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 mu g/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 mu g/mL resulted in greater than IC90, whereas BCNU concentration of 150-175 mu g/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. (C) 2005 Elsevier Ltd. All rights reserved.