ABSTRACT
Gliomas are the most common primary brain tumors. To date, therapies do not allow curing patients, and glioblastomas (GBMs) are associated with remarkably poor prognosis. This situation is at least partly due to intrinsic or acquired resistance to treatment, especially to chemotherapy. In 2005, temozolomide (TMZ) has become the first chemotherapeutic drug validated for GBM. Nevertheless TMZ efficacy depends on Mgmt status. While the methylation of Mgmt promoter was considered so far as a prognostic marker, its targeting is becoming an effective therapeutic opportunity. Thus, arrival of both TMZ and Mgmt illustrated that considerable progress can still be realized by optimizing adjuvant chemotherapy. A part of this progress could be accomplished in the future by overcoming residual resistance. The aim of the present study was to investigate the involvement of a set of other DNA-repair genes in glioma resistance to temozolomide. We focused on DNA-repair genes located in the commonly deleted chromosomal region in oligodendroglioma (1p/19q) highly correlated with patient response to chemotherapy. We measured effects of inhibition of ten DNA-repair genes expression using siRNAs on astrocytoma cell response to cisplatin (CDDP) and TMZ. SiRNAs targeting ercc1, ercc2, mutyh, and pnkp significantly sensitized cells to chemotherapy, increasing cell death by up to 25%. In vivo we observed a decrease of subcutaneous glioma tumor growth after injection of siRNA in conjunction with absorption of TMZ. We demonstrated in this pre-clinical study that targeting of DNA-repair genes such as Ercc1 could be used as an adjuvant chemosensitization treatment, similarly to Mgmt inhibition.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Brain Neoplasms/drug therapy , DNA Modification Methylases/metabolism , DNA Repair Enzymes/metabolism , DNA Repair , DNA-Binding Proteins/metabolism , Dacarbazine/analogs & derivatives , Endonucleases/metabolism , Glioma/drug therapy , RNAi Therapeutics , Tumor Suppressor Proteins/metabolism , Animals , Brain Neoplasms/enzymology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/pharmacology , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , DNA-Binding Proteins/genetics , Dacarbazine/pharmacology , Drug Resistance, Neoplasm , Endonucleases/genetics , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Glioma/enzymology , Glioma/genetics , Glioma/pathology , Humans , Mice, Nude , RNA Interference , Temozolomide , Time Factors , Transfection , Tumor Burden/drug effects , Tumor Suppressor Proteins/genetics , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: To present the imaging and perfusion data obtained in nine patients with pilocytic astrocytomas (PA) and to discuss the original functional issues of this technique. METHOD: Nine patients with pathologically proven PA underwent conventional and perfusion MR imaging. Various areas of relative cerebral blood volume (rCBV) within the tumors were obtained. The maximum rCBV ratios were identified and considered as representative of the tumor. The results were compared with the pathological findings. RESULTS: In all patients, rCBV was <1.5 (mean 1) and the signal intensity curve overshot the baseline. CONCLUSION: PA tend to have low rCBV values and a first-pass curve that crosses the baseline. These characteristics may be explained by the histological profile of the tumoral vascularity and are of relevance in the identification of these rare tumors.
