title: Drug-induced caspase-3 activation in a Ewing tumor cell line and primary Ewing tumor cells.
abstract: Ewing sarcoma is a rare malignancy occurring in childhood and adolescence which has a prognosis of about 50% long-term event-free survival, depending on risk factors such as tumor volume, initial metastases at the time of diagnosis and tumor response to presurgical chemotherapy. In order to tailor therapy to the individual patient, new prognostic factors need to be identified. In this study, we showed that etoposide and actinomycin D kill Ewing tumor cells (RD-ES cell line) mainly via a caspase-dependent mechanism. Both drugs induced a significant caspase-3 activation, which can be detected with a new caspase-3 assay. Dose-response analyses showed that induction of cell death and caspase-3 activation is mediated by similar concentration ranges of both drugs. In addition to the cell line, caspase-3 activation was also shown during drug-mediated stimulation of freshly isolated cells from tumor biopsies. In conclusion, actinomycin D and etoposide stimulated caspase-3 activation in a Ewing tumor cell line and in freshly isolated tumor cells, causing drug-induced cell death. Thus, determination of caspase-3 activation might be a suitable method for drug sensitivity testing in patients with Ewing tumors before initiating treatment. This assay could therefore help individualize therapy in future tumor patients.
authors.affiliation: Division of Pediatric Hematology, Oncology and Hemostaseology, Department of Pediatrics, University of Leipzig Medical Center, Leipzig, Germany. mauc@medizin.uni-leipzig.de
authors.forename: Christine
authors.initials: C
authors.lastname: Mauz-Körholz
authors.forename: Martin
authors.initials: M
authors.lastname: Kachel
authors.forename: Britt
authors.initials: B
authors.lastname: Harms-Schirra
authors.forename: Anne
authors.initials: A
authors.lastname: Klein-Vehne
authors.forename: Peter-Ulrich
authors.initials: PU
authors.lastname: Tunn
authors.forename: Dieter
authors.initials: D
authors.lastname: Körholz
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D008297:Male; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000201:enzymology*; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D003609:Dactinomycin; D005047:Etoposide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases