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.     

Clinical relevance of drug interactions with lithium

Although lithium continues to be regarded as the treatment of choice for bipolar disorders, the clinical use of this mood stabiliser is associated with an extremely narrow therapeutic range. Relatively minor increases in serum concentrations may induce serious adverse sequelae, and concentrations within the therapeutic range may result in toxic reactions. The safety of combining lithium with other medications, therefore, is a major concern, and extensive clinical experience has served to identify several significant drug interactions. Lithium removal from the body is achieved almost exclusively via renal means. As a result, any medication that alters glomerular filtration rates or affects electrolyte exchange in the nephron may influence the pharmacokinetic disposition of lithium. Concomitant use of diuretics has long been associated with the development of lithium toxicity, but the risk of significant interactions varies with the site of pharmacological action of the diuretic in the renal tubule. Thiazide diuretics have demonstrated the greatest potential to increase lithium concentrations, with a 25 to 40% increase in concentrations often evident after initiation of therapy. Osmotic diuretics and methyl xanthines appear to have the opposite effect on lithium clearance and have been advocated historically as antidotes for lithium toxicity. Loop diuretics and potassium-sparing agents have minor variable effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been associated with lithium toxicity, although the relative interactive potential of specific NSAIDs is difficult to determine. Small prospective studies have demonstrated large interindividual differences in lithium clearance values associated with different NSAIDs. A growing body of evidence also suggests that ACE inhibitors may impair lithium elimination, but further investigations are needed to identify patients at risk. Anecdotal reports have linked numerous medications with the development of neurotoxicity without an apparent effect on the pharmacokinetic disposition of lithium. Antipsychotics, anticonvulsants and calcium antagonists have all be implicated in a sufficient number of case reports to warrant concern. As these medications have all been commonly coadministered with lithium, the relative risk of serious interactions appears to be quite low, but caution is advised.     

Does palpability of primary cutaneous melanoma predict dermal invasion?

BACKGROUND: Relatively few studies have addressed the question of whether clinical estimation of melanoma thickness by palpation can accurately predict its histologic thickness. If palpability was a reliable predictor of dermal invasion, it could be used to define the surgical margin. OBJECTIVE: We sought to determine whether clinical elevation of melanoma could be used to predict the presence or absence and the degree of dermal invasion in patients with stage 1 cutaneous melanoma. METHODS: Melanomas in 165 patients were categorized by one observer as flat, just palpable, palpable, or nodular. This was compared with histologic measurements of tumor thickness. RESULTS: Overall there was significant correlation between the degree of palpability of melanoma and the presence or absence of dermal invasion (p<0.001), Breslow thickness (p<0.0001), and Clark level (p<0.001). However, the relation between palpability and Breslow thickness for invasive melanomas less than 1 mm thick was weaker (n=62, p=0.053), and the correlation between elevation and Clark level was not significant for invasive melanomas less than 4 mm thick (n=111, p>0.999). CONCLUSION: We conclude that palpability of melanoma is an inadequate guide to the presence or absence and degree of dermal invasion in melanomas less than 1 mm thick and cannot be used to determine the surgical margin.     

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.     

Intestinal obstruction. The experience of the Emergency Service of S. José Hospital 1981-1991

The results of 3679 patients, with intestinal obstruction, submitted to emergency surgery at the UUC-HCL between November 1981 and November 1991, were analysed in a general way, with the use of a graphic presentation. In the mechanical group, hernia (1604 cases), adhesions and bands (568 cases) and cancer (713 cases) were the most common pathologies; intestinal ischaemia (143 cases) was the most frequent form in the neurogenic group. Surgical therapy was evaluated in a general way. However, we comment on the evolution of primary surgical treatment of colorectal cancer in obstruction (625 cases). The mortality rate was in general: 10.8% (adults). In relative terms, the main features were intestinal ischaemia (39%), cancer (23%) and intestinal volvulus (22%).     

A comparison of bond strengths of complete crowns using two types of cements and three cleaning agents

In the past, biomechanical investigations on the dorsal pelvic ring have generally been performed on a small number of cadaveric pelves in various non-standardized procedures. Significant differences in stability between different internal fixation methods of unstable pelvic ring fractures were not found. The experimental design presented here was based as closely as possible on the physiological loading of the pelvis in one-leg stance. This method made it possible to carry out standardized, reproducible tests on different osteosytheses of the sacroiliac joint. Furthermore, the suitability of artificial bones for such investigations can be assessed on the basis of a larger number of similar experiments on artificial and human pelves and the number of human pelves required for such studies could be reduced.     

The rate of CD4 decline as a determinant of progression to AIDS independent of the most recent CD4 count. The Italian Seroconversion Study

Horse liver alcohol dehydrogenase contains two tryptophan residues per subunit, Trp-15 on the surface of the catalytic domain and Trp-314 buried in the interface between the subunits of the dimer. We studied the contributions of the tryptophans to fluorescence and catalytic dynamics by substituting Trp-314 with a leucine residue and making two compensatory mutations that were required to obtain a stable protein, leading to the triple mutant M303F-L308I-W314L enzyme. The substitutions increased by two- to sixfold the turnover numbers for ethanol oxidation, acetaldehyde reduction, and the dissociation constants of the coenzymes. The rate of the exponential burst phase for the transient oxidation of ethanol increased slightly, but the rate of dissociation of the enzyme-NADH complex still limited turnover of ethanol, as for wild-type enzyme. The three substitutions at the dimer interface apparently activate the enzyme by allowing more rapid conformational changes that accompany coenzyme binding, probably due to movement of the loop containing residues 293 to 298. The emission spectrum of M303F-L308I-W314L enzyme, which contains Trp-15, was redshifted compared to wild-type enzyme. Time-resolved fluorescence measurements with the triple mutant show that the decay of Trp-15 is dominated by a approximately 7-ns component. In the mutant enzyme with Trp-15 substituted with phenylalanine, the decay of Trp-314 is dominated by a approximately 4-ns component. Solute quenching data for wild-type enzyme and the mutants show that only Trp-15 is exposed to iodide and acrylamide, whereas Trp-314 is inaccessible. The luminescence properties of the tryptophan residues in the mutated enzymes are consistent with conclusions from studies of the wild-type enzyme [M. R. Eftink, 1992, Adv. Biophys. Chem. 2, 81-114].     

Coronary artery fistula after cardiac transplantation

A cardiac transplant recipient with multiple coronary artery fistulae draining into the right ventricle is described. These fistulae presumably resulted from repeated endomyocardial biopsies. The diagnosis of coronary artery fistulae was made at the annual coronary arteriography. The magnitude of the shunt remained small over eight years of follow-up.     

The relational self revealed: Integrative conceptualization and implications for interpersonal life.

The authors offer a new, integrative conceptualization of the relational self based on a synthesis of recent approaches to the self and significant others. This conceptualization provides a sharper and fuller definition of the relational self than does any existing approach alone and a common framework to interpret findings from separate literatures. The authors then present 5 propositions and evidence to support the thesis that relational selves exert a pervasive influence on interpersonal life. Specifically, relational selves (a) shape a wide range of psychological processes and outcomes, (b) exert their influence automatically, (c) serve basic orientation and meaning functions, (d) provide continuity and context-specific variability in personality, and (e) carry implications for psychological well-being. Discussion focuses on remaining issues and implications for future research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased mortality after successful treatment for Hodgkin's disease

PURPOSE: To determine the impact of treatment toxicity on long-term survival in pediatric Hodgkin's disease. PATIENTS AND METHODS: We studied late events in 387 patients treated for pediatric Hodgkin's disease on four consecutive clinical trials at St Jude Children's Research Hospital from 1968 to 1990. Relative risks, actuarial risks, and absolute excess risks for cause-specific deaths were calculated. RESULTS: As of April 1997, 316 (82%) of patients were alive, with a median follow-up of 15.1 (range, 2.9 to 28.6) years. In this cohort, which represented 5,623 person-years of follow-up, 71 fatal events resulted from Hodgkin's disease (n=36), second malignancies (n=14), infections (n=7), accidents (n=7), cardiac disease (n=6), and asphyxiation (n=1). The 5-year estimated event-free survival (EFS) for the entire cohort was 79.6%+/-2.1 %, which declined to 63.1%+/-4.4% by 20 years. Cumulative incidences of cause-specific deaths at 25 years were 9.8%+/-1.6% for Hodgkin's disease, 8.1%+/-2.6% for second malignancy, 4.0%+/-1.8% for cardiac disease, 3.9%+/-1.5% for infection, and 2.1%+/-0.8% for accidents. Standardized incidence ratios showed excess risk for all second malignancies (12; 95% confidence interval [CI], 8 to 17), acute myeloid leukemia (81; 95% CI, 16 to 237), solid tumors (11; 95% CI, 7 to 16), and breast cancer (33; 95% CI, 12 to 72). Standardized mortality ratios also showed excess mortality from cardiac disease (22; 95% CI, 8 to 48) and infection (18; 95% CI, 7 to 38). CONCLUSION: Compared with age- and sex-matched control populations, survivors of pediatric Hodgkin's disease who were treated before 1990 face an increased risk of early mortality related to second cancers, cardiac disease, and infection.