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The Schedule-Dependent Effects of the Novel Antifolate Pralatrexate and Gemcitabine Are Superior to Methotrexate and Cytarabine in Models of Human Non-Hodgkin's Lymphoma

Authors' Affiliations: Laboratories of ¹ Experimental Therapeutics for the Lymphoproliferative Malignancies and ² Molecular and Cellular Hematology; ³ Leukemia, ⁴ Lymphoma, and ⁵ Developmental Chemotherapy Services, Division of Hematological Oncology, Department of Medicine; Departments of ⁶ Biostatistics and ⁷ Pathology; and ⁸ Molecular Pharmacology and Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York

Requests for reprints: Owen A. O'Connor, Department of Medicine, Memorial Sloan Kettering Cancer Center, Box 329, 1275 York Avenue, New York, NY 10021. Phone: 212-639-8889; Fax: 212-639-2767; E-mail: oconnoro{at}mskcc.org.

Purpose: Methotrexate is known to synergize with cytarabine [1-ß-D-arabinofuranosylcytosine (ara-C)] in a schedule-dependent manner. The purpose of this article is to compare and contrast the activity of pralatrexate (10-propargyl-10-deazaminopterin)/gemcitabine to the standard combination of methotrexate/ara-C and to determine if schedule dependency of this combination is important in lymphoma.

Experiment Design: Cytotoxicity assays using the standard trypan blue exclusion assay were used to explore the in vitro activity of pralatrexate and gemcitabine against a panel of lymphoma cell lines. Both severe combined imunodeficient beige and irradiated nonobese diabetic/severe combined imunodeficient mouse xenograft models were used to compare and contrast the in vivo activity of these combinations as a function of schedule. In addition, apoptosis assays were conducted.

Results: Compared with methotrexate-containing combinations, pralatrexate plus gemcitabine combinations displayed improved therapeutic activity with some schedule dependency. The combination of pralatrexate and gemcitabine was superior to any methotrexate and ara-C combination in inducing apoptosis and in activating caspase-3. In vivo, the best therapeutic effects were obtained with the sequence of pralatrexate gemcitabine. Complete remissions were only appreciated in animals receiving pralatrexate followed by gemcitabine.

Conclusions: These data show that the combination of pralatrexate followed by gemcitabine was superior to methotrexate/ara-C in vitro and in vivo, and was far more potent in inducing apoptosis in a large B-cell lymphoma. These data provide strong rationale for further study of this combination in lymphomas where methotrexate and ara-C are used.

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