title: Distinct responses of xenografted gliomas to different alkylating agents are related to histology and genetic alterations.
abstract: A series of 12 human gliomas was established as xenografts in nude mice and used to evaluate the relationship between histology, genetic parameters, and response to alkylating agents. Eight were high-grade oligodendroglial tumors, and four were glioblastoma. They were characterized for their genetic alterations, including those considered as "early" alterations, namely loss of chromosome 1 +/- loss of chromosome 19q, TP53 mutation, and those considered as "late" alterations, namely loss of chromosome 10, loss of chromosome 9p, EGFR genomic amplification, PTEN mutation, CDKN2A homozygous deletion, and telomerase reactivation. Chemosensitivity of xenografts to four alkylating agents, temozolomide (42 mg/kg, days 1-5, p.o.), 1,3-bis(2-chloroethyl)-1-nitrosourea (5 mg/kg, day 1, i.p.), Ifosfamide (90 mg/kg, days 1-3, i.p.), and carboplatin (66 mg/kg, day 1, i.p.) was tested by administration of drugs to tumor-bearing mice. Although each tumor presented an individual response pattern, glioblastoma had a lower chemosensitivity than oligodendrogliomas, and temozolomide was the most effective drug. Deletion of 1p +/- 19q was associated with higher chemosensitivity, whereas late molecular alterations, particularly EGFR amplification, were associated with chemoresistance. These results suggest that the combined use of histology and molecular markers should eventually be helpful selecting the most appropriate agents for treatment of malignant oligodendrogliomas and astrocytomas.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U495, Laboratoire de Biologie des Interactions Neurones-Glie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Leuraud
authors.forename: Luc
authors.initials: L
authors.lastname: Taillandier
authors.forename: Jacques
authors.initials: J
authors.lastname: Medioni
authors.forename: Lucinda
authors.initials: L
authors.lastname: Aguirre-Cruz
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Crinière
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.forename: Michèle
authors.initials: M
authors.lastname: Kujas
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Golmard
authors.forename: Adrien
authors.initials: A
authors.lastname: Duprez
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Delattre
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Poupon
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D002869:Chromosome Aberrations; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007069:Ifosfamide / Q000494:pharmacology; D019656:Loss of Heterozygosity; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009837:Oligodendroglioma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D016190:Carboplatin; D002330:Carmustine; D007069:Ifosfamide; D000077204:Temozolomide