Biomedical subjects

J N Bruce

Publications and source records attributed to J N Bruce.

39 records · Page 3Linked to original sources

PubMedDate not supplied

Giant cell tumors of the jugular foramen.

PURPOSE: To review the diagnosis and treatment of giant cell tumors of the jugular foramen. MATERIALS AND METHODS: A typical case is reported. Symptoms, signs, and diagnostic studies are reviewed. Photomicrographs and angiographic studies showing the differences between these and glomus jugulare tumors are provided. A coherent approach to their management is presented. RESULTS: These hypervascular, traditionally radioresistant tumors may cause pulsatile tinnitus, conductive hearing loss, and lower cranial nerve paresis. Angiographic studies showed a hypervascular lesion supplied by numerous small branches of the external carotid artery, making embolization difficult. Complete resection was achieved by an infratemporal fossa approach with preoperative embolization. CONCLUSION: Giant cell tumors of the temporal bone may mimic glomus jugulare tumors with respect to anatomic location, cranial nerve deficits, and vascularity.

Adult↗

PubMedDate not supplied

Treatment of human glioblastoma cells with the staurosporine derivative CGP 41251 inhibits CDC2 and CDK2 kinase activity and increases radiation sensitivity.

CGP, 41251, a staurosporine derivative, is a potent inhibitor of protein kinase C (PKC). In recent studies we found that this compound causes growth inhibition and induces apoptosis in human glioblastoma cell lines and also inhibits the growth of xenografts of a human astrocytoma. In this study we investigate its effects on cell cycle control. Treatment of glioblastoma or gliosarcoma cells with CGP 41251 lead to a time and dose dependent increase of the percentage of cells in the G2-M phase of the cell cycle. This correlated with a decrease of CDC2- and CDK2-associated histone H1 kinase activities as well as a decrease in the cellular level of the CDC2 protein. The decrease of CDC2- associated histone H1 kinase activity was detected within 5 hours, and there was complete inhibition after 24 hours. Assays of mixtures of cell extracts obtained from cultures treated with CGP 41251, the inactive analog CGP 42700, or untreated cultures indicated that this decrease was due to a decrease in the CDC2 kinase itself rather than the accumulation of an inhibitor of this kinase. In vitro assays in which CGP 41251 was added directly to the in vitro assay system revealed marked inhibition of both CDC2- and CDK2-associated kinase activity at about 1 microM. Thus CGP 41251 inhibits CDC2- and CDK2-associated kinase activities both in vivo and in vitro. Its biologic effects may, therefore, not be due simply to inhibition of PKC. Since cells in the G2-M phase of the cell cycle are relatively more sensitive to killing by gamma- radiation than cells in other phases of the cell cycle, we carried out radiosensitization studies. We found that CGP 41251 was a radiation sensitizer in two glioblastoma cell lines. Therefore, this compound may be useful in the treatment of glioblastomas, possibly in combination with radiation therapy.

Antineoplastic Agents↗

PubMedDate not supplied

Growth inhibition induced by Ro 31-8220 and calphostin C in human glioblastoma cell lines is associated with apoptosis and inhibition of CDC2 kinase.

Protein kinase C (PKC) is a central component in signal transduction and growth control and might be an appropriate target for the chemotherapy of human brain tumors. This study demonstrates that the staurosporine derivative Ro 31-8220, a potent PKC inhibitor, inhibited the growth of 7 human brain tumor cell lines with an IC50 of about 2 microM. Calphostin C, a structurally unrelated PKC inhibitor, inhibited the growth of two of these cell lines with an IC50 of about 100 to 300 nM. Drug withdrawal and clonogenicity assays indicated that the growth inhibition by both of these compounds was irreversible. Morphologic studies, DNA fragmentation studies and flow cytometric assays showed that the treated glioblastoma cells underwent apoptosis. Treatment of glioblastoma cells with Ro 31-8220 lead to a rapid decline in the level of the anti-apoptosis protein bcl-2. At least three of the glioblastoma cell lines carried mutant p53 alleles with missense mutations in the DNA binding domain of p53. Therefore, the induction of apoptosis in these cell lines occurred through a p53-independent mechanism. Furthermore treatment of these glioblastoma cell lines with Ro 31-8220 or calphostin C led to an increase of cells in the G2-M phase of the cell cycle. This correlated with a decrease in CDC2-associated histone H1 kinase activity, as well as a decrease in the level of the CDC2 protein as shown by immunoblotting. When added to subcellular assays Ro 31-8220 markedly inhibited CDC2 histone H1 kinase activity with an IC50 of 100 nM, but calphostin C directly inhibited this kinase activity only at very high concentrations (above 100 microM). Thus these compounds inhibit the growth of glioblastoma cells through novel mechanisms. Ro 31-8220, in particular, might be a useful agent for the treatment of human brain tumors.

Anticarcinogenic Agents↗