Distinct responses of xenografted gliomas to different alkylating agents are related to histology and genetic alterations.
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.
Leuraud
Pascal
P
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.
Taillandier
Luc
L
Medioni
Jacques
J
Aguirre-Cruz
Lucinda
L
Crinière
Emmanuelle
E
Marie
Yannick
Y
Kujas
Michèle
M
Golmard
Jean-Louis
JL
Duprez
Adrien
A
Delattre
Jean-Yves
JY
Sanson
Marc
M
Poupon
Marie-France
MF
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
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D016190:Carboplatin; D002330:Carmustine; D007069:Ifosfamide; D000077204:Temozolomide