| Abstract: |
Purpose: Pralatrexate (10-propargyl-10-deazaaminopterin) is an antifolate with improved cellular uptake and retention due to greater affinity for the reduced folate carrier (RFC-1) and folyl-polyglutamyl synthase. Based on the PROPEL data, pralatrexate was the first drug approved for patients with relapsed and refractory peripheral T-cell lymphoma. Bortezomib is a proteasome inhibitor that has shown some activity in patients with T-cell lymphoma. Experimental Design: Assays for cytotoxicity including mathematical analysis for synergism, flow cytometry, immunoblotting, and a xenograft severe combined immunodeficient-beige mouse model were used to explore the in vitro and in vivo activities of pralatrexate alone and in combination with bortezomib in T-cell lymphoid malignancies. Results: In vitro, pralatrexate and bortezomib exhibited concentration- and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines. Pralatrexate showed synergism when combined with bortezomib in all cell lines studied. Pralatrexate also induced potent apoptosis and caspase activation when combined with bortezomib across the panel. Cytotoxicity studies on normal peripheral blood mononuclear cells showed that the combination was not more toxic than the single agents. Western blot assays for proteins involved in broad growth and survival pathways showed that p27, NOXA, HH3, and RFC-1 were all significantly modulated by the combination. In a severe combined immunodeficient-beige mouse model of transformed cutaneous T-cell lymphoma, the addition of pralatrexate to bortezomib enhanced efficacy compared with either drug alone. Conclusion: Collectively, these data suggest that pralatrexate in combination with bortezomib represents a novel and potentially important platform for the treatment of T-cell malignancies. ©2010 AACR. |
| Keywords: |
controlled study; protein expression; survival rate; human cell; drug efficacy; drug potentiation; monotherapy; nonhuman; methotrexate; flow cytometry; t lymphocyte; mouse; animals; mice; animal tissue; apoptosis; bortezomib; boronic acids; pyrazines; animal experiment; animal model; in vivo study; cytotoxicity; enzyme activation; in vitro study; tumor xenograft; dose-response relationship, drug; mice, scid; xenograft model antitumor assays; caspase; cell line, tumor; drug synergism; cutaneous t cell lymphoma; t cell lymphoma; lymphoma, t-cell; drug therapy, combination; protein p27; western blotting; immunoblotting; caspase 8; caspase 9; neoplasm transplantation; disease models, animal; pralatrexate; aminopterin; peripheral blood mononuclear cell; lymphatic system disease
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