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


Authors: Budak-Alpdogan, T.; Alpdogan, O.; Banerjee, D.; Wang, E.; Moore, M. A. S.; Bertino, J. R.
Article Title: Methotrexate and cytarabine inhibit progression of human lymphoma in NOD/SCID mice carrying a mutant dihydrofolate reductase and cytidine deaminase fusion gene
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, ×3) was unable to control tumor growth. Transfer of the fusion gene allowed doses of MTX/ara-C (25/15 mg/kg/day, ×4) 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 clinical studies using this retroviral fusion gene construct. © 2004 The American Society of Gene Therapy.
Keywords: cancer survival; controlled study; human cell; mutation; nonhuman; combined modality therapy; chemotherapy; cytarabine; methotrexate; flow cytometry; polymerase chain reaction; animal cell; mouse; animals; mice; gene expression; antineoplastic combined chemotherapy protocols; animal experiment; animal model; antineoplastic activity; in vitro study; mice, scid; cell line, tumor; statistical analysis; statistical significance; cytidine deaminase; genetic transfection; lymphoma cell; lymphoma; gene therapy; transplantation, heterologous; maximum tolerated dose; dihydrofolate reductase; tetrahydrofolate dehydrogenase; bone marrow transplantation; drug dose regimen; scid mouse; complementary dna; retroviridae; gene construct; humans; human; female; article; artificial gene fusion; drug resistance fusion gene; human lymphoma; nod-scid mouse; posttransplant; ara
Journal Title: Molecular Therapy
Volume: 10
Issue: 3
ISSN: 1525-0016
Publisher: Nature Publishing Group  
Date Published: 2004-09-01
Start Page: 574
End Page: 584
Language: English
DOI: 10.1016/j.ymthe.2004.06.115
PROVIDER: scopus
PUBMED: 15336657
DOI/URL:
Notes: Mol. Ther. -- Cited By (since 1996):13 -- Export Date: 16 June 2014 -- CODEN: MTOHC -- Source: Scopus
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MSK Authors
  1. Eunice S Wang
    13 Wang
  2. Malcolm A S Moore
    427 Moore