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Biomedical subjects

A H Kaye

Publications and source records attributed to A H Kaye.

At least 37 records · Page 2Linked to original sources
PubMed2000

Multichannel auditory brainstem implantation: the Australian experience.

The multichannel auditory brainstem implant (ABI) provides the potential for hearing restoration in patients with neurofibromatosis type 2 (NF2). Programmes for auditory brainstem implantation have been established in two Australian centres. Eight patients have been implanted under the protocol of an international multi-centre clinical trial. Three patients had ABI insertion at the time of first side tumour removal, four at second side tumour removal and one after previous bilateral surgery where there was some residual tumour. The translabyrinthine approach was used in all cases. Successful positioning of the electrode array was achieved in seven of eight patients, all of whom achieved auditory perception with electrical stimulation. Intra-operative electrically evoked auditory brainstem response testing was successful in four patients and was useful in confirming correct electrode position. In six cases post-operative psychophysical and auditory perception testing demonstrated that useful auditory sensations were achieved. Five of these patients regularly used the implant. In one patient electrode placement was unsuccessful and only non-auditory sensations occurred on stimulation. In the remaining patients non-auditory sensations were minimal and avoidable by selective electrode programming. Auditory brainstem implantation should be considered in patients with NF2. The greatest benefit is seen in patients without debilitating disease who have non-aidable hearing in the contralateral ear.

Adolescent↗
PubMed1999

Hyaluronidase-2 overexpression accelerates intracerebral but not subcutaneous tumor formation of murine astrocytoma cells.

Gliomas are highly invasive, invariably fatal intracerebral tumors. It seems that receptors for hyaluronan are required for the invasive process. Hyaluronan is a major component of the extracellular matrix in the brain, and all of the gliomas express CD44, the principal receptor for hyaluronan. To investigate the role of lysosomal hyaluronidases on tumor invasion we overexpressed hyaluronidase-2 (HYAL2) in murine astrocytoma cells. We found that high expression of HYAL2 accelerated intracerebral tumor growth dramatically, whereas the same cells formed s.c. tumors within the same time as the parental cells. The brain tumors were highly vascularized and more invasive than the control tumors. It seems that the interactions of the HYAL2-expressing tumor cells with the hyaluronan-containing extracellular matrix in the brain mediate these effects, whereas the same cells in a s.c. environment, which lacks the high hyaluronan level, behave like the parental cells.

Animals↗
PubMed1999

Effect of in situ retroviral interleukin-4 transfer on established intracranial tumors.

BACKGROUND: Current therapies for malignant gliomas remain largely ineffective. We have previously demonstrated that interleukin 4 (IL-4) exhibits antitumorigenic activity in athymic nude mice by promoting both eosinophil infiltration and inhibition of tumor angiogenesis (formation of new blood vessels). In this study, we investigated treatment of established rat C6 cell gliomas by retroviral delivery of IL-4 in situ. METHODS: Tumors grown subcutaneously in athymic nude mice or implanted intracranially in immunocompetent Wistar rats were implanted with ecotropic retrovirus (i.e., will replicate only in cells of closely related species) packaging cells (RPCs) that were transfected with a retroviral vector encoding mouse IL-4 (1C5 cells) or a control vector (SV cells). For the demonstration of the long-term effects of such treatment, C6 cells were also implanted into the contralateral hemisphere of the brains of rats previously treated with 1C5 RPCs. Tumor volume measurements and immunohistochemical analyses were performed. RESULTS: Implantation of 1C5 RPCs into subcutaneous C6 cell tumors resulted in tumor growth arrest that was associated with eosinophil infiltration and inhibition of angiogenesis. When 1C5 RPCs were stereotactically implanted into established intracranial tumors in rats, tumor volumes were dramatically smaller than in control animals (approximately 1.8 mm3 versus 70-80 mm3, respectively) 7 days after treatment. All 1C5 RPC-treated rats survived to 106 days after C6 cell implantation (99 days after treatment; an arbitrary end point), whereas control rats had to be killed 14 days after C6 cell implantation because of extensive tumor growth. Histologic analysis demonstrated that treated tumors were completely eradicated, and immunohistochemical analysis revealed an inhibition of tumor angiogenesis and infiltration by CD8+ cells and macrophages. C6 cells implanted contralaterally into the brains of long-term-surviving rats treated with 1C5 RPCs were also rapidly and completely rejected. CONCLUSIONS: Implantation of packaging cells producing IL-4 retrovirus leads to rapid eradication of rat C6 cell gliomas and provides sustained protection against further intracranial challenge.

Animals↗
PubMed1999

KRN8602 (MX2-hydrochloride): an active new agent for the treatment of recurrent high-grade glioma.

PURPOSE: To assess the efficacy and toxicity of KRN8602 when administered as an intravenous bolus to patients with recurrent high-grade malignant glioma. PATIENTS AND METHODS: Patients with recurrent or persistent anaplastic astrocytoma or glioblastoma multiforme who had not received recent chemotherapy or radiotherapy and were of good performance status (Eastern Cooperative Oncology Group score < or = 2) were treated with an intravenous bolus of 40 mg/m(2) KRN8602 every 28 days. Tumor responses were assessed radiologically and clinically after every second cycle of therapy. Treatment was continued until documented progression or a total of six cycles. RESULTS: A median of three cycles (range, one to six cycles) of KRN8602 was administered to 55 patients, 49 of whom received at least two cycles and were, therefore, assessable for response. The overall response rate (disease stabilization or better) was 43% (95% confidence interval, 29% to 58%). There were three complete responses, one partial response, seven minor responses, and 10 patients with stable disease. The median time to progression was 2 months (range, 1.5 to 37 months) and overall survival was 11 months (range, 1.5 to 40 months). Neutropenia was the most common toxicity, although it was generally of brief duration, and there were only seven episodes of febrile neutropenia in 176 cycles delivered. Nonhematologic toxicity was mostly gastrointestinal (nausea and vomiting, diarrhea) and events were grade 2 or lower except for a single episode of grade 3 vomiting. CONCLUSION: KRN8602 is an active new agent with minimal toxicity in the treatment of relapsed or refractory high-grade glioma. Further studies with KRN8602 in combination with other cytotoxics and in adjuvant treatment of gliomas are warranted.

Adolescent↗
PubMed1998

Effect of filgrastim on the pharmacokinetics of MX2 hydrochloride in patients with advanced malignant disease.

PURPOSE: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. METHODS: A total of 25 patients with advanced malignant disease participated in a dose-escalation study in the first cycle of treatment given i.v. at doses of 50-80 mg/m2 (74-152 mg) with concomitant filgrastim (G-CSF, 5 microg/kg) given daily beginning at 24 h after the dose of MX2. RESULTS: The mean fast distribution half-life (1.5 +/- 1.0 min) and the mean plasma clearance (2.18 +/- 0.95 l/min) were significantly lower than the respective mean values found in a previous study in which 27 patients had received MX2 (16.8-107.5 mg) alone (3.3 +/- 2.2 min and 2.98 +/- 1.68 l/min, respectively; P < 0.05). There was no correlation between plasma clearance and the delivered dose for the combined MX2-alone and MX2-filgrastim groups, indicating that the lower clearance observed in the G-CSF group was probably not due to the higher dose. Elimination half-lives of the metabolites M1 and M4 were significantly greater in the filgrastim group (19.8 +/- 14.7 and 11.8 +/- 5.0 h for M1 and 14.8 +/- 4.1 and 12.3 +/- 6.3 h for M2, respectively). Unlike the MX2-alone group, there was no relationship in the MX2-filgrastim group between the relative nadir neutrophil count and the dose or between the duration of grade IV neutropenia and the dose of MX2. CONCLUSIONS: This study shows that filgrastim decreased the plasma clearance of MX2 by approximately 25%, possibly by inhibition of metabolism.

Antibiotics, Antineoplastic↗
PubMed1998

Phase I and pharmacokinetic study of KRN8602 alone and with filgrastim in patients with advanced cancer.

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of KRN8602 (MX2-hydrochloride), a novel morpholino anthracycline with potent cytotoxicity against anthracycline-sensitive and resistant experimental tumors in vitro and in vivo. PATIENTS AND METHODS: KRN8602 was administered alone in increasing doses to patients with advanced cancer or high-grade gliomas until dose-limiting toxicity (DLT) was observed in three or more of five patients treated in a dose level. Because neutropenia was dose limiting, further escalation was investigated with filgrastim support. RESULTS: Fifty-six assessable patients completed at least one cycle of chemotherapy. The recommended dose of KRN8602 alone was 40 mg/m2. Dose escalation was limited by neutropenia. The recommended dose of KRN8602 with filgrastim was 70 mg/m2, and limiting toxicities were neutropenia, diarrhea, and vomiting. The most commonly experienced nonhematologic toxicity was nausea and vomiting. Alopecia and mucositis were infrequent and mild. Pharmacokinetic parameters showed substantial variation, although the area under the plasma concentration-time curve (AUC) and maximum concentration both increased with dose. There was no relationship between pharmacokinetic parameters and toxicity. CONCLUSION: KRN8602 at doses of 40 mg/m2 when administered alone and 70 mg/m2 when administered with filgrastim appeared to be manageable. The major DLTs were neutropenia and, at higher doses, diarrhea and vomiting. The efficacy of this drug is currently being tested in phase II studies.

Adult↗
PubMed1997

Pharmacokinetics and pharmacodynamics of MX2 hydrochloride in patients with advanced malignant disease.

The purpose of the present study was to investigate the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. A total of 27 patients with advanced cancer participated in a dose-escalation study in the first cycle of treatment with drug given i.v. at doses of 10-50 mg/m2 (total dose 16.8-107.5 mg). The mean total systemic plasma clearance (CL) of MX2 was 2.98 +/- 1.68 l/min, the mean volume of distribution at steady state was 1460 +/- 749 l and mean elimination half-life was 10.8 +/- 5.1 h. The area under the plasma concentration-time curve (AUC) of MX2 was linearly related to the dose per kilogram and the dose per body surface area (r2 = 0.43, P < 0.01 and r2 = 0.44, P < 0.01, respectively). CL did not correlate with total body weight, lean body mass or body surface area. The mean elimination half-lives of the metabolites M1, M2, M3 and M4 were 11.8 +/- 5.0, 21.9 +/- 11.8, 19.0 +/- 11.3 and 12.3 +/- 6.3 h, respectively. The fractional Emax model produced a much better fit to the relative nadir neutrophil count versus dose data (r2 = 0.42) than to the relative nadir neutrophil count versus AUC or peak concentration (Cmax) data (r2 = 0.15 and 0.09, respectively). There seemed to be a threshold dose of about 65 mg of MX2 at or above which a large proportion of patients had a nadir neutrophil count of less than 0.5 x 10(9)/l. This study shows that the pharmacokinetics of MX2 are similar to those of other anthracyclines. With other anthracyclines the degree of myelosuppression seems to depend more on the AUC and Cmax than on the delivered dose; however, with MX2 the degree of myelosuppression depends more on the dose given than on drug exposure expressed as the AUC or Cmax.

Adult↗
PubMed1997

Multicellular tumor spheroids grown from pancreatic carcinoma cell lines: use as an orthotopic xenograft in athymic nude mice.

Carcinoma of the pancreas is the fifth leading cause of cancer death, with the majority of patients presenting with unresectable disease. Research into new adjuvant therapies is hampered by the lack of suitable in vivo and in vitro models. We have examined the potential of seven pancreatic carcinoma cell lines to grow as multicellular tumor spheroids (MTS). Three of seven (43%) cell lines were scored positive for MTS formation, and the growth characteristics for spheroid models of the cell lines PANC1 and MIAPaCa2 are presented. Implantation of PANC1 MTS into the pancreas of athymic nude mice produces tumors with reproducible growth characteristics and histology.

Animals↗
PubMed1996

Evaluation of porphyrin C analogues for photodynamic therapy of cerebral glioma.

A series of monomeric porphyrins (2-8) based on porphyrin C (1) have been tested as sensitisers for photodynamic therapy (PDT) of cerebral glioma using the in vitro/in vivo C6 intracerebral animal tumour model. The in vivo screening, consisting of cytotoxicity, phototoxicity (red light) and subcellular localisation studies, revealed two sensitisers (porphyrin 7, molecular weight 863 Da and porphyrin 8, molecular weight 889 Da), which had greater photoactivity than porphyrin C and similar photoactivity to haematoporphyrin derivative (HpD) although at a 5-fold higher dose than HpD. Both sensitisers showed intracellular localisation to discrete organelle sites and exhibited considerably less 'dark' cytotoxicity than HpD. The kinetics of uptake of porphyrins 7 and 8 was studied in the mouse C6 glioma model as well as in biopsy samples from normal brain, liver, spleen and blood. Maximal drug uptake levels in tumour occurred 9 and 6 h after intraperitoneal injection for 7 and 8 respectively, at which time the tumour to normal brain ratios were 15:1 and 13:1 respectively. The effect of PDT using porphyrin 7 activated by the gold metal vapour laser tuned to 627.8 nm was studied in Wistar rats bearing intracerebral C6 glioma. At a drug dose of 10 mg porphyrin 7 kg-1 body weight and laser doses of up to 400 J cm-2 light, selective tumour kill with sparing of normal brain was achieved, with a maximal depth of tumour kill of 1.77+/-0.40. mm. Irradiation following a higher drug dose of 75 mg porphyrin 7 kg-1 body weight resulted in a greater depth of tumour kill, but also significantly increased the likelihood and extent of necrosis in normal brain.

Animals↗
PubMed1996

Photodynamic therapy of brain tumors.

Photodynamic therapy (PDT) for the treatment of a variety of brain tumors, particularly gliomas, has been extensively investigated in laboratory studies and has been studied in clinical trials. The main advantage of PDT lies in its ability to select out tumor cells that are infiltrating brain parenchyma and that are responsible for local tumor recurrence, the major therapeutic dilemma in the treatment of gliomas. PDT has been shown to be safe clinically but adequate trials have yet to be undertaken to prove its efficacy and much work remains to be done to optimize treatment. The laboratory studies and clinical trials involving PDT in the treatment of cerebral tumors, particularly the commonest brain tumors, gliomas, are discussed.

Animals↗
PubMed1995

Selective tumor kill of cerebral glioma by photodynamic therapy using a boronated porphyrin photosensitizer.

The prognosis for patients with the high-grade cerebral glioma glioblastoma multiforme is poor. The median survival for primary tumors is < 12 months, with most recurring at the site of the original tumor, indicating that a more aggressive local therapy is required to eradicate the unresectable "nests" of tumor cells invading into adjacent brain. Two adjuvant therapies with the potential to destroy these cells are porphyrin-sensitized photodynamic therapy (PDT) and boron-sensitized boron neutron capture therapy (BNCT). The ability of a boronated porphyrin, 2,4-(alpha, beta-dihydroxyethyl) deuteroporphyrin IX tetrakiscarborane carboxylate ester (BOPP), to act as a photosensitizing agent was investigated in vitro with the C6 rat glioma cell line and in vivo with C6 cells grown as an intracerebral tumor after implantation into Wistar rats. These studies determined the doses of BOPP and light required to achieve maximal cell kill in vitro and selective tumor kill in vivo. The data show that BOPP is more dose effective in vivo by a factor of 10 than the current clinically used photosensitizer hematoporphyrin derivative and suggest that BOPP may have potential as a dual PDT/BNCT sensitizer.

Animals↗
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↗