Search PubMed⌕ Search

Biomedical subjects

J F Bishop

Publications and source records attributed to J F Bishop.

At least 91 records · Page 5Linked to original sources
PubMed1991

Etoposide in the management of leukemia: a review.

Single-agent etoposide (VP16-213, NSC 141540) induces complete response (CR) in 15% to 25% of previously treated patients with acute nonlymphocytic leukemia (ANLL). Etoposide has been used successfully in combination with cytarabine, daunorubicin, and amsacrine as salvage and consolidation therapy. Patients aged 15 to 70 years with previously untreated ANLL were randomized to therapy with either 7-3 (cytarabine 100 mg/m2/d days 1 to 7 and daunorubicin 50 mg/m2/d days 1 to 3) or 7-3-7 (7-3 plus etoposide 75 mg/m2/d days 1 to 7). Patients achieving CR received two consolidation courses of the same drugs for shorter duration (5-2 or 5-2-5). Of 264 eligible patients, 7-3 induced CR in 56%, 7-3-7 in 59%. Remission duration was significantly improved with 7-3-7 (median, 12 months 7-3, 18 months 7-3-7, P = .01) but not survival. Subset analysis in patients under 55 years of age revealed prolonged remission (median, 12 months 7-3 v 27 months 7-3-7, P = .01) and survival (median, 9 months 7-3 v 17 months 7-3-7, P = .04) with 7-3-7. Hematologic toxicity was similar during induction but significantly more severe in consolidation. Etoposide is active in ANLL and prolongs remission when used as induction therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

A putative AP-2 binding site in the 5' flanking region of the mouse POMC gene.

Using extracts of AtT-20 cell nuclei, protein binding sites on the POMC gene 5'-flanking region were examined with an exonuclease protection approach. One such binding site, located from -119 to -106 bp upstream from the mouse POMC gene transcription initiation site, which exhibited a close homology to the activator protein-2 (AP-2) site [1]. A double-stranded oligonucleotide containing this site was subsequently used in gel shift assays to demonstrate AP-2 consensus sequence binding activity in extracts of AtT-20 cell nuclei. Gel shift competition experiments using both homologous and heterologous competitor DNA sequences revealed that the AP-2 like factor(s) exhibited specific binding to the mouse AP-2 consensus sequence. Furthermore, AP-2 factor binding was also modulated by a CTF/NF1-like factor. Pretreatment of AtT-20 cell nuclear extracts with alkaline phosphatase prior to inclusion in gel shift assays led to a reduction in the intensities of AP-2 factor-specific bands, indicating a potential involvement of protein phosphorylation in AP-2 factor binding in AtT-20 cells.

Animals↗
PubMed1990

Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group.

Previously untreated patients with acute nonlymphocytic leukemia (ANLL) aged 15 to 70 years were randomized to either cytosine arabinoside 100 mg/m2/d continuous intravenous (IV) infusion days 1 through 7, daunorubicin 50 mg/m2/d IV days 1 through 3 (7-3), or the same drugs intensified with etoposide 75 mg/m2/d IV days 1 through 7 (7-3-7) as induction therapy. Patients achieving complete remission (CR) received two courses of consolidation therapy (5-2 or 5-2-5) followed by maintenance therapy. Of 264 eligible patients, CR occurred in 56% of 7-3 and 59% of 7-3-7 patients; 7-3-7 significantly improved remission duration (P = .01). The median remission duration was 12 months for 7-3 and 18 months for 7-3-7. Survival was similar when the two arms were compared overall. Subset analysis performed to identify patients with the most benefit showed that etoposide significantly prolonged remission duration in younger patients (less than 55 years) with a median of 12 months for 7-3 and 27 months for 7-3-7 (P = .01). Survival appeared to be prolonged with 7-3-7 in patients aged less than 55 years, with a median of 9 months for 7-3 as compared with 17 months for 7-3-7 (P = .03). In older patients (aged greater than or equal to 55 years), 7-3-7 was more toxic, with significantly more severe [World Health Organization (WHO) grade 3 or 4] stomatitis (P = .02) and no additional clinical benefit. Hematologic toxicity for induction courses was similar, with granulocytopenia less than 0.5 x 10(9)/L for a median of 16 days per course for 7-3 and 15 days for 7-3-7. Hematologic toxicity was more severe for 5-2-5 consolidation courses (P = .003). Induction and consolidation therapy intensified with etoposide resulted in significantly improved remission duration but not survival.

Adolescent↗
PubMed1990

Pharmacokinetic study of doxifluridine given by 5-day stepped-dose infusion.

Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) metabolism has been reported to be saturable and associated with a fall in clearance of the drug as the dose is increased. The aim of the present study was to determine the disposition of 5'-dFUR and 5-fluorouracil (5-FU) when 5'-dFUR was given as a 5-day infusion, with the infusion rate increased stepwise every 24 h. Measurement of plasma and urinary levels of 5'-dFUR and 5-FU at steady state for each infusion rate enabled the estimation of 5'-dFUR renal (ClR) and nonrenal (ClNR) clearance and 5-FU renal clearance. A total of 28 patients with histologically proven malignancy received 5-day courses of 5'-dFUR ranging in dose from 3.75 to 20 g/m2 per 120 h. The lowest dose given over 24 h was 0.25 g/m2, and the highest was 5 g/m2. Steady-state plasma levels of 5'-dFUR ranged from 167 to 6,519 ng/ml. At these plasma levels there was no evidence of significant saturation of 5'-dFUR metabolism; steady-state plasma levels of 5'-dFUR increased approximately linearly with dose, and nonrenal clearance did not change significantly with dose. There was also no evidence of nonlinearity in 5'-dFUR renal clearance. The mean (+/- SD) ClR of 5'-dFUR was 108.9 +/- 53.6 ml/min per m2 (range, 45.7-210 ml/min per m2), and the ClNR was 728 +/- 181 ml/min per m2 (range, 444-1,119 ml/min per m2). Renal clearance comprised 13% of the total 5'-dFUR clearance. The mean renal clearance of 5-FU was 100.8 +/- 48.6 ml/min per m2 (range, 23.5-198 ml/min per m2). There was considerable interpatient variability in 5'-dFUR renal and nonrenal clearance, even at the same dose level. We concluded that the administration of 5'-dFUR by the infusion method described avoided the saturation of nonrenal elimination processes reported to occur with shorter infusion schedules.

Adult↗
PubMed1990

Etoposide, carboplatin, cyclophosphamide and vincristine in previously untreated patients with small-cell lung cancer.

The efficacy and toxicity of 120 mg/m2 etoposide and 100 mg/m2 carboplatin given i.v. daily x 3 together with 750 mg/m2 cyclophosphamide and 1.4 mg/m2 vincristine given i.v. on day 1 (ECCO) in a regimen given every 28 days for 6 courses was assessed in 90 (40 limited stage, 50 extensive stage) previously untreated patients with small-cell lung cancer. Mediastinal irradiation using 50 Gy in 25 fractions was given to limited-stage patients without progression after 3 courses of chemotherapy. Cranial irradiation with 30 Gy in 10 fractions was given to all patients attaining a complete response (CR). Objective responses were seen in 83% [CR, 60%; partial response (PR), 23%] of patients with limited and 76% (CR, 22%; PR, 54%) of those with extensive disease. The median relapse-free survival for objective responders with limited disease was 13.4 months, with a median of 8.0 months for extensive-stage patients. The median relapse-free survival for patients achieving a CR was 13.4 months, with a median of 7.8 months for those undergoing a PR. The median survival was 13.3 months for patients with limited disease, with a median of 9.6 months for those with extensive disease. The median survival following a CR was 18.2 months, with a median survival of 9.9 months for those showing a PR. The combination was well tolerated, with either no nausea or nausea only (WHO grade 0 or 1) in 56% of patients and minimal mucositis, renal toxicity, neurotoxicity or ototoxicity. Neutropenia measuring less than 1.0 x 10(9) WBC/l (WHO grade 3 or 4) was seen in 74% of patients, with two deaths due to infection occurring during neutropenia. Thrombocytopenia of less than 50 x 10(9) platelets/l (WHO grade 3 or 4) occurred in 24% of patients. ECCO is a new, active, well-tolerated program for previously untreated patients with small-cell lung cancer.

Adult↗
PubMed1990

Dose-intense weekly cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisolone (CMFP) in advanced breast cancer.

Weekly chemotherapy with cyclophosphamide 80 mg m-2 day-1 p.o. continuously, methotrexate 35 mg m-2 week-1 i.v., 5-fluorouracil 500 mg m-2 week-1 i.v., vincristine 1.4 mg m-2 i.v. every two weeks and prednisolone 20 mg m-2 day-1 p.o. continuously (CMFVP) was prospectively studied in 45 previously untreated outpatients with advanced breast cancer to determine the feasibility of delivering a dose-intense regimen. Of 40 evaluable patients, complete response (CR) occurred in one patient, partial response (PR) in 20 (CR + PR 53%), stable in eight, progression in 11 and five were unevaluable for response. The median relapse-free survival for responders was 25 weeks and median survival for all patients was 31 weeks. The mean dose intensity relative to the Cooper regimen fell from 1.02 to 0.6 within the first 4 weeks of treatment and the median dose intensity achieved for all patients on study was only 0.52. Eighty-seven per cent of patients had treatment delays with a mean of 3.9 delays per patient and 71% had dose reductions. Neutropenia was the major toxicity with WHO grade 3 or 4 neutropenia (less than 1.0 x 10(9) l-1) in 62% of patients and three septic deaths while neutropenic. Dose-intense weekly CMFVP in this schedule cannot be delivered to previously untreated outpatients with advanced breast cancer.

Adult↗
PubMed1990

Interleukin 1 induces early protein phosphorylation and requires only a short exposure for late induced secretion of beta-endorphin in a mouse pituitary cell line.

Previous work has shown that prolonged pretreatment of a mouse anterior pituitary cell line, AtT-20 cells, with the cytokine interleukin 1 (IL-1) stimulates beta-endorphin release and potentiates the secretion induced by many secretagogues. Desensitization of protein kinase C (PKC) by pretreatment with phorbol ester [phorbol 12-tetradecanoate 13-acetate (TPA)] for 8 hr abolished the secretion induced by TPA as well as the enhancement of TPA-induced beta-endorphin release produced by IL-1. Desensitization of PKC only partly abolished the potentiating effects of IL-1 on corticotropin-releasing factor-induced beta-endorphin secretion. In contrast, IL-1-induced beta-endorphin release was independent of PKC. We observed that treatment of AtT-20 cells with IL-1 markedly phosphorylated 19-, 20-, and 60-kDa proteins within minutes, presumably by early activation of protein kinases. Prolonged treatment with TPA, which was shown to desensitize an 87-kDa protein (a substrate for PKC), had no effect on IL-1-induced phosphorylation of 20-, 60-, and 87-kDa proteins, indicating that the phosphorylation of these proteins does not involve PKC. IL-1 does not generate cAMP in AtT-20 cells, suggesting that a cAMP-dependent protein kinase is also not involved. Prolonged treatment with IL-1 abolishes the capacity of cytokine to induce the phosphorylation of 20- and 60-kDa proteins. The presence of IL-1 was required initially only for a short time to induce late secretion in AtT-20 cells. These observations indicate that once IL-1 generates an early signal, its presence is no longer necessary for the subsequent secretion of beta-endorphin.

Animals↗
PubMed1990

A phase I study of doxifluridine as a five-day stepped-dose continuous infusion.

Doxifluridine (5'-dFUR) is a prodrug of 5 fluorouracil (5-FU) synthesized in an attempt to improve the therapeutic index compared with 5-FU. In this phase I study, cohorts of three patients were treated by a 5-day continuous infusion with the dose increased daily, total doses ranging from 3.75 g/m2 to 20 g/m2/120 h. Twenty-nine patients received 54 courses (median 2, range 1-4). The dose-limiting toxicities were mucositis (Miller grade 3 in three patients and grade 4 in another) and grade 4 neutropenia and thrombocytopenia in two patients. Other toxicities included nausea, vomiting, and diarrhea, rash, and fever. Neurological toxicity was mild and no cardiovascular toxicity was recorded. Plasma and urine levels of 5'-dFUR and 5-FU were quantitated by high-performance liquid chromatography. Steady-state plasma levels between 167 ng/ml and 6,519 ng/ml were recorded and at these levels there was no evidence of saturation of doxifluridine metabolism. One patient at the maximum tolerated dose of 20 g/m2/120 h had a complete response in a nasopharyngeal carcinoma.

Adult↗
PubMed1990

Effects of protein kinase C down-regulation on secretory events and proopiomelanocortin gene expression in anterior pituitary tumor (AtT-20) cells.

To elucidate the role of the diacylglycerol-protein kinase C (PKC) pathway in beta-endorphin synthesis and secretion in anterior pituitary corticotrope tumor cells (AtT-20), a procedure for down-regulating PKC activity in the cells was developed. Treatment of AtT-20 cells with 12-O-tetradecanoylphorbol 13-acetate (TPA) led to an increase in [3H]phorbol 12,13-dibutyrate binding to PKC in the membrane fraction of these cells 30 s after its addition to the culture medium. Thereafter, a decrease in both [3H]phorbol 12,13-dibutyrate binding and PKC-specific phosphotransferase activity occurred in a time- and dose-dependent manner in both the cytosolic and membrane fractions. For example, treatment of the cells with 100 nM TPA for 24 h resulted in an almost complete depletion of PKC activity. Immunoreactive beta-endorphin secretion was found to be stimulated two- to fourfold in the control cells after incubation with corticotropin-releasing factor (10(-7) M), forskolin (10(-6) M), or TPA (10(-7) M) for 4 h. In cells rendered PKC deficient, TPA-stimulated immunoreactive beta-endorphin release was abolished, forskolin-stimulated release was unaffected, and corticotropin-releasing factor-stimulated release was depressed. Treatment of control cells with any one of the three stimulatory agents led to an increase in proopiomelanocortin mRNA levels, and these responses were also depressed after TPA pretreatment. The results suggest that physiological processes thought to be entirely cyclic AMP dependent, such as corticotropin-releasing factor-elicited secretion, may be partially dependent on PKC-mediated biochemical events.

Animals↗
PubMed1989

A phase I study of trimetrexate (NSC 352122) administered by 5-day continuous intravenous infusion.

Trimetrexate (TMTX) is a potent inhibitor of dihydrofolate reductase that circumvents the transport resistance seen with methotrexate and has a wide spectrum of preclinical activity. A total of 18 patients with advanced cancer were treated in a clinical and pharmacological phase I trial with TMTX given as a continuous 5-day intravenous infusion. Neutropenia, thrombocytopenia and stomatitis were the dose-limiting toxicities at the maximum tolerated dose of 50 mg/m2 per 120 h (10 mg/m2 per day for 5 days). There was one septic death associated with neutropenia. Other toxicities were mild rash, mild nausea and transiently raised serum transminase levels. Significant relationships between the dose given and the AUC of plasma TMTX and the steady-state plasma level were established. Significant, although weak, relationships between the percentage of change in neutrophils and platelets and both the AUC and steady-state plasma level of TMTX were also observed. No objective tumour responses were seen, although six patients had stable disease. The recommended phase II dose for a continuous infusion of trimetrexate is 40 mg/m2 per 120 h.

Adult↗
PubMed1989

Carboplatin and continuous infusion 5-fluorouracil for advanced head and neck cancer.

Fifty-one patients with recurrent or advanced squamous cell carcinoma of the head and neck received carboplatin 70 mg/m2/day bolus X 5 days i.v. and 5-fluorouracil (5-FU) 1000 mg/m2/day by continuous infusion i.v. for 5 days as initial chemotherapy. There were four complete responders (CR) and 12 partial responders (PR). Durations of CR were 6.8 months, 7.2+ months and 14.8+ months with one patient lost to follow up after achieving CR. For objective responders the median relapse-free survival from the time of response was 5.3 months and survival from registration 11.7 months. The median survival for all patients was 4.8 months. The major toxicities were myelosuppression and mucositis. Neutropenia (less than 1.0 X 10(9)/l) occurred in 19% of patients, thrombocytopenia (less than 50 X 10(9)/l) in 17% and severe (WHO grade three or four) mucositis was experienced by 28% patients. This combination had less gastrointestinal and nephrotoxicity than platinum containing combinations and can be used in patients with a poorer performance status.

Adult↗
PubMed1989

A dose finding study of prochlorperazine as an antiemetic for cancer chemotherapy.

This phase I study determined the maximum tolerated dose of prochlorperazine when used as an antiemetic prior to cytotoxic chemotherapy. Initially, cohorts of three patients were given prochlorperazine at escalating doses of 0.2, 0.4, 0.6, 0.8, 1.0 and 1.2 mg/kg as an intravenous infusion over 20 min. The maximum tolerated dose was 1.2 mg/kg. The dose-limiting toxicity was hypotension which was reversed by a fluid load. The other major toxicities were extrapyramidal reactions which were dose related. All patients at the 1.2 mg/kg dose reported restlessness while five of six were restless and two of six at 1.0 mg/kg had muscle spasms. Two of seven patients reported restlessness at the 0.8 mg/kg level. Sedation and dry mouth were reported at all dose levels but were more common at higher doses. Prochlorperazine in plasma was assayed by high performance liquid chromatography with electrochemical detection and pharmacokinetics were determined for three patients at the 1.0 mg/kg dose level. The average terminal elimination half life was 7.6 +/- 0.4 h, plasma clearance 27 +/- 5 ml/min/kg and volume of distribution 17.7 +/- 4.5 l/kg. The dose of prochlorperazine recommended for further studies of antiemetic efficacy is 0.8 mg/kg intravenously.

Antiemetics↗
PubMed1988

Nuclear protein kinase substrates in AtT-20 cells: translocation of a 14 kDa phosphoprotein.

In this work we characterize some acidic nuclear substrates of protein kinase C (PKC) and cyclic AMP-dependent protein kinase (PKA), using intact anterior pituitary corticotrophic tumor cells (AtT-20/D16-16). It was found that, as in the cytosolic fraction, substrates for both PKC and PKA exist in the nucleus and that changes in the phosphorylation states of a few of these phosphoproteins are mediated by both kinases. One of the phosphoproteins examined, a 14 kDa phosphoprotein (pp14) described previously, exhibited a phorbol-ester induced translocation from nucleus to cytosol in pulse-chase experiments utilizing 35S-methionine labeling. These results suggest that pp14 may be involved in signal transduction in AtT-20 cells. Although its identity remains to be determined, a 14 kDa DNA-binding protein was also seen in nuclear extracts of AtT-20 cells.

Animals↗
PubMed1988

Rat intermediate lobe in culture: dopaminergic regulation of POMC biosynthesis and cell proliferation.

The effects of the selective D-2 selective agonist, quinpirole, on biosynthesis of proopiomelanocortin (POMC) and cell proliferation rate of cultures of rat intermediate lobe (IL) have been examined. Primary cultures of rat IL were prepared by mechanically dispersing IL lobules in medium. Following a six day incubation, approximately 25% of the cells settled onto the culture plate and began to extend into a monolayer. Quinpirole markedly reduced immunoreactive beta-endorphin levels in the medium and POMC mRNA in both the attached and floating lobules. The incorporation of 35S-methionine into 32 kDa POMC, a 18-22 kDa complex of proteins, a 16 kDa protein and a 15 kDa protein was decreased significantly in both the attached and floating lobules. In contrast, the proliferation in the floating, but not the attached, cells was inhibited by quinpirole. The floating IL lobule appears to provide a reasonably faithful model of the dopaminergic regulation of IL function in vivo, while the attached IL cells may provide an interesting tool to study the regulation of IL cell proliferation.

Animals↗
PubMed1988

Rat intermediate lobe in culture: a histological and biochemical characterization.

The histology, immunohistochemistry, peptide synthesis and secretion as well as proliferation rate of rat intermediate lobe (IL) were studied in primary cultures. The cultures contained two populations of cells: melanotrophs either organized in free floating lobules or in lobules which attached to the dishes and formed a monolayer. Both populations retained their in vivo morphology: polyhedral cells with smooth, ovoid nuclei and a large number of cytoplasmic secretory coated vesicles, a well developed Golgi apparatus, abundant mitochondria and extensive areas of rough endoplasmic reticulum. The melanotrophs stained with varying intensity for alpha-MSH and in situ hybridization showed the presence of pro-opiomelanocortin (POMC) mRNA. 35S-methionine incorporation combined with 2-D gel electrophoresis demonstrated POMC peptide synthesis and radioimmunoassay confirmed its secretion into the medium. 3H-thymidine uptake in the attached melanotrophs was considerably higher than that in the free-floating melanotrophs, demonstrating the dependency of proliferation rate on the cytoarchitecture of the explant. The retention of melanotroph morphology, biosynthetic and proliferative capacity in vitro affords a valid model system for studying POMC gene expression.

Animals↗
PubMed1988

A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation.

Twenty patients with extravasation of anthracyclines were treated on a single-arm pilot study with topical 99% dimethyl sulfoxide (DMSO) and observed for 3 months with regular examinations and photographs. DMSO was applied to approximately twice the area affected by the extravasation and allowed to air dry. This was repeated every six hours for 14 days. The initial signs of extravasation included swelling in 17 patients, erythema in 15, and pain in 12. The median area of damage was 8.25 cm2 and a median of 25 minutes elapsed between extravasation and application of DMSO with one patient not treated until seven days postextravasation. Sixteen patients were observed for 3 months, two died of disease earlier after receiving 2 weeks of DMSO and three days of DMSO, respectively, and two were lost to follow-up having received one day and five days of DMSO. In no patient did extravasation progress to ulceration or require surgical intervention, suggesting with 95% confidence a true ulceration rate of between 1% and 17%. At 3 months there was no sign of residual damage in six patients, while a pigmented indurated area remained in ten. Two patients had a recall reaction with increased pain at the extravasation site when further intravenous (IV) doxorubicin was administered. The only toxicities of DMSO included a burning feeling on application subsequently associated with itch, erythema, and mild scaling. Blisters occurred in four patients. Six patients reported a characteristic breath odor associated with DMSO. Topical DMSO appears to be a safe and effective treatment for anthracycline extravasation.

Administration, Topical↗