A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models.

Intervention of cancer cell mitosis by antitubulin drugs is among the most effective cancer chemotherapies. However, antitubulin drugs have dose-limiting side effects due to important functions of microtubules in resting normal cells and are often rendered ineffective by rapid emergence of resistance. Antimitotic agents with different mechanisms of action and improved safety profiles are needed as new treatment options. Mitosis-specific kinesin Eg5 represents an attractive anticancer target for discovering such new antimitotic agents, because Eg5 is essential only in mitotic progression and has no roles in resting, nondividing cells. Here, we show that a novel selective Eg5 inhibitor, LY2523355, has broad target-mediated anticancer activity in vitro and in vivo. LY2523355 arrests cancer cells at mitosis and causes rapid cell death that requires sustained spindle-assembly checkpoint (SAC) activation with a required threshold concentration. In vivo efficacy of LY2523355 is highly dose/schedule-dependent, achieving complete remission in a number of xenograft tumor models, including patient-derived xenograft (PDX) tumor models. We further establish that histone-H3 phosphorylation of tumor and proliferating skin cells is a promising pharmacodynamic biomarker for in vivo anticancer activity of LY2523355.

Synthetic studies on mitotic kinesin Eg5 inhibitors: synthesis and structure-activity relationships of novel 2,4,5-substituted-1,3,4-thiadiazoline derivatives.

The 2,4,5-substituted-1,3,4-thiadiazoline derivative 1a has been identified as a new class of mitotic kinesin Eg5 inhibitor. With the aim of enhancement of the mitotic phase accumulation activity, structure optimization of side chains at the 2-, 4-, and 5-positions of the 1,3,4-thiadiazoline ring of 1a was performed. The introduction of sulfonylamino group at the side chain at the 5-position and bulky acyl group at the 2- and 4-position contributed to a significant increase in the mitotic phase accumulation activity and Eg5 inhibitory activity. As a result, a series of optically active compounds exhibited an increased antitumor activity in a human ovarian cancer xenograft mouse model that was induced by oral administration.

Increased binding of inhibitory neuronal receptors in the hippocampus in kainate-treated rats with spontaneous limbic seizures.

To gain a better understanding of the relationship between epileptogenicity and inhibitory neuronal mechanisms, we examined variations in A1 adenosine (A1A) receptor binding in the hippocampi of rats with spontaneous limbic seizures in the chronic phase after systemic kainic acid treatment. Six weeks after kainate treatment, rats with spontaneous limbic seizures were killed for histological and in vitro autoradiographic analyses of the brain. The analyses were performed using [(3)H] 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1A receptor antagonist. Relative to controls, DPCPX binding was increased in the CA3 region and in the molecular layer of the dentate gyrus in the kainate-treated rats. This is the first evidence of upregulation of the A1A receptor in a model of chronic temporal lobe epilepsy. Increased binding of the A1A receptor may contribute to epileptogenesis in the epileptic focus.

[Solitary brain metastasis of thyroid papillary carcinoma mimicking a cavernous angioma by MRI].

We report a case of a brain metastasis of thyroid papillary carcinoma. A 50-year-old man suffered generalized convulsion. MRI showed a mixed intensity mass with a perifocal low intensity rim in T2WI, mimicking cavernous angioma. The patient underwent craniotomy and total removal of the mass. The resected specimen revealed thyroid papillary carcinoma. Further examination showed a mass in his thyroid gland. Other distant metastases were not revealed. This is a case of a solitary brain metastasis of thyroid papillary carcinoma and the patient's initial symptom was caused by brain metastasis. Such cases are extremely rare. The mass was presurgically diagnosed as a cavernous angioma but was actually a case of brain metastasis. If we had not performed mass removal, we would not have been able to diagnose it as brain metastasis from thyroid papillary carcinoma and would have not taken appropriate steps toward further examinations and treatment. We must manage carefully a mass resembling cavemous angioma in MRI in consideration of the possibility of its being another diseases such as a metastatic tumor.

Voxel- and ROI-based statistical analyses of PET parameters for guidance in the surgical treatment of intractable mesial temporal lobe epilepsy.

OBJECTIVE: Positron emission tomography (PET) can be used to locate epileptic foci in patients with mesial temporal lobe epilepsy (MTLE) by measuring multiple parameters of the brain. We investigated a series of patients with MTLE using PET measurements of three parameters: the cerebral blood flow measured with [15 O] H2O, the uptake of [18F] fluorodeoxyglucose (FDG), an index of the cerebral metabolism rate of glucose, and the distribution volume (DV) of [11C] flumazenil (FMZ), an index of the binding potential of central benzodiazepine receptor. We compared predictive values obtained from two methods: a voxel-based statistical analysis using statistical parametric mapping (SPM) and an asymmetry index obtained by placing regions of interest (ROIs) on PET images. METHODS: Preoperative PET data of 11 patients with surgically confirmed MTLE were retrospectively examined. In the voxel-based analysis, the PET data were analyzed using SPM99 by statistically comparing the voxel values of PET parameters between individual patients and the mean values of 12 normal volunteers. Voxels with values significantly lower than the normal control values were mapped on a standard brain atlas. In the ROI-based analysis, the asymmetry index was calculated to depict ROIs with abnormally decreased values when compared with the contralateral side. RESULTS: (1) Statistical parametric mapping and ROI analyses of the FDG uptake correctly determined epileptic temporal lobe in 73% and 82%, respectively. (2) The decreased DV of FMZ depicted by SPM revealed the mesial temporal pathology in 91%. CONCLUSIONS: Positron emission tomography measurement of FDG uptake was most sensitive in detecting the side of the epileptic focus. On the other hand, SPM analysis of the DV of FMZ was the most sensitive method for delineating the actual epileptic focus.

[Analysis of unknown cause subarachnoid hemorrhage with repeated negative angiogram].

Seven hundred and fifty five cases of acute non-traumatic subarachnoid hemorrhage were admitted to the department of neurosurgery of our hospital from July, 1995 to March, 2004. In 555 patients cerebral angiography was conducted but initial angiography was negative in 30 patients. Except 10 general condition poor patients, in 20 initial angiogram-negative patients were undergone repeated angiography. The cause of SAH could not be demonstrated in 13 cases. The SAH in perimesencephalic and non-perimesencephalic cisturns was seen in 7 and 6 cases, respectively. Occipital and/or neck pain on admission was statistically more common among patients with perimesencephalic SAH than those with non-perimesencephalic SAH (p = 0.029), and the prognosis of perimesencephalic SAH was good. We conclude that repeat angiography should not be recommended in patients with perimesencephalic SAH. Patients with non-perimesencephalic SAH had a higher rate of complication. In the non-perimesencephalic group, 3 patients developed hydrocephalus and 3 patients had vasospasm, which were found by repeated angiography. Therefore, repeated angiography is recommended for better clinical outcome by early detection and management of serious complications in this group of patients.

Imaging of somatotopic representation of sensory cortex with intrinsic optical signals as guides for brain tumor surgery.

OBJECT: Intrinsic optical signals in response to somatosensory stimuli were intraoperatively recorded during brain tumor surgery. In the present study, the authors report on the use of this technique as an intraoperative guide for the safe resection of tumors adjacent to or within the sensorimotor cortex. METHODS: In 14 patients with tumors adjacent to or within the sensorimotor cortex, intrinsic optical signals in response to somatosensory stimuli were recorded by illuminating the brain surface with Xe white light and imaging the reflected light passing through a bandpass filter (605 nm). Results were compared with intraoperative recordings of sensory evoked potentials in all 14 patients and with noninvasive mapping modalities such as magnetoencephalography and positron emission tomography in selected patients. In all but two patients, the somatosensory optical signals were recorded on the primary sensory cortex. Optical signals elicited by stimulation of the first and fifth digits and the three branches of the trigeminal nerve were recorded at different locations on the sensory strip. This somatotopic information was useful in determining the resection border in patients with glioma located in the sensorimotor cortex. CONCLUSIONS: Optical imaging of intrinsic signals is a useful technique with superior spatial resolution for delineating the somatotopic representation of human primary sensory cortex. Furthermore, it can be used as an intraoperative monitoring tool to improve the safety and accuracy of resections of brain tumors adjacent to or within the sensorimotor cortex.

Intraoperative intrinsic optical imaging of neuronal activity from subdivisions of the human primary somatosensory cortex.

We performed intrinsic optical imaging of neuronal activity induced by peripheral stimulation from the human primary somatosensory cortex during brain tumor surgery for 11 patients. After craniotomy and dura reflection, the cortical surface was illuminated with a xenon light through an operating microscope. The reflected light passed through a bandpass filter, and we acquired functional images using an intrinsic optical imaging system. Electrical stimulation of the median nerve, or the first and fifth digits, induced biphasic intrinsic optical signals which consisted of a decrease in light reflectance followed by an increase. The decrease in light reflectance was imaged, and we identified a neural response area within the crown of the postcentral gyrus. In experiments on first and fifth digit stimulation, we identified optical responses in separated areas within the crown of the postcentral gyrus, i.e. near the central sulcus and near the postcentral sulcus. In the former response area, separate representations of the two fingers were observed, whereas in the latter response area, the two fingers were represented in the same region. A similar somatotopic representation was observed with electrical stimulation of the first and third branches of the trigeminal nerve. These results seem to support the hypothesis of hierarchical organization in the human primary somatosensory cortex.