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J Jacob

Publications and source records attributed to J Jacob.

At least 91 records · Page 5Linked to original sources
PubMed1996

A phase I study of paclitaxel and cyclophosphamide in recurrent adenocarcinoma of the ovary.

We have conducted a disease specific phase I study of paclitaxel and cyclophosphamide in recurrent adenocarcinoma of the ovary. This was done to take advantage of the cellular and molecular synergism between paclitaxel and DNA-damaging agents, with the hope of avoiding paclitaxel-cisplatin toxicities. Paclitaxel was given as a 24-hr CIVI, after which cyclophosphamide was given as a 60-min infusion. Cycles of therapy were repeated every 3 weeks; and granulocyte colony-simulating factor (G-CSF) was given in a "flexible" dosing fashion. Starting doses were 170 mg/m2 paclitaxel and 750 mg/m2 cyclophosphamide. Dose-limiting toxicity (DLT) was seen at the doses of 250 mg/m2 paclitaxel and 1250 mg/m2 cyclophosphamide. DLT was cumulative thrombocytopenia. There were six nonhematologic grade 3 or 4 toxicities experienced in the study. Eleven of 20 evaluable patients (55%) have achieved an objective response (4 CCR;7 PR). Three of four CCRs were confirmed by negative findings at peritoneoscopy. The median number of prior therapies was 2 (range 1-4) and 17 individuals had platinum-refractory disease. We conclude that paclitaxel followed by cyclophosphamide is an active combination in recurrent ovarian cancer and that further study is needed to determine if this combination is truly better than paclitaxel alone.

Adenocarcinoma↗
PubMed1996

A phase I/II study of dose-intense paclitaxel with cisplatin and cyclophosphamide as initial therapy of poor-prognosis advanced-stage epithelial ovarian cancer.

Epithelial ovarian cancer patients with bulky residual tumor have a poor response to therapy and limited survival. We investigated the addition of dose-intense paclitaxel to cisplatin and cyclophosphamide for patients with FIGO III/IV epithelial ovarian cancer. Paclitaxel dose was intensified from 135 to 250 mg/m2 and administered in combination with cisplatin at > or = 75 mg/m2 and cyclophosphamide at 750 mg/m2. Thirty-one of 36 patients (86%) and 25 (70%) had > or = 2 and > or = 3 cm residual disease after surgery, respectively. One-third had stage IV disease, and 80% had grade 3 tumors. The maximally tolerated doses (MTD) were paclitaxel at 250 mg/m2, cisplatin at 75 mg/m2, and cyclophosphamide at 750 mg/m2 on a 21-day cycle with G-CSF, 10 micrograms/kg/day. Administered dose intensity at the MTD was > or = 86%. Reversible grade 3 peripheral neuropathy occurred in 28% of patients and fever during neutropenia in 2/352 cycles (0.5%). The pathologic response rate is 36% with an additional 25% having minimal microscopic disease. Median progression-free and overall survivals for patients receiving paclitaxel at 250 mg/m2 at a median potential follow-up of 22 months have not been reached for the cohort nor for the > or = 3-cm subgroup. This regimen should be evaluated in a prospective, randomized clinical trial.

Adult↗
PubMed1996

Improvements in the determination of eight polycyclic aromatic hydrocarbons through a stepwise interlaboratory study approach.

A summarising account of a systematic stepwise approach based on interlaboratory studies carried out by a number of laboratories from European Union and EFTA countries is given. This approach has been designed to improve the analytical state of the art in the determination of selected polycyclic aromatic hydrocarbons in different environmental matrices. The approach resulted in a certification exercise to produce a sewage sludge as Certified Reference Material (CRM). The results of the programme showed that HPLC and GC are equally reliable for PAH analysis at submicrogram to microgram per gram levels in various environmental matrices. Major improvements were achieved during the programme, resulting in reduced coefficients of variation and between-laboratory differences. Several recommendations emerging from the programme experience are presented.

Journal Article↗
PubMed1996

PCR-mediated DNA fingerprinting of atypical campylobacter strains isolated from surface and drinking water.

This study shows that typing through polymerase chain reaction (PCR) can be used to differentiate between strains of Campylobacter and Arcobacter, whereas by means of conventional biotyping Arcobacter might be identified as atypical Campylobacter. Microaerophilic "campylobacter-like" organisms were isolated from several drinking water treatment plants as well as environmental sources. The strains were characterized by biotyping and PCR amplification of Campylobacter flaA/flaB and 16s-rRNA Arcobacter butzleri-specific genes.

Animals↗
PubMed1996

Metabolism and excretion of polycyclic aromatic hydrocarbons in rat and in human.

Polycyclic aromatic hydrocarbons have shown to be an important class of environmental and occupational carcinogens. By balancing the carcinogenic potential PAH were found to predominantly contribute to the biological activity of environmental matter such as vehicle exhaust, used motor oil, and hard-coal combustion effluents. Due to the individual ratio of toxifying and detoxifying processes PAH-exposure measurements are not appropriate to be used for risk assessment without any further information on their metabolic fate. Accordingly, metabolite profiles of phenanthrene, pyrene, chrysene, benz(a)anthracene and fluoranthene have been recorded in both tar-pitch exposed Wistar rats and coke plant workers. The results show that metabolite profiles are invariant individual parameters which, however, vary from one individual to another. Significant differences with regard to the ratio of k-region and non-k-region hydroxylation of phenanthrene have been observed in a greater number of coke plant workers. This ratio might be helpful for risk assessment studies since it reflects the various cytochrome P450-dependent monooxygenase isoforms participating in the metabolism of PAH. Studies of this kind can only be carried out with substrates possessing several nonequivalent double bonds (phenanthrene, chrysene) whereas pyrene--commonly used for biomonitoring--does not satisfy this condition. The excretion rate (excretion versus exposure) seems to be an individual parameter.

Animals↗
PubMed1996

[The sat4 streptothricin acetyltransferase gene of Campylobacter coli: its distribution in the environment and use as epidemiological marker].

The main of this study is to give evidence about the spread of streptothricin resistance within Campylobacters which were isolated from animals, men and environmental sources. Streptothricin resistant Campylobacters were isolated over a five years period, when the use of streptothricin for ergotropic purposes was not allowed, from slurry of swine, slurry of cattle, waste water of a goose farm and waste water of a communal sewage treatment plant. The streptothricin resistance was found to be connected with resistances to kanamycin and streptomycin (MIC > 1024 micrograms/ml). For DNA-DNA-hybridisation we used a gene probe derived from the streptothricin acetyltransferase determinant sat4 from Campylobacter coli to find out epidemiological associations between Campylobacters of different origin. The hybridisation experiments show that all streptothricin resistant strains, which were isolated from one ecosystem or where an epidemiological link seems given, have sat4 positive signals at identical positions of the digested and blotted chromosomal DNA. The detection of the sat4 gene seems to be a good tool to discriminate clonal diversities within multiple antibiotic resistant Campylobacters.

Acetyltransferases↗
PubMed1995

Urinary metabolite profile of PAH as a potential mirror of the genetic disposition for cancer.

Polycyclic aromatic compounds such as polycyclic aromatic hydrocarbons or aromatic amines presently are considerably underestimated with regard to the formation of environmentally caused cancer diseases. The individual urinary metabolite profile raising from the PAH inhaled is invariant. This holds for tar-pitch aerosol exposed Wistar rats as well as for PAH-exposed workers. Significant individual differences of the urinary metabolite profile can be observed in different individuals. The differences reflect the different individual enzyme equipment. There is an individual correlation between the PAH-masses inhaled and the masses of their metabolites excreted in the urine; e.g. the excretion of phenanthrene varies from 5% to 20% for different coke workers. The PAH metabolite profile analysis appears to be a suitable tool to estimate the individual cancer.risk at PAH-exposed working places since the PAH-induced malign transformation is caused by specific PAH metabolites.

Animals↗
PubMed1995

Cytochrome P450 mediated reactions studied in genetically engineered V79 Chinese hamster cells.

V79 Chinese hamster cells genetically engineered for stable expression of rat and human CYP have been shown to serve as analytical tools for studying metabolism related problems in toxicology and pharmacology. Here, the application of rat and human CYP1A1 and CYP1A2 is demonstrated for comparative studies on the oxidation of polycyclic aromatic hydrocarbons, such as phenanthrene, benz[a]anthracene, and benzo[a]pyrene. Live cells were cultivated for 2 days in the presence of these chemicals. Thereafter, the supernatant medium was checked for metabolites by gas chromatography and mass spectrometry. Marked cytochromes P450 and species dependent differences in the metabolite profiles were observed. Most important was the finding, that human cytochrome P450 1A1 almost exclusively oxidized benzo[a]pyrene in the 7,8,9,10-position, yielding the ultimate carcinogen 7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene whereas the rat cytochrome P450 1A1 oxidized benzo[]pyrene in the 4,5-position and 7,8,9,10-position. The importance of this finding is underlined by results from cytotoxicity studies. Benzo[a]pyrene was twice as cytotoxic in the human cytochrome P450 1A1 than in the rat cytochrome P450 1A1 expressing V79 cells. Species and cytochrome P450 specific metabolite profiles were also observed for phenanthrene and benz[a]anthracene.

Animals↗
PubMed1995

A report on the use of technician ophthalmoscopy combined with the use of the Canon non-mydriatic camera in screening for diabetic retinopathy in the community.

This paper describes a general practice based diabetic retinopathy screening service employing a technician trained in direct and indirect ophthalmoscopy and taking photographs with a Canon CR3 45 NM non-mydriatic polaroid camera analysed by a consultant ophthalmologist to provide a comparison with the screener's opinion. Prospective data is presented from the first 1050 patients screened for diabetic retinopathy in the Exeter Health Authority area. Analysis of data collected showed a prevalence of diabetic retinopathy in the screened population of 27%, 14% previously undetected with a 0.5% prevalence of sight-threatening retinopathy. There was almost complete agreement between ophthalmoscopy findings and the consultant analysis of photographs. Screening costs were calculated at 10.38 pounds per patient screened. A specially trained non-medically qualified technician can provide a good quality cost-effective screening service for diabetic retinopathy within a primary care setting.

Adolescent↗
PubMed1995

Paclitaxel, cisplatin, and cyclophosphamide in human ovarian cancer: molecular rationale and early clinical results.

The three most active types of agents in the treatment of cancer of the ovary are platinum compounds (cisplatin or carboplatin), bifunctional alkylating agents (cyclophosphamide, melphalan, etc), and the recently developed natural product paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). In an effort to improve long-term disease-free survival in patients with advanced disease, we have developed a three-drug regimen consisting of cisplatin, paclitaxel, and cyclophosphamide. Granulocyte-colony stimulating factor is given as bone marrow support using a flexible dosing approach. The molecular basis for this approach is founded in the positive molecular interactions between cisplatin and bifunctional alkylating agents and between paclitaxel and DNA-damaging agents. Cisplatin and cyclophosphamide damage DNA by two very different mechanisms; the respective importance of DNA strand "kinking" versus DNA strand "cross-linking" may explain the positive cell kill interaction between these two drugs. Paclitaxel appears to markedly slow the repair of DNA lesions caused by DNA-damaging agents, which may include radiation-induced lesions, cisplatin adducts, and cyclophosphamide cross-links. Clinical data to date from several different groups strongly suggest that these molecular interactions translate into positive clinical benefit in human ovarian cancer. Preliminary data from our clinical trial show that these three agents are well tolerated in the doses administered and that this combination shows exceptional promise as a possible therapeutic advance in this disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Pharmacokinetics of orally administered carboxyamido-triazole, an inhibitor of calcium-mediated signal transduction.

Carboxyamido-triazole (CAI), inhibits proliferation, invasion, and metastatic potential of a number of cancer cell lines at concentrations greater than 0.4 microgram/ml. The objective of this study was to characterize the pharmacokinetic profile from the first Phase I clinical trial of CAI for the single test dose and multiple daily dosing schedule. Two different p.o. formulations (liquid and gelcap) of CAI were administered. Thirty-nine patients with cancer were enrolled. The dose escalation schema was 100, 125, and 150 mg/m2/day and 200 and 330 mg/m2 every other day of the liquid formulation, plus 100 and 125 mg/m2/day and 200 mg/m2 every other day of the gelcap. The CAI pharmacokinetics are best described by a two-compartment open linear model. The gelcap was more rapidly absorbed than the liquid [time to maximum plasma concentration (Tmax) = 2.06 +/- 1.02 versus 5.31 +/- 3.59 h, P2 = 0.0012] which resulted in higher peak plasma concentrations. There was no evidence of saturable elimination as the dose was increased. The mean steady-state peak concentration was 5.1 +/- 1.0 microgram/ml for the 150 mg/m2/day multiple daily dosing regimen. The terminal half-life of CAI was relatively prolonged, 111 h, and the total body p.o. clearance was low (1.87 liters/h). The peak concentration for all dose levels explored was greater than the targeted concentration suggested by in vitro data for activity. Thus, these data suggest that an effective cytostatic exposure of CAI may be obtained with daily or every other day dosing without severe toxicity.

Administration, Oral↗
PubMed1994

Characterization of the sat4 gene encoding a streptothricin acetyltransferase in Campylobacter coli BE/G4.

The sat4 streptothricin resistance gene from Campylobacter coli BE/G4 was cloned into pUC18, and its nucleotide sequence was determined. Streptothricin acetyltransferase activity was detected in Escherichia coli cells containing recombinant plasmid pAT132 which carries the sat4 gene as an insert. The deduced amino acid sequence displayed 21-27% amino acid identity with streptothricin acetyltransferases from E. coli and streptothricin producers Streptomyces lavendulae and Streptomyces noursei. The sat4 gene was detected by hybridization in clinical and environmental isolates of Campylobacter spp.

Acetyltransferases↗
PubMed1993

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells.

In the murine spleen, germinal centers are the anatomic sites for antigen-driven hypermutation and selection of immunoglobulin (Ig) genes. To detail the kinetics of Ig mutation and selection, 178 VDJ sequences from 16 antigen-induced germinal centers were analyzed. Although germinal centers appeared by day 4, mutation was not observed in germinal center B cells until day 8 postimmunization; thereafter, point mutations favoring asymmetrical transversions accumulated until day 14. During this period, strong phenotypic selection on the mutant B lymphocytes was inferred from progressively biased distributions of mutations within the Ig variable region, the loss of crippling mutations, decreased relative clonal diversity, and increasingly restricted use of canonical gene segments. The period of most intense selection on germinal center B cell populations preceded significant levels of mutation and may represent a physiologically determined restriction on B cells permitted to enter the memory pathway. Noncanonical Ig genes recovered from germinal centers were mostly unmutated although they probably came from antigen-reactive cells. Together, these observations demonstrate that the germinal center microenvironment is rich and temporally complex but may not be constitutive for somatic hypermutation.

Animals↗