Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines

BACKGROUND: Topotecan (TPT) is a topoisomerase I poison that exhibits antineoplastic activity. Analysis of the cytotoxic effects of combinations of TPT and other anticancer agents has been limited. PURPOSE: We assessed the cytotoxic effects produced by combinations of TPT and other antineoplastic agents in experiments involving multiple human cancer cell lines of diverse histologic origins. METHODS: The cytotoxic effects of various antimetabolites (fluorouracil, methotrexate, or cytarabine), antimicrotubule agents (vincristine or paclitaxel [Taxol]), DNA alkylating agents (melphalan, bis[chloroethyl]nitrosourea [BCNU], or 4-hydroperoxycyclophosphamide [4HC]), and a DNA-platinating agent (cisplatin), alone and in combination with TPT, were measured in clonogenic (i.e., colony-forming) assays. HCT8 ileocecal adenocarcinoma, A549 non-small-cell lung carcinoma, NCI-H82ras(H) lung cancer, T98G glioblastoma, and MCF-7 breast cancer cell lines were used in these assays. The data were analyzed by the median effect method, primarily under the assumption that drug mechanisms of action were mutually nonexclusive (i.e., completely independent of one another). For each level of cytotoxicity (ranging from 5% to 95%), a drug combination index (CI) was calculated. A CI less than 1 indicated synergy (i.e., the effect of the combination was greater than that expected from the additive effects of the component agents), a CI equal to 1 indicated additivity, and a CI greater than 1 indicated antagonism (the effect of the combination was less than that expected from the additive effects of the component agents). RESULTS: When the mechanisms of drug action were assumed to be mutually nonexclusive, virtually all CIs for combinations of TPT and either antimetabolites or antimicrotubule agents revealed cytotoxic effects that were less than additive. The CIs calculated at low-to-intermediate levels of cytotoxicity for combinations of TPT and the DNA alkylating agents melphalan, BCNU, and 4HC also showed drug effects that were less than additive; in most cases, however, nearly additive or even synergistic effects were observed with these same drug combinations at high levels of cytotoxicity (i.e., at > or = 90% inhibition of colony formation). Results obtained with combinations of TPT and cisplatin varied according to the cell line examined. With A549 cells, less than additive effects were seen at low-to-intermediate levels of cytotoxicity, and more than additive effects were seen at high levels of cytotoxicity. With NCI-H82ras(H) cells, synergy was observed over most of the cytotoxicity range. CONCLUSIONS AND IMPLICATIONS: TPT cytotoxicity appears to be enhanced more by combination with certain DNA-damaging agents than by combination with antimetabolites or antimicrotubule agents. Interactions between TPT and other drugs can vary depending on the cell type examined. Further investigation is required to determine the basis of the observed effects and to determine whether these in vitro findings are predictive of results obtained in vivo.     

Development and characterization of a biocompatible OH-modified copolymer based on polyurethane

Different polyurethanes were synthesized by varying the diol as well as the diisocyanate components and chain extenders. Polyurethanes with OH-groups were obtained by photo- and thermoinitiation of the radical polymerization of hydroxy alkyl acrylates in the presence of the polyurethanes. The polymers were evaluated with respect to their biocompatibility by measuring the cell spreading, the rates of DNA- and protein synthesis and the swelling behaviour. The differences in the surfaces and the bulks between the selected basic polyurethane and the functionalized modification were determined and characterized by XPS, FTIR-ATR and ¹³C-FT-NMR-spectroscopy. The mechanical data of Tecoflex EG 60D® and Pellethane 2363–80AE® were compared with the data of the synthesized polyurethanes.     

Reduced epicardial coronary vasodilator capacity in patients with left ventricular hypertrophy

BACKGROUND: Enlargement of the epicardial coronary arteries occurs in left ventricular (LV) hypertrophy as an adaptation to the increased coronary blood flow. METHODS AND RESULTS: Vasodilator capacity of the epicardial coronary arteries was determined in 44 patients. The dose-response relation of intracoronary nitroglycerin was assessed in 14 patients (7 control subjects and 7 patients with aortic stenosis [study A]) using quantitative coronary angiography. In a second study (B), vasodilator capacity of the epicardial coronary arteries was determined in 15 control subjects and 15 patients with valvular heart disease. In study A, a curvilinear dose-response relation with maximal vasodilation after 90 micrograms intracoronary nitroglycerin was found in both control subjects and patients with aortic stenosis. Vasodilator capacity was reduced in those with aortic stenosis, although sensitivity to nitroglycerin was similar in both groups. In study B, coronary circumferential length at baseline was larger in those with LV hypertrophy (12.2 +/- 2.2 mm) than in control subjects (8.6 +/- 1.5 mm; P < .001); after 100 micrograms intracoronary nitroglycerin, it increased to 12.9 +/- 2.2 mm (6 +/- 5%) in those with LV hypertrophy and to 10.3 +/- 1.5 mm (21 +/- 8%; P < .001) in control subjects. An inverse relation between baseline circumferential length and its percent increase after nitroglycerin was found (r = -.71, P < .001). CONCLUSIONS: Vasodilator capacity of the epicardial coronary arteries is reduced in patients with LV hypertrophy, although sensitivity to nitroglycerin is normal. This may be due to a flow-mediated decrease in coronary vasomotor tone and/or the occurrence of vascular remodeling with an enlargement of the coronary arteries.     

Linear-Time Algorithms for Hole-free Rectilinear Proportional Contact Graph Representations

In a proportional contact representation of a planar graph, each vertex is represented by a simple polygon with area proportional to a given weight, and edges are represented by adjacencies between the corresponding pairs of polygons. In this paper we first study proportional contact representations that use rectilinear polygons without wasted areas (white space). In this setting, the best known algorithm for proportional contact representation of a maximal planar graph uses 12-sided rectilinear polygons and takes O(nlogn) time. We describe a new algorithm that guarantees 10-sided rectilinear polygons and runs in O(n) time. We also describe a linear-time algorithm for proportional contact representation of planar 3-trees with 8-sided rectilinear polygons and show that this is optimal, as there exist planar 3-trees that require 8-sided polygons. We then show that a maximal outer-planar graph admits a proportional contact representation using rectilinear polygons with 6 sides when the outer-boundary is a rectangle and with 4 sides otherwise. Finally we study maximal series-parallel graphs. Here we show that O(1)-sided rectilinear polygons are not possible unless we allow holes, but 6-sided polygons can be achieved with arbitrarily small holes.     

CuIn1−xGaxSe2‐based thin‐film solar cells by the selenization of sequentially evaporated metallic layers

Polycrystalline CuIn_1−xGa_xSe₂ (CIGS) thin films were deposited by the non‐vacuum, near‐atmospheric‐pressure selenization of stacked metallic precursor layers. A study was carried out to investigate the influence of significant factors of the absorber on the solar cells performance. An efficiency enhancement was obtained for Cu/(In+Ga) atomic ratios between 0·93 and 0·95. The slope of the observed energy bandgap grading showed a strong influence on the V_OC and the short circuit current density J_SC. An increase of the Ga content in the active region of the absorber was achieved by the introduction of a thin Ga layer on the Mo back contact. This led to an improvement of efficiency and V_OC. Furthermore, an enhanced carrier collection was detected by quantum efficiency measurements when the absorber layer thickness was slightly decreased. Conversion efficiencies close to 10% have been obtained for these devices. Copyright © 2005 John Wiley & Sons, Ltd.     

Simultaneous Detection of Positive and Negative Ions From Single Airborne Particles by Real-time Laser Mass Spectrometry

ABSTRACT

The instrumental setup used for simultaneous bipolar ion detection in on-line single-particle analysis by laser mass spectrometry is described. Particle size calibration has been performed using aerodynamic time-of-flight techniques. Mass spectra of several hundred ambient particles with aerodynamic diameters of 0.8 μm have been evaluated for statistical classification (Principal Components Analysis [PCA]) in order to identify main chemical components of the prominent particle classes.     

Surface Cu depletion of Cu(In,Ga)Se2 films: An investigation by hard X-ray photoelectron spectroscopy

The origin of surface Cu depletion of polycrystalline chalcopyrite thin films and its consequences for the physics of related solar cells have been discussed for the past 15 years. In order to shed light on the composition and thickness of this Cu-depleted surface layer, depth-dependent compositional analysis by hard X-ray photoelectron spectroscopy was performed. The data from Cu-poor grown Cu(In,Ga)Se₂ samples point to a surface layer in the sub-nanometer regime, which is completely depleted of Cu. This result supports the surface reconstruction model proposed by first-principles calculations by other authors. Analysis of the surface morphology of the investigated samples confirms the conjunction of Cu depletion and faceting of the surface. Theoretical considerations show that the apparent surface concentration ratio of [Cu]/([In] + [Ga]) = 1/3 found by conventional photoelectron spectroscopy studies can be explained by the surface reconstruction model.     

TGF-alpha sustains clonal expansion by promoter-dependent, chemically initiated rat hepatocytes

A series of promoting and non-promoting barbiturates and hydantoins were examined for their ability to sustain the growth of a phenobarbital (PB)-dependent hepatocyte line in cell culture. The effective liver tumor promoters, pentobarbital, allobarbital and 5-ethyl-5-phenylhydantoin, replaced PB and supported 6/27C1 hepatocyte colony formation in vitro at 52-87% of the level induced by PB. The weak promoters secobarbital and amobarbital supported colony formation at only 11-19% of the PB control. A significant correlation was observed for in vivo and in vitro promotion activities of barbiturates and hydantoins, indicating that clonal expansion by 6/27C1 hepatocytes was promoter-dependent. Cell density also appeared to influence hepatocyte growth in vitro. Hepatocyte colonies acquired the ability to grow in the absence of PB, such that after 10 days incubation with PB, approximately 50% of colonies continued to grow in the absence of promoter. This phenomenon of clone-size-dependent hepatocyte growth suggested the operation of an autocrine growth factor pathway. Addition of the hepatocyte mitogen and autocrine growth factor, transforming growth factor-alpha (TGF-alpha), to culture medium lacking PB induced a dose-dependent increase in 6/27C1 hepatocyte colony formation. At the optimal concentration of 3 ng/ml, TGF-alpha sustained hepatocyte clonal expansion at 84% of the level induced by 2 mM PB. Individual 6/27C1 colonies that grew from single cells in the presence of TGF-alpha were tested for promoter-dependent colony formation. Either PB or TGF-alpha supported colony formation by these cells at similar levels and when combined at optimal concentrations, the response appeared to be saturated. When these factors were tested in combination at suboptimal concentrations, the two compounds were additive for supporting colony formation by the parental 6/27C1 line. The ability of TGF-alpha to replace PB and sustain hepatocyte clonal expansion was confirmed with the tumorigenic 6/15 hepatocyte line. These results suggest that TGF-alpha and PB may promote hepatocarcinogenesis by stimulating a common signal transduction pathway.