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Biomedical subjects

A H Kaye

Publications and source records attributed to A H Kaye.

At least 19 recordsLinked to original sources
PubMed1995

Transformation of astrocytes in transgenic mice expressing SV40 T antigen under the transcriptional control of the glial fibrillary acidic protein promoter.

There are many animal models of glioma, but few that represent the biology of low-grade tumors and allow the study of the genetic mechanisms of glial oncogenesis. We report the in vivo transformation of astrocytic cells in transgenic mice by the SV40 T antigen under the control of the 5'-flanking sequence of the murine glial fibrillary acidic protein (GFAP) gene. High levels of T antigen expression were detectable in a tissue distribution that mirrored the normal expression of GFAP. This was associated with a consistent phenotype in the founder mice. Diffuse proliferation occurred in cells of the periventricular subependymal zone with diffuse invasion into the brain parenchyma, leading to death by 19-30 days postnatally. Transformed cells exhibited secondary structuring, a typical histopathological feature of human astrocytomas. Early passage cultures of these cells expressed GFAP in vitro and were transformed on the basis of tumor formation after transplantation into nude mice. These results demonstrate the susceptibility of periventricular astrocytic cells in the immature brain to malignant transformation. Furthermore, this study demonstrates the potential of the transgenic approach for the in vivo determination of genetic events involved in astrocyte transformation and for the development of novel models of astrocytoma.

Animals↗
PubMed1995

Homozygous deletions of the MTS1 gene are rare in non-astrocytic brain tumors.

Several studies support a role for the multiple tumor suppressor gene (MTS1) in the malignant progression of different tumor types. In this study we have examined the status of the MTS1 gene in a variety of non-astrocytic tumors of the central nervous system. It was not possible, using multiplex PCR with primers for MTS1 and D9S196, a chromosome 9q marker, to demonstrate deletions of MTS1 in 59 primary non-astrocytic tumors. Two out of 5 (40%) secondary tumors showed evidence of homozygous deletion of MTS1. The results obtained here for primary non-astrocytic tumors contrast with those previously described for astrocytic tumors where a high frequency of deletions of MTS1 was associated with tumor progression.

Astrocytoma↗
PubMed1995

Homozygous deletions of the multiple tumor suppressor gene 1 in the progression of human astrocytomas.

The multiple tumor suppressor gene 1 (MTS1) located on chromosome 9p has recently been implicated as a candidate tumor suppressor gene in many different tumor types. Cytogenetic analysis and deletion mapping studies have revealed that deletion of chromosome 9p occurs in a significant number of primary human astrocytomas. Using multiplex PCR with primers for exon 2 of MTS1 and for D9S196 from chromosome 9q, we have analyzed 78 primary astrocytic tumors for the deletion of MTS1. After controlling for the contamination of tumor samples with normal cells, homozygous loss of MTS1 was found in 13 of 25 anaplastic astrocytomas (WHO grade III) and in 27 of 46 cases of glioblastomas (WHO grade IV) but in none of seven astrocytomas (WHO grade II). These data suggest that MTS1 is an important tumor suppressor gene in the malignant progression of astrocytomas.

Adult↗
PubMed1995

Aberrant p53 expression does not correlate with the prognosis in anaplastic astrocytoma.

Mutations of the p53 tumor-suppressor gene, as determined by the immunohistochemistry of archival formalin-fixed specimens, have been correlated with the prognosis for patients with many different types of malignancy. Similar correlations have been shown in series including patients with all grades of astrocytoma. We hypothesized that this might be a clinically useful prognostic indicator for patients with a defined grade of astrocytoma, anaplastic astrocytoma. This series comprised 54 consecutive patients with biopsy-proven anaplastic astrocytoma treated at one institution. When the CM-1 antiserum was used for testing, 33 (61%) of the 54 biopsies exhibited positive nuclear staining for p53, indicating an abnormal accumulation of the protein. This staining was graded according to the number of positive cells per high-power field. Positive immunohistochemical staining for p53 in the tumor cell nuclei did not correlate with the patient's outcome. Significant correlates of improved patient survival were the presentation with epilepsy in the absence of a neurological deficit (P = 0.005) and the surgeon's performance of a macroscopically complete surgical resection of the tumor (P = 0.01).

Adult↗
PubMed1994

Insertional mutagenesis inducing hypomyelination in transgenic mice.

Investigations of myelin disorders, in particular multiple sclerosis (MS), have concentrated on immunemediated damage to formed myelin, while there has been less emphasis on the molecular genetics of myelin formation. We have generated a transgenic mouse mutant (designated 2-50) which carries an insertional mutation in a locus regulating myelination. These mice carry a transgene comprising 1.3 Kb of the mouse myelin basic protein (MBP) promoter conjugated to a fragment containing exons 2 and 3 of the human c-myc gene. Positive mice show a significant reduction in myelin compared to controls and a shivering phenotype. Unlike other myelin mutants, all 2-50 mice lose the shivering phenotype and breed normally. Expression of c-myc is detectable in only 65% of transgene-carrying mice, and when present occurs at extremely low levels. This shows that the phenotype is caused by insertional inactivation of a gene necessary for myelination rather than ectopic expression of the transgene. The transgene was found by in situ hybridization to be inserted into a single site which is very distally located on chromosome 9. The 2-50 mice represent a unique model which will be ideal for investigating the molecular basis of myelin assembly and for developing gene therapy to promote remyelination in conditions such as MS.

Animals↗
PubMed1994

Evaluation of a morpholinothiolporphyrin for use in photodynamic therapy.

The photonecrotic effectiveness of a morpholinothiolporphyrin derived from haematoporphyrin was measured in an animal model of cerebral glioma. The dose administered was 20 mg kg-1 and the laser dose varied from 0 to 200 J cm-2. The tumour necrosis was at least as good as that of HpD, and this therapeutic response may be attributed to the targeting of specific 'photopotent' subcellular sites.

Animals↗
PubMed1992

Selective tumor uptake of a boronated porphyrin in an animal model of cerebral glioma.

The prognosis for patients with high-grade cerebral glioma is poor. Most treatment failures are due to local recurrence of tumor, indicating that a more aggressive local therapy could be beneficial. Adjuvant treatments such as porphyrin-sensitized photodynamic therapy (PDT) or boron neutron capture therapy (BNCT) have the potential to control local recurrence. The selective tumor uptake of a boronated porphyrin was studied in CBA mice bearing an implanted intracerebral glioma. Biopsy samples of tumor, normal brain, and blood were analyzed by a fluorometric assay following intraperitoneal and intravenous administration of boronated protoporphyrin (BOPP). This compound was selectively localized to tumor at ratios as high as 400:1 relative to normal brain. Confocal laser scanning microscopy of glioma cells in vitro and in vivo showed that BOPP was localized within mitochondria and excluded from the nucleus of these cells. This discrete subcellular localization was confirmed by density gradient ultracentrifugation after homogenization of mouse tumor biopsies. The selective discrete localization of these compounds within the tumor suggests that this compound may be used as a dual PDT/BNCT sensitizer.

Animals↗
PubMed1992

Overexpression of multiple oncogenes related to histological grade of astrocytic glioma.

The expression of the c-erbB-1, c-myc, Ha/N-ras and c-fos oncogenes was investigated in 62 astrocytomas of low, intermediate and high grades by immunogold silver histochemistry. Elevated expression of c-erbB-1 was observed in 95%, 48% and 86% of low, intermediate and high grade tumours respectively, c-myc in 5%, 33% and 76% respectively, Ha/N-ras in 0, 43% and 71% respectively and c-fos in 55%, 48% and 52% respectively. Controls included normal brain and tumour sections immunoreacted with pre-immune serum or with antisera absorbed with synthetic peptides. Analysis of co-overexpression revealed that low grade tumours co-overexpressed a maximum of two of these genes, intermediate grade tumours a maximum of three of these genes, while co-overexpression of all four genes was observed in some high grade tumours. Co-overexpression of c-erbB-1 and c-fos was frequently observed in low grade astrocytomas and may be predictive of non-progression. On the other hand, there was a statistically significant increase in the number of tumours overexpressing Ha/N-ras or c-myc with increasing grade of tumour, suggesting that overexpression of these two oncogenes may be indicative of progression.

Astrocytoma↗
PubMed1992

Evaluation of tumour and tissue distribution of porphyrins for use in photodynamic therapy.

A range of pure, monomeric porphyrins were synthesised and their localising capacities compared to HpD and Hp at 6 h and 24 h post injection in the mouse C6 intracerebral glioma model as well as in normal brain, skin, muscle, kidney, spleen, liver, lung and whole blood. The partition coefficients were examined between PBS and 2-octanol over the pH range 7.4-6.6 and pH profiles were established. A parabolic relationship was observed between log (porphyrin tumour concentration) at pH 7.4, with maximal tumour localisation at log (partition coefficient), pi, of approximately zero. Porphyrins with side chains with nett cationic character also exhibited up upward (parabolic) dependence on pi for most tissues studied, with maximal porphyrin localisation at pi of 0-0.5. In contrast, those porphyrins with nett anionic character exhibited a downward (negative) parabolic trend for all eight tissues studied, with minimal porphyrin localisation at pi of approximately zero. Four porphyrins (4, 11, 12, 13) exhibited similar or better tumour localisation than HpD, and two (11 and 12) offer promise as lead compounds for the design of improved porphyrins for use in PDT.

Animals↗
PubMed1992

Delayed cerebrospinal fluid rhinorrhoea: a case report.

Post-traumatic cerebrospinal fluid (CSF) rhinorrhoea is a well recognized complication of closed head injury. Most cases occur soon after injury and a delay in presentation of more than 1 month is unusual. A case is reported of CSF rhinorrhoea presenting 15 years after initial trauma which was complicated by meningitis after 12 months. The management of this condition is reviewed.

Adult↗
PubMed1992

Photodynamic therapy in the treatment of subcutaneously implanted human bladder tumour.

Photodynamic therapy (PDT) is an experimental treatment modality for malignant tumours. The effect of PDT with haematoporphyrin derivative (HpD) was studied using a human bladder tumour (BL-17) which was implanted subcutaneously (s.c.) into immunodeficient Balb/c nude mice. This model is only suitable for short-term investigation of PDT because of the high mortality that arises due to the immune deficiency of the animals. In a short-term observation (2 weeks post-treatment), HpD sensitized PDT was effective in the control of tumour growth, with 71% of tumours cured. The effect of PDT was found to be highly dependent on doses of HpD and/or the activating laser light. The comparison of PDT effects of the gold metal vapour laser (GMVL) and argon ion pumped dye laser (AIPDL) indicated that no significant difference exists between these two different laser sources for PDT. The irradiation with laser light alone and the administration of HpD alone had no significant effect on tumour growth.

Animals↗
PubMed1992

Evaluation of porphyrin characteristics required for photodynamic therapy.

The cytotoxicity (in the dark), phototoxicity (red light) and subcellular localization (using confocal laser scanning microscopy) were determined for 15 porphyrins (1-15) in C6 glioma cells. The partition coefficient in 2-octanol was also determined for each porphyrin at pH 7.4. The cytotoxicity increased with pi (log of partition coefficient) up to pi values of +2. The 7 porphyrins with cationic side chains exhibited a classical parabolic correlation between phototoxicity and pi, with maximal activity at a pi value of approximately 1.0. There was also a significant correlation between subcellular localization and degree of phototoxicity, with the three most photosensitive porphyrins all possessing cationic side chains, and all three localizing in mitochondria.

Cell Survival↗
PubMed1992

Correlations between cerebral arterial velocities, blood flow, and delayed ischemia after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Elevated middle cerebral erythrocyte velocities and tissue hypoperfusion have been correlated with delayed ischemia after subarachnoid hemorrhage, but few studies have compared serial arterial velocities with cerebral blood flow and neurological deficits. METHODS: Serial measurements of middle cerebral velocities, using transcranial Doppler ultrasonography, were performed in 34 patients after subarachnoid hemorrhage and correlated with cerebral blood flow, measured in 20 of the 34 using single-photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime and neurological evidence of delayed ischemia. RESULTS: In 16 patients without delayed ischemia, eight had evidence of vasospasm (greater than 120 cm/sec), but only one of seven had hypoperfusion, suggesting that vasospasm might be more common than hypoperfusion in this group (p = 0.1). In 10 patients with delayed ischemia and a lateralizing deficit, both asymmetrical middle cerebral vasospasm (eight of nine with vasospasm) and hypoperfusion (six of six studied) were concordant with the clinically ischemic hemisphere (p less than 0.05). Vasospasm occurred with nonlateralized delayed ischemia in seven of eight patients and with hypoperfusion in five of six, affecting the anterior cerebral territory in three. CONCLUSIONS: Concordant vasospasm and hypoperfusion were most often present in patients with delayed ischemia and lateralizing neurological deficits. Discordant results reflect inherent limitations and the different levels of the circulation monitored by the two techniques.

Adult↗
PubMed1992

Chemotherapy of gliomas.

Gliomas are usually incurable with current treatment regimens. The mainstay of current therapy is surgery and radiotherapy. Adjuvant chemotherapy with nitrosourea-based regimens for high-grade glioma has now been established as a means of improving survival times, although the results are disappointing and the treatment may entail significant morbidity and does not offer the prospect of cure. The role of chemotherapy for low-grade glioma is controversial, and its possible role as a primary therapy aimed at delaying the need for radiotherapy in young children must be better defined. The literature regarding chemotherapy of glioma is reviewed with particular emphasis on recent publications.

Antineoplastic Agents↗