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.     

Effect of transluminal angioplasty on cerebral blood flow in the management of symptomatic vasospasm following aneurysmal subarachnoid hemorrhage

In this study the authors have examined the effects of transluminal angioplasty on cerebral blood flow (CBF) in the management of intractable vasospasm following aneurysmal subarachnoid hemorrhage (SAH). Fourteen consecutively enrolled patients underwent attempted angioplasty with or without intraarterial infusion of papaverine. Twelve patients underwent pre- and postangioplasty xenon-enhanced computerized tomography (Xe-CT) scanning to measure regional CBF in 55 to 65 regions of interest (ROIs) per patient. Angioplasty was possible in 13 (93%) of 14 patients, with angiographically demonstrated improvement in all 13. Twelve (92%) of the 13 patients were neurologically improved following angioplasty; seven (58%) of the 12 patients who improved had a complete reversal of all delayed ischemic deficits. Angioplasty significantly decreased the mean number of ROIs at risk (11.4 ROIs pre- and 0.9 ROIs postangioplasty) (p < 0.00005, t-test). All patients had a reduction in the number of ROIs at risk after angioplasty; six (50%) of 12 no longer had any ROIs remaining at risk after angioplasty. Angioplasty significantly increased the mean CBF within at-risk ROIs (13 ml/100 g/minute pre- and 44 ml/100 g/minute postangioplasty) (p < 0.00005, t-test). All patients experienced an improvement in mean CBF in at-risk ROIs after angioplasty, with the mean CBF improving to above 20 ml/100 g/minute in all cases. No differences in the degree of improvement were found in patients who received intraarterial papaverine compared with those who did not. In the majority of patients with refractory vasospasm following SAH, angioplasty effectively dilated spastic arteries, reversed delayed neurological deficits, and significantly improved CBF in areas of brain at risk of infarction.     

Prevention and Mitigation Strategies to Address Recent Brittle Fractures in Steel Bridges

Brittle fracture results in unplanned loss of service, very costly repairs, concern regarding the future safety of the structure, and potential loss of life. These types of failures are most critical when there is no evidence of fatigue cracking leading up to the fracture and the fracture origin is concealed from view. Hence, the failure occurs without warning and the details are, essentially, noninspectable. In these cases, it appears desirable to take a proactive approach and introduce preventative retrofits to reduce the potential for future crack development. These efforts will help ensure that the likelihood of unexpected fractures is minimized. This paper examines the behavior of two bridge structures in which brittle fractures have developed in recent times, discusses the causes of the failures, and offers suggested design strategies for prevention and retrofit mitigation techniques. In situations where considerable uncertainty exists in the prediction of accumulated damage or in the ability to reliably inspect critical details, preemptive retrofit strategies appear to be highly desirable.     

Flavopiridol: a cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells

Flavopiridol (NSC 649890, L86-8275), a potent inhibitor of cyclin-dependent kinase 1/p34cdc2 phosphorylation and kinase activity, is currently undergoing Phase I clinical testing as a potential antineoplastic agent. Previous studies have suggested that flavopiridol is cytostatic but not cytotoxic when applied to exponentially growing cells. In the present study, various human tumor cell lines were assayed for trypan blue exclusion and ability to form colonies after exposure to flavopiridol under a variety of growth conditions. When log phase A549 non-small cell lung cancer cells were examined 72 h after the start of a 24-h flavopiridol exposure, as many as 90% of the cells accumulated trypan blue. A 24-h exposure to 250-300 nM resulted in trypan blue uptake in 50% of A549 cells at 72 h and a 50% reduction in colony formation. Similar results were observed in HCT8 ileocecal adenocarcinoma, T98G glioblastoma, MCF-7 breast adenocarcinoma, and HL-60 leukemia cells. With A549 cells, identical results were obtained in actively growing logarithmic phase cells and growth-arrested confluent cells. Treatment with the DNA synthesis inhibitor aphidicolin only minimally affected the cytotoxicity of flavopiridol. In contrast, the RNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole or the protein synthesis inhibitor cycloheximide reduced the cytotoxicity of flavopiridol. These results suggest that: (a) flavopiridol is not only cytostatic, but also cytotoxic to a variety of human tumor cell lines; (b) flavopiridol is equally active against cycling and noncycling A549 cells; and (c) RNA and protein synthesis appear to play a role in flavopiridol-induced cytotoxicity.     

Implementation of sustainable sanitation in existing urban areas: long-term strategies for an optimised solution.

If technologies for decentralised sanitation and reuse (DESAR) and for natural stormwater management should at least partially replace existing systems, then intensive reconstruction work becomes essential. A conversion can only be realised successively over a long period due to high construction and financial expenses and requires new strategies. This paper presents the development and practical implementation of a mathematical tool to find an optimised strategy for the realisation of alternative and more decentralised drainage and sanitation concepts in existing urban areas. The succession of construction measures (e.g. the implementation of decentralised greywater recycling) for the whole period of consideration is determined based upon a mathematical optimisation model on the condition that the favoured future state is known. The model describes the complex interdependencies of the urban water and nutrient cycle and enables the minimisation of both financial efforts and ecological impacts on the way toward the future state. The results of the implementation for a rural area in Germany show that the mathematical optimisation is an adequate instrument to support decision-making processes in finding strategies for the realisation of sustainable urban water management.     

Electrical and optical properties of oxygen doped GaN grown by MOCVD using N2O

Oxygen doped GaN has been grown by metalorganic chemical vapor deposition using N₂O as oxygen dopant source. The layers were deposited on 2″ sapphire substrates from trimethylgallium and especially dried ammonia using nitrogen (N₂) as carrier gas. Prior to the growth of the films, an AIN nucleation layer with a thickness of about 300? was grown using trimethylaluminum. The films were deposited at 1085°C at a growth rate of 1.0 μm/h and showed a specular, mirrorlike surface. Not intentionally doped layers have high resistivity (>20 kW/square). The gas phase concentration of the N₂O was varied between 25 and 400 ppm with respect to the total gas volume. The doped layers were n-type with carrier concentrations in the range of 4×10¹⁶ cm⁻³ to 4×10¹⁸ cm⁻³ as measured by Hall effect. The observed carrier concentration increased with increasing N₂O concentration. Low temperature photoluminescence experiments performed on the doped layers revealed besides free A and B exciton emission an exciton bound to a shallow donor. With increasing N₂O concentration in the gas phase, the intensity of the donor bound exciton increased relative to that of the free excitons. These observations indicate that oxygen behaves as a shallow donor in GaN. This interpretation is supported by covalent radius and electronegativity arguments.     

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.