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Biomedical subjects

L Edler

Publications and source records attributed to L Edler.

At least 73 records · Page 4Linked to original sources
PubMed1991

Pharmacokinetics of 5-fluorouracil after short systemic infusion: plasma level at the end of the distribution phase as an indicator of the total area under the plasma concentration-time curve.

The correlation between single plasma concentration (CP) values of 5-fluorouracil (FU) after a 10-minute i.v. infusion and the total area under the plasma concentration-time curve (AUC) has been studied in 26 cancer patients. FU dose was either 320-550 mg/m2 (seven patients, 13 treatments) or 610-960 mg/m2 (19 patients, 30 treatments). Linear single CP-AUC relationships were found in both dose groups with the CPs at 1, 5, 10, 15, and 30 minutes after the end of infusion. Parameters of linear regression of AUC on single CP differed between the two dose groups. For the high-dose group, the single CPs at repeated treatments were tested as estimators of the total AUC at these treatments, using calibration lines relating total AUC to single CP, which were derived from the data of the first (or only) treatments of all patients. The "best" AUC estimators of the total AUC were the CPs at 10 and 15 minutes after the end of infusion, with a bias of only 2% and an imprecision of only 11% of the AUC values directly determined from the complete concentration-time profiles of the repeated treatments. Because of the close correlation between these single CPs and the total AUC, these CPs should be considered equivalent to the AUC as an overall index of individual FU kinetics after brief infusion of high doses.

Adult↗
PubMed1990

Evaluation of the kinetics of the intracellular reduction of 2,6-dichlorophenolindophenol in normal and transformed hepatocytes measured by amperometric methods.

Amperometric methods were used to study the kinetics of intracellular reduction of 2,6-dichlorophenolindophenol (DCIP) in normal and transformed hepatocytes with glucose and succinate as substrates. The curves showing the formation of DCIPred as a function of time were biphasic, the first part obeying the equation of a pseudo-first-order reaction, the final part corresponding to Michaelis-Menten kinetics. A statistical method was used to estimate pseudo-first-order rate constants k as well as Km and Vmax values. At saturating glucose concentrations k, Km and Vmax values were higher in normal compared to transformed cells. Decreasing glucose concentrations revealed lowered saturation concentrations in tumour cells compared to normal cells. With succinate as substrate for hepatocytes, k values were higher than with glucose, while Km and Vmax were about the same. Hepatoma cells did not metabolize succinate. K values could be attributed to intracellular dehydrogenase activities including cytosolic and mitochondrial processes. Differences in pseudo-first-order rate constants between normal and tumour cells may therefore represent characteristic alterations associated with transformation.

2,6-Dichloroindophenol↗
PubMed1990

Investigation by amperometric methods of intracellular reduction of 2,6-dichlorophenolindophenol in normal and transformed hepatocytes in the presence of different inhibitors of cellular metabolism.

The reduction of 2,6-dichlorophenolindophenol (DCIP) was measured by amperometric methods in Morris hepatoma 3924A cells, normal isolated rat hepatocytes and in mitochondria isolated from normal rat liver. The influence of aerobic and anaerobic atmospheres and of various inhibitors of cellular metabolism, especially of the respiratory chain (KCN, NaN3, oligomycin), on DCIP-reduction were studied using glucose, succinate, beta-hydroxybutyrate, alpha-keto-glutarate and oxalacetate as substrates. Under the influence of KCN and oligomycin the velocity of DCIP-reduction was increased in both cell types. Azide showed a similar effect on tumour cells and to a lower extent on hepatocytes. Using isolated mitochondria total DCIPred was increased by KCN and azide using various mitochondrial metabolites as substrates and with ADP/Pi present. The effects of KCN, azide and oligomycin could be explained by taking DCIP as an artificial coupling site in mitochondria which is only used when oxygen is absent or when the respiratory chain is blocked by inhibitors of cytochrome oxidase. Evaluation of the reaction kinetics revealed differences between normal and transformed cells in terms of the pseudo-first-order rate constants and the activity of overall oxidoreductases. The results apparently reflect quantitative differences in enzymatic equipment and the metabolic pathways predominating in normal and neoplastic cells.

2,6-Dichloroindophenol↗
PubMed1990

DNA analysis, chemoresistance testing and hormone receptor levels as prognostic factors in advanced ovarian carcinoma.

Fifty patients with advanced (stage III or IV) ovarian carcinoma were followed-up until the date of their death or their fifth year of survival. Prognostic factors, including those currently in use, as well as ploidy and proliferation, chemoresistance testing and hormone receptor levels of the tumours were analysed for predictive value and independence from each other. In the univariate analysis, only stage, residual tumour, second-look status, chemoresistance, ploidy and proliferation were significantly correlated with survival. After being tested in a multivariate Cox regression model, however, only the results of chemoresistance testing at initiation of therapy, and second-look status at a later point, retained prognostic significance. Within the group of patients with a positive second-look, i.e., with the worst prognosis, the chemoresistance test was still able to discriminate between two subgroups with significantly different survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Two-stage models of carcinogenesis, classification of agents, and design of experiments.

The implications of a clonal two-stage model of carcinogenesis on the design and analysis of 2-year in vivo tumorigenesis experiments are addressed. Using a simple classification scheme for labelling test agents as initiators, promoters, and completers, it is shown that the standard experimental design has very little ability to differentiate between these different modes of action. Even when chemicals in one class (e.g., promoters) follow a highly nonlinear dose-response relationship and chemicals in another class (e.g., initiators) follow a linear dose-response relationship, it is difficult to reject one mode of action versus the other. A simple modification of the design using age-dependent dosing schemes produces patterns of tumor incidence which are unique to the particular class, making it slightly easier to differentiate between the assumed mechanisms of action. The implications of this finding on study design are discussed.

Aging↗
PubMed1990

[Diabetes mellitus and breast cancer. A retrospective follow-up study].

The influence of diabetes mellitus on the course of breast cancer was investigated retrospectively in 752 patients. Possible unfavourable prognostic factors like overweight, lipid disorders, age and menopausal status were considered as confounders in a Cochran-Mantel-Haensel analysis. There was no difference in primary tumor status and lymph node involvement between patients with diabetes mellitus and nondiabetic patients. Diabetic patients had more often overweight, lipid disorders and were older than nondiabetic patients. Metastatic disease was highly significant correlated with primary tumor status (p less than 10(-6)) lymph node involvement (p less than 10(-10)) and diabetes mellitus (p less than 10(-5)). Overweight, lipid disorders, age and menopausal status were not correlated with metastatic disease. A possible explanation of the correlation between diabetes mellitus and metastatic disease could be hyperinsulinism in type IIB diabetes. A type IIB diabetes in most of the patients included in this study is very plausible because of the correlation between overweight, lipid disorders, old age and diabetes mellitus. This type of diabetes is characterised by a relative resistence to insulin in the target tissues and a prolonged and exceeding insulin secretion. Experimental data demonstrate that insulin stimulates the growth of breast cancer cell in vivo and in vitro.

Adult↗
PubMed1990

[Treatment of advanced pancreatic cancer with 5-fluorouracil, 4-epidoxorubicin and mitomycin C (FEM II). From the Chemotherapy of Gastrointestinal Tumors Group].

In a multicentre phase II trial, 20 patients with advanced pancreatic carcinoma were treated with 5-fluorouracil, 4-epidoxorubicin and mitomycin C, in which 4-epidoxorubicin was administered by escalated dose and split course (FEM II). From among 12 patients evaluable for response, 2 partial and 1 minimal remission were observed, suggesting a response rate of 25%. Four patients (30%) showed a no change and 5 progression. The median survival of all patients was 3.4 months, of the responders 8.4 months, of those with no change 5.2, and of those showing progression 3.4 months. Considerable nausea/vomiting and leukopenia was observed. The preliminary data suggest that the FEM II regimen does not offer any progress in terms of efficacy, survival and toxicity for advanced pancreatic carcinoma.

Adult↗
PubMed1990

Statistical requirements of phase I studies.

Methodological aspects of planning and evaluating phase I studies in oncology--the link between preclinical research and approval of clinical efficacy--include the human starting dose, maximum tolerable dose and dose escalation schemes. Statistical requirements of phase I studies are presented here, emphasizing the urgency of their application in current practice. For the maximum tolerable dose a distinction will be made between an individual- and a population-based approach, which is crucial for a correct definition and statistical parameter estimation. Weaknesses of the dose escalation scheme according to the modified Fibonacci scheme are shown and contrasted with the recently proposed pharmacokinetically guided dose escalation. Comprehensive phase I/II information processing is recommended for validating current practice.

Antineoplastic Agents↗
PubMed1990

Phase II study of pirarubicin in metastatic breast cancer.

Pirarubicin is a more lipophilic derivative of doxorubicin, with a higher uptake rate of cells, lower cardiotoxicity and better antitumor efficacy in preclinical models. Thirty-four patients with metastatic breast cancer were treated in a multicenter phase II study with pirarubicin (THP) using a dosage of 75 mg/m2/every 3 weeks. The patients had a median age of 56 years (range 41-73) and a performance status of WHO grade 0-2. Patients pretreated with anthracyclines, or who were older than 75 years and without sufficient bone marrow reserve were excluded. The 32 evaluable patients received a median number of 4 cycles (range 2-8). The myelosuppression was dose-limiting and led to infections (grades 1 and 2) in 5 patients. Twenty-eight patients developed leukocytopenia grade 3 and 4 toxicity and 7 patients experienced thrombocytopenia grade 1 and 2. The drug was subjectively well tolerated and nausea, vomiting and alopecia were mild. One complete remission with a duration of 15.4 months (67 weeks) and 7 partial remissions with a median duration of 9.3 months (40 weeks) were achieved, which resulted in an overall response rate of 25%. Twenty-one patients were stable for 17 weeks (median) under the treatment with pirarubicin.

Adult↗
PubMed1990

Pirarubicin in advanced non-small cell lung cancer. A trial of the Phase I/II Study Group of the Association for Medical Oncology of the German Cancer Society.

Forty-seven patients with advanced non-small cell lung cancer (NSCLC) were treated in a multicentre phase II study with pirarubicin (THP), 4'-O-tetrahydropyranyl-doxorubicin using a dosage of 70 mg/m2 every 3 weeks. The median age of the patients was 59 years (range 45-70) and the performance status grade 0-2 (WHO). Thirty-eight patients had stage IV and 9 stage III (UICC). Twenty-six patients had an adenocarcinoma. 19 a squamous cell carcinoma, and 2 a polymorphocellular carcinoma. Six out of 45 evaluable patients achieved a partial remission leading to an overall response rate of 13%. Eighteen patients showed no change (NC), 12 were progressive (PD), 2 patients had early progression (EP), and 7 patients died during the first course with clinical signs of tumor progression (early death). The median survival time was 4.6 months. Leukocytopenia and thrombocytopenia (WHO grade 4) was experienced in 8.5% and 2.1%, nausea and vomiting (grade 2 and 3) by 32% of the patients. There was no cardiotoxicity or other severe side effects. Pirarubicin has only a moderate antineoplastic activity in patients with advanced NSCLC. Observed response rates are similar to those reported for doxorubicin, but the toxic side effects are milder.

Aged↗
PubMed1990

Chemotherapy with tauromustine in advanced non-small cell lung cancer. A trial of the Phase II Study Group of the Association for Medical Oncology of the German Cancer Society.

Tauromustine (TCNU) is a newly developed nitrosourea compound. As a result of molecular modification, TCNU is more hydrophilic than BCNU and CCNU. In experimental data there was a high therapeutic index, especially in Walker 256 carcinosarcoma in rats, and in phase I trials antitumor activity was observed in NSCLC (10/33 remissions). There was also activity in melanoma, breast cancer, pleuramesotheliomas and ovarian cancer. To determine the effectiveness, duration of response and toxicity of TCNU the following phase II trial was performed. Patients received 130 mg/m2 TCNU every 35 days orally. Twenty-five patients were treated; 22 were evaluable. The female/male ratio was 18/4, 1 patient was stage III, 21 patients stage IV, the mean age was 62.3 years (range 32-70). Between 1 and 4 courses (mean 1.9) were administered. Histology was as follows: 6 squamous cell, 11 adenocarcinoma, 2 large cell and 3 polymorph cell carcinomas. No objective response (CR + PR) was observed; 6/18 patients had stable disease, 7/18 progression and 5/18 early progression. The median survival time is 4.9 months. The most severe side effect was thrombocytopenia (WHO grade 3 + 4, 4/22 patients). TCNU administered at this dose and schedule does not show substantial antitumor activity in patients with NSCLC. The fact that no objective tumor remission was observed suggests that the true response rate is less than 20% (p less than 0.05). It is improbable that TCNU has a relevant impact on the course of inoperable NSCLC.

Antineoplastic Agents↗
PubMed1990

Phase II evaluation of carboplatin in advanced esophageal carcinoma. A trial of the Phase I/II Study Group of the Association for Medical Oncology of the German Cancer Society.

Eighteen patients with advanced squamous cell carcinoma of the esophagus without prior chemotherapy were treated with carboplatin. Based on experimental data a split dose of carboplatin of 130 mg/m2 given on days 1, 3 and 5 was administered. In cases showing no WBC and platelet suppression, an escalated dose of 160 mg/m2 was proposed. Out of 18 evaluable patients no complete and partial responses were observed and there were only 5 patients with stable disease (27.8%) lasting 2-7 months. Therefore, carboplatin in the regimen used shows no meaningful antitumor activity in patients with advanced esophageal carcinoma. The escalated dose (mean 107-123% of the starting dose) was well tolerated and was followed by only minor gastrointestinal and hematological toxicity. Therefore, this regimen can be recommended for future trials.

Adult↗
PubMed1990

Etoposide, adriamycin, and cisplatinum (EAP) combination chemotherapy for advanced gastric cancer. A phase II trial by the "Chemotherapiegruppe Gastrointestinaler Tumoren (CGT)".

In a multicenter trial, 49 patients with histologically proven advanced gastric cancer were treated with a combination chemotherapy consisting of etoposide 120 mg/m2 d 4, 5, 6 adriamycin 20 mg/m2 d 1, 7 and cisplatinum 40 mg/m2 d 2, 8. Therapy was repeated every 4 weeks, 45 patients were evaluable for response after 8 weeks of treatment. Eight patients achieved a partial remission (PR: 18%), 17 patients had no change (NC: 38%), and 20 patients showed tumor progression (P: 44%). Four patients with primarily inoperable tumor and without distant metastases who achieved a partial remission, underwent second look operation with curative intention. All 4 patients died within 12 months after second look operation due to tumor recurrence. Median survival time of all patients was 9 months. Toxicity was considerable. WHO grade 3/4 toxicity appeared in 20-30% of patients (nausea, vomiting, loss of appetite, leucopenia). After 3 cycles complete alopecia was present in 70% of patients. Severe infection, requiring treatment, occurred in 10 patients. Five patients discontinued therapy because of intolerable subjective toxicity. The observed response rate of 18% objective partial remissions is disappointing and does not give support to the communications reporting response rates over 50% with EAP and other regimens including cisplatinum. In conclusion, and considering the high subjective and objective toxicity of this regimen, it can not be recommended for standard use in patients with advanced gastric cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Tumor necrosis factor in advanced colorectal cancer: a phase II study. A trial of the phase I/II study group of the Association for Medical Oncology of the German Cancer Society.

In a phase II study, the efficacy and toxicity of human recombinant tumor necrosis factor (rh TNF-alpha) were evaluated in patients with advanced colorectal carcinoma. Rh TNF-alpha was given as short term infusion at a dose of 3 x 10(5) U/m2 on three successive days. Treatment was repeated after a two week interval. The response was evaluated after four treatment cycles. In 15 patients entering the study, we found one partial response, one stable disease, 9 progressive diseases, and four patients who were not evaluable for tumor remission. There were numerous side effects of the treatment, mainly fever, chills, loss of appetite, leukopenia, and hepatotoxicity. In this regimen, rh TNF-alpha does not suggest a therapeutic advantage for treatment of advanced colorectal carcinoma.

Adenocarcinoma↗
PubMed1989

Dose escalation and split course of 4-epidoxorubicin in combination chemotherapy (FEM II) of advanced gastric carcinoma. A phase-II trail of the 'Chemotherapiegruppe Gastrointestinaler Tumoren (CGT)'.

In a phase II trial 46 patients with advanced gastric carcinoma were treated with FEM combination chemotherapy (5-fluorouracil, 4-epidoxorubicin and mitomycin C) in which 4-epidoxorubicin was administered by escalated dose and split course (FEM II). Twenty-nine patients with measurable disease were evaluable for response. One complete remission and 7 partial remissions were achieved, suggesting an overall response rate of 28%; 2 minimal responses (7%) and 9 patients with no change were observed (31%); 10 patients had tumor progression (34%). Median survival time for all patients was 6.2 months, for patients with CR + PR + MR 16.2 months, for patients with no change 8.4 months, and with tumor progression 3.5 months. WHO grade 2 and 3 leukopenia appeared in 6%, thrombocytopenia in 0% and alopecia in 27% of the patients after the first cycle. Nausea and vomiting grade 2 and 3 were seen in 21%. Comparing these results with our earlier data achieved with FEM I, FEM II showed a tendency towards better response and survival, and subjective toxicity (nausea/vomiting) was significantly reduced. Therefore, in our opinion FEM II is preferable for practical use.

Adult↗
PubMed1987

6-Methylguanine and 6-methylguanosine inhibit colony-forming ability in a malignant xeroderma pigmentosum cell line but not in other xeroderma pigmentosum and normal human fibroblast strains after treatment with 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)-urea.

The XP cell strain XP29MA, its malignant counterpart XP29MAmal and a normal human fibroblast strain were tested for colony-forming ability after treatment with HECNU in the presence of m6G, m6Gua, and he7G. In XP29MAmal, inhibition of post-HECNU colony-forming ability was 35% when 0.25 mM of either m6G or m6Gua were present, whereas in XP29MA and the normal fibroblast strain no inhibition was detected. The he7G caused a similar but smaller inhibitory effect in XP29MAmal, but failed to do so in XP29MA. HECNU predominantly exerts its killing effect by alkylating O-6 of DNA-bound guanine and causing DNA interstrand crosslinks. Alkylation of O-6 of guanine can be repaired by 6-methylguanine-DNA methyltransferase. From our experiments we conclude that in XP29MAmal this methyltransferase was inhibited in the presence of the 6-alkylguanines, thus leaving more 2-chloroethylated sites in DNA unrepaired. This results in sensitization in terms of decreased colony-forming ability observed only in the malignant cell line.

Cell Division↗