Glial cell-line derived neurotrophic factor (GDNF) family of ligands confer chemoresistance in a ligand-specific fashion in malignant gliomas.

Glial cell-line derived neurotrophic factor (GDNF) is a neurotrophic factor known to promote neuronal survival of dopaminergic neurons in the embryonic midbrain as well as contribute to carcinogenesis in many cancers. Its ubiquitous presence in the central nervous system suggests a role in the mitogenesis of high-grade astrocytoma. GDNF is overexpressed in glioblastoma cell lines and human gliomas. GFRalpha1b is the predominant spliced receptor isoform in human gliomas and RET9 is the predominant co-receptor. Significantly there is differential overexpression of the GFRalpha1b spliced isoform compared to the GFRalpha1a spliced variant. Pre-treatment of glioblastoma cell lines with GDNF but not the alternative ligand neurturin, promoted mitogenic behaviour and conferred chemoresistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Signaling mapping of BCNU and GDNF suggest that the ability of GDNF to promote Akt activity and inhibit JNK activity may contribute to the increased cellular survival after BCNU chemotherapy.

Higher glioblastoma tumour burden reduces efficacy of chemotherapeutic agents: in vitro evidence.

INTRODUCTION: Glioblastoma is the most common primary brain tumour with poor overall survival. Surgical resection followed by radiation and chemotherapy is the mainstay of treatment. The role of aggressive resection in improving overall survival remains contentious, although there is evolving data to suggest this trend. Definitive evidence will necessitate a well-designed randomized prospective trial, although it is not likely that this will be possible or feasible. One possible advantage of aggressive tumour resection is a rapid reduction in oncological burden which may augment the effect of adjuvant chemotherapy. MATERIALS AND METHODS: Three glioblastoma cell lines were seeded in concentrations from 5000-20,000 cells per well onto 96-well plates. The cells were incubated for 24 hours before treatment with varying concentrations of 1,3-Bis(2- chloroethyl)-1-nitrosourea (BCNU) ranging from 25 to 175 microg/mL. After 24 hours of treatment with BCNU, the cells were then examined microscopically and subjected to a cell proliferation assay to determine cytotoxicity effects of BCNU. RESULTS: The drug concentration required to achieve greater than 90% growth inhibition (IC90) was taken as the reference for efficacy of chemotherapy dose. With tumour loading of 5000 cells per well, BCNU concentrations of 75-100 microg/mL resulted in greater than IC90, whereas BCNU concentration of 150-175 microg/mL was required with tumour loading of 20,000 cells per well. A higher concentration of chemotherapeutic agent is therefore required to bring about cell death in the presence of greater tumour burden. CONCLUSION: Higher glioblastoma loading confers chemoresistance to BCNU. This is possibly secondary to complex interactions between tumour cells and neighbouring cells acting via autocrine or paracrine signaling pathways.