Evaluation of cytarabine against Ewing sarcoma xenografts by the pediatric preclinical testing program.
Treatment with the nucleoside analog cytarabine has been shown to mimic changes in gene expression associated with downregulation of the EWS-FLI1 oncogene in Ewing sarcoma cell lines, selectively inhibit their growth in vitro, and cause tumor regression in athymic nude mice. For this report cytarabine was studied in vitro against a panel of 23 pediatric cancer cell lines and in vivo against 6 Ewing sarcoma xenografts. Acute lymphoblastic leukemia cell lines were the most sensitive to cytarabine in vitro (median IC(50) 9 nM), while Ewing sarcoma cell lines showed intermediate sensitivity (median IC(50) 232 nM). Cytarabine at a dose of 150 mg/kg administered daily 5× failed to significantly inhibit growth of five xenograft models, but reduced growth rate of the A673 xenograft by 50%. Cytarabine shows no differential in vitro activity against Ewing sarcoma cell lines and is ineffective in vivo against Ewing sarcoma xenografts at the dose and schedule studied.
Houghton
Peter J
PJ
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. peter.houghton@stjude.org
Morton
Christopher L
CL
Kang
Min
M
Reynolds
C Patrick
CP
Billups
Catherine A
CA
Favours
Edward
E
Payne-Turner
Debbie
D
Tucker
Chandra
C
Smith
Malcolm A
MA
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D003561:Cytarabine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics; D034802:RNA-Binding Protein EWS; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000473:pathology; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology; D014178:Translocation, Genetic / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D003561:Cytarabine