Effects of adenovirus-mediated expression of p27Kip1, p21Waf1 and p16INK4A in cell lines derived from t(2;5) anaplastic large cell lymphoma and Hodgkin's disease.
We investigated the response of SUDHL-1 and L428 cells, derived from t(2;5)-anaplastic large cell lymphoma (ALCL) and Hodgkin's disease (HD), respectively, to recombinant adenoviruses expressing cyclin-dependent kinase inhibitors (CDKIs) p27Kip1 (Adp27), p21Waf1 (Adp21) and p16INK4A (Adp16). Cell cycle analysis of SUDHL-1 cells after 24 h of infection with 200 multiplicity of infection (MOI) of Adp27, Adp21, and Adp16, showed very high levels of cell debris in the subG1 area. The magnitude of cell debris-events was Adp27/Adp21 > Adp16. Cell cycle analysis of L428 cells revealed absence of cell debris and increased G2 phase in all the groups of cells tested as compared to the controls (mock and AdNull). A minimal increase in G1 phase was also evident in cells infected with Adp27 (52%) compared to uninfected cells (43%), AdNull (45%) and to cells infected with Adp21 (37%) and Adp16 (31%). The presence of significant levels of Coxsackie-adenovirus receptor (CAR) on the cell surface of L428 cells excluded the cell membrane-barrier as responsible for the differences in cell observed in response to the recombinant adenovirus-mediated CDKIs expression as compared to SUDHL-1. We also showed that the recombinant adenovirus-mediated cytotoxicity measured as apoptosis was MOI- and vector-dependent in SUDHL-1 cells at lower MOI (100). In conclusion, the therapeutic effect induced by recombinant adenoviruses expressing p27Kip1, p21Waf1 and p16INK4A is cell-dependent in cells derived from selected lymphoid malignancies. Biochemical cellular differences more than cell surface barriers seem to be responsible for differences in response to recombinant adenovirus-mediated expression of cytotoxic genes. Moreover, the cytotoxicity of recombinant adenoviruses expressing p27Kip1, p21Waf1 and p16INK4A may be further explored as a tool for gene therapy of t(2;5)-derived ALCL.
Turturro
Franceso
F
turturfm@ihs.org
Arnold
Marilyn D
MD
Frist
Audrey Y
AY
Seth
Prem
P
D000260:Adenoviruses, Human / Q000235:genetics*; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D005136:Eye Proteins; D015967:Gene Expression Regulation, Viral; D019942:Genes, p16; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D051597:Hippocalcin; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis / Q000235:genetics; D008074:Lipoproteins; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009419:Nerve Tissue Proteins; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D051603:Recoverin; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000821:virology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
C493956:CDKN1A protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D005136:Eye Proteins; D039302:Integrin alphaVbeta3; D008074:Lipoproteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C496731:RCVRN protein, human; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D051603:Recoverin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051597:Hippocalcin