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.     

Cardiac- versus diaphragm-based respiratory navigation for proton spectroscopy of the heart

Magnetic Resonance Materials in Physics, Biology and Medicine - To study inter-individual differences of the relation between diaphragm and heart motion, the objective of the present study was to...     

Measuring nursing workload: understanding the variability

We reanalyzed parasitaemia profiles of the trypanotolerant N'Dama cattle (Bos taurus), consecutively infected with the same four clones of Trypanosoma congolense. Our analysis shows that each individual parasitaemia is characterized by progressively longer intervals between parasites waves. This pattern is most visible during the chronic phase of infection. In addition, the last of the four infections had a significantly larger overall duration of inter-wave intervals. We retrieved these patterns by numerical simulations of a mathematical model, which incorporates assumptions about the molecular basis of antigenic variation and about the anti-parasitic major immune processes. Six potential factors that may determine parasitaemia pattern were studied: carrying capacity of the host environment, intrinsic growth rate of the parasite, affinity maturation of the immune response, immune cell birth and death rate, levels of antibodies to variant surface glycoprotein and levels of antibodies to invariant antigens. Our simulations suggest that the first five factors are not likely to determine the chronic phase parasitaemia pattern whereas the sixth one, namely, antibody response to invariant antigens, yielded profiles consistent with the experimental data. Being cumulative, the immune response to anti-invariant antigens may be increasingly effective as infection proceeds and in successive infections. Comparisons between N'Dama and Zebu and between chronic and acute phases will be needed to make a statement on the role of this phenomenon in trypanotolerance.     

Urinary antigen test as a screen for the diagnosis of beta-hemolytic streptococcal infections in newborn infants

OBJECTIVE: To differentiate between neonates with high and low risk of infections caused by group B beta-haemolytic streptococci (GBS), by using the urinary group B streptococcal antigen test. DESIGN: Retrospective. SETTING: Medical Centre Leeuwarden and Public Health Laboratory, Friesland, the Netherlands. METHODS: In a period of two years clinical, haematological and microbiological (including urinary group B streptococcal antigen detection) data were collected in newborns and their mothers who met one or more of the following criteria: a previous affected child, prolonged (> or = 12 hrs) rupture of membranes, fever in labour, unexpected preterm delivery, unexplained perinatal asphyxia. On the basis of surveillance cultures a colonization rate was made. GBS infection was 'suspected' in an unwell infant with a 'high' colonization rate; infection with GBS was 'proved' by a positive blood culture with GBS. RESULTS: 6 of 342 neonates had an infection with GBS. Risk of invasive infection increased with higher colonization rates. Sensitivity of the antigen test to detect colonization was low, sensitivity to detect neonatal infection was high (51 versus 100%). The negative predictive value of urinary antigen testing was 100%. Prolonged rupture of membranes (1.5% risk of infection) and maternal fever (5%) were the most important risk factors. CONCLUSION: In healthy neonates with risk factors but with a negative antigen detection test the risk of GBS infection is extremely low. In children with a risk factor a positive test result can indicate heavy colonization or infection. These children should be carefully observed and examined.     

Modern Views on the Physical Structure of the Membrane of the Fat Globules in Milk and Cream and a Possible Relation with the Migration of Copper During Butter Manufacture

The different models proposed in the literature for the membrane of the milk fat globules are reviewed. On the basis of recent investigations, in particular of those of S. Hayashi, a new model is proposed, according to which the membrane is constituted by two layers which can easily be fractionated. The inner layer of cytoplasmic origin has a matrix structure, constituted by a complex lipid-protein aggregate. On this inner membrane an outer layer composed of numerous lipoprotein particles is associated. This new model will enable a better understanding of the alterations occurring in the fat globules phase during the various treatments in dairy chemistry. As an instance a tentative model is proposed for the copper migration during butter manufacture and the copper content of these butters.     

Kinetics of the biacetyl-sensitised photo-oxidation of CI Acid Orange 7

A kinetic model for the biacetyl-sensitised photo-oxidation of Cl Acid Orange 7 in aqueous solution during continuous irradiation at 365 nm is presented. Biacetyl was taken as a model for naturally occurring carbonyl species in polymers such as oxidised celluloseand lignin involved in photosensitised degradation of azo dyes. Quenching of triplet biacetyl by the dye and by oxidation products as well as quenching of singlet oxygen by waterand by oxidation products was accounted for. The equations derived from the model describe the relationship between the measured quantum yield of dye fading and dye concentration, as well as that between measured quantum yield of oxygen demand and dye concentration. Reaction rate parameters were calculated by a nonlinear least squares method, and were in accordance with literature values and values measured by flash photolysis. The relative amount of dye faded by singlet oxygen was estimated as 1.4–14%, indicating that singlet oxygen was of minor importance as an oxidative species.     

Successful re-treatment with taxol after major hypersensitivity reactions

PURPOSE: To describe the successful re-treatment of eight patients who had major hypersensitivity reactions (HSRs) to taxol and to suggest a regimen for re-treating patients who develop major HSRs. PATIENTS AND METHODS: The treatment courses of eight patients who developed major HSRs and were rechallenged with taxol were reviewed. Patients in this report represent all patients who are known to have been rechallenged with taxol after major HSRs. RESULTS: The most common approach used to rechallenge patients consisted of premedication with multiple high doses of corticosteroids and H1- and H2-histamine antagonists followed by the initiation of the taxol infusion at a reduced rate. All patients who experienced major HSRs were rechallenged successfully. After the rechallenge, these patients received 32 additional courses of taxol without HSRs. CONCLUSION: Re-treatment with taxol after major HSRs is feasible using multiple high doses of corticosteroids and antihistamine premedications and a reduced taxol infusion rate under close supervision. This approach may represent a valid alternative to the termination of taxol; however, a prospective evaluation is required to determine the true efficacy of this approach.     

Aqueous-phase adsorption of glycerol and propylene glycol onto activated carbon

Adsorption of reactant and product species can have a major effect on local pore concentrations in activated carbon-supported metal catalysts. Individual and combined adsorption of glycerol (GO) and propylene glycol (PG) onto activated carbon in aqueous solution is reported here at concentration ranges of 0.05-2.0 M and temperatures from 25 °C to 160 °C. Langmuir and Freundlich isotherms are used to model the single component data, with the Langmuir model best describing results below 0.75 M. The extended Langmuir model has been used to model the competitive adsorption system - model parameters determined from single component experiments accurately predict two component adsorption data over the temperature and concentration ranges studied. Propylene glycol adsorbs more strongly than GO onto the activated carbon supports studied, and also adsorbs to a somewhat greater extent compared to GO. This is attributed to the greater organic character of PG, which favors its selective adsorption onto the support material.     

Phase I/II trial of all-trans retinoic acid and tamoxifen in patients with advanced breast cancer

Because tamoxifen and all-trans-retinoic acid (ATRA) have additive antitumor effects in preclinical systems, we performed a Phase I/II clinical trial of this combination in patients with advanced breast cancer. Patients with potentially hormone-responsive advanced breast cancer were enrolled. All received 20 mg of tamoxifen by mouth daily. Consecutive cohorts of 3-6 patients were treated on odd-numbered weeks with ATRA at doses of 70, 110, 150, 190, or 230 mg/m2/day. Twenty-six patients were entered in this trial; 25 were evaluable. A dose of 230 mg/m2 ATRA produced unacceptable headache and dermatological toxicity, but doses < or = 190 mg/m2 were tolerable. Two of 7 patients with measurable disease responded. Seven of 18 patients with evaluable, nonmeasurable disease achieved disease stability for more than 6 months. Plasma AUCs on day 1 of successive weeks of treatment were stable over time. A nonsignificant decrease in serum insulin-like growth factor I levels was noted during treatment, but this trend was similar to that observed in three "control" patients treated with tamoxifen alone. When given with daily tamoxifen, the maximum tolerated dose of ATRA that could be given on alternate weeks was 190 mg/m2/day. This schedule of ATRA resulted in repeated periods of exposure to potentially therapeutic concentrations of ATRA. Declines in the serum insulin-like growth factor I concentrations observed in patients treated with tamoxifen and ATRA were similar to those observed in patients treated with tamoxifen alone. Objective responses were observed, some in patients who had previously progressed while receiving tamoxifen, suggesting that further studies would be of interest.