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 Journal Article
| Authors: | Toner, L. E.; Vrhovac, R.; Smith, E. A.; Gardner, J.; Heaney, M.; Gonen, M.; Teruya-Feldstein, J.; Sirotnak, F.; O'Connor, O. A. |
| Article Title: | 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-β-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. © 2006 American Association for Cancer Research. |
| Keywords: | immunohistochemistry; controlled study; unclassified drug; human cell; drug activity; nonhuman; gemcitabine; cytarabine; methotrexate; flow cytometry; animal cell; mouse; animals; mice; cell cycle; apoptosis; antineoplastic combined chemotherapy protocols; drug administration schedule; animal model; in vivo study; caspase 3; antineoplastic activity; cancer cell culture; cytotoxicity; drug potency; enzyme activation; dose-response relationship, drug; mice, scid; xenograft model antitumor assays; drug evaluation, preclinical; time factors; disease model; b cell lymphoma; cancer regression; nonhodgkin lymphoma; statistical analysis; xenograft; lymphoma, non-hodgkin; cell cycle arrest; disease models, animal; folic acid antagonist; deoxycytidine; pralatrexate; aminopterin |
| Journal Title: | Clinical Cancer Research |
| Volume: | 12 |
| Issue: | 3 Part 1 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2006-02-01 |
| Start Page: | 924 |
| End Page: | 932 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-05-0331 |
| PUBMED: | 16467107 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 June 2012" - "CODEN: CCREF" - "Source: Scopus" |
