Methotrexate and cytarabine inhibit progression of human lymphoma in NOD/SCID mice carrying a mutant dihydrofolate reductase and cytidine deaminase fusion gene.
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 clinical studies using this retroviral fusion gene construct.
Budak-Alpdogan
Tulin
T
Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
Alpdogan
Onder
O
Banerjee
Debabrata
D
Wang
Eunice
E
Moore
Malcolm A S
MA
Bertino
Joseph R
JR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019677:Artificial Gene Fusion; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage; D003564:Cytidine Deaminase / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008223:Lymphoma / Q000628:therapy*; D008727:Methotrexate / Q000008:administration & dosage; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D012190:Retroviridae / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D014183:Transplantation, Heterologous
D003561:Cytarabine; D013762:Tetrahydrofolate Dehydrogenase; D003564:Cytidine Deaminase; D008727:Methotrexate