Treatment of Ewing's sarcoma using an antisense oligodeoxynucleotide to regulate the cell cycle.
Ewing's sarcoma (ES) is one of the most malignant tumors of bone and soft tissue in children and young adults. ES belongs to a group of small round cell tumors (SRCTs) that also includes neuroblastoma, rhabdomyosarcoma, and malignant lymphoma. However, ES exhibits several specific chimeric genes (EWS-FLI1, EWS-ERG, EWS-ETV1, EWS-E1AF, and EWS-FEV) caused by chromosomal translocations that are not shared by other SRCTs. These chimeric genes regulate the expression of various other genes; that is, they activate inhibitors of DNA binding 2 (Id2) gene expression or they suppress transforming growth factor beta II (TbetaRII) receptor gene expression. The regulation of these chimeric genes may affect critical cell signal transductions, such as signals involved in cell cycle and apoptosis in ES tumor cells. Using an antisense oligodeoxynucleotide against a sequence containing the ATG initiation codon of the EWS-FLI1 chimeric gene that specifically reacts with the EWS-FLI1 and EWS-ERG chimeric genes, we were able to regulate the cell cycle through the down-regulation of Id2. Here, we report that treatment with an antisense oligodeoxynucleotide against this chimeric gene was very useful for inducing the regression of ES tumor growth; thus, this chimeric gene may be an important target for the treatment of ES patients.
Asami
Satoru
S
Research Unit of Clinical Medicine, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
Chin
Motoaki
M
Shichino
Hiroyuki
H
Yoshida
Yukihiro
Y
Nemoto
Norimichi
N
Mugishima
Hideo
H
Suzuki
Takashi
T
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics; D034802:RNA-Binding Protein EWS; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000187:drug effects* / Q000235:genetics; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics
C450460:EWS-ERG fusion protein, human; C106031:EWS-FLI fusion protein; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D020319:Oligodeoxyribonucleotides, Antisense; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II