Journal of Neurological Sciences 155 (1998) 68–75 BCL-2 family protein expression in human malignant glioma: a clinical- pathological correlative study a ,b b a b b Lorenz Rieger , Michael Weller , Antje Bornemann , Martin Schabet , Johannes Dichgans , a, * Richard Meyermann a ¨ ¨ Institute for Brain Research, University of Tubingen, Medical School, Tubingen, Germany b ¨ ¨ Department of Neurology, University of Tubingen, Medical School, Tubingen, Germany Received 3 April 1997; received in revised form 7 August 1997; accepted 20 August 1997 Abstract Malignant gliomas are rather refractory to current therapeutic approaches including surgery, radiotherapy, chemotherapy and immunotherapy. Acquired alterations in the pathways required for apoptotic cell death are thought to be responsible to the failure of glioma to respond to therapy. Here we have examined the expression of several proteins involved in the susceptibility to apoptosis in 20 human gliomas, including the BCL-2 family proteins BCL-2, BCL-X, BAX and MCL-1, as well as p53 and RB. Most gliomas expressed several BCL-2 family proteins. There was good correlation between expression of the functional antagonists, BCL-2 / BCL-X and BAX, suggesting that changes in the BCL-21BCL-X / BAX ratio are not responsible for the differential response of glioma patients to chemotherapy. The immunochemistry data were also analysed in regard to response to therapy and clinical outcome. All patients had cytoreductive surgery and received radiotherapy and nitrosourea-based adjuvant chemotherapy. There was no prominent association of outcome with the expression patterns of p53, RB, BCL-2, BCL-X or BAX. We find, however, that expression of the MCL-1 protein is associated with early tumour recurrence and shorter survival in this group of glioma patients. This preliminary observation will have to be confirmed in a larger independent sample of glioma patients.  1998 Elsevier Science B.V. Keywords: Malignant glioma; p53; BCL-2; BAX; BCL-X; MCL-1 1. Introduction protocol of the German Cancer Society compares ACNU plus teniposide with ACNU plus cytarabine as adjuvant Median survival in malignant glioma is in the range of chemotherapy after surgery and irradiation. Although one year even with cytoreductive surgery, irradiation and chemotherapy prolongs median survival only for a few adjuvant chemotherapy (Shapiro et al., 1989). Nitrosoureas weeks, the percentage of patients surviving for 18 months such as BCNU, ACNU and CCNU are the most commonly or more increases from 5% without chemotherapy to 20– used in malignant glioma patients and are included in most 25% with chemotherapy (Shapiro et al., 1989). Identifying combination chemotherapy protocols currently evaluated. this minority of patients that will significantly benefit from One such protocol is the PCV (procarbazine, CCNU, adjuvant chemotherapy by means of biological markers vincristin) protocol (Levin et al., 1989) that is clearly would be a great advance in the medical management of effective in anaplastic oligodendroglioma but has also malignant glioma. There are probably multiple reasons shown effects in some glioma patients. The current NOA why malignant gliomas are rather refractory to radiotherapy and chemotherapy, including aberrant growth signal transduction pathways, enhanced repair of DNA * damage caused by therapeutic irradiation or chemothera- Corresponding author. Tel.: 149 7071 2982283; fax: 149 7071 294846. peutic agents, failure to achieve significant concentrations 0022-510X / 98 / $19.00  1998 Elsevier Science B.V. All rights reserved. PII S0022-510X(97)00277-3