Drugs targeting the mitochondrial pore act as cytotoxic and cytostatic agents in temozolomide-resistant glioma cells.

BACKGROUND: High grade gliomas are one of the most difficult cancers to treat and despite surgery, radiotherapy and temozolomide-based chemotherapy, the prognosis of glioma patients is poor. Resistance to temozolomide is the major barrier to effective therapy. Alternative therapeutic approaches have been shown to be ineffective for the treatment of genetically unselected glioma patients. Thus, novel therapies are needed. Mitochondria-directed chemotherapy is an emerging tool to combat cancer, and inner mitochondrial permeability transition (MPT) represents a target for the development of cytotoxic drugs. A number of agents are able to induce MPT and some of them target MPT-pore (MPTP) components that are selectively up-regulated in cancer, making these agents putative cancer cell-specific drugs. OBJECTIVE: The aim of this paper is to report a comprehensive analysis of the effects produced by selected MPT-inducing drugs (Betulinic Acid, Lonidamine, CD437) in a temozolomide-resistant glioblastoma cell line (ADF cells). METHODS: EGFRvIII expression has been assayed by RT-PCR. EGFR amplification and PTEN deletion have been assayed by differential-PCR. Drugs effect on cell viability has been tested by crystal violet assay. MPT has been tested by JC1 staining. Drug cytostatic effect has been tested by mitotic index analysis. Drug cytotoxic effect has been tested by calcein AM staining. Apoptosis has been assayed by Hoechst incorporation and Annexine V binding assay. Authophagy has been tested by acridine orange staining. RESULTS: We performed a molecular and genetic characterization of ADF cells and demonstrated that this line does not express the EGFRvIII and does not show EGFR amplification. ADF cells do not show PTEN mutation but differential PCR data indicate a hemizygous deletion of PTEN gene. We analyzed the response of ADF cells to Betulinic Acid, Lonidamine, and CD437. Our data demonstrate that MPT-inducing agents produce concentration-dependent cytostatic and cytotoxic effects in parallel with MPT induction triggered through MPTP. CD437, Lonidamine and Betulinic acid trigger apoptosis as principal death modality. CONCLUSION: The obtained data suggest that these pharmacological agents could be selected as adjuvant drugs for the treatment of high grade astrocytomas that resist conventional therapies or that do not show any peculiar genetic alteration that can be targeted by specific drugs.

Parenchymal perianeurysmal cyst in the brain: case report.

OBJECTIVE AND IMPORTANCE: Parenchymal perianeurysmal cysts are rare, and only seven cases have been reported. We present a case report with a 30 month follow-up on this topic. The possible etiopathogenetic mechanisms of cyst formation are discussed. CLINICAL PRESENTATION: A 54-year-old man with a 5-month history of headache and a computed tomography scan showing a giant parenchymal cyst located in the right temporal lobe with a mural enhanced nodule was admitted to our neurosurgical department with the diagnosis of cystic brain tumor. Magnetic resonance imaging followed by digital subtraction angiography identified the enhancing nodule as a large right middle cerebral artery aneurysm. INTERVENTION: Surgical treatment was performed; the aneurysm was clipped and the cyst evacuated. Postoperative digital subtraction angiography confirmed the clipping of the aneurysm at the neck. Serial magnetic resonance imaging controls showed the permanent collapse of the cyst. CONCLUSION: Parenchymal perianeurysmal cysts are rare. In the presence of parenchymal cysts neighboring main vessels, the possibility of a perianeurysmal cyst should be considered. In regard to the etiopathogenetic mechanisms responsible for the cyst development, the action of multiple coexisting factors seems to be the most applicable.

Automated three-dimensional volume rendering of helical computed tomographic angiography for aneurysms: an advanced application of neuronavigation technology.

OBJECTIVE: To introduce the possibility of volume-rendered helical computed tomographic (CT) angiographic data sets by use of Medtronic StealthStation Treon surgical navigation technology (Medtronic Surgical Navigation Technologies, Louisville, CO) and to evaluate the clinical usefulness of the method in planning and performing surgical treatment of intracranial aneurysms. METHODS: Between November 2002 and July 2003, we studied 15 patients with suspected intracranial aneurysms. All patients but two received conventional digital subtraction angiography, which failed to provide the requested information. Helical CT angiography was performed in all patients, and data sets were transferred to the StealthStation system across an electronic network to be automatically postprocessed by use of three-dimensional (3-D) volume rendering. The 3-D volume-rendered images were accurately analyzed to obtain more complete information about the aneurysm and to provide accurate treatment planning. In all patients, the 3-D volume-rendered model was displayed on the screen of the StealthStation system for the duration of the surgical procedure and compared with the intraoperative image. RESULTS: Data sets from CT angiography were automatically postprocessed by the StealthStation in seconds with excellent results, providing us, before and during surgery, with additional information not always available on traditional digital subtraction angiographic investigation. Because of the very short time necessary to complete this process (<5 min to obtain 3-D volume-rendered images), it was possible to perform emergency clipping of the aneurysms in two patients who had been admitted in very compromised neurological conditions. In 12 patients, integrated digital subtraction angiography and automated 3-D volume-rendered images allowed an accurate presurgical evaluation. Furthermore, in all patients on whom surgery was performed, aneurysms were found in the exact location and with the same anatomic features as depicted by the 3-D volume-rendered models. CONCLUSION: Reports in the literature indicate that information gathered by CT angiography with volume rendering shows a significant impact on aneurysm management. The StealthStation system upgraded with the adequate algorithm seems to provide a time- and cost-effective method of performing automated 3-D volume rendering of CT angiography and provides an interesting alternative to the available investigation modalities in case of emergency.