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

Abstract

Purpose: Methotrexate is known to synergize with cytarabine [1-h-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.

Phase II-I-II Study of Two Different Doses and Schedules of Pralatrexate, a High-Affinity Substrate for the Reduced Folate Carrier, in Patients With Relapsed or Refractory Lymphoma Reveals Marked Activity in T-Cell Malignancies

“…This pattern of activity was observed in B-and T-cell lymphomas, both in vitro and in vivo. 9,10 Recent studies have established that pralatrexate synergizes with gemcitabine and that this synergy is superior to traditional MTX plus cytarabine. 10 With this rationale, a phase II study of pralatrexate (135 mg/m 2 every other week [QOW]) was initiated in patients with relapsed/ refractory lymphoma.…”

“…9,10 Recent studies have established that pralatrexate synergizes with gemcitabine and that this synergy is superior to traditional MTX plus cytarabine. 10 With this rationale, a phase II study of pralatrexate (135 mg/m 2 every other week [QOW]) was initiated in patients with relapsed/ refractory lymphoma. This phase II study, which used the maximumtolerated dose (MTD) identified in patients with non-small-cell lung cancer, 11,12 revealed a higher incidence of stomatitis in patients with lymphoma.…”

Lymph cancer chemotherapy: delivery of doxorubicin-gemcitabine prodrug and vincristine by nanostructured lipid carriers

“…1,[4][5][6][7] The single drug regimen, such as liposomal DOX, 1,8 gemcitabine (GEM), [9][10][11][12][13][14] and liposomal VCR, 1,15 has been proven to treat B-cell lymphoma in clinical trials. Based on their (DOX, GEM and VCR [DGV]) different mechanisms of action, the combination chemotherapies of DGV are effective and well tolerated in relapse and refractory NHL.…”

Safety and efficacy of pralatrexate in the treatment of patients with relapsed or refractory peripheral T-cell lymphoma

“…It is already known that methotrexate synergizes with cytarabine (1-h-D-arabinofuranosylcytosine [ara-C]) in a schedule-dependent manner. Toner and colleagues [Toner et al 2006] compared the activity of pralatrexate plus gemcitabine with the standard combination of methotrexate plus ara-C. The study demonstrated that the combination of pralatrexate followed by gemcitabine was superior to methotrexate/ara-C in the in vitro and in vivo models and was far more potent in inducing apoptosis in DLBCL.…”