Strong inhibition of Ewing tumor xenograft growth by combination of human interferon-alpha or interferon-beta with ifosfamide.
Ewing sarcoma is the second most common bone tumor in childhood. Despite aggressive chemotherapy and radiotherapy strategies, the prognosis of patients with metastatic disease remains poor. We have recently reported that Ewing tumor cell proliferation was strongly inhibited by IFN-beta and to a lesser degree by IFN-alpha. Moreover, under IFN-beta treatment, some cell lines undergo apoptosis. Since the possibility of using IFNs for Ewing tumor treatments may be of interest, we have evaluated the efficacy of Hu-IFNs in a nude mice model of Ewing tumor xenografts. The results reported here show that human type I IFNs, Hu-IFN-alpha and Hu-IFN-beta impaired tumor xenograft take and displayed an anti-growth effect toward established xenografts. Furthermore, we have also shown that combined therapy with Hu-IFNs and ifosfamide (IFO), an alkylating agent widely used in high-dose chemotherapy of Ewing tumors, results in a strong antitumor effect. Pathological analysis showed that Hu-IFN-alpha/IFO and Hu-IFN-beta/IFO were characterized by a dramatic decrease in the mitotic index and marked necrosis, as well as extensive fibrosis associated with numerous calcifications. To our knowledge, this is the first demonstration of a potential antitumor effect of human type I IFNs and IFO on Ewing tumors, providing a rational foundation for a promising therapeutic approach to Ewing sarcoma.
Sancéau
Josiane
J
INSERM U365, Institut Curie, Section Recherche 26, rue d'Ulm, 75 248 - Paris Cedex 05, France.
Poupon
Marie-France
MF
Delattre
Olivier
O
Sastre-Garau
Xavier
X
Wietzerbin
Juana
J
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D016898:Interferon-alpha / Q000008:administration & dosage; D016899:Interferon-beta / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D050794:STAT1 Transcription Factor; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D016899:Interferon-beta; D007069:Ifosfamide