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.     

Apoptosis and delayed neuronal damage after carbon monoxide poisoning in the rat

Delayed neurological damage after CO hypoxia was studied in rats to determine whether programmed cell death (PCD), in addition to necrosis, is involved in neuronal death. In rats exposed to either air or CO (2500 ppm), microdialysis in brain cortex and hippocampus was performed to determine the extent of glutamate release and hydroxyl radical generation during the exposures. Groups of control and CO-exposed rats also were tested in a radial maze to assess the effects of the CO exposures on learning and memory. At 3, 7, and 21 days after CO exposure brains were perfusion-fixed and hematoxylin-eosin (H&E) was used to assess injury and to select regions for further examination. DNA fragmentation was sought by examining cryosections with the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) reaction. We found significant increases in glutamate release and .OH generation during and immediately after CO hypoxia. CO-exposed rats showed learning and memory deficits after exposure associated with heterogeneous cell loss in cortex, globus pallidus, and cerebellum. The frontal cortex was affected most seriously; the damage was slight at Day 3, increased at Day 7, and persistent at Day 21 after CO exposure. TUNEL staining was positive at all three time points, and TUNEL-labeled cells were distributed similarly to eosinophilic cells. The number of cells stained by TUNEL was less than by H&E and amounted to 2 to 5% of all cell nuclei in regions of injury. Ultrastructural features of both neuronal necrosis and apoptosis also were observed readily by electron microscopy. These findings indicate that both necrosis and apoptosis (PCD) contribute to CO poisoning-induced brain cell death.     

Surveillance of developmental disabilities with an emphasis on special studies

The developing central nervous system seems to be particularly vulnerable to chemical insults. A model for developmental disabilities surveillance is presented that provides a reasonable framework for monitoring the prevalence of various developmental abnormalities in human populations. Effective monitoring will not only increase the likelihood of detecting the adverse effects of new physical or chemical agents in the environment but will provide a readily available case series for specially directed case-control studies. A specific example is provided of a large case-control study of cerebral palsy and intrapartum magnesium exposure among very low birth weight children, which is being conducted within the framework of a developmental disabilities surveillance program.     

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.     

Fuzzy Weirstrass theorem and convex fuzzy mappings

The convexity and continuity of fuzzy mappings are defined through a linear ordering and a metric on the set of fuzzy numbers. The local-global minimum property of real-valued convex functions is extended to convex fuzzy mappings. It is proved that a strict local minimizer of a quasiconvex fuzzy mapping is also a strict global minimizer. Characterizations for convex fuzzy mappings and quasiconvex fuzzy mappings are given. In addition, the Weirstrass theorem is extended from real-valued functions to fuzzy mappings.     

Nitric oxide reduction at noble metal electrodes: a voltammetric study in acid solution

Features of the electrochemical reduction of nitric oxide on platinum, palladium, rhodium and ruthenium in aqueous perchloric acid solutions (0.33–1.0 M) are compared. The results from voltammetric studies (ie linear potential sweep and rotating disc electrode) using the bulk metal electrodes are described and compared with residual current voltage plots in acid electrolyte alone. In general, three nitric oxide reduction peaks are observed on the metals. The most anodic peak, at ca E = 0.15 V vs sce is attributed to the one-electron reduction of nitric oxide to an adsorbed NOH intermediate on a bare metal surface (ie one free of oxides or adsorbed hydrogen). The other two peaks occur in potential regions where adsorbed hydrogen is present on the metal surface (ca E = 0.0 and −0.20 V, respectively). The co-adsorbed hydrogen complicates the analysis and precludes an unambiguous interpretation of these two peaks. However, they apparently reflect nitric oxide reduction to nitrogen, hydroxylamine and/or ammonia. In a cathodic scan on the rhodium electrode, a current plateau is seen instead of the first (most anodic) peak, a probable consequence of oxide film formation with subsequent chemical complications. On the ruthenium electrode the first two (most anodic) peaks are not observed probably due to a relatively stable oxide layer. Reaction selectivities at metal black gas diffusion cathodes operating in an electrogenerative (ie galvanic) mode with perchloric acid electrolyte are compared with the voltammetric results at the corresponding bulk electrodes. Dinitrogen formation is observed on the platinum and rhodium black electrodes as suggested from voltammetric results. A series-parallel reaction sequence is proposed to explain the results. Limitations of using simple voltammetric techniques for predicting behavior of large scale preparative electrochemical reactors are discussed.     

Missed opportunities for immunisation at hospitals in the western Cape--a reappraisal

Immunisation practices were examined at 6 hospitals in the western Cape during the latter half of 1992 to determine whether these practices had improved subsequent to the February 1991 resolution of the Health Matters Committee (HMC) on immunisation in hospitals, and since a similar study was undertaken in 1990. Exit interviews were conducted with the escorts of all children aged 3-59 months who attended the study hospitals on the days designated for the study. In the second study, 88 of the 311 children studied (28.3%) were in need of immunisation on arrival, but only 12 of the 88 (13.6%) were immunised during the hospital visit. There was no evidence of an increase in requests to see children's Road-to-Health cards (37.1% compared with 35.2% previously). The incidence of missed opportunities for measles immunisation in children aged 6-59 months remained unacceptably high (51.4% compared with 63.7% previously, when a strict definition was used; and 15.7% compared with 18.1% previously, when a lenient definition was used). Health authorities at all levels need to take urgent action to address the problem of missed opportunities for immunisation at hospitals.