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Biomedical subjects

M Proctor

Publications and source records attributed to M Proctor.

At least 19 recordsLinked to original sources
PubMed1998

BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.

We have identified a novel protein, BAP1, which binds to the RING finger domain of the Breast/Ovarian Cancer Susceptibility Gene product, BRCA1. BAP1 is a nuclear-localized, ubiquitin carboxy-terminal hydrolase, suggesting that deubiquitinating enzymes may play a role in BRCA1 function. BAP1 binds to the wild-type BRCA1-RING finger, but not to germline mutants of the BRCA1-RING finger found in breast cancer kindreds. BAP1 and BRCA1 are temporally and spatially co-expressed during murine breast development and remodeling, and show overlapping patterns of subnuclear distribution. BAP1 resides on human chromosome 3p21.3; intragenic homozygous rearrangements and deletions of BAP1 have been found in lung carcinoma cell lines. BAP1 enhances BRCA1-mediated inhibition of breast cancer cell growth and is the first nuclear-localized ubiquitin carboxy-terminal hydrolase to be identified. BAP1 may be a new tumor suppressor gene which functions in the BRCA1 growth control pathway.

Amino Acid Sequence↗
PubMed1997

The solution structure of the S1 RNA binding domain: a member of an ancient nucleic acid-binding fold.

The S1 domain, originally identified in ribosomal protein S1, is found in a large number of RNA-associated proteins. The structure of the S1 RNA-binding domain from the E. coli polynucleotide phosphorylase has been determined using NMR methods and consists of a five-stranded antiparallel beta barrel. Conserved residues on one face of the barrel and adjacent loops form the putative RNA-binding site. The structure of the S1 domain is very similar to that of cold shock protein, suggesting that they are both derived from an ancient nucleic acid-binding protein. Enhanced sequence searches reveal hitherto unidentified S1 domains in RNase E, RNase II, NusA, EMB-5, and other proteins.

Amino Acid Sequence↗
PubMed1996

Structure and stability of an immunoglobulin superfamily domain from twitchin, a muscle protein of the nematode Caenorhabditis elegans.

The NMR solution structure of an immunoglobulin superfamily module of twitchin (Ig 18') has been determined and the kinetic and equilibrium folding behaviour characterised. Thirty molecular coordinates were calculated using a hybrid distance geometry-simulated annealing protocol based on 1207 distance and 48 dihedral restraints. The atomic rms distributions about the mean coordinate for the ensemble of structures is 0.55( +/- 0.09) A for backbone atoms and 1.10( +/- 0.08) A for all heavy atoms. The protein has a topology very similar to that of telokin and the titin Ig domains and thus it falls into the I set of the immunoglobulin superfamily. The close agreement between the predicted and observed structures of Ig 18' demonstrates clearly that the I set profile can be applied in the structure prediction of immunoglobulin-like domains of diverse modular proteins. Folding studies reveal that the protein has relatively low thermodynamic stability, deltaG(H2O)U-F = 4.0 kcal mol(-1) at physiological pH. Unfolding studies suggest that the protein has considerable kinetic stability, the half life of the unfolding is greater than 40 minutes in the absence of denaturant.

Amino Acid Sequence↗
PubMed1996

A phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid.

Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.

Acyltransferases↗
PubMed1996

Phase I study of pharmacologically based dosing of carboplatin with filgrastim support in women with epithelial ovarian cancer.

PURPOSE: The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA). PATIENTS AND METHODS: A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle. RESULTS: We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level. CONCLUSION: An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.

Adult↗
PubMed1995

NMR solution structure of a dsRNA binding domain from Drosophila staufen protein reveals homology to the N-terminal domain of ribosomal protein S5.

The double-stranded RNA binding domain (dsRBD) is an approximately 65 amino acid motif that is found in a variety of proteins that interact with double-stranded (ds) RNA, such as Escherichia coli RNase III and the dsRNA-dependent kinase, PKR. Drosophila staufen protein contains five copies of this motif, and the third of these binds dsRNA in vitro. Using multinuclear/multidimensional NMR methods, we have determined that staufen dsRBD3 forms a compact protein domain with an alpha-beta-beta-beta-alpha structure in which the two alpha-helices lie on one face of a three-stranded anti-parallel beta-sheet. This structure is very similar to that of the N-terminal domain of a prokaryotic ribosomal protein S5. Furthermore, the consensus derived from all known S5p family sequences shares several conserved residues with the dsRBD consensus sequence, indicating that the two domains share a common evolutionary origin. Using in vitro mutagenesis, we have identified several surface residues which are important for the RNA binding of the dsRBD, and these all lie on the same side of the domain. Two residues that are essential for RNA binding, F32 and K50, are also conserved in the S5 protein family, suggesting that the two domains interact with RNA in a similar way.

Amino Acid Sequence↗
PubMed1995

Assignment of the backbone 1H,15N,13C NMR resonances and secondary structure of a double-stranded RNA binding domain from the Drosophila protein staufen.

NMR spectroscopy has been used to determine the secondary structure of one of the double-stranded RNA binding domains from the Drosophila protein staufen. The domain has an alpha beta beta beta alpha arrangement of secondary structure, with the beta strands forming an antiparallel beta sheet. The secondary structure differs from that found in the RNP RNA binding domain.

Amino Acid Sequence↗
PubMed1995

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer.

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0-24 h) 1.95 +/- 0.87 mg/ml per min (mean +/- SD), apparent oral clearance 60.9 +/- 21.7 ml/min per 1.73 m2, peak plasma concentration 5.6 +/- 2.5 micrograms/ml, time to peak concentration 73 +/- 35 min and half-life 220 +/- 83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal Emax equation. A good fit was found between day 1 AUC and neutrophil toxicity (R2 = 0.77). All patients who had a day 1 AUC > 2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m2). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R2 = 98.9%). The equation AUCpr = -0.376 + 0.631 x C4h + 0.336 x C6h was validated on the test set with a relative mean predictive error of -0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.

Administration, Oral↗
PubMed1995

Pharmacokinetics, metabolism and clinical effect of ifosfamide in breast cancer patients.

Ifosfamide (IFO) at a dose of 5 g/m2, was administered as a 24-h infusion to 15 patients with metastatic (12) or locally advanced (3) breast cancer (age range 33-59 years, median 46). Concurrent chemotherapy was doxorubicin (40 mg/m2) or epirubicin (60 mg/m2). Ifosfamide and its metabolites were measured in plasma and urine during and for 24 h after the infusion using a high performance thin layer chromatography (HPTLC) technique. Patients' haematological toxicity and biochemistry were monitored during treatment and patients were followed for up to 2 years after therapy. At the time of evaluation, 5 of the patients were alive, 2 of whom had not relapsed. A marked variation was observed in the pharmacokinetics and metabolism of ifosfamide in the evaluable patients. Clearance, volume of distribution and half-life of the drug were 3.48 +/- 0.88 1/h/m2, 0.56 +/- 0.22 l/kg and 4.68 +/- 2.01 h, respectively. There was no apparent correlation between these pharmacokinetic variables and patient age, weight or renal function. AUCs of the ultimate alkylating species isophosphoramide mustard (IPM) varied over 6-fold, as did those of the inactivated metabolite carboxyifosfamide (CX). AUCs of dechloroethylated metabolites varied 4-fold (3-dechloroethylifosfamide, 3-DCI) or 8-fold (2-DCI), while that of the parent compound varied only 2.5-fold. Variation in recovery of the metabolites in urine varied over an even wider range, total recovery varying from 17.5 to 81.8% of the dose administered. There was little apparent correlation between pharmacokinetic and metabolite parameters of IFO and haematological toxicity. However, there was a marked negative correlation between both progression-free interval and survival and the AUCs of the products of IFO activation (IPM and CX). In addition, the recovery of IPM in urine was higher in patients experiencing a partial response compared to those with progressive or stable disease. Recovery of dechloroethylated metabolites correlated positively with survival, if 1 poor prognosis patient was excluded. Although far from conclusive, these results give some insight into a possible mechanism of action of ifosfamide and indicate that some species other than IPM, as measured systemically, is responsible for the pharmacological effects of this drug.

Adult↗
PubMed1995

Phase I and pharmacokinetic study of a water-soluble etoposide prodrug, etoposide phosphate (BMY-40481).

Etoposide phosphate is a water-soluble prodrug of etoposide. A phase I and pharmacokinetic study has been performed over the dose range 25-110 mg/m2/day for 5 days (etoposide equivalent doses). The maximum tolerated dose (MTD) was 110 mg/m2/day for 5 days every 3 weeks and the dose-limiting toxicity was neutropenia. Other toxicities were mild, with the exception of 2 patients who displayed significant hypersensitivity reactions. The etoposide phosphate:etoposide area under the plasma concentration versus time curve (AUC) ratio was < 1% and the pharmacokinetic parameters for etoposide were within previously reported ranges. Pharmacodynamic analyses demonstrated that etoposide AUC and baseline white blood cell count were significant determinants of leucopenia (model r2 = 0.51).

Adult↗
PubMed1995

Post-intensive care interviews: implications for future practice.

The measurement of outcome from intensive care, including the long-term physiological and psychological effects of disease and intensive therapy has tended to receive scanty attention. Little consideration has been given to the implications this may have for the patients, relatives and for future practice. Patients were interviewed in their own homes after 6 months of recovery, to allow freedom of expression and comfort within their own environment (territory). This study demonstrates that data generated by face-to-face interviews can be of immense importance to intensivists in assessing the effectiveness of services and promoting changes in clinical practice. It also shows a need for a long-term follow-up service encompassing community and hospital.

Adolescent↗
PubMed1995

The use of granulocyte colony-stimulating factor to deliver four cycles of ifosfamide and epirubicin every 14 days in women with advanced or metastatic breast cancer.

Twenty patients with locally advanced or metastatic breast cancer were treated with four cycles of ifosfamide/mesna 5 g m-2 and epirubicin 60 mg m-2 every 14 days with granulocyte colony-stimulating factor (G-CSF, Filgrastim). Complete remission occurred in six out of the 20 patients (30%, 95% confidence interval 12-54%) and there were 12 partial responders (60%, 95% confidence interval 37-81%), thus giving an overall response rate of 90% (95% confidence interval 63-97%). Two patients had progressive disease. The median duration of response for those patients with metastatic disease was 7.3 (1.3-20.1+) months. The median survival time for these patients was 15 (5.3-27.9+) months. Of the four patients treated with locally advanced disease three achieved a complete clinical response and one a partial response. Three out of four of these patients subsequently underwent a mastectomy, and in one of these no viable tumour was seen. Our conclusion is that this regimen is excellent palliation for metastatic disease and possibly useful neoadjuvant treatment.

Adult↗
PubMed1994

Gastrointestinal upsets associated with ingestion of copper-contaminated water.

During 1992 and 1993 the Wisconsin Division of Health investigated five cases in which copper-contaminated drinking water was suspected of causing gastrointestinal upsets. Each of these case studies was conducted after our office was notified of high copper levels in drinking water or notified of unexplained illnesses. Our findings suggest that drinking water that contains copper at levels above the federal action limit of 1.3 mg/l may be a relatively common cause of diarrhea, abdominal cramps, and nausea. These symptoms occurred most frequently in infants and young children and among resident of newly constructed or renovated homes.

Adult↗
PubMed1994

Carboplatin and granulocyte colony-stimulating factor as first-line treatment for epithelial ovarian cancer: a phase I dose-intensity escalation study.

A phase I study of frequently administered carboplatin with recombinant human granulocyte colony-stimulating factor (filgrastim) has been performed in patients with newly diagnosed epithelial ovarian cancer. Recombinant human granulocyte colony-stimulating factor was administered at a dose of 5 micrograms/kg/d for days 1 through 12 after carboplatin treatment. Carboplatin doses were calculated using a pharmacokinetic formula on an area under the curve (AUC) basis. Four doses of carboplatin were planned for each patient. The first cohort of patients received an AUC of 5 mg/mL x min every 3 weeks. Subsequently four additional cohorts received AUCs of 5, 7, 9, and 8 every 2 weeks. Non-hematologic toxicities were mild and not significant. The dose-limiting toxicity was thrombocytopenia and occurred at an AUC of 9. Most patients could complete treatment at an AUC of 7. Results for AUC 8 are awaited. Complete and partial responses were seen in most patients at all dose levels.

Adenocarcinoma↗
PubMed1993

Long-term oral etoposide in metastatic breast cancer: clinical and pharmacokinetic results.

To evaluate the activity of long-term, single-agent oral etoposide against advanced breast cancer, this study employed etoposide 50 mg/day and 100 mg/day (given over 14 days) in previously treated and chemotherapy-naive patients with histologically confirmed, recurrent or metastatic breast cancer. Of 38 patients, 24 had had chemotherapy, 34 had prior radiotherapy, and 31 had received hormone therapy. Etoposide courses in both treatment groups were repeated every 4 weeks for at least two courses; delays were instituted when patients' total leukocyte nadir fell to or below 3.0 x 10(9)/l. Dose reductions were made in the 100-mg group (to 50 mg/day) if World Health Organization leukopenia grade 3 or higher was present. Plasma pharmacokinetic profiles were measured in selected patients to assess inter- and intrapatient variability in etoposide's oral bioavailability. No complete responses were achieved among the 36 patients evaluable for response, but eight patients had a partial response. Responses were more frequent at the 100-mg dose and in previously untreated patients (seven of eight partial responders had not had previous chemotherapy). Median duration of response was 16 weeks (range, 7 to 46). Myelosuppression (variable and unpredictable) and alopecia (universal) were the notable toxicities. Pharmacokinetic analyses of oral bioavailability revealed significant interpatient variability, but much less intrapatient variability when successive etoposide courses in individual patients were evaluated. Despite the relatively small number of patients in this study, the responses achieved by previously untreated patients suggest etoposide's value against breast cancer. Further trials should use pharmacokinetic studies to assess bioavailability as well as to help define 'target' etoposide doses, based on plasma etoposide levels, during treatment.

Administration, Oral↗
PubMed1992

Continuous monitoring of mixed venous saturation (SvO2): an adjunct to nursing assessment?

Technological advances in oximetry have enabled the development of a pulmonary artery catheter which allows the continuous monitoring of a patient's mixed venous oxygen saturation (SvO2), which is recognised as a valuable indication of cardiac output and the balance between oxygen supply and demand (delivery and consumption). This paper briefly explains the rationale for monitoring SvO2 and highlights possible areas where the data it provides could influence the assessment and implementation of nursing interventions undertaken within intensive care units, and enable those decisions to be made more safely.

Catheterization, Swan-Ganz↗
PubMed1992

A phase II trial of goserelin (Zoladex) in relapsed epithelial ovarian cancer.

Thirty patients with advanced epithelial ovarian cancer were treated with the luteinising hormone releasing agonist, goserelin. There were two partial responses lasting 40 and 105 weeks respectively. In addition five patients had disease stabilisation lasting 25, 35, 40, 66 and 70 weeks respectively and 23 patients had progressive disease. No significant or unexpected toxicities occurred. This minimally toxic therapy halted disease progression for 6 months or more in 23% of patients, the majority of whom were heavily pretreated. There were five early deaths due to disease progression. The use of goserelin in patients with epithelial ovarian cancers resistant to or relapsing soon after first line platinum based chemotherapy needs to be further evaluated.

Adult↗