Methotrexate and cytarabine inhibit progression of human lymphoma in NOD/SCID mice carrying a mutant dihydrofolate reductase and cytidine deaminase fusion gene

Molecular Therapy : the Journal of the American Society of Gene Therapy
Tulin Budak-AlpdoganJ R Bertino

Abstract

An SFG-based retroviral bicistronic vector containing a double-mutant dihydrofolate reductase-cytidine deaminase fusion cDNA (F/S DHFR-CD) with IRES-eGFP confers resistance to both methotrexate (MTX) and cytarabine (ara-C). Two weeks after transplantation with marrow transduced with either a fusion or a control gene (eGFP-IRES-NeoR), human lymphoma (SKI-DLCL-1) cells were injected sc into the flanks of nonobese diabetic/severe combined immune deficiency mice. In mock-transplanted mice, maximal tolerated dose (MTD) of posttransplant MTX/ara-C (15/10 mg/kg/day, x3) was unable to control tumor growth. Transfer of the fusion gene allowed doses of MTX/ara-C (25/15 mg/kg/day, x4) twofold higher than the MTD to be tolerated. The tumor burden defined the efficiency of posttransplant chemotherapy; early treatment, 48 h after tumor inoculation, provided tumor-free survival, while starting treatment after having palpable tumor growth (7 days) delayed tumor growth a median time of 28 days. In addition, the early treated group had higher gene expression in peripheral blood and marrow cells than the late treated group (P < 0.05), suggesting that early treatment allowed for enrichment of transduced marrow progenitors. These results encourage ...Continue Reading

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Citations

Jul 23, 2005·Cancer Gene Therapy·Tulin Budak-AlpdoganJoseph R Bertino
Dec 5, 2009·Best Practice & Research. Clinical Haematology·Joseph R Bertino
Dec 15, 2015·Journal of Experimental & Clinical Cancer Research : CR·Sebastian BrennigThomas Moritz
Jul 16, 2015·Human Gene Therapy·Kendra A HylandR Scott McIvor
May 11, 2016·Protein Engineering, Design & Selection : PEDS·Hongmei RuanMargaret E Black
Jun 26, 2007·The Journal of Pharmacology and Experimental Therapeutics·Jennifer L GoriR Scott McIvor

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