Dibenzocyclooctadiene lignans overcome drug resistance in lung cancer cells--study of structure-activity relationship.

A panel of nine dibenzo[a,c]cyclooctadiene lignans, schizandrin, gomisin A, gomisin N, gomisin J, angeloylgomisin H, tigloylgomisin P, deoxyschizandrin, gamma-schizandrin and wuweizisu C was examined for their effect on multidrug resistance, as well as their anti-proliferative activities. COR-L23/R, a multidrug resistant sub-line, which has been reported to over-express multidrug resistance-associated protein (MRP1), was used for the experiments together with its parent cell line COR-L23 (human lung cell carcinoma). We found that lignans deoxyschizandrin and gamma-schizandrin at relatively non-toxic concentrations restored the cytotoxic action of doxorubicin to COR-L23/R cells. Deoxyschizandrin and gamma-schizandrin also significantly enhanced the accumulation of doxorubicin in drug resistant cells. Both lignans alone had no effect on the cell cycle; however, when combined with sub-toxic doses of doxorubicin, they induced cell cycle arrest in the G2/M phase, which is typical for toxic doses of doxorubicin. Our results suggest that deoxyschizandrin and gamma-schizandrin potentiate the cytotoxic effect of doxorubicin in doxorubicin resistant lung cancer cells COR-L23/R by increasing the accumulation of doxorubicin inside the cells. The common structural feature of both active lignans is the R-biaryl configuration and the absence of a hydroxy group at C-8. Unlike the reversal effect, the cytotoxicity of lignans with the R-biaryl configuration was similar to that observed for lignans with the S-biaryl configuration.

UVC-protective effect of caffeic acid on normal and transformed human skin cells in vitro.

Possible UVC-protective properties of CA, a plant phenolic compound with antioxidant activity, were investigated on human KF1 diploid fibroblast and A431 epidermoid carcinoma cell lines. Cell populations, untreated and treated by antioxidants (CA and alpha-tocopherol), were irradiated by UVC at the wavelength of 254 nm and their proliferation activity was determined by the MTT assay. The results show a strong protective effect of CA at both concentrations used (55.5 and 166.5 microM): a significant increase of proliferation activity after UVC irradiation was detected in both cell populations growing in the presence of CA in comparison with cells in DMEM only. The described protective effect of CA was more obvious in transformed cells than in normal diploid cells. This protective ability is probably based on the antioxidant and scavenging activities of CA, which seems to be more efficient than alpha-tocopherol in protection against the cytotoxic effect caused by UVC irradiation.

Short-term temporal variation in PM2.5 mass and chemical composition during the Atlanta Supersite Experiment, 1999.

Measurements in urban Atlanta of transient aerosol events in which PM2.5 mass concentrations rapidly rise and fall over a period of 3-6 hr are reported. The data are based on new measurement techniques demonstrated at the U.S. Environmental Protection Agency (EPA) Atlanta Supersite Experiment in August 1999. These independent instruments for aerosol chemical speciation of NO3-, SO4(2-), NH4+, and organic and elemental carbon (OC and EC), reconstructed the observed hourly dry PM2.5 mass to within 20% or better. Data from the experiment indicated that transient PM2.5 events were ubiquitous in Atlanta and were typically characterized by a sudden increase of EC (soot) and OC in the early morning or SO4(2-) in the late afternoon. The frequent temporal decoupling of these events provides insights into their origins, suggesting mobile sources in metro Atlanta as the main contributor to early morning PM2.5 and more regionally located point SO2 sources for afternoon PM2.5 events. The transient events may also have health implications. New data suggest that short-term PM2.5 exposures may lead to adverse health effects. Standard integrated filter-based techniques used in PM2.5 compliance monitoring networks and in most past PM2.5 epidemiologic studies collect samples over 24-hr periods and thus are unable to capture these transient events. Moreover, health-effects studies that focus on daily PM2.5 mass alone cannot evaluate the health implications of the unique and variable chemical properties of these episodes.

Diurnal variations of aerosol chemical compositions and related gaseous pollutants in Beijing and Guangzhou.

A new apparatus, Steam Jet Aerosol Collector (SJAC) combined with on-line Mobile Ion Chromatograph provides a reliable way to measure both aerosol components and related gas species simultaneously. The SJAC was applied in the field campaigns in Beijing and Guangzhou to investigate aerosol chemical compositions and related gaseous pollutants. The concentration levels and diurnal variations are discussed, which implies differences in atmospheric chemistry of gas-to-particle conversions in Beijing and Guangzhou.

Interaction of benzo[c]phenanthridine and protoberberine alkaloids with animal and yeast cells.

We compared the effects of four quaternary benzo[c]phenanthridine alkaloids--chelerythrine, chelilutine, sanguinarine, and sanguilutine--and two quaternary protoberberine alkaloids-berberine and coptisine--on the human cell line HeLa (cervix carcinoma cells) and the yeasts Saccharomyces cerevisiae and Schizosaccharomyces japonicus var. versatilis. The ability of alkaloids to display primary fluorescence, allowed us to record their dynamics and localization in cells. Cytotoxic, anti-microtubular, and anti-actin effects in living cells were studied. In the yeasts, neither microtubules nor cell growth was seriously affected even at the alkaloid concentration of 100 microg/ml. The HeLa cells, however, responded to the toxic effect of alkaloids at concentrations ranging from 1 to 50 microg/ml. IC50 values for individual alkaloids were: sanguinarine IC50 = 0.8 microg/ml, sanguilutine IC50 = 8.3 microg/ml, chelerythrine IC50 = 6.2 microg/ml, chelilutine IC50 = 5.2 microg/ml, coptisine IC50 = 2.6 microg/ml and berberine IC50 > 10.0 microg/ml. In living cells, sanguinarine produced a decrease in microtubule numbers, particularly at the cell periphery, at a concentration of 0.1 microg/ml. The other alkaloids showed a similar effect but at higher concentrations (5-50 microg/ml). The strongest effects of sanguinarine were explained as a consequence of its easy penetration through the cell membrane owing to nonpolar pseudobase formation and to a high degree of molecular planarity.

Application of capillary electrochromatography using macroporous polyacrylamide columns for the analysis of lignans from seeds of Schisandra chinensis.

Capillary electrochromatography (CEC) using polymer-based monolithic stationary phase has been developed as a promising method for the determination of lignans of Schisandra chinensis. The columns were prepared by in situ copolymerisation of acrylamide, N,N'-methylenebisacrylamide, vinylsulfonic acid and lauryl acrylate in presence of poly(ethylene glycol) as a porogenic agent. The columns [33 cm (24.5 cm effective length) x 75 microm I.D.] were successfully used to analyse and quantify the major lignans in extract of the seeds of Schisandra chinensis. Good separations were achieved in less than 35 min. The calibration graphs were linear in the range 0.025-1.0 mg/ml of given lignan with correlation coefficients between 0.9951 and 0.9996. The inter-day reproducibility of the peak area were below 3.9% and the inter-day reproducibility of the migration time were below 4.2%. The results of quantitative CEC analyses were compared with those obtained by reversed-phase HPLC, the levels of schizandrin, gomisin A, gomisin N and wuweizisu C determined by CEC were in a good agreement with those determined by HPLC.

[Second malignancies after the therapy of Hodgkin's disease: the Freiburg collective 1940 to 1991]. / Zweitmalignome nach Therapie des Morbus Hodgkin: das Freiburger Kollektiv 1940 bis 1991.

AIM: To quantify the risk of second malignancies in patients with Hodgkin's disease treated at the Department of Radiotherapy, University Clinic Freiburg, with the object of comparing this risk with the international experience and as a contribution to the discussion about future treatment. PATIENTS AND METHODS: Second malignancies were reviewed in 1,588 patients treated for Hodgkin's disease between 1940 and 1991. Treatment consisted of involved or extended field radiotherapy as a single modality or in combination with chemotherapy. Before the early 1970's, chemotherapy used (sequential) monodrug regimens. The mean follow-up was 8.3 years. The cumulative risk was calculated using the Kaplan-Meier method and related to the risk of a normal population taken from epidemiological data of the National Cancer Institute. An estimate of radiation dose at the site of origin of the second malignancy was obtained from representative measurements employing an Alderson phantom. RESULTS: After 5, 10, 15 and 20 years the cumulative risk for all malignancies was 1.5%, 4.2%, 9.4% and 21%, respectively; for solid tumors it came to 1.2%, 3.1%, 7.9% and 19%; for non-Hodgkin lymphoma (NHL) the risk amounted to 0.1%, 0.9%, 1.4% and 1.9%; and for leukemia it was 0.1%, 0.3%, 0.6% and 0.6%. For the same time points the relative risk for all malignancies was calculated to be 1.1, 1.4, 1.8 and 2.5; for solid tumors it came to 1.0, 1.1, 1.6 and 2.5; for NHL it amounted to 3.3, 11.8, 9.3 and 8.0; and for leukemia it was 3.3, 3.1, 3.4 and 2.1. For combinations of radiotherapy and chemotherapy the risk for second malignancies was highest in patients receiving ABVD any time during their treatment. 51% of the second malignancies were located infield, 22% at the field border and 27% outfield. In those cases for which the cause of death was known, Hodgkin's disease accounted for 79% followed by second malignancies accounting for 8%. The results obtained in Freiburg fell within the range reported in international publications. CONCLUSION: The increased incidence of second malignancies in cured Hodgkin's patients is along-term risk making regular follow-up mandatory. Although part of the second malignancies are unrelated to therapy, there is a need to carefully collect the data from patients treated according to new protocols in order to detect any changes in the number or kind of second malignancies in due time. This may well lead to a reassessment of therapeutic concepts.

Fate of products of degradation processes: consequences for climatic change.

The end products of atmospheric degradation are not only CO2 and H2O but also sulfate and nitrate depending on the chemical composition of the substances which are subject to degradation processes. Atmospheric degradation has thus a direct influence on the radiative balance of the earth not only due to formation of greenhouse gases but also of aerosols. Aerosols of a diameter of 0.1 to 2 micrometer, reflect short wave sunlight very efficiently leading to a radiative forcing which is estimated to be about -0.8 watt per m2 by IPCC. Aerosols also influence the radiative balance by way of cloud formation. If more aerosols are present, clouds are formed with more and smaller droplets and these clouds have a higher albedo and are more stable compared to clouds with larger droplets. Not only sulfate, but also nitrate and polar organic compounds, formed as intermediates in degradation processes, contribute to this direct and indirect aerosol effect. Estimates for the Netherlands indicate a direct effect of -4 watt m-2 and an indirect effect of as large as -5 watt m-2. About one third is caused by sulfates, one third by nitrates and last third by polar organic compounds. This large radiative forcing is obviously non-uniform and depends on local conditions.

Lignans in the seeds and fruits of Schisandra chinensis cultured in Europe.

The fruits of Schisandra chinensis (Turcz.) Baill. (Schisandraceae/Magnoliaceae) are a traditional Oriental medicine possessing adaptogenic and hepatoprotective activities. The lignan content in seeds and fruits of the species cultured in various European locations has been investigated. The lignans were extracted from 17 samples of the seeds with supercritical CO2 and the major components--schizandrin (1), gomisin A (2), de-oxyschizandrin (3), gomisin N (4), and wuweizisu C (5)--were quantified by HPLC. Compounds 1-5 were present in the seeds in the range 0.75-1.86, 0.13-0.90, 0.07-1.09, 0.24-1.49, and 0.01 -0.34 %, respectively. It was found that the plants cultivated in Europe accumulated comparable amounts of lignans as those of the natural distribution range.

[Indications for percutaneous radiotherapy in carcinoma of the thyroid gland. Freiburg consensus]. / Indikationen zur perkutanen Strahlentherapie beim Karzinom der Schilddrüse. Freiburger Konsensus.

At the University of Freiburg, a consensus was arrived at concerning the place of external radiotherapy in the management of thyroid cancer. External irradiation is always indicated in papillary and folliculary carcinoma in the pT4 stage of pTNM classification but not in those in pT1-3 pN0 stage. In the presence of lymph-node metastases and distant metastases, an individual treatment concept is recommended, which should be set up in an interdisciplinary conference regarding all risk factors, especially the age and sex of the patient, the histology and grading of the tumor and the completeness of tumor resection. Finally, radiotherapy is usually not indicated in medullary thyroid carcinoma, whereas it is always indicated in anaplastic carcinoma.

Persistence of circulating t(14;18)-positive cells in long-term remission after radiation therapy for localized-stage follicular lymphoma.

PURPOSE: To determine the prevalence of circulating t(14;18)-positive cells in patients with long-term remission after radiation therapy for stage I and II follicular lymphoma. PATIENTS AND METHODS: Peripheral-blood mononuclear cells from 21 patients in continuous remission were examined by a two-step polymerase chain reaction (PCR) assay for the detection of cells carrying a t(14;18) translocation with a breakpoint within the major breakpoint region (MBR) or minor cluster region (mcr). RESULTS: Follow-up duration was between 25 and 160 months, with a median of 6.5 years. Thirteen patients (62%) showed negative results on repetitive testing. Cells that were t(14;18)-positive were found in eight patients (38%), all carrying a breakpoint in the MBR. One patient relapsed in each group. CONCLUSION: Circulating t(14;18)-positive cells can persist in a high percentage of follicular lymphoma patients in long-term complete remission (CR) after radiation treatment for stage I and II disease. The significance of minimal residual t(14;18)-positive cells with regard to the risk of relapse needs to be investigated in further prospective long-term studies.

Measurement of dry deposition of ammonia on a forest.

Ammonia concentration gradients above a Douglas fir canopy were measured from 16 August to 31 December 1989 by two automated high-precision thermodenuders at the location Speulderbos in The Netherlands. Concentration gradients were used to calculate the dry deposition flux of ammonia via flux-gradient theory. Meteorological data were obtained from a nearby tower. Ammonia concentrations were highly variable with highest values during the night. Concentration gradients were very small during daytime and quite large at night. Median values of the calculated deposition flux and deposition velocity were 0.1 microg m(-2) s(-1) and 3.2 cm s(-1) respectively (N=1624).

[The combined radiation and hormonal therapy of prostatic carcinoma: a conceptual analysis]. / Kombinierte Strahlen- und Hormontherapie des Prostatakarzinoms: eine Konzeptanalyse.

The concept of a combination of radiotherapy and hormonal therapy for the treatment of locally advanced carcinoma of the prostate was evaluated in view of an improved success rate compared to radiotherapy alone. At present, however, radiotherapy still remains the central mode of therapy in the treatment of the local tumor. The time sequence in a combination with hormonal therapy is of importance. Antecedent hormonal treatment can reduce tumor size, thus improving local conditions for percutaneous--and especially interstitial--radiotherapy; it is indicated in patients with voiding problems. An improvement in survival rates has so far not been achieved, however, local tumor remission rates are better. With concomitant hormonal therapy, compared to radiotherapy alone, tumor progression rates are lower. It remains to be seen, whether these results can be improved by using newer pharmacological ways of androgen blockade. The application of androgen withdrawal as a secondary measure with local tumor persistence or progression after radiotherapy remains a palliative treatment of limited efficacy. Due to the heterogeneity of the available study reports and the concurrent lack of controlled, randomized trials, a conclusive evaluation of the concept of combined radio- and hormonal therapy of prostatic cancer is as yet not possible.

Alterations of IgE immunoglobulin concentration in the serum after megavoltage radiotherapy with large-field technique in patients with Hodgkin's disease.

In patients with Hodgkin's disease, the serum IgE concentrations were determined with the PRIST radioimmunoassay before commencing and after ending systemic megavoltage radiotherapy. 57 patients showed mainly raised serum IgE concentrations before radiotherapy. After the end of radiotherapy, 44 patients were investigated, and a highly significant fall of the IgE concentration was shown in the serum following the radiotherapy. The decrease of IgE concentration was most pronounced in the patients in whom large areas of irradiation were necessary or who displayed B symptoms. In a proportion of the patients, the IgE concentration in the serum could be measured once more six and twelve months after the end of radiotherapy. Although the IgE concentrations rose again after radiotherapy, the initial values before the beginning of radiotherapy had not yet been reached again even twelve months after treatment in 21 patients investigated. A long-lasting immunosuppressant effect of radiotherapy on the serum IgE concentration could thus be demonstrated which corresponds to the effect on the serum IgM concentration described earlier.