title: Zoledronic acid as a new adjuvant therapeutic strategy for Ewing's sarcoma patients.
abstract: Ewing's sarcoma (ES) is the second most frequent pediatric bone tumor also arising in soft tissues (15% of cases). The prognosis of patients with clinically detectable metastases at diagnosis, not responding to therapy or with disease relapse, is still very poor. Among new therapeutic approaches, bisphosphonates represent promising adjuvant molecules to chemotherapy to limit the osteolytic component of bone tumors and to protect from bone metastases. The combined effects of zoledronic acid and mafosfamide were investigated on cell proliferation, viability, apoptosis, and cell cycle distribution of human ES cell lines differing in their p53 and p16/ink4 status. ES models were developed to reproduce both soft tissue and intraosseous tumor development. Mice were treated with 100 μg/kg zoledronic acid (two or four times per week) and/or ifosfamide (30 mg/kg, one to three cycles of three injections). ES cell lines showed different sensitivities to zoledronic acid and mafosfamide at the cell proliferation level, with no correlation with their molecular status. Both drugs induced cell cycle arrest, but in the S or G(2)M phase, respectively. In vivo, zoledronic acid had no effect on soft tissue tumor progression, although it dramatically inhibited ES development in bone. When combined with ifosfamide, zoledronic acid exerted synergistic effects in the soft tissue model: Its combination with one cycle of ifosfamide resulted in an inhibitory effect similar to three cycles of ifosfamide alone. This very promising result could allow clinicians to diminish the doses of chemotherapy.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U957, Nantes, France.
authors.forename: Guillaume A
authors.initials: GA
authors.lastname: Odri
authors.forename: Sophie
authors.initials: S
authors.lastname: Dumoucel
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Picarda
authors.forename: Séverine
authors.initials: S
authors.lastname: Battaglia
authors.forename: François
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Nadège
authors.initials: N
authors.lastname: Corradini
authors.forename: Julie
authors.initials: J
authors.lastname: Rousseau
authors.forename: Franck
authors.initials: F
authors.lastname: Tirode
authors.forename: Karine
authors.initials: K
authors.lastname: Laud
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: François
authors.initials: F
authors.lastname: Gouin
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; C048341:mafosfamide; D000077211:Zoledronic Acid; D003520:Cyclophosphamide; D007069:Ifosfamide