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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
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↗
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↗
PubMed1993

Primary central nervous system tumours in Australia: a profile of clinical practice from the Australian Brain Tumour Register.

An epidemiological survey of all primary central nervous system tumours in Australia was commenced in 1986. Cases was reported by the treating physician to the Australian Brain Tumour Register, located at the Victorian Cancer Registry. Ninety-three per cent of tumours were histologically confirmed and 69% were reviewed by an independent pathology panel. During the initial 3 years of the survey a total of 4577 brain tumours and 266 primary spinal cord tumours were reported to the Register. The age standardized rates for malignant tumours of the central nervous system, sum to 5.0/100,000 males and 3.4/100,000 females. Twenty-eight per cent of gliomas were biopsied only. Radiotherapy was administered to 57% of cerebral gliomas and 2% of these tumours were treated with adjuvant chemotherapy. Forty per cent of meningiomas were considered to have had a complete tumour resection.

Age Factors↗
PubMed1993

Photodynamic therapy of brain tumours.

Photodynamic therapy is a binary treatment combining the selective uptake of a photosensitizer into a tumour followed by irradiation of the tumour with light of the appropriate wavelength to cause activation of the sensitizer as selective tumour kill. Photodynamic therapy has been extensively investigated in laboratory studies in the treatment of cerebral tumours and has been utilised in clinical trials to treat a variety of tumours including cerebral glioma. The clinical trials have usually used PDT as an adjuvant therapy following tumour resection but studies are being undertaken to use the treatment in combination with stereotactic techniques. The photosensitizer haematoporphyrin derivative (HpD) has been shown to be selectively localised into all grades of glioma with a direct correlation between the grade of glioma and HpD level in the tumour. The levels were highest in the glioblastoma multiforme (mean uptake of 5.9 micrograms HpD/g tumour wet weight) and lower in the intermediate grade anaplastic astrocytoma (2.4 micrograms/g) and low grade astrocytoma (1.6 micrograms/g). Uptake into normal brain tissue taken from HpD sensitized patients was 0.2 microgram/g. HpD was also localised into the brain adjacent to the tumour region.

Adult↗