitoring efficacy.
Keywords: central nervous system lymphoma, MRI, methotrexate, rat model, rituximab
Received July 8, 2008; Accepted December 7, 2008