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Drug resistance-associated factors in primary and secondary glioblastomas and their precursor tumors
1Division of Neuropathology, Johannes Gutenberg-University Medical Center, Mainz, Germany. tews@mail.Uni-Mainz.de
Abstract:
Malignant gliomas are largely resistant to current chemotherapeutic strategies often displaying a multidrug-resistant phenotype. Mechanisms involved in drug resistance are reduced cellular drug accumulation through membrane efflux pumps, drug detoxification as well as alterations in drug target specificity. 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 alpha. 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 resistance-related factors were expressed in varying proportions. Metallothionein, also found in normal and activated astrocytes, was retained in all neoplastic phenotypes. Furthermore, metallothionein, P-gp, LRP, and topoisomerase II alpha were strongly expressed by normal and neoplastic vessels which may confer to impaired penetration of therapeutic agents through the blood-brain and blood-tumor barrier. However, the expression profiles of drug resistance-related proteins neither differed between primary and secondary glioblastomas nor revealed any correlation to precursor or recurrent tumors. Nevertheless, inhibition of these factors may be promising approaches to the management of malignant gliomas.
Insights
Malignant gliomas exhibit drug resistance due to proteins like lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP). Targeting these resistance factors offers a promising strategy for glioma treatment.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Pharmacology
Background:
- Malignant gliomas demonstrate significant resistance to chemotherapy, often linked to multidrug-resistant phenotypes.
- Key mechanisms include reduced drug accumulation via efflux pumps, drug detoxification, and altered drug target specificity.
Purpose of the Study:
- To investigate the immunohistochemical expression of drug resistance-related proteins in primary and secondary glioblastomas and their precursor tumors.
- To evaluate the role of these proteins in therapeutic resistance and their potential as targets.
Main Methods:
- Immunohistochemical analysis of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), metallothionein, and topoisomerase II alpha.
- Study included 27 primary and 17 secondary glioblastomas and their precursor tumors.
Main Results:
- Consistent upregulation of LRP, MRP, and topoisomerase II alpha observed in all glioblastomas.
- P-gp detected in 90% of primary and 60% of secondary glioblastomas.
- Expression of these proteins, along with metallothionein, was also noted in tumor vasculature, potentially hindering drug penetration.
Conclusions:
- Drug resistance proteins are upregulated in malignant gliomas, with no significant difference between primary and secondary types.
- Expression profiles did not correlate with tumor progression or recurrence.
- Inhibiting these resistance factors presents a potential therapeutic strategy for managing malignant gliomas.