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L Edler

Publications and source records attributed to L Edler.

At least 55 records · Page 3Linked to original sources

The 1p deletion is not a reliable marker for the prognosis of patients with neuroblastoma.

Human neuroblastoma cells often have deletions of the distal short arm of chromosome 1 (1p). Earlier studies using chromosome analysis had suggested that the 1p deletion is correlated with a poor survival chance for the patient. We have reevaluated this possibility by analyzing 51 neuroblastomas for loss of heterozygosity (LOH) at 1p. We detected LOH in 32% of the cases. LOH did not correlate with the age of the patients at diagnosis or with tumor stage but was correlated significantly with amplification of the MYCN proto-oncogene. Nine of 10 MYCN-amplified tumors had deletions in 1p (P < 0.001). Survival chances of patients with tumors carrying MYCN amplification together with the deletion at 1p were decreased significantly (eight of nine affected patients died) compared with a patient group without any of these aberrations (P < 0.001). However, the deletion of 1p alone without MYCN amplification was not associated with a poor outcome compared with patients who had neither deletion nor amplification (only two of eight affected patients died; P = 0.803). From these data we conclude that 1p deletions are not reliable markers to determine a patient's prognosis. They may, however, identify a subgroup of neuroblastomas in which MYCN is amplified readily, resulting in rapid tumor progression.

Adult↗

Tumor induction and prophylaxis following different forms of intestinal urinary diversion in a rat model.

Eighty Wistar rats were randomized into two groups. In group 1 vesicosigmoidostomy with proximal colostomy was performed, in group 2, vesicosigmoidostomy. The total tumor incidence did not significantly (group 1 10/40, 25%; group 2 13/40, 32.5%). The tumor spectrum differed, with more adenocarcinomas in group 2 (11/40, 27.5% vs 4/40, 10%; P = 0.047) and urothelial carcinomas only in group 1 (5/40, 2.5%). One hundred and ten other Wistar rats were randomized into three groups. Animals in group A received vesicoileosigmoidostomy, group B, two-step vesicosigmoidostomy with initial separation of urine and the urocolonic anastomosis, group C, vesicosigmoidostomy. Significantly fewer adenocarcinomas were observed in group A (2/40, 5%) than in group B (16/40, 40%; P < 0.002) and group C (9/30, 30%; P < 0.007). These results indicate a similar cancer risk in all continent forms of urinary diversion, at least via colon. Ileal interposition seems to be an effective carcinoma prophylaxis following ureterosigmoidostomy. The proliferative instability at the urointestinal anastomosis is crucial for the pathogenesis and prophylaxis of this form of carcinogenesis, whereas urine seems to play only a minor role.

Adenocarcinoma↗

DNA repair synthesis following irradiation with 254-nm and 312-nm ultraviolet light is not diminished in fibroblasts from patients with dysplastic nevus syndrome.

The DNA excision repair capacity of 23 primary fibroblast lines from patients with dysplastic nevus syndrome was investigated and DNA repair synthesis ("unscheduled DNA synthesis") was determined after UV exposure. Seventeen fibroblast lines from normal donors served as controls. The dose/response experiments included up to ten dose levels and two wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial "sunlamp" radiation centering around 312-nm light). For each dose level, silver grains over fibroblast nuclei were counted by visual inspection. Twelve cell lines were also evaluated for both UV wavelength ranges using a new semi-automatic image analyzing system. This system included components for rapid sequential identification of both fibroblast nuclei and silver grains sited above them. Silver grains over 100 nuclei were determined for each UV dose level. Dose/response curves were established and analyzed by linear regression. As a quantitative term for assessing DNA excision repair capacity of a cell line we calculated the linear increase (G0) in the number of grains per nucleus, when the UV dose was multiplied by the factor e (i.e. 2.72). The sensitivity of grain detection and resolution of overlapping grains was approximately threefold better in visual than in automatic counting, especially when there were more than 70 grains over nuclei. The time required for visual counting, however, was tenfold that of automatic counting. The variance-weighted mean G0v.w of all fibroblast lines from patients with dysplastic nevus syndrome was found to be 79.1 (+/- 1.8- grains/nucleus, that of fibroblast lines from normal donors was 74.2 (+/- 1.7) grains/nucleus. This difference revealed a slightly better repair capability for cell lines from patients but was at the borderline of detection and, therefore, should not be overinterpreted. From the experimental accuracy achieved by determination of the variance-weighted means of the two groups, we would have been able to detect a difference of 7 and more grains [> 2 x (sigma normal+sigma patients)]. The variance-weighted mean G0v.w of all fibroblast lines from patients with dysplastic nevus syndrome was found to be 76.4 (+/- 1.4) grains/nucleus, whereas that of fibroblast lines from normal donors was only 66.6 (+/- 1.8) grains/nucleus. This difference was statistically significant and, contrary to expectation, revealed better, not worse post-UV DNA repair capability in cell lines from patients that in those from normal donors.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoradiography↗

Effect of glutathione depletion and oral N-acetyl-cysteine treatment on CD4+ and CD8+ cells.

HIV-infected individuals and SIV-infected rhesus macaques have, on the average, decreased plasma cysteine and cystine concentrations and decreased intracellular glutathione levels. We show that the cysteine supply and the intracellular glutathione levels have a strong influence on the T cell system. A study of healthy human subjects revealed that persons with intracellular glutathione levels of 20-30 nmol/mg protein had significantly higher numbers of CD4+ T cells than persons with either lower or higher glutathione levels. Persons who moved during a 4-week observation period from the optimal to the suboptimal range (10-20 nmol/mg) experienced, on the average, a 30% decrease in CD4+ T cell numbers. This decrease was prevented by treatment with N-acetyl-cysteine (NAC). NAC caused this relative increase of CD4+ T cell numbers in spite of decreasing glutathione levels and not by increasing the glutathione level. Our studies suggest that the immune system may be exquisitely sensitive not only against a cysteine and glutathione deficiency but also against an excess of cysteine.

Acetylcysteine↗

Porphyrin studies in TCDD-exposed workers.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to inhibit uroporphyrinogen decarboxylase activity resulting in chronic hepatic porphyria. From a cross-sectional study of 170 workers in chemical industry 68 showed elevated coproporphyrin levels, interpreted as secondary coproporphyrinuria. Three persons suffered from chronic hepatic porphyria in subclinical stages. None of the workers showed an overt porphyria cutanea tarda. A low-grade zinc protoporphyrinemia was observed in three persons. Forty-three of the 170 workers were evaluable for investigating the effect of TCDD on porphyrin levels. No significant correlation was found between TCDD concentration in adipose tissue and the level of uroporphyrin and coproporphyrin. The influence of a chloracne history is described.

Adipose Tissue↗

Biostatistical issues in the design and analysis of multiple or repeated genotoxicity assays.

Tests for genotoxic or mutagenic effects of chemicals have prompted efficient biostatistical methods for the quantification of dose-response data, especially from the Ames Salmonella/microsome assay. A decision about the genotoxicity of a compound is, however, always based on several assays, and results from multiple or repeated genotoxicity assays have to be combined either qualitatively or, even better, quantitatively. The latter problem is considered here, and issues for design and analysis are addressed. General recommendations for designing genotoxicity assays are given. A long-known methodology for combining quantitative parameters from different experiments is updated and other statistical methods suitable for the combined analyses of multiple assays are presented. Some aspects of design and analysis are elucidated on count data from unscheduled DNA synthesis assays.

Biometry↗

Ligand/receptor binding for 2,3,7,8-TCDD: implications for risk assessment.

There is renewed controversy regarding safe exposure levels for dioxin. At the heart of this controversy is the hypothesis that toxic effects of dioxin are receptor-mediated and therefore a "threshold" should exist below which no toxic effects can occur. Our research focuses on the ability of dioxin to alter protein levels in rodent livers. Established effects of exposure to dioxin are the induction of cytochrome P450-1A1 and P450-1A2 and a reduction in the maximal binding of the epidermal growth factor receptor in rat livers. An initiation-promotion protocol was used to study the effects of dioxin in female Sprague-Dawley rats. Animals were administered a single initiating dose of diethylnitrosamine followed by 16 biweekly gavage doses of 2,3,7,8-TCDD. Steady-state pharmacodynamic models were fit to these data assuming a combination of Hill kinetics and Michaelis-Menten kinetics. Two classes of models were developed which postulate two different mechanisms for the constitutive expression and TCDD-induced alterations in the levels of these proteins. The results are consistent with models which follow proportionate response in the low-dose region (no threshold) and with models which allow for a low-dose threshold. In all cases studied, the best fitting model exhibited no "threshold" for the effects of TCDD on the modulation of these proteins. The finding is consistent with the knowledge that for some receptor-mediated responses, there is a proportional relationship between receptor occupancy and biological response, even at low ligand concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Randomized phase II study of single-agent epirubicin +/- verapamil in patients with advanced metastatic breast cancer. An AIO clinical trial. Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society.

BACKGROUND: Anthracyclines are the most active cytostatic agents in patients with metastatic breast cancer. Drug resistance and dose intensity are relevant issues in the treatment of cancer. METHODS: A randomized phase II study in 51 patients with advanced progressive metastatic breast cancer was performed. Twenty-six were treated with epirubicin (EPI) 120 mg/m2 i.v. bolus injection divided over three days combined with a daily dose of 480 mg verapamil (VPL) orally administered one day before and during EPI. Twenty-five patients received the same dose and schedule of EPI without VPL. Evaluation of response was carried out after three 21-day cycles. Study endpoints were objective response rate and overall survival. RESULTS: Among the 24 evaluable patients treated with EPI+VPL 1 CR (4%), 7 PR (29%), 9 NC (38%) and 7 PD (29%) were observed. Two patients were excluded because of toxicity. Among the 24 evaluable patients treated with EPI alone 8 PR (28%), 6 NC (24%) and 10 PD (40%) were observed, and one patient was excluded because of toxicity. Myelotoxicity was the major side effect followed by alopecia, stomatitis/mucositis and nausea. The patient group treated with VPL had lower blood pressure levels during therapy, with complete normalization after discontinuation of VPL. The median overall survival times were similar: 7.4 month in the EPI group and 8.9 month in the EPI+VPL group. CONCLUSION: In both treatment groups the objective response rate was about 30% and the overall survival rates were also the same. No clinical relevance could be demonstrated for the hypothesized resistance modifying action of VPL. Furthermore, VPL did not increase the toxicity of EPI.

Adult↗

Statistical methods for short-term tests in genetic toxicology: the first fifteen years.

Short-term tests (STTs) for detecting and assessing genotoxic or mutagenic effects have catalyzed the development of biostatistical methods for more than one decade. Most notably, the Ames Salmonella/microsome assay created statistical methodology with a range of applications going beyond genotoxicity. Early approaches with parametric statistical methods appeared to be insufficient and have been replaced by non-parametric ones requiring less restrictive distributional assumptions. There have also been successful attempts to use biomathematical models for establishing dose-response relationships. Overdispersion has been recognized as a major problem for the evaluation of mutagenic count data and methods to cope with it have became available. A theory of generalized linear modelling is emerging to combine dose-response modeling with much less restrictive distributional assumptions, while allowing the inclusion of concomitant factors arising from the experimental conditions. The methodological survey below reviews the present state of this development and is intended to promote further research into biostatistical issues and methods of analysis. Appropriate methods for the design and analysis of STTs are discussed. The progress for the Ames assay was only partially transmitted to the analysis of the large number of other short-term assays. Several such assays are reviewed with respect to their present state of statistical evaluation.

Animals↗

Long term tumorigenicity of a single application of indomethacin or Amuno in adolescent and in adult male Sprague Dawley rats.

200 adolescent (Group I) and 200 adult male Sprague Dawley rats (Group II) were divided into 4 subgroups of 50 animals each. Animals were treated on the 29th (Group I) or 98th day of life (Group II) either with acetone or Amuno carrier in acetone or Amuno on acetone (2.5 mg indomethacin/100 g animal weight in acetone) or with the pure substance indomethacin 2.5 mg/100 g of animal weight in acetone, giving a single application on the shaved dorsal skin. Subsequently the animals remained under observation until their deaths, followed by autopsy and histopathologic examination of several organs. The rats treated with Amuno of indomethacin in the adolescent stage showed lower body weights and a shorter total survival time. The adolescent animals treated with Amuno or indomethacin showed a significantly higher rate of interstitial testicular tumors of the Leydig tumor type, adenomas and adenocarcinomas of the small and large intestine as well as hepatocellular tumors. The total number of neoplasias was higher in the animals treated with Amuno or indomethacin compared to those treated with acetone or carrier with acetone. Application of Amuno or indomethacin also resulted in a higher rate of hyperplasias (sole of foot, lymph nodes, prostate). The impairment of the synthesis of prostaglandins caused by indomethacin apparently results in starting complex pathomechanisms which have effects until the late death of the animals. Adolescent animals were affected more frequently by the application of indomethacin as were already adult animals.

Aging↗

Clinical symptoms and DNA repair characteristics of xeroderma pigmentosum patients from Germany.

Sixty-one xeroderma pigmentosum (XP) patients living in the Federal Republic of Germany were investigated. Clinical symptoms were correlated with DNA repair parameters measured in fibroblasts grown from skin biopsies. Classification according to the international complementation groups revealed that of the 61 patients 3 belonged to group A, 26 to group C, 16 to group D, 3 to group E, and 2 to group F; 11 were of the XP variant type. A striking clinical aspect was the frequency of histogenetically different skin tumors varying from one XP complementation group to the other: squamous and basal cell carcinomas predominated in XP group C; lentigo maligna melanomas were most frequent in group D; basal cell carcinomas occurred preferentially in group E and XP variants. Three DNA repair parameters were determined for 46 fibroblast strains: colony-forming ability (D0); DNA repair synthesis (G0); and DNA-incising capacity (E0). Dose-response experiments with up to 13 dose levels were performed throughout to achieve sufficient experimental accuracy. DNA-damaging treatments included UV light, the "UV-like" carcinogen N-acetoxy-2-acetylaminofluorene, and the alkylating carcinogens methyl methanesulfonate and N-methyl-N-nitrosourea. Comparison of clinical signs and repair data was made on the basis of D0, G0, and E0 values of both individual cell strains and weighted means of XP complementation groups. Despite considerable clinical and biochemical heterogeneity within complementation groups distinctive features emerged. In general, D0, G0, and E0 values of all XP strains investigated, including XP variants, were found to be reduced upon treatment with UV light or N-acetoxy-2-acetylaminofluorene. After treatment with UV light or N-acetoxy-2-acetylaminofluorene, cell strains in which DNA-incising capacity was reduced also showed a similar reduction in both colony-forming ability and DNA repair synthesis. Consequently, the weighted mean D0, G0, and E0 values of XP complementation groups and XP variants correlated with each other. Furthermore, the onset of both early dermatological symptoms of XP and tumor growth correlated with the extent of DNA repair defects. Of 45 XP fibroblast strains checked for colony-forming ability after treatment with methyl methanesulfonate only 3 cell strains from group D were found to be more sensitive than normal controls, suggesting that overall repair in XP strains was equal to that in controls. Weighted means of DNA repair synthesis of XP complementation groups, however, showed reductions hinting at impaired excision of distinct alkylated bases.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetoxyacetylaminofluorene↗

The effects of inhibitors of topoisomerase II and quinacrine on ultraviolet-light-induced DNA incision in normal and xeroderma pigmentosum fibroblasts.

The aim of our work was to investigate whether DNA topoisomerase II participates in the repair-specific incision of UV-irradiated genomic DNA. Therefore, the influence upon DNA incision of the topoisomerase II inhibitors (nalidixic and oxolinic acid, novobiocin and coumermycin A1) as well as the intercalating agent quinacrine has been measured in normal human fibroblasts using the alkaline elution technique. In addition, inhibition by novobiocin has been determined in fibroblast strains from 11 normal donors and from 16 xeroderma pigmentosum (XP) patients belonging to the complementation groups A, C, D, E, and XP variant. Nalidixic and oxolonic acid did not inhibit endonucleolytic cleavage, whereas novobiocin was a potent inhibitor of DNA incision. It was observed that in normal and in all XP strains 50% inhibition by novobiocin occurred on average in the dose range 315-590 microM. Since inhibition by novobiocin was not paralleled by that with the other topoisomerase II inhibitors nalidixic and oxolinic acid, it must be concluded that reduction of enzyme-catalysed breaks was not due to the participation of topoisomerase II in the incision step, but to the displacement of ATP at the binding site of the DNA-incising enzyme. This enzyme absolutely requires ATP as a cofactor for endonucleolytic cleavage. Quinacrine, however, inhibited DNA incision in normal fibroblasts at a mean Ki of 318 microM. Inhibition by this intercalating agent seems to be caused by structural perturbations in DNA, which render it a poor substrate for endonucleolytic cleavage.

Aminocoumarins↗

Fibroblasts derived from patients with dysplastic nevus syndrome are not more sensitive towards 254-nm and 312-nm ultraviolet light than fibroblasts from normal donors.

DNA repair capacity of 18 fibroblast strains from patients with dysplastic nevus syndrome, 5 of them with malignant melanoma, was investigated and their colony-forming ability (D0) after UV exposure was determined as a measurement of this. Seventeen fibroblast strains from normal donors served as controls. The dose/response experiments included up to 11 dose levels and two UV wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial "sunlamp" radiation centering around 312-nm light). The exponential segments of the dose/response curves were analysed by linear regression and the negative reciprocals of the regression coefficients, D0, were calculated for each cell strain and each wavelength range. When comparing D0 values of individual cell strains from patients with and without melanomas with the mean value for all normal donors, only 4 out of 18 showed increased sensitivity towards UV-B. This difference, however, was not statistically significant. On the contrary, weighted-mean D0 values for fibroblast strains from patients with and without melanoma were found to be slightly but significantly higher than those for normal donors (significance level: 5%), indicating that cell strains from these patients were less sensitive to UV light (UV-C and UV-B) of both wavelength. This result, which on the basis of current literature data is somewhat unexpected, holds true within the limits of experimental accuracy of +/- 12%.

DNA Repair↗

Biological assays for irritant, tumor-initiating and -promoting activities. III. Computer-assisted management and validation of biodata generated by standardized initiation/promotion protocols in skin of mice.

The initiation/promotion standard protocol 28 (protocol 28), developed and used previously as an experimental model to verify the cancerogenic process of initiation/promotion in mouse skin, was revised in three aspects: (a) statistically it was shown sufficient to use, per promoter dose group, 16 colony-outbred female NMRI mice: (b) by weekly individual records of tumor response (and health status) of each mouse in a dose group, cumulative tumor incidences (and mean and extreme body weights) are determined; from these data the collective records (tumor response, health status), the only data accessible from protocol 28, may be generated in addition; (c) the details of dose groups and all data on tumor response and health status are processed by computer using the program package PAPILLOM. The latter was developed specifically for this purpose, is written in the programming language APL and designed for easy handling by staff of animal laboratories. The program package calculates, from the individual records per promoter dose group, cumulative tumor incidences (and survival data) with confidence limits for any one exposure time, and the package may be linked to programs for statistical validations. In addition, from the collective records it calculates the tumor rates, tumor yields and survival rates for any one exposure time. These data, obtained by either of the standard protocols (16 or 28), are fully comparable. For pure compounds they may be used to calculate semiquantitative tumor-promoting potencies. These values for more than 80 polyfunctional diterpenes of the tigliane, ingenane and daphnane type, scattered in or calculated from previous papers, together with their irritancies, were compiled. Within recent years, computer-assisted standard protocol 16 has been used to handle and evaluate about 1000 promoter dose groups. Protocol 16 allows one to extract and utilize more and better toxicological information on tumor response and health status from any one dose group, utilizing significantly fewer experimental animals than required by protocol 28. Thus, the computer-assisted standard protocol 16 optimizes the utility of the experimental model of mouse skin for the amount, quality and management of experimental data as well as for the requirements of animal protection.

Animals↗

Detection of Epstein-Barr virus-DNA in tongue epithelium of human immunodeficiency virus-infected patients.

Oral hairy leukoplakia is a lesion on the lateral part of the tongue that contains replicating Epstein-Barr virus (EBV) and presages progression from human immunodeficiency virus (HIV) infection to AIDS. To clarify the role of EBV in the development of the lesions, we used filter in situ DNA hybridization to determine the prevalence of EBV and of human papillomavirus (HPV) in epithelial cells obtained on swabs from the tongue of HIV-infected patients who had hairy leukoplakia, HIV-infected patients who did not have hairy leukoplakia, and healthy uninfected control persons. In samples collected from the 35 uninfected control persons, EBV DNA could not be detected except at low concentrations in three people. In contrast, all but one of the samples from 11 HIV-infected patients who had hairy leukoplakia contained EBV DNA. Of greatest interest, in 19 of 32 HIV-infected patients who had no signs of hairy leukoplakia, EBV DNA was also detected on the epithelium of the tongue. DNA filter in situ hybridization for the detection of HPV serotypes 6, 11, 16, and 18 in all cases yielded negative results. Statistical analysis showed that the presence of EBV DNA was significantly correlated with the clinical status of the HIV-infected persons, as determined by Walter Reed staging classification, whereas hairy leukoplakia was not. It is concluded that detection of EBV DNA in oral epithelium may be an earlier and more powerful predictor of progression to AIDS than is hairy leukoplakia.

DNA, Viral↗

Phase II study of vinorelbine by oral route (in a hard gelatine capsule) for metastatic breast cancer patients. A trial of the phase I/II study group of the Association for Medical Oncology of the German Cancer Society.

17 patients with advanced low-risk breast carcinoma not previously pretreated by cytostatic agents were treated by Vinorelbine (VIN), 5'-Nor-anhydro-vinblastine, a new semisynthetic compound of the vinca alkaloid series. A dose of 130 mg per week was administered in a hard gelatine formulation for at least eight weeks. Out of 15 evaluable patients, no complete or partial remission was observed. However, there were 9 patients (60%) achieving no change and tumor stabilization, respectively, lasting for a median of 3.0 months. Main toxicities were leukopenia (17.7%, WHO grade 3-4), nausea and vomiting (17.7%, WHO grade 3-4), and acute diarrhea (70.6%, WHO grade 1-4). Thus, further trials with the oral medication used for this study are not recommended.

Aged↗

Relationship between dose and risk reduction: statistical evaluation of a combination experiment with three hepatocarcinogenic N-nitrosamines in rats.

Data from an experiment on the single and combination effects of very low doses of N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR) and N-nitrosodiethanolamine (NDELA) in 1800 male Sprague-Dawley rats were analysed for age-specific incidence (time to death with liver tumour) by Cox's proportional hazards model. The model revealed a linear relationship between daily exposure to low levels of N-nitrosamine and time to death with liver tumour within the dose range investigated: an increase in individual dose resulted in a proportional decrease in liver tumour-free survival. The finding was established for the three individual carcinogens as well as for their combination. NDEA was 40 times more active than NDELA. Extrapolation to N-nitrosamine exposure levels lower than those used in the experiment revealed only a minor reduction in age-specific liver tumour incidence compared to that achieved by an equivalent reduction within the experimental dose range. In rats at advanced age a further reduction in carcinogen-induced liver tumour incidence did not contribute to longer overall survival, due to competitive, probably independent causes of death. The data thus support the idea of a quasi-threshold in terms of a 'no observed effect level'.

Age Factors↗