Evaluation of the efficiency of chemotherapy in in vivo orthotopic models of human glioma cells with and without 1p19q deletions and in C6 rat orthotopic allografts serving for the evaluation of surgery combined with chemotherapy.
BACKGROUND
Malignant gliomas of the central nervous system remain associated with dismal prognoses because of their diffuse invasion of the brain parenchyma. Very few experimental models that mimic clinical reality are available today to test potentially new therapies. The authors set up experimental in vivo glioma models of anaplastic astrocytomas of human and rat origins and anaplastic oligodendroglioma of human origin. Standard hospital chemotherapies were employed to test the validity of these models.


METHODS
Three glioma cells lines obtained from the American Type Culture Collection (i.e., human Hs683 and U373 cells and rat C6 cells) were implanted into nude mouse brains (Hs683 and U373 cells) and rat brains (C6 cells). The astrocytic nature, as opposed to the oligodendrocytic nature, of the Hs683 and U373 models was investigated by using quantitative (computer-assisted microscopy) immunohistochemical characterizations of nestin, vimentin, glutathione-S-transferase alpha (GSTalpha), GSTmu, GSTpi, and p53 expression. Comparative genomic hybridization (CGH) was employed to investigate 1p19q losses. Chronic administrations of carmustine (BCNU), fotemustin, or temozolomide were assayed in the xenografted U373 and Hs683 models. Both BCNU-related chemotherapy and surgery were assayed in the C6 model.


RESULTS
The quantitative phenotypic analyses pointed to the oligodendroglial nature of the Hs683 cell line and the astrocytic nature of the U373 cell line. The Hs683 cells exhibited 1p19q losses, whereas the U373 cells did not. BCNU, fotemustin, and temozolomide dramatically increased the time of survival of the Hs683 oligodendroglioma-bearing mice, whereas temozolomide only induced a weak but nevertheless statistically significant increase in the U373 glioma-bearing mice. In the C6 rat glioma model, surgery and BCNU chemotherapy were more efficient than either treatment alone.


CONCLUSIONS
The in vivo models of gliomas of the central nervous system developed in the current work best mimicked clinical reality. They can be used either to identify new therapies against human gliomas or to optimize existing therapies.
Branle
Fabrice
F
Department of Oncology, Erasmus University Hospital, Brussels, Belgium.
Lefranc
Florence
F
Camby
Isabelle
I
Jeuken
Judith
J
Geurts-Moespot
Anneke
A
Sprenger
Sandra
S
Sweep
Fred
F
Kiss
Robert
R
Salmon
Isabelle
I
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002330:Carmustine / Q000008:administration & dosage; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003131:Combined Modality Therapy; D016172:DNA Fingerprinting; D004273:DNA, Neoplasm / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005982:Glutathione Transferase / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000032:analysis; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D009419:Nerve Tissue Proteins; D064231:Nestin; D009607:Nitrosourea Compounds / Q000008:administration & dosage; D009693:Nucleic Acid Hybridization; D009943:Organophosphorus Compounds / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D014746:Vimentin / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
D004273:DNA, Neoplasm; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; C577486:Nes protein, rat; D064231:Nestin; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D016159:Tumor Suppressor Protein p53; D014746:Vimentin; D003606:Dacarbazine; D005982:Glutathione Transferase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C054368:fotemustine; D002330:Carmustine; D000077204:Temozolomide