Cellular pharmacology of mu-[1,2-bis(diphenylphosphino)ethane]bis[(1-thio-beta-D-gluco pyranosato-S)gold(I)]: a novel antitumor agent

SK&F 102912 (mu-[1,2-bis(diphenylphosphino)ethane]bis[(1-thio-beta-D- glucopyranosato-S)gold(I)], [(Autg)2(dppe)]) has shown reproducible and significant activity in transplantable murine tumor models and represents a structurally unique class of antineoplastic agents. A number of in vitro studies were performed to elucidate the cellular pharmacology of this gold-containing complex. [(Autg)2(dppe)] is a potent cytotoxic agent in vitro as demonstrated by its ability to inhibit the clonogenic capacity of a variety of tumor cell lines following a brief exposure to the drug. Cell-cycle analysis using HL-60 cells showed that low concentrations (2 microM) of [(Autg)2(dppe)] induced an S-phase block and higher concentrations induced a secondary block at the G1/S boundary. [(Autg)2(dppe)] had several effects on DNA metabolism and structure including preferential inhibition in cells of DNA synthesis (relative to RNA and protein synthesis) and the production of DNA single- and double-strand breaks as measured by alkaline elution. The cytoxic mechanism of this gold complex appears to be distinct from that of the monophosphine-gold complex auranofin.     

Pharmacological characterization of [Leu-13-psi-CH2NH-Leu14]-bombesin as a specific bombesin receptor antagonist on isolated smooth muscle cells

Isolated smooth muscle cells from guinea pig stomach were used to study the pharmacological characteristics of a newly synthetized bombesin analog, [Leu13-psi-CH2NH-Leu14]-bombesin (psi 13,14-BN) to function as antagonist of bombesin-induced contractile response. The antagonism caused by this new analog was compared to that obtained with the substance P analog [D-Arg1,D-Pro2,D-Trp7,9,Leu11]Substance P [( APTTL]SP), which has been used until now to characterize bombesin receptors on smooth muscle cells. psi 13,14-BN resulted to be more potent than [APTTL]SP as antagonist of bombesin action on smooth muscle. Comparing the IC50, psi 13,14-BN (IC50 70 nM) was 8 times more potent than [APTTL]SP (IC50 600 nM). In contrast to [APTTL] SP, the action of psi 13,14-BN was shown to be specific toward bombesin receptors in that it does not interfere with receptors for other agents (i.e., cholecystokinin, acetylcholine or substance P). The antagonism induced by both compounds was competitive inasmuch as the slope of the regression lines obtained by Schild plot analysis were not significantly different from the unity. The apparent affinity for the bombesin receptor was 0.8 nM for psi 13,14-BN and 7.8 nM for [APTTL]SP. These results indicate that psi 13,14-BN acts on isolated gastric smooth muscle cells as a competitive bombesin receptor antagonist, with a higher affinity and specificity than the substance P analog used previously.     

Support of the pregnant soldier in the workplace: a comparison of her assessment with that of her supervisor

Comparison of pregnant soldiers' responses to statements concerning job performance, job satisfaction, and support in the workplace with those of their supervisors reveal no significant difference in how the two groups view the work situation prior to pregnancy. Although the pregnant soldiers do not feel less supported during the pregnancy than before, they do not appreciate the significant increase in support during the pregnancy that is reported by the supervisors. Interviews of pregnant soldiers suggest that they and their supervisors define support differently, and this difference in perception may have negative implications for the optimal utilization of servicewomen during pregnancy.     

Bacteria and their products peptidoglycan and teichoic acid potentiate antigen-induced histamine release in allergic patients

Histamine release was examined in leukocyte suspensions from patients allergic to grass pollen, mite or cat dander or to bacteria (antigen). When the cells were challenged with specific antigen plus bacteria to which the person was not sensitized, these bacteria were found to potentiate the allergic histamine release. The potentiating effect by bacteria might be due to the bacterial cell wall components, peptidoglycan and teichoic acid, which mimic the effect of bacteria.     

Magnesium and acute myocardial infarction. Transient hypomagnesemia not induced by renal magnesium loss in patients with acute myocardial infarction

Serum magnesium concentrations and the rate of urine magnesium excretion were studied in 24 patients with suspected acute myocardial infarction (AMI). Blood and urine samples were taken on admission, at three-hour intervals for the first 24 hours after admission, and every eight hours for the next 24 hours. Thirteen of the patients were found to have AMI, and the 11 who did not have AMI served as a control. During the first 32 hours, the AMI group had significantly low serum magnesium concentrations. The serum magnesium concentrations were unchanged in the control group. Results of the urine samples disproved our hypothesis that the drop in serum magnesium concentrations was due to an increased renal magnesium loss. These results indicate a magnesium migration associated with AMI, from extracellular to intracellular space.     

Different short-term effect of protein and carbohydrate intake on TSH, growth hormone (GH), insulin, C-peptide, and glucagon in humans

The effect of isocaloric (500 kcal) protein and carbohydrate ingestion was studied in a crossover study in nine healthy humans. Subjects were studied twice after overnight fasting, with an interval of 3 to 7 days. Blood was collected for 240 min after food ingestion. The initial reaction of growth hormone (GH) and thyroid stimulating hormone (TSH) to protein and carbohydrate was identical, with a reduction in both GH and TSH, and nadir occurring after 45-60 min and 120 min, respectively. During the next 120 min TSH returned to starting level after carbohydrate intake but was still reduced after protein intake (p less than 0.04). After both diets GH increased after the initial decline, the increase was greatest after protein intake and maximum was reached at 180 min (p less than 0.02). It has been reported that the 5'-deiodination of T4 is stimulated by insulin and inhibited by glucagon. The physiological increase in insulin after carbohydrate ingestion (p less than 0.05), and the physiological increase in glucagon after protein ingestion (p less than 0.05) was not associated with any changes in TT4, FT4, TT3, FT3, or rT3 that could indicate changes in the 5'-deiodinase activity.     

Somatic development in cleidocranial dysplasia

As part of a more comprehensive investigation of general and craniofacial development in cleidocranial dysplasia (CCD), the present study describes general somatic development and analyzes longitudinal growth of 17 patients (seven males, ten females, aged 5-46 years) with CCD. Eleven were followed longitudinally. Data included family history, anthropometric measurements, and radiographs of the right hand and forearm. Height and radius length were significantly decreased, being most pronounced in females. The longitudinal growth data showed growth retardation and slightly retarded skeletal maturity throughout childhood. Metacarpophalangeal pattern profile analysis demonstrated great variation in bone lengths, presumably resulting from extra epiphyses in the 2nd and 5th metacarpals and from multiple cone-shaped epiphyses. Findings of the present study support the view that CCD is a generalized skeletal dysplasia.     

Arsenicals produce stable progressive changes in DNA methylation patterns that are linked to malignant transformation of immortalized urothelial cells

Aberrant DNA methylation participates in carcinogenesis and is a molecular hallmark of a tumor cell. Tumor cells generally exhibit a redistribution of DNA methylation resulting in global hypomethylation with regional hypermethylation; however, the speed in which these changes emerge has not been fully elucidated and may depend on the temporal location of the cell in the path from normal, finite lifespan to malignant transformation. We used a model of arsenical-induced malignant transformation of immortalized human urothelial cells and DNA methylation microarrays to examine the extent and temporal nature of changes in DNA methylation that occur during the transition from immortal to malignantly transformed. Our data presented herein suggest that during arsenical-induced malignant transformation, aberrant DNA methylation occurs non-randomly, progresses gradually at hundreds of gene promoters, and alters expression of the associated gene, and these changes are coincident with the acquisition of malignant properties, such as anchorage independent growth and tumor formation in immunocompromised mice. The DNA methylation changes appear stable, since malignantly transformed cells removed from the transforming arsenical exhibited no reversion in DNA methylation levels, associated gene expression, or malignant phenotype. These data suggest that arsenicals act as epimutagens and directly link their ability to induce malignant transformation to their actions on the epigenome.