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Biomedical subjects

E Frei

Publications and source records attributed to E Frei.

At least 235 records · Page 13Linked to original sources
PubMed1985

Influence of a prolonged treatment with disulfiram and D-penicillamine on nitrosodiethylamine-induced biological and biochemical effects. II. Investigations on trace elements in the liver.

The influence of a 28-week treatment with disulfiram (DSF), D-penicillamine (PA), and nitrosodiethylamine (NDEA), as well as with a combination of DSF or PA with NDEA on the concentrations of eight essential trace elements in the whole liver tissue of rats was measured by means of neutron activation analysis. While NDEA treatment lowered the Zn content of the liver, DSF alone or in combination with NDEA enhanced the Zn and Se concentration by 50%-80%. Co, Cu, and Cd levels were increased by factors of 10, 60, and 110, respectively. The Mo concentration was decreased by 50% after DSF administration. PA reduced Cu, Co, and Zn in the liver. PA/NDEA treatment also lowered Cu, Co, and Zn content, but there was no strengthening effect of PA on the decrease in Zn observed with NDEA. The change of trace element concentrations, especially of Cu, is discussed with regard to the observed tumor induction in the liver, which tended to be increased by a combined NDEA/PA administration compared with NDEA treatment alone, whereas a protective action of DSF against NDEA induced liver tumors could not be established.

Animals↗
PubMed1985

Reduced glutathione inhibits the alkylation by N-nitrosodimethylamine of liver DNA in vivo and microsomal fraction in vitro.

The transfer of radioactivity from N-nitroso-[14C]dimethylamine to trichloroacetic acid precipitable macromolecules in the microsomal fraction of rat liver was investigated. This transfer was found to depend on N-nitrosodimethylamine being metabolized. Cytosolic fraction and cytosol enriched with reduced glutathione inhibited the binding of radioactivity to acid insoluble proteins. Depletion of glutathione in rat liver with diethylmaleate prior to i.v. administration of 10 mg N-nitroso-[14C]dimethylamine/kg led to an increase in O6-methylguanine and N-7-methylguanine in DNA. If rats were fed disulfiram for 6 days (2 g/kg feed), glutathione and glutathione S-transferase were enhanced, and the degree of methylation of guanine by N-nitrosodimethylamine was greatly reduced, as was the metabolism of N-nitrosodimethylamine in the intact animal. Fasting rats for 24 h did not change the N-nitrosodimethylamine-demethylase activity in vitro but greatly enhanced the methylation of guanine in vivo, while the glutathione content and glutathione S-transferase activity were not changed compared to fed animals.

Alkylation↗
PubMed1985

Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.

gamma-tert-Butylaminopterin (gamma-tBAMT), the first example of an aminopterin (AMT) gamma-monoester, was synthesized, and new routes to the known N10-methyl analogue gamma-tert-butyl methotrexate (gamma-tBMTX) were developed. The inhibitory effects of gamma-tBAMT on the activity of purified dihydrofolate reductase (DHFR) from L1210 murine leukemia cells, the growth of L1210 cells and CEM human leukemic lymphoblasts in suspension culture, and the growth of several lines of human squamous cell carcinoma of the head and neck in monolayer culture were compared with the effects of gamma-tBMTX and the parent acids AMT and methotrexate (MTX). Patterns of cross-resistance to gamma-tBAMT, gamma-tBMTX, and AMT among several MTX-resistant cell lines were examined. In vivo antitumor activities of gamma-tBAMT and gamma-tBMTX were compared in mice with L1210 leukemia. While the activity of gamma-tBAMT was very close to that of gamma-tBMTX in the DHFR inhibition assay, the AMT ester was more potent than the MTX ester against cells in culture and against L1210 leukemia in vivo. Only partial cross-resistance was shown against gamma-tBMTX and gamma-tBAMT in cultured cells that were resistant to MTX by virtue of a transport defect or a combination of defective transport and elevated DHFR activity.

Aminopterin↗
PubMed1985

Alkylating agent resistance: in vitro studies with human cell lines.

Development of in vitro resistance to HN2 (also called mustargen or mechlorethamine hydrochloride), N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), and cisplatin [cis-diamminedichloroplatinum(II)] was achieved in two human cell lines, the Raji/Burkitt lymphoma and a squamous cell carcinoma of the tongue. A 10- to 20-fold increase in resistance relative to the parental line was achieved in 3-4 months of continuous selection pressure. At this time, further increase in selection pressure resulted in cell death, while removal of drug led to rapid loss of resistance. However, by holding selection pressure constant over 8-12 months, semistable clones ranging in resistance up to 8- to 12-fold were obtained. The half-life for resistance loss upon removal of drug was 2-3 months. In the presence of intermittent low concentrations of the alkylating agent, resistance has been maintained in excess of 9 months. With one exception, the growth kinetics of the resistant clones were slightly slower than those of the parental lines. Cross-resistance studies were performed against HN2, BCNU, cisplatin, phenylalanine mustard, and hydroperoxycyclophosphamide. There was, in general, a lack of cross-resistance. We conclude that stable resistance to alkylating agents is produced with difficulty. We propose that these semistable cloned human tumor lines represent clinically relevant models for the study of alkylating agent resistance and that the cross-resistance patterns among these cells have important therapeutic and mechanistic implications.

Alkylating Agents↗
PubMed1985

Selection bias in clinical trials.

Of 90 patients with intermediate or high-grade sarcoma eligible for a randomized trial of adjuvant doxorubicin (Adriamycin, Adria Laboratories, Columbus, Ohio), 48 were not entered: 24 (27%) by physician's choice and 24 refused randomization. Sixty-five percent of lower stage patients were randomized compared with 37% of those with higher stage (P = .02). Patients with extremity lesions were more frequently offered participation in the study (P = .07). Patients with lower stage lesions accepted randomization more readily than those with higher stage lesions (P = .01). As predicted by the higher stage and percentage of central lesions, the disease-free survival of nonrandomized patients was inferior to that of randomized patients (P = .15). Thus, patients at high risk appeared to avoid randomization and adjuvant doxorubicin in this trial, resulting in an inferior disease-free survival for the nonrandomized control group. Important questions generally require randomized trials that reliably determine relative treatment differences. If, however, the patients in a clinical trial are not representative of the entire patient population because of patient and physician selection biases, the generalizability of the results to the entire patient population may be compromised. For example, the prognosis of the general population cannot necessarily be inferred from the selected group in the study. In this study, the randomized and nonrandomized series yielded differing conclusions regarding treatment efficacy, even when an adjustment was made for known prognostic facts.

Clinical Trials as Topic↗
PubMed1985

Phenotypic heterogeneity in cultured human head and neck squamous cell carcinoma lines with low-level methotrexate resistance.

Low-level methotrexate (MTX) resistance (less than 20-fold) was induced by gradual selection pressure in four human head and neck squamous cell carcinoma lines established in culture from biopsies of patients not previously treated with MTX. Each parental and resistant line was characterized with respect to MTX uptake and polyglutamylation, dihydrofolate reductase (DHFR) content, and growth rate. Relative DHFR gene copy numbers and amounts of DHFR-related cytoplasmic messenger RNA were analyzed by plasmid complementary DNA hybridization in a dot blot assay and were correlated with the amount of gene product. The resistant lines were not cloned in order to simulate in vitro the conditions which might exist in an in vivo setting, where multiple resistant subpopulations of cells may be present in a tumor. The study was restricted to cells with low-level resistance since these are likely to be the clinically most relevant type. Of the four resistant lines characterized, one showed a severe defect in MTX uptake and polyglutamylation, another was a DHFR overproducer with only small changes in uptake and polyglutamylation, a third was likewise a DHFR overproducer but also showed lower MTX uptake, and the fourth was minimally altered except for growth rate. The diversity in resistance phenotype among these cells in vitro suggests that in vivo resistance in patients with head and neck carcinoma who are treated with MTX may similarly involve multiple mechanisms and that further therapeutic intervention using MTX or other antifolates should take this into account.

Biological Transport↗
PubMed1985

Combination chemotherapy followed by radiation therapy in patients with regional stage III unresectable non-small cell lung cancer.

A chemotherapy combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) was administered to 30 patients with stage III M0 or M1 (supraclavicular nodes) unresectable non-small cell lung cancer before and after radiotherapy. All patients had mediastinal metastases and most had T2 or T3 primary lesions. The response rate (complete plus partial) after two cycles of CAP was 47%, which increased to 66% (24% complete response rate) following radiotherapy. The overall median survival from initiation of chemotherapy was 9 months. CNS relapse occurred in five (26%) of 19 responding patients who did not receive prophylactic cranial irradiation in the early part of the study.

Adenocarcinoma↗
PubMed1985

Curative cancer chemotherapy.

Cancer chemotherapy provides variably effective treatment for the majority of forms of human cancer and curative treatment for some 12 categories of cancer. Curative treatment is defined as the proportion of patients who survive beyond the time after which the risk of treatment failure approaches zero, i.e., the disease-free survival plateau. This progress has resulted from a closely integrated scientific effort, including drug development, pharmacology, preclinical modeling, experimental design with respect to clinical trials, quantitative criteria for response, and a series of clinical trials (initially in children with acute lymphocytic leukemia) in which the importance of complete remission, of dose and schedule, of sequencing chemotherapeutic agents, of pharmacological sanctuaries, and particularly of combination chemotherapy was studied. The principles derived from these studies, particularly those relating to combination chemotherapy, resulted in curative treatment for disseminated Hodgkin's disease, non-Hodgkin's lymphoma, pediatric solid tumors, testicular cancer, and limited small cell lung cancer. Many patients with certain stages of solid tumors, such as breast cancer and osteogenic sarcoma, are at high risk of having disseminated microscopic disease. Experimental studies indicate that treatment which is only partially effective against macroscopic disease is much more effective against microscopic tumors. Therefore chemotherapy is administered immediately following control of the primary tumor in patients at high risk of having disseminated microscopic disease, a treatment known as adjuvant chemotherapy. This program has been highly successful in increasing the cure rate in patients with pediatric solid tumors and in prolonging disease-free survival in patients with premenopausal breast cancer. Given dissemination of the technology, it is estimated that 15,000-30,000 patients per year are potentially curable in the United States. Curability of cancer by chemotherapy generally is inversely related to age, i.e., the above tumors are most common in children and young adults. There are new and promising treatment strategies, such as neoadjuvant chemotherapy and autologous bone marrow transplantation. The revolution in molecular and cellular biology is providing an increase in targets, rationale, and opportunity for more effective and novel chemotherapeutic approaches.

Antineoplastic Agents↗
PubMed1984

Development of methotrexate resistance in a human squamous cell carcinoma of the head and neck in culture.

Four methotrexate (MTX)-resistant sublines of a human squamous cell carcinoma (SCC15) were established in culture by progressive dose escalation. The biochemical basis of resistance was studied. The line with the lowest resistance (R1) had a normal dihydrofolate reductase (DHFR) content but showed decreased MTX transport and polyglutamation. Lines of intermediate resistance (R2 and R3) showed an increased DHFR content and DHFR gene copy number and a defect in MTX transport. The line with the greatest resistance (R4) showed increased DHFR content and gene copy number but nearly normal MTX transport. These results demonstrate that multiple mechanisms of MTX resistance occur in human epithelial cells in culture. We also find evidence of alterations in DHFR gene expression. The MTX-resistant cells were either not cross-resistant or only partly cross-resistant to two lipophilic MTX ester derivatives. These compounds are of potential therapeutic interest for the treatment of MTX-resistant tumors.

Biological Transport↗
PubMed1984

Formaldehyde as a possible mutagenic metabolite of N-nitrodimethylamine and of other agents which are suggested to yield non-alkylating species in vitro.

N-Nitramines are biologically active compounds of environmental significance. In this study the suggested bioactivation of N- nitrodimethylamine via oxidation at the methyl-group was confirmed, as was indicated by formaldehyde liberation. N- Nitrodimethylamine and formaldehyde as well as the suggested metabolites, N- nitrohydroxymethylmethylamine and N- nitromethylamine were tested for mutagenicity in histidine auxotrophic Salmonella typhimurium strains in a variety of conditions. N- Nitrodimethylamine was mutagenic only in S. typhimurium TA 100 after pre-incubation with bacteria and a complete metabolizing mixture containing 9000 g liver supernatant and NADPH-regenerating cofactors. N- Nitrohydroxymethylmethylamine and formaldehyde were approximately equally mutagenic without the metabolizing mixture in TA 100 and TA 98, but not in TA 1535. The addition of the 9000 g supernatant of homogenized liver increased the yield of his+ revertants induced by the two compounds. N- Nitromethylamine was not mutagenic with or without the metabolic activation system. The results suggest that formaldehyde is possibly the mutagenically active intermediate formed during in vitro metabolism of N- nitrodimethylamine . Furthermore the participation of formaldehyde as the mutagenic intermediate of other non-alkylating N-nitro and N-nitroso compounds is demonstrated.

Animals↗
PubMed1984

Antithrombin III and related parameters in surgical patients receiving blood components.

We examined the intra- and postoperative behavior of antithrombin III (AT), factor V, VIII, and fibrinogen in 27 elective surgical patients without evidence of disseminated intravascular coagulation (DIC) and treated according to the concept of blood component therapy inaugurated at our hospital in 1975. The intraoperative depletions of AT and fibrinogen were proportional to the transfusion volumes and correlated significantly. AT, fibrinogen, and especially factor V and VIII were significantly mobilized during surgery. A greater intraoperative depletion of AT was significantly associated with a faster recovery during the first 24 postoperative h. The AT activity was virtually stable over a period of 4 weeks in CPD-adenine red cell concentrates; fresh frozen plasma and whole blood are thus not essential as a source of AT. The application of our concept did not increase the frequency of thromboembolic complications, despite the fact that the intraoperative AT values fell below the presumed 'critical' level of 60-70% in some patients. The probable reasons are the brief duration of such levels, the simultaneous depletion of coagulation-promoting plasma constituents (e.g. fibrinogen), and the use of antithrombotic prophylaxis. Our results suggest no reasons for a routine use of fresh frozen plasma in patients with a loss and replacement of less than about 75% of their blood volume.

Antithrombin III↗
PubMed1984

Biochemical and biological properties of prospective N-nitrodialkylamine metabolites and their derivatives.

The metabolic conversion of N-nitrodimethylamine and of N-nitrosodimethylamine was compared in vitro. The biochemical properties of the two compounds were nearly identical; however, the biological activities (carcinogenicity, mutagenicity and toxicity) of the nitramine are many times less potent. N-Nitrodimethylamine was found to be mutagenic to Salmonella typhimurium TA100 when applied at above 200 mumol/plate with metabolic activation. Its suggested metabolite, N-nitromethylamine, was not mutagenic, N-Nitromethylhydroxymethylamine, N-nitromethylacetoxymethylamine and formaldehyde were mutagenic only to S. typhimurium TA100 at low concentrations and toxic above 2 mumol/ plate. The evidence suggests that formaldehyde is the intermediate responsible for the mutagenicity of the nitramine derivatives and of the parent compound, N-nitrodimethylamine.

Animals↗