Drug resistance-associated factors in primary and secondary glioblastomas and their precursor tumors

Malignant gliomas are largely resistant to current chemotherapeutic strateg ies often displaying a multidrug-resistant phenotype. Mechanisms involved i n drug resistance are reduced cellular drug accumulation through membrane e fflux pumps, drug detoxification as well as alterations in drug target spec ificity. In 27 primary and 17 secondary glioblastomas and their astrocytic precursor tumors, we studied the immunohistochemical expression profile of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), metallothionein, and topoisomerase II alp ha. Glial tumor cells in all glioblastomas showed constant up-regulation of LRP, MRP, and topoisomerase II alpha. P-gp was found in 90% of the primary and 60% of the secondary glioblastomas. In precursor tumors, these drug re sistance-related factors were expressed in varying proportions. Metallothio nein, also found in normal and activated astrocytes, was retained in all ne oplastic phenotypes. Furthermore, metallothionein, P-gp, LRP, and topoisome rase II alpha were strongly expressed by normal and neoplastic vessels whic h may confer to impaired penetration of therapeutic agents through the bloo d-brain and blood-tumor barrier. However, the expression profiles of drug r esistance-related proteins neither differed between primary and secondary g lioblastomas nor revealed any correlation to precursor or recurrent tumors. Nevertheless, inhibition of these factors may be promising approaches to t he management of malignant gliomas.