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Distinct Responses of Xenografted Gliomas to Different Alkylating Agents Are Related to Histology and Genetic Alterations

¹ 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; ² Laboratoire d’Anatomopathologie et de Microchirurgie Expérimentale, Faculté de Médecine, Vanduvre-lès-Nancy, France; ³ Unité Fonctionnelle de Biostatistiques, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France; ⁴ Centre d’Investigations Cliniques, Hôpital Saint Louis, AP-HP, Paris, France; ⁵ Fédération de Neurologie Mazarin, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France; ⁶ FRE 2584, Section de Recherche, Institut Curie, Paris, France; ⁷ Laboratoire de Neuropathologie Escourolle, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France; ⁸ Unidad de Investigación del Sistema Nervioso, Instituto Nacional de Neurología y Neurocirugía de México, Mexico D.F., Mexico

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.

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