Selective chemosensitization of rhabdomyosarcoma cell lines following wild-type p53 adenoviral transduction.
Rhabdomyosarcoma (RMS) cell lines were transduced with an adenoviral vector containing the wild-type p53 (wtp53) cDNA (Ad-p53) and then exposed to four cytotoxic agents: actinomycin D, vincristine, 5-fluorouracil and bleomycin. Potentiation of cytotoxicity following wild-type p53 expression varied from 0- to 20-fold for different drugs and between cell lines. It appeared that alveolar RMS cells (n = 2) were more susceptible to p53-mediated chemosensitization than embryonal RMS cells (n = 3), although this was independent of pax3-FKHR expression. Overall, cells that were most chemosensitive prior to Ad-p53 exposure were those that were most susceptible to p53 potentiation of cytotoxicity. The different results obtained with these RMS cell lines does not appear to be related to expression of pax3-FKHR, p21, Bax or Bcl-2 but may in part be due to differential regulation of p53 target genes, such as MDM2. In conclusion, exogenous wild-type expression selectively chemosensitizes RMS cells to cytotoxic agents. However, expression of transcriptionally active wtp53 does not predict a chemosensitive phenotype.
Shetty
Sheetal
S
Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Taylor
Alan C
AC
Harris
Linda C
LC
D000256:Adenoviridae / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016158:Genes, p53; D006801:Humans; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051736:Proto-Oncogene Proteins c-mdm2; D012208:Rhabdomyosarcoma / Q000188:drug therapy*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2