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.     

Indicators for inspection and maintenance planning of concrete structures

Based on an idea introduced by Benjamin and Cornell (1970. Probability, statistics and decision for civil engineers. New York: McGaw Hill) and previous works by the authors it is demonstrated how condition indicators may be formulated for the general purpose of quality control and for assessment and inspection planning in particular. The formulation facilitates quality control based on sampling of indirect information about the condition of the considered components. This allows for a Bayesian formulation of the indicators whereby the experience and expertise of the inspection personnel may be fully utilized and consistently updated as frequentistic information is collected. The approach is illustrated on an example considering a concrete structure subject to corrosion. It is shown how half-cell potential measurements may be utilized to update the probability of excessive repair after 50 years. Furthermore in the same example it is shown how the concept of condition indicators might be applied to develop a cost optimal maintenance strategy composed of preventive and corrective repair measures.     

Evidence for distinct signaling mechanisms in two mammalian olfactory sense organs

In mammals, olfactory stimuli are detected by sensory neurons at two distinct sites: the olfactory epithelium (OE) of the nasal cavity and the neuroepithelium of the vomeronasal organ (VNO). While the OE can detect volatile chemicals released from numerous sources, the VNO appears to be specialized to detect pheromones that are emitted by other animals and that convey information of behavioral or physiological importance. The mechanisms underlying sensory transduction in the OE have been well studied and a number of components of the transduction cascade have been cloned. Here, we investigated sensory transduction in the VNO by asking whether VNO neurons express molecules that have been implicated in sensory transduction in the OE. Using in situ hybridization and Northern blot analyses, we found that most of the olfactory transduction components examined, including the guanine nucleotide binding protein alpha subunit (G-alpha-olf), adenylyl cyclase type III, and an olfactory cyclic nucleotide-gated (CNG) channel subunit (oCNC1), are not expressed by VNO sensory neurons. In contrast, VNO neurons do express a second olfactory CNG channel subunit (oCNC2). These results indicate that VNO sensory transduction is distinct from that in the OE but raise the possibility that, like OE sensory transduction, sensory transduction in the VNO might involve cyclic nucleotide-gated ion channels.     

Role of hepatic resection in surgery for bilateral intrahepatic stones

The effect of phenylephrine-induced reflex parasympathetic stimulation on QT interval and its dispersion was studied in 16 healthy subjects with a history of paroxysmal supraventricular tachycardia, both during sinus rhythm and during atrial pacing. Results demonstrate that rapid reflex parasympathetic stimulation does not influence QT interval duration or QT dispersion, and also emphasize the inappropriateness of Bazett's formula, the need for comparison of QT intervals during identical heart rates, and the importance of analyzing all 12 leads of a standard electrocardiogram when assessing the effects of various interventions on the QT interval.     

Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT1 receptor

Angiotensin II is the effector molecule of the renin-angiotensin system. Virtually all of its biochemical actions are mediated through a single class of cell-surface receptors called AT1. These receptors contain the structural features of the seven-transmembrane, G-protein-coupled receptor superfamily. Angiotensin II, acting through the AT1 receptor, also stimulates the Jak/STAT pathway by inducing ligand-dependent Jak2 tyrosine phosphorylation and activation. Here, we show that a glutathione S-transferase fusion protein containing the carboxyl-terminal 54 amino acids of the rat AT1A receptor physically binds to Jak2 in an angiotensin II-dependent manner. Deletional analysis, using both in vitro protocols and cell transfection analysis, showed that this association is dependent on the AT1A receptor motif YIPP (amino acids 319-322). The wild-type AT1A receptor can induce Jak2 tyrosine phosphorylation. In contrast, an AT1A receptor lacking the YIPP motif is unable to induce ligand-dependent phosphorylation of Jak2. Competition experiments with synthetic peptides suggest that each of the YIPP amino acids, including tyrosine 319, is important in Jak2 binding to the AT1A receptor. The binding of the AT1A receptor to the intracellular tyrosine kinase Jak2 supports the concept that the seven-transmembrane superfamily of receptors can physically associate with enzymatically active intracellular proteins, creating a signaling complex mechanistically similar to that observed with growth factor and cytokine receptors.     

Worksite characteristics and changes in worksite tobacco-control initiatives. Results from the COMMIT study

Few studies have prospectively examined the characteristics associated with worksite adoption of tobacco-control initiatives. Data were collected as part of the Community Intervention Trial (COMMIT) for Smoking Cessation, which conducted interventions in 11 communities. This smoking cessation intervention was based on community organization principles and delivered through multiple community channels, including worksites, health care providers, the media, and cessation resources. This article reports results from telephone interviews of intervention community worksites having 50 or more employees, conducted at baseline and the end of the intervention period. Among worksites that responded to both baseline and final surveys, 83% had not adopted a smoke-free policy at baseline, and 61% did not offer any cessation aid or quitting resources at baseline. By the final survey, 34% of those with no smoking ban at baseline had become smoke-free, and 36% of those offering no cessation assistance at baseline were offering cessation resources at the follow-up. The prevalence of policy adoption was higher among worksites employing more female employees and offering other health-promotion activities; manufacturing businesses were significantly less likely than businesses other than service and wholesale/retail businesses to adopt policies. Adoption of cessation programs was significantly more likely among worksites employing 100 to 249 workers, compared with those employing 50 to 99 workers; those predominantly employing men; those offering other types of health-promotion activities; and those with a higher rate of turnover. These results provide important information about the characteristics of worksites likely to engage in tobacco-control efforts. Health educators and others may choose to target those worksites most ready for adoption of tobacco control policies and programs, as indicated by these findings.     

Control of locomotion in the marine mollusc Clione limacina. XI. Effects of serotonin

The locomotor activity in the marine mollusc Clione limacina has been found to be strongly excited by serotonergic mechanisms. In the present study putative serotonergic cerebropedal neurons were recorded simultaneously with pedal locomotor motoneurons and interneurons. Stimulation of serotonergic neurons produced acceleration of the locomotor rhythm and strengthening of motoneuron discharges. These effects were accompanied by depolarization of motoneurons, while depolarization of the generator interneurons was considerably lower (if it occurred at all). Effects of serotonin application on isolated locomotor and non-locomotor pedal neurons were studied. Serotonin (5 x 10(-7) to 1 x 10(-6) M) affected most pedal neurons. All locomotor neurons were excited by serotonin. This suggests that serotonergic command neurons exert direct influence on locomotor neurons. Effects of serotonin on nonlocomotor neurons were diverse, most neurons being inhibited by serotonin. Some effects of serotonin on locomotor neurons could not be reproduced by neuron depolarization. This suggests that, along with depolarization, serotonin modulates voltage-sensitive membrane properties of the neurons. As a result, serotonin promotes the endogenous rhythmical activity in neurons of the C. limacina locomotor central pattern generator.     

Outbreak of serogroup C meningococcal disease associated with campus bar patronage

Between February 1991 and April 1992, eight undergraduates at a US residential university and one at a nearby 2-year college contracted serogroup C meningococcal disease. A case-control investigation with 20 controls per case, oropharyngeal carriage surveys, and multilocus enzyme electrophoresis (MEE) of serogroup C isolates were used to identify factors contributing to the outbreak. All eight sterile-site isolates from cases were closely related by MEE and were similar (though not identical) to the strain associated with the 1991-1992 epidemic of meningococcal disease in eastern Canada. Disease was associated with cigarette smoking (p = 0.012), recent patronage of campus-area bars (p = 0.034), estimated amount of time spent in campus-area bars (p = 0.0003), and, especially, recent patronage of one specific bar, bar A (p = 0.0006; odds ratio = 23.1, 95% confidence interval 3.0-571.5). In carriage surveys, 1,528 throat cultures taken from (primarily student) noncases yielded only five (0.3%) strains that were identical by MEE to those from cases. Two of these were found among 22 cultures obtained from bar A employees in spring 1992. Some cases in this outbreak may have followed transmission of the epidemic strain in bar A. Campus bar environments may facilitate the spread of meningococcal disease among teenagers and young adults.