Strong inhibition of Ewing tumor xenograft growth by combination of human interferon-alpha or interferon-beta with ifosfamide

Abstract

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-b and to a lesser degree by IFN-a. Moreover, under IFN-b 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-a and Hu-IFN-b impaired tumor xenograft take and displayed an antigrowth 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-a/IFO and Hu-IFN-b/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.

Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice

“…The relative tumor volume (RTV) was defined as [TV x /TV 0 ], where TV x is the tumor volume in mm 3 at a given time x and TV 0 the tumor volume at day 0. The efficacy of 47 Sc-cm10-based therapy was expressed as the percentage tumor growth inhibition (TGI), calculated using the equation [100 2 (T/C · 100)], where T is the mean RTV of the treated mice and C is the mean RTV in the control group at the time of euthanasia of the first mouse of the control group (20). Tumor growth delay (TGD x ) was calculated as the time required for the tumor volume to increase x-fold over the initial volume at the day 0.…”

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

“…Tumor growth delay (TGD) was calculated for the time that passed until the RTVs reached 4-fold the value of day 0. The tumor growth delay index (TGDI) was calculated as the ratio of TGDs among treated animals and control animals (41).…”

Interferon-β lipofection II. Mechanisms involved in cell death and bystander effect induced by cationic lipid-mediated interferon-β gene transfer to human tumor cells

“…Human ES (EW7 and COH), 14 melanoma (M8), 15 mammary carcinoma (MCF7, ATCC, Manassas, VA, no. HTB-22) and colorectal adenocarcinoma (HT-29, ATCC no.…”

“…This proposal was based on: (1) our previous encouraging clinical data from veterinary soft tissue sarcoma patients 11 and (2) the demonstration that recombinant human IFNa and IFNb inhibited the in vivo growth of established ES xenografts generated by the same cell lines used by us (EW7, COH). 14 The study of the mechanisms achieving to cell death and bystander effect induced by hIFNb gene lipofection, probably involving reactive oxygen species, may provide a deeper insight on the action of this approach for gene therapy.…”