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Biomedical subjects

M J Boyer

Publications and source records attributed to M J Boyer.

At least 37 records · Page 2Linked to original sources
PubMed1997

Phase I study of paclitaxel and oral etoposide in previously untreated non-small-cell and extensive small-cell lung cancer.

PURPOSE: This phase I study of paclitaxel and oral etoposide was performed to determine the safety of the combination in patients with advanced lung cancer who had received no prior chemotherapy, and to identify a dose for phase II testing. PATIENTS AND METHODS: Patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) or extensive small-cell lung cancer (SCLC), who had received no prior chemotherapy were treated with intravenous paclitaxel given as a three hour infusion (starting dose 100 mg/m2) and oral etoposide, 100 mg daily for five days. Two schedules of administration were used with the paclitaxel given on day 1 (schedule A) or day 5 (schedule B) of a 21 day cycle. RESULTS: Forty-nine patients were entered on the study, four of whom had SCLC. All patients were evaluable for toxicity. The maximum tolerated dose was paclitaxel 200 mg/m2 on day 1, in combination with oral etoposide 100 mg daily on days 1 to 5 (schedule A). The dose limiting toxicities were mucositis, myalgia, diarrhoea, and paraesthesiae. Using schedule B, myelosuppression, with febrile neutropenia was dose limiting at a paclitaxel dose of 160 mg/m2. Amongst the 45 patients with NSCLC there were three complete and eight partial responses (24%; 95% CI 13% 40%), while there was one complete response in the four patients with SCLC. CONCLUSION: Paclitaxel 200 mg/m2 on day 1, with oral etoposide 100 mg daily on days 1 to 5 can be administered safely, and is the recommended dose for phase II studies.

Administration, Oral↗
PubMed1997

Androgen deprivation is associated with enhanced endothelium-dependent dilatation in adult men.

Male gender is an independent risk factor for coronary artery disease, and androgen administration has been associated with increased atherosclerosis in experimental animals. Since endothelial dysfunction is an important event in the atherogenic process, we hypothesized that androgen deprivation in adult men might be associated with enhanced arterial endothelial function. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilatation) and after nitroglycerin (an endothelium-independent dilator). We studied 30 adult males aged 40 to 70 years: 10 had had bilateral orchidectomy and/or maximal androgen blockade for > or = 6 months for treatment of prostate cancer, and all were in complete remission (group 1). Ten healthy controls (group 2) and 10 controls who had remission from nonprostate cancers (group 3) were matched for age and smoking history. Testosterone levels were lower in men in group 1 versus groups 2 or 3 (0.8 +/- 0.1 versus 19.2 +/- 8.4 or 16.1 +/- 4.9 nmol/L, P < .001). By contrast, endothelium-dependent dilatation was markedly higher in group 1 than in groups 2 or 3 (6.2 +/- 3 versus 2.7 +/- 2 or 2.0 +/- 1.9%, P < .001). The nitroglycerin response was similar in all three groups (P = .92). On multivariate analysis, increased endothelium-dependent dilatation was significantly associated with low serum testosterone levels (P = .001) but not with cholesterol levels or with a past history of malignancy (P > .25). The withdrawal of male sex hormones may be associated with enhanced endothelial function in adult men. This is consistent with a deleterious effect of physiologic levels of male sex steroids on the arterial wall.

Adult↗
PubMed1997

Bioreductive agents: a clinical update.

Bioreductive agents are drugs that must undergo reduction to form an active cytotoxic species. The existence within solid tumors of regions of hypoxia offers the possibility of using such bioreductive agents to exert tumor-specific cytotoxicity. The only drug with bioreductive properties that is in routine clinical use in mitomycin C. This is a relatively old drug that has cytotoxicity independent of its bioreductive properties. However, the results of recent randomized clinical trials of mitomycin C in combination with radiotherapy have suggested that its bioreductive properties may play an important part in its activity. EO9 is a new bioreductive agent. Phase I and II clinical trials with EO9 have failed to demonstrate any significant antitumor activity. However, the design of these studies was such that activity based on bioreductive properties may have been difficult to demonstrate. Tirapazamine is the lead compound of a novel class of bioreductive agents. It is currently undergoing extensive clinical evaluation alone, combined with radiotherapy, and in combination with other cytotoxic drugs. Although early results of these trials are encouraging, the results of randomized studies will be required before the true value of this drug can be assessed.

Antineoplastic Agents↗
PubMed1994

[Production of oxygen free radicals in myocardial infarction treated by thrombolysis. Analysis of glutathione peroxidase, superoxide dismutase and malondialdehyde].

Many enzyme systems such as glutathione peroxidase (GPx) or superoxide dismutase (SOD) neutralise the oxygen derived free radicals produced during myocardial reperfusion by thrombolysis. Erythrocytic SOD, plasma and erythrocytic GPx and their cofactor selenium, substances reacting with thiobarbituric acid (TBARS) were analysed by repeated sampling between T0 and 48 hours in 24 patients treated by thrombolysis for acute myocardial infarction. Angiographic control was undertaken systematically between 60 and 180 minutes after initiating thrombolytic therapy: 18 patients had a patent vessel and 6 patients had an occluded vessel recanalised in 5 cases by angioplasty. Biological analysis was performed in the 23 patients successfully revascularised by thrombolysis, eventually completed by angioplasty. The plasma GPx decreased non-significantly between T0 and 2 hours from 246.8 +/- 53.3 to 233 +/- 39 U/ml with a significant increase between 2 and 48 hours from 233 +/- 39.2 to 294 +/- 76 U/ml, whereas the erythrocytic GPx rose significantly and constantly between T0 and 48 hours from 34.8 +/- 7.1 to 37.6 +/- 7.5 U/gHb with significant consumption of selenium between T0 and 4 hours from 81.2 +/- 14 to 68.5 +/- 12.6 micrograms/l. The erythrocytic SOD increased significantly between T0 and 48 hours from 318.9 +/- 40.8 to 337 +/- 59 U/gHb. Finally, the analysis of plasma TBARS showed a non-significant rise between T0 and 30 minutes from 1.59 +/- 0.30 to 1.71 +/- 1.43 mm/l with a return to the basic line values after about 2 hours. These results show a significant increase in the activity of enzymes protecting against the liberation of oxygen free radicals, such as erythrocyte or plasma GPx and erythrocyte SOD between T0 and 48 hours with consumption of selenium, cofactor of GPx, and an increase in circulating lipid peroxydes in acute myocardial infarction treated by thrombolysis. They also illustrate the oxidative stress which occurs in this situation.

Adult↗
PubMed1994

Crosslinking of the surface immunoglobulin receptor in B lymphocytes induces a redistribution of neurofibromin but not p120-GAP.

The activation of Ras proteins is a key step in the signal transduction pathways triggered by ligand-bound cell surface receptors. The GTPase activating proteins (GAPs) p120-GAP and neurofibromin, the neurofibromatosis-type 1 (NF1) gene product, are thought to play an essential role in the regulation of Ras activity by increasing the GTPase activity of wild type, but not activated Ras in vitro. Both GAPs are widely expressed in mammalian tissues thus raising the question of whether or not they have different regulatory functions. In this study, we have analysed the distribution of p120-GAP and neurofibromin in splenic B lymphocytes by immunofluorescent staining. Crosslinking of surface immunoglobulin (slg), the B-lymphocyte antigen receptor, induced the redistribution of neurofibromin. In contrast, no apparent change in the cellular localization of p120-GAP occurred followed the cross-linking of slg. The redistribution of neurofibromin coincided both spatially and temporally with the relocalization of crosslinked slg and was inhibited by the cytoskeletal disrupting agents colchicine and cytochalasin D. These findings indicated that neurofibromin and p120-GAP can be differentially regulated in vivo and suggest that neurofibromin is a component of the signaling pathway initiated by crosslinking of B lymphocyte slg. Furthermore, our observations that cocapping neurofibromin with slg is independent of the p21ras redistribution suggests that the role of neurofibromin in B cells is not solely related to its ability to act as a Ras regulator.

Animals↗
PubMed1993

Ectopic corticotropin syndrome and small-cell carcinoma of the lung. Clinical features, outcome, and complications.

BACKGROUND: Ectopic corticotropin syndrome is a rare complication of small-cell lung cancer (SCLC). There is little information concerning this syndrome available in the literature. We therefore reviewed all cases of ectopic corticotropin syndrome seen at our institution during a 20-year period. METHODS: Cases were identified by searching a computerized database and reviewing the charts of all 840 patients with SCLC seen between 1971 and 1991. Patients were included if they met at least two of the following criteria: spontaneous hypokalemia (potassium level, < 3.2 mmol/L); plasma cortisol level greater than 600 nmol/L; 24-hour urinary free cortisol level greater than 400 nmol/d; and plasma corticotropin level greater than 22 pmol/L. Data were abstracted from the patients' medical records. RESULTS: Of 840 patients with SCLC, 14 (1.6%) had ectopic corticotropin production. This was diagnosed at the time of presentation with SCLC in seven patients and from 3 to 19 months later in the remainder. Five patients had limited disease and nine had extensive disease. One or more features of Cushing's syndrome were observed in 57% of patients, but the entire syndrome occurred rarely. Spontaneous hypokalemia was present in all patients, and 10 patients (71%) had hyperglycemia. There were two complete responses and one partial response to chemotherapy, giving an overall response rate of 21%, and the median survival was 5.5 months. Ten patients died of progressive growth of tumor, while three patients died of infections. In one other patient, infection probably contributed to death. A high rate of nonfatal infections was also seen. CONCLUSIONS: The occurrence of SCLC with ectopic corticotropin syndrome is associated with poor survival, and a high incidence of infective complications, in patients treated with chemotherapy.

ACTH Syndrome, Ectopic↗
PubMed1993

pH dependent cytotoxicity of N-dodecylimidazole: a compound that acquires detergent properties under acidic conditions.

N-dodecylimidazole is a compound which acquires detergent properties under acidic conditions and might be useful in killing selectively cells in those regions of solid tumours which have a reduced extracellular pH (pHe). We have therefore studied the effects of N-dodecylimidazole against malignant cells in tissue culture. N-dodecylimidazole displayed pHe-dependent cytotoxicity against EMT-6 and MGH U1 cells; cell killing was dose dependent and was 100-fold greater at pHe 6.0 than pHe 7.0. Reduced toxicity of N-dodecylimidazole was observed at higher cell concentrations (> 10(6) cells ml-1), and only minor effects were observed against multicellular tumour spheroids. Potential mechanisms of action of N-dodecylimidazole include detergent-mediated lysis of the cell membrane at low pHe, and selective uptake into lysosomes where detergent activity leads to rupture of the lysosomal membrane and release of cytolytic enzymes. Inhibition of activity of cysteine proteases by the inhibitor E-64 did not protect cells against the toxicity of N-dodecylimidazole, suggesting that these lysosomal enzymes do not play a major role in the mechanism of action of this compound. Lysis of erythrocytes (which contain no lysosomes) was observed with low concentrations of N-dodecylimidazole. Dependence of cell lysis on cell concentration was similar to that observed for two other detergents that act on the plasma membrane, Triton X-100 and sodium dodecyl sulfate. We conclude that N-dodecylimidazole causes pHe dependent cell killing in two cultured tumour cell lines, and that its mechanism of action is probably due to acid mediated production of detergent activity which acts primarily on the cell plasma membrane.

Animals↗
PubMed1993

Regulation of intracellular pH in subpopulations of cells derived from spheroids and solid tumours.

Solid tumours are known to develop regions of extracellular acidity and survival of tumour cells in such regions depends on membrane-based mechanisms which regulate intracellular pH (pHi). We have therefore developed a method, based on dual staining of cells and flow cytometry, to study the regulation of pHi in subpopulations of tumours and spheroids. The activity of membrane-based pHi regulating transporters was studied in EMT-6 and MGH U1 cells grown in monolayer culture, spheroids, and tumours. pHi was measured with the fluorescent pH probe 2'7'-bis-(2-carboxyethyl)-5-(and-6)carboxyfluorescein, and Hoechst 33342 was used to identify cells from different regions of tumours and spheroids. In monolayer culture, incubation of cells for 18 h at pHe 6.6 led to a 1.3-1.5-fold enhancement in the activity of both the Na+/H+ exchanger and the Na(+)-dependent Cl-@HCO3- exchanger. This effect was prevented by the protein synthesis inhibitor cycloheximide. Cells from the centre of EMT-6 spheroids had increased activity of the Na+/H+ exchanger compared to cells from the periphery, when spheroids were grown in medium at pH 6.6, but not at 7.4. By contrast, in MGH U1 spheroids, cells from the centre had increased activity of the Na+/H+ antiport under both sets of conditions. There was no significant difference in the activity of the Na+/H+ exchanger in cells derived from different subpopulations of EMT-6 tumours or MGH U1 xenografts in nude mice. Although upregulation of Na+/H+ exchange occurs after exposure to acidic conditions in vitro, the microenvironmental conditions found within solid tumours do not appear to cause this effect. Our results suggest the feasibility of pharmacological inhibition of Na+/H+ exchange activity as an approach to therapy directed against nutrient-deprived tumour cells.

Animals↗
PubMed1992

Regulation of intracellular pH in tumor cell lines: influence of microenvironmental conditions.

The effect of microenvironmental factors on the regulation of intracellular pH (pHi) in MGH U1 cells and EMT-6 cells was studied using the fluorescent pH probe 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. Na+/H+ exchange and Na(+)-dependent Cl-/HCO3- exchange were found to be present in both cell types. The activity of both exchangers was dependent on pHi, with low levels of activity at neutral pH and an increase in activity as pHi fell. The level of extracellular pH (pHe) also influenced the operation of the exchangers, with a fall in activity as pHe was reduced over the range 7.4-6.6. This effect was more marked for the Na(+)-dependent Cl-/HCO3- exchanger than for the Na+/H+ antiporter, suggesting that under conditions of reduced pHe the Na+/H+ antiporter is the major mechanism for regulation of pHi. Neither 6 h of radiobiological hypoxia nor variations in the extracellular [Ca2+] over the range 1-6 mM had an effect on the regulation of pHi, while extracellular lactate (5-10 mM) caused a small, concentration-dependent decrease in the combined activity of both exchangers. We conclude that under the microenvironmental conditions found in some regions of tumors, Na+/H+ exchange may be the major method of regulation of pHi.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

Pericardiocentesis for symptomatic malignant pericardial effusion: a study of 36 patients.

We reviewed 36 cases of symptomatic malignant pericardial effusion managed with pericardiocentesis at our institution from 1982 to 1989. There were 13 men and 23 women, aged 49 +/- 12 years (range, 33-76 years). The commonest underlying tumours were lung cancer (12 cases, 33%) and breast cancer (11 cases, 30%). Pericardiocentesis was successful as the initial management in 34 of 36 patients (94%); one patient died as a result of the procedure and another required subxiphoid incision and tube drainage of the effusion. When intrapericardial sclerotherapy was performed, only three of 28 patients required repeat pericardiocentesis, and when sclerotherapy was not performed initially, four of seven patients had recurrent symptomatic effusions. Median survival following pericardiocentesis in breast cancer patients was 10 months (range, 0-36 months) and in all other malignancies was four months (range, 0-12 months). We conclude that pericardiocentesis with intrapericardial sclerotherapy provides good local control for symptomatic malignant pericardial effusion in the majority of patients. In spite of this, the median survival of such patients is poor, especially in patients with malignancies other than breast cancer, with few patients surviving more than a few months.

Adult↗
PubMed1990

Diethylstilbestrol revisited in advanced breast cancer management.

Prior to the introduction of tamoxifen, diethylstilbestrol (DES) was widely used as the first-line endocrine therapy in postmenopausal women with advanced breast cancer. Since randomized trials reported that tamoxifen has a similar response rate but fewer side effects than DES, its use has declined markedly. We administered DES in a dose of 10-20 mg daily to 11 postmenopausal women with advanced breast cancer, all of whom had received previous endocrine and some cytotoxic therapy also. Four women showed tumour responses to DES (1 complete and 3 partial), 5 had stable disease, and 2 progressive disease. Amongst the patients who responded, 2 had previously been unresponsive to other endocrine treatments. Of the women with stable disease, 3 had prolonged relief of symptoms. No withdrawal responses were noted. The major side effects were nausea (severe in 2 patients, mild in 1) and cardiac failure (2 patients). We conclude that DES remains a useful, active agent in the management of advanced breast cancer in postmenopausal women, even in patients with tumours unresponsive to other endocrine therapy.

Aged↗
PubMed1990

mu-Opioid receptors and not kappa-opioid receptors are coupled to the adenylate cyclase in the cerebellum.

The putative regulatory effect of opioids on adenylate cyclase was investigated in two different preparations containing, respectively, two different populations of opioid receptors: the rabbit cerebellum (greater than 75% mu-opioid receptors) and the guinea pig cerebellum (greater than 80% kappa-opioid receptors). In the mu-preparation, but not in the kappa-preparation, opioids inhibited the basal and the forskolin-stimulated adenylate cyclase activity in a dose-dependent manner and stereospecifically. The inhibition was in the 20-30% range, required the presence in the assay medium of Mg2+ and of GTP, but was independent of the presence of Na+. Pharmacological characterization of the inhibitory response in the rabbit cerebellum clearly showed that it was under the control of a mu-opioid binding site, with the effect being elicited by non-selective (etorphine and morphine) and mu-selective (Tyr-D-Ala-Gly-Me-Phe-Gly-ol) agonists, whereas delta- and kappa-selective agonists were almost totally ineffective. ADP ribosylation of inhibitory GTP-binding protein by pertussis toxin failed to block the inhibitory effect of opioids, and data presented suggest that this failure is likely to be the consequence of a limited access of the toxin to its substrate in rabbit cerebellum membranes.

Adenylate Cyclase Toxin↗