Cytokines and oncogene activity

Cytokines play a part in the control of cellular growth, differentiation and development. Given such pleiotropic activities, it is not unexpected that the expression of the cytokines is tightly regulated. When cytokine-mediated processes are altered by mutation and/or overexpression of some cytokine or cytokine receptor genes, oncogenic transformation can occur. Oncogenes which derive their transforming potential through this mechanism include sis, which represents the activated form of the platelet-derived growth factor B chain, hst1/K-fgflint-2, which share appreciable homology with the gene family of fibroblast growth factors, fms, which is related to the cell surface receptor for macrophage-colony stimulating factor, and erbB-1, which encodes a truncated form of the epidermal growth factor receptor. Cytokine treatment has resulted in modulation of aberrant oncogene activity in some model systems.     

Effects of verapamil on the pharmacokinetics and metabolism of epirubicin

Summary Experimental data suggest that multidrug resistance in cancer may be overcome by using an increased dose of anticancer agent(s) in combination with a resistance-modifying agent (RMA). We studied the pharmacokinetics and metabolism of both epirubicin (EPI) and verapamil (VPL) to explore the possible pharmacokinetic interactions between these two drugs. Ten patients with advanced breast cancer were given EPI (40 mg/m² in a daily i.v. bolus for 3 consecutive days), and five of them also received VPL (4×120 mg/daily p.o. for 4 consecutive days). The data indicated a significant interaction between these two drugs that affected their metabolism. The areas under the concentration-time curves (AUC) obtained for epirubicin glucuronide, epirubicinol glucuronide, and both of the 7-deoxy-aglycones were higher in the EPI+VPL group as compared with the EPI group. The AUC, terminal half-life, mean residence time, volume of distribution at steady state, and plasma clearance of EPI alone as compared with EPI+VPL did not differ significantly. These results suggest either an induction of enzymes necessary for drug metabolism or an increase in the liver blood flow, resulting in an enhanced generation of metabolites with time or in an inhibition of excretion processes. Comparisons of the AUC values obtained for EPI and its metabolites after the first, second, and third injections of EPI revealed a cumulative effect for the metabolites that was more pronounced in the EPI+VPL group, being significant (P<0.05) for epirubicin glucuronide in both treatment groups and for epirubicinol glucuronide in the EPI+VPL group. Maximal concentrations of VPL and nor-VPL reached 705±473 and 308±122 ng/ml, respectively, with the steady-state concentrations being 265±42 ng/ml for VPL and 180±12 ng/ml for nor-VPL.This study was supported by the Erich und Gertrud Roggenbuck-Stiftung zur Förderung der Krebsforschung (Hamburg). The anthracycline metabolites were kindly provided by Dr. A. Suarato (Farmitalia, Milano, Italy); nor verapamil was provided by Dr. Traugott (Knoll, Ludwigshafen, Germany)     

The clinical relevance of t(14; 18)/BCL-2 rearrangement and DEL 6q in diffuse large cell lymphoma and immunoblastic lymphoma

Background: t(14; 18)/bcl-2 gene rearrangement (R) is claimedto impart a worse rate of complete remission and disease-freesurvival in diffuse large cell lymphoma (DLCL). DEL 6q has alsobeen associated with poor outcome. Design: Retrospective studyof 54 patients with either diffuse large cell or immunoblasticlymphoma who had cytogenetics and/or molecular studies performed.Results: Patient characteristics, complete remission rate, andtime to treatment failure (TTF) were similar at three year follow-upfor groups with and without t(14; 18)/BCL-2R Survival was worsefor the former but the difference was not statistically significant.For DEL 6q, patient characteristics and survival rates weresimilar at three year follow-up for patients with and withoutthe abnormality. TTF was worse for the former but this was notstatistically significant. Conclusion: This study, with equalor greater number of patients with t(14; 18) than previous reports,fails to show a worse prognosis for patients with the t(14;18) chromosomal abnormality. A definite association will awaitfurther accrual of patients and a meaningul multivariate analysis. lymphoma, BCL-2, cytogenetics, DEL 6q     

Innervation of the sheep adrenal cortex: an immunohistochemical study with rat corticotrophin-releasing factor antiserum

Using indirect immunohistochemistry and an antiserum raised against rat corticotrophin-releasing factor (CRF) we have outlined an asymmetric network of cells and varicose fibers in sheep adrenal cortex. This network was not associated with the larger splanchnic nerves, but was occasionally found in small bundles or with blood vessels; in most instances fibers were found weaving independently through cortical parenchyma. A plexus of fibers was found in the zona reticularis, with a few fibers ramifying into adjacent medulla. Uni or bipolar cells were found throughout the cortex, with the greatest frequency at the corticomedullary junction; a multipolar-type cell was also found in this area. Staining of varicose structures and most cells was abolished by incubation with excess rat CRF 1-41, but not by ovine CRF or a range of other peptides. Though the immunoreactive species has not as yet been identified, it may thus share homology with sequences present in rat but not ovine CRF.     

Effects of focusing attention on breathing with and without apparatus on the face

In an attempt to identify a cause for the alteration in breathing pattern seen when conventional respiratory apparatus is applied to the face, we have studied the effects of causing the subject to focus attention on breathing by counting breaths in threes for 5 min. We used the respiratory inductance plethysmograph in 18 naive subjects who were unaware that their breathing was being measured. In the control periods, distraction was provided by a recorded story played through head-phones. The experiment was repeated with the rim of a facemask applied to the face. Focusing attention on breathing caused a prolongation of inspiration at a constant mean inspiratory flow, and lengthening of expiration. Tidal volume but not ventilation was increased. The facemask rim caused no significant change. It is concluded that conscious awareness of breathing could account for a major part of the effect of conventional respiratory apparatus.