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Biomedical subjects

M R Berger

Publications and source records attributed to M R Berger.

At least 73 records · Page 4Linked to original sources
PubMed1990

An oestradiol-linked nitrosourea and site-directed chemotherapy in mammary carcinoma.

The half-life, peak concentration, peak accumulation and tissue availability of the DNA-crosslinking nitrosourea 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine (CNC-alanine) and its oestradiol-linked derivate (CNC-alanine-oestradiol-17-ester) were studied in liver, lung, spleen, uterus and mammary carcinomas in female Sprague-Dawley rats with chemically induced mammary carcinomas. Compared with CNC-alanine, the ester had a longer half-life, higher peak concentration, increased peak accumulation and enhanced tissue availability in all tissues. In oestradiol receptor positive mammary carcinomas, the oestradiol-linked drug showed a 2 times higher peak concentration, a 5 times longer half-life, a 10 times increased peak accumulation and a 20 times greater tissue availability compared with CNC-alanine. Oestradiol-linked nitrosoureas may offer new perspectives for site-directed chemotherapy of oestradiol receptor positive breast cancer.

Alanine↗
PubMed1990

Effect of 3,7-bis-(4-trifluoromethylphenyl)-1,5,3,7-dioxadiazocane on pyrimidine and DNA synthesis in rat organs.

The administration of the lipophilic 3,7-bis-(4-trifluoromethylphenyl)- 1,5,3,7-dioxadiazocane (TFMPD) to rats induced the following effects on the biosynthesis of DNA in the liver, kidney, thymus and spleen: (a) The utilization of [3H]thymidine for the synthesis of liver DNA thymine was decreased after the administration of a single dose of the drug. The depression of the specific activities of DNA pyrimidines of liver DNA in experimental groups was observed also after an injection of [14C]orotic acid. (b) A decreased incorporation of labeled thymidine had occurred also in the spleen during the prereplicative period. Thereafter the specific activity of DNA thymine was higher than in the control group. (c) The observed mitogenic response in the spleen showed a protracted effect; after the administration of a single dose of the drug the specific activity of DNA thymine as well as the thymidine kinase activity of spleen cytosol have been rising up to the ninth day. The same holds true for DNA thymine of the thymus; the activity of thymidine kinase was not affected. (d) Both the single and repeated doses of TFMPD had no marked effect on the levels of microsomal cytochromes P-450 and b5 in the liver and kidney.

Administration, Oral↗
PubMed1990

Modulation of cytosolic sexual steroid receptors in autochthonous methylnitrosourea-induced rat mammary carcinoma following application of 2-chloroethylnitrosocarbamoyl-L-alanine linked to oestradiol or dihydrotestosterone.

This study concentrated on the influence of 2-chloroethylnitrosocarbamoyl-L-alanine (CNC-L-ala) linked to oestradiol (CNA-L-ala-E2) or dihydrotestosterone (CNC-L-ala-DHT) in position 17 of the respective steroid hormone on tumour growth and receptor kinetics of methylnitrosourea-induced rat mammary carcinoma. Both compounds almost completely arrested logarithmically growing mammary carcinoma of Sprague-Dawley rats: in the first week CNC-L-ala-E2 blocked the growth of these tumours by 92% compared to untreated control animals while, in animals treated with the physically equimolar mixture of CNC-L-ala and oestradiol (positive control), tumour growth was inhibited by 51% only. CNC-L-ala-DHT arrested the tumour growth in the first week by 95%, while the respective positive control (CNC-L-ala plus dihydrotestosterone) effected a growth inhibition of 71% compared to the untreated control. These results correlate well with the influence of both drugs on the cytosolic receptor content of sexual steroid hormones in the tumours. CNC-L-ala-E2 depleted the content of oestradiol receptors and kept it down for a week, while concomitantly the content of progesterone receptors increased considerably and that of androgen receptors showed a short-lived decrease. CNC-L-ala-DHT depleted androgen receptors as well as progesterone receptors. The content of androgen receptors remained low for a week, while that of progesterone receptors recovered within 8 days. The content of oestrogen receptors showed a moderate decrease.

Animals↗
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

A new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis by means of high-pressure liquid chromatography for pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites.

Estradiol-linked nitrosoureas are offering new perspectives in the antineoplastic chemotherapy of estradiol-receptor positive mammary carcinomas. In such a molecule estradiol has the function of a carrier which brings about a specific accumulation of the anticancer drug in estradiol-receptor containing tumor cells. However, there is only little knowledge about the pharmacokinetic behavior of this new group of anticancer agents. For that reason a new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis with high-pressure liquid chromatography (HPLC) for preclinical pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites has been developed. N-(2-Chloroethyl)-N-nitroso-carbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) and N-(2-chloroethyl)-N-nitroso-carbamoyl-L-alanine (CNC-alanine) were used as test compounds. The drugs were tested in female Sprague-Dawley rats with chemically induced mammary carcinomas. The laboratory animals were supplied with two catheters prior to the pharmacokinetic experiments. The blood samples were drawn from the vena cava catheter after the drug had been applied through a vena jugularis catheter. The compounds were extracted from plasma with C18 silicagel reversed phase cartridges. The clean-up technique delivered clear samples only slightly contaminated with the biological matrix. The recovery from plasma was 75 +/- 5% for the hormone-linked CNC-alanine-estradiol-17-ester and 70 +/- 5% for the unlinked CNC-alanine. The analysis was carried out by means of HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1990

Effects of different levels of dietary fat on methyl-nitrosourea-induced mammary carcinogenesis in correlation with parameters of fat metabolism in female Sprague-Dawley rats.

The aim of this study was to elucidate the effects of different levels of dietary fat on methyl-nitrosourea-induced rat mammary carcinogenesis in correlation with parameters of the fat metabolism. 90 female Sprague-Dawley rats were initiated i.v. with 25 mg MNU/kg on day 50 of life. For a period of 6 months, beginning after the day of initiation, the animals received either a control diet (12% of total energy as fat, Group I) or one of the fat-enriched semisynthetic diets (25 en% of fat, Group II, or 45 en%, Group III, respectively) at an isocaloric level of 50 kcal/rat/day. The principal observations of this experiment were: (1) The fat content of diet did not significantly influence mammary carcinogenesis. (2) The values of plasma total lipids, cholesterol and triglycerides and their density separated VLDL and LDL-fractions showed a significant time-dependent increase. (3) HDL-values of cholesterol and triglycerides showed no changes in dependence to time and fat content of the diet. (4) The liver lipid concentrations of groups increased significantly with dietary fat content.

Animals↗
PubMed1990

Cancer incidence rates in Turkey and two regions in the Federal Republic of Germany: a comparison.

Cancer incidence rates in Turkey are compared to those in two regions of West Germany, namely Hamburg and Saarland. Incidence rates of laryngeal, colorectal and prostatic cancer are significantly different in males of the two countries. Additionally, incidence rates of skin and trachea, bronchus, lung cancer show statistically significant differences in males of Turkey and Saarland. Between females, only the incidence of colorectal cancer is significantly different in both countries. These variations in cancer occurrence may be due to differences in tobacco and alcohol consumption, age distribution of the two populations and exposure to sunlight.

Age Factors↗
PubMed1990

In vitro evaluation of 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)urea linked to 4-acetoxy-bisdesmethyltamoxifen, estradiol and dihydrotestosterone.

The anticancer efficacies of three 1-(2-chloroethyl)-1-nitroso-3-(2- hydroxyethyl)urea (HECNU) derivatives--4-acetoxybisdesmethyltamoxifen-1,4-hemisuccinate-H ECNU (4-OAc-BDMT-hs-HECNU), 17-beta-estradiol-1,4-hemisuccinate-HECNU (E2-hs-HECNU) and 17-dihydrotestosterone-1,4-hemisuccinate-HECNU (DHT-hs-HECNU)--are compared with their unlinked equimolar mixtures using the estrogen and androgen receptor positive cell line MCF-7. Following 72 h incubation at a concentration of 100 mumol/l, 4-OAc-BDMT-hs-HECNU and DHT-hs-HECNU have a growth inhibitory effect of 76% and 73%, respectively, whereas E2-hs-HECNU causes an inhibition of 55%. Within this time period, DHT-hs-HECNU (100 mumol/l) is more effective as compared to the unlinked equimolar combination of HECNU plus dihydrotestosterone; E2-hs-HECNU (100 mumol/l) is slightly more and 4-OAc-BDMT-hs-HECNU (100 mumol/l) is even less effective than the respective unlinked equimolar mixtures. At this concentration (100 mumol/l) the growth inhibitory effect of 4-OAc-BDMT-hs-HECNU is not antagonized by coincubation with estradiol.

Animals↗
PubMed1989

Causes of cancer--an alternative view to Doll and Peto (1981).

This paper presents an alternative view to a commonly held misconception. The extent to which the causes of human cancer can be known is less than generally believed on the basis of the formal summation of estimates on the causal role of certain carcinogenic factors that have been tabulated by Doll and Peto (1981). Here it is stressed that the factors with known causal relation in the etiology have not as yet been ascertained for up to 97% of human cancers. Currently only one-third of the cancer deaths registered in the Federal Republic of Germany can be assigned etiologically to known exogenous carcinogenic agents or lifestyle. Accordingly, the causes of less than 50% of all malignant neoplasms are known and amenable to direct causal primary prevention. This, however, does not preclude a concept of "indirect primary prevention" which, based on the probable summation of subcarcinogenic effects of single carcinogens, enables removal from the environment of compounds that show carcinogenicity in animals, even if these compounds lack epidemiological evidence of carcinogenic activity.

Cocarcinogenesis↗
PubMed1989

[In vitro study of estradiol-linked nitrosourea in breast cancers in the mouse, rat and human: interspecies comparison].

In vitro activity of 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine-oestradiol-17-ester (CNC-ala-17-E2) at three concentrations in transplanted MXT mammary carcinoma in mice and autochthonous methylnitrosourea (MNU)-induced mammary carcinoma in Sprague-Dawley rats, as well as in 30 human primary breast carcinomas using the bilayer soft agar assay is described. Eighty-five percent of MXT tumours showed a more than 70% inhibition of colony formation in response to CNC-ala-17-E2. The MNU-induced model did not show this high degree of inhibition; only 5% of tumours showed an inhibition of up to 70%, but a superiority of the hormone-linked agent over the unlinked single agents was nevertheless discernible. By contrast, in human breast carcinomas there was no statistically superior response to the hormone-linked preparation as opposed to the single agents. Thus, in MXT mammary carcinoma the in vitro results parallelled previous findings in vivo, whereas in the MNU-induced autochthonous tumour model this close in vivo-in vitro correlation was not observed. The discrepancy between in vivo and in vitro results found in the autochthonous rat model indicates that hormone-linked nitrosoureas should not necessarily be abandoned for the treatment of human breast carcinoma on the basis of negative in vitro results alone.

Animals↗
PubMed1989

Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine]dichloroplatinum(II)-compl exe s, Part I: Synthesis.

The synthesis of the stereoisomeric 1,2-bis(3-hydroxyphenyl)ethylenediamines (1-4) from meso-1,2-bis(2-hydroxyphenyl)ethylenediamine and 3-methoxybenzaldehyde by a diaza-Cope-rearrangement and subsequent ether cleavage with BBr3 and their conversion into the [1,2-bis(3-hydroxyphenyl)ethylenediamine]dichloroplatinum(II)-complexes with K2PtCl4 (1-PtCl2 - 4-PtCl2) is described.

Antineoplastic Agents↗
PubMed1989

Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl) ethylenediamine]dichloroplatinum(II)-complexes, Part II: Biological properties.

The activity of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine] dichloroplatinum(II)-complexes (1-PtCl2,R,S; 2-PtCl2, R,R/S,S; 3-PtCl2, R,R; 4-PtCl2, S,S) on several tumor models (MDA-MB 231 breast cancer cell line; P 388 leukemia, mouse; L 1210 leukemia, mouse; L 5222 leukemia, rat; Ehrlich ascites tumor, mouse--wildtype; cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.) is described. For comparison the analogous [1,2-bis(4-hydroxyphenyl)ethylendiamine]dichloroplatinum (II)-complexes (5-PtCl2, R, S; 6-PtCl2, R,R/S,S; 7-PtCl2, R,R; 8-PtCl2, S,S) and cisplatin are used. 1-PtCl2 to 4-PtCl2 (OH in 3,3'-positions) show their maximum antitumor effect at lower doses than 5-PtCl2 to 8-PtCl2 (OH in 4,4'-positions). 2-PtCl2 and 6-PtCl2 (R,R/S,S) are more active than 1-PtCl2 and 5-PtCl2 (R,S). 4-PtCl2 and 8-PtCl2 (S,S) are superior to 3-PtCl2 and 7-PtCl2 (R,R). On the L 5222 leukemia 2-PtCl2 (R,R/S,S), 4-PtCl2 (S,S) and 8-PtCl2 (S,S) markedly surpass cisplatin. Strong effects are produced by 2-PtCl2 to 4-PtCl2 on the Ehrlich ascites tumor (wildtype, cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.). The combination of 4-PtCl2 with cisplatin results in a weakly synergistic effect.

Animals↗
PubMed1989

Nicotine and estrogen metabolism--possible implications of smoking for growth and outcome of treatment of hormone-dependent cancer? Discussion of experimental results.

The combination treatment of hormone-dependent autochthonous mammary carcinomas in the rat with nicotine plus HECNU, a water-soluble nitrosourea, resulted in a potentiation of antitumor action. Nicotine and its metabolite cotinine are strong inhibitors of the aromatase. With regard to investigations in smoking women, suggesting a decreased endogenous estrogen production, our results indicate that smoking might influence growth and treatment results of hormone-dependent human cancer.

Animals↗
PubMed1989

New estradiol-linked nitrosoureas: can the pharmacokinetic properties help to explain the pharmacodynamic activities?

The pharmacokinetics of 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) a new estradiol-linked anticancer drug and the unlinked DNA-crosslinking agent 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine (CNC-alanine) have been studied in methylnitrosourea-induced female Sprague-Dawley rats after equimolar intravenous and oral administration. In comparison with the unlinked single agent, the CNC-alanine-estradiol-17-ester showed a 3-fold longer halflife in plasma and a three times larger volume of distribution. The distribution after intravenous administration was nearly three times faster. The absorption after peroral administration was likewise two times faster. The bioavailability of the estradiol-linked drug was determined to be 52%. After application of CNC-alanine-estradiol-17-ester the cytostatic metabolite CNC-alanine was found, indicating the cleavage of the ester bond. CNC-alanine generated from CNC-alanine-estradiol-17-ester showed a 50% longer halflife than when applied directly. The results indicate that linking 2-chloroethyl-nitrosoureas to estradiol can result in new anticancer agents with modified properties in comparison to the unlinked single agent. The higher antineoplastic activity of the hormone-linked drug can mainly be attributed to differences in the pharmacokinetic behaviour.

Administration, Oral↗
PubMed1989

Long-term carcinogenicity of cyclophosphamide in two mouse strains with different spontaneous leukemia incidence.

The aim of the present study was to investigate to what extent the induction of leukemia by the carcinogenic agent cyclophosphamide (CPA) might be influenced by the genetic predisposition. CPA was s.c. administered at 26 mg/kg and 13 mg/kg weekly for lifetime to AKR mice which are genetically predisposed to develop leukemias, and to NMRI mice, that exhibit a low spontaneous leukemia rate. CPA dose-dependently increased the median life span in AKR mice by 27% and 76% (P less than 0.001), and decreased the incidence in leukemias by 17% and 37% (P less than 0.01), respectively. In NMRI mice, CPA significantly increased the incidence of leukemias by 46% at the low dose (P less than 0.02) and 26% at the high dose (P less than 0.03), respectively. The apparently parallel observations of the lower leukemia incidences following the higher CPA-dosage in both strains probably are related to different mechanisms of action: in the susceptible, genetically determined AKR mice the therapeutic effect of CPA prevailed its carcinogenic potential and the genetic host factors whereas in the resistant NMRI mice the cytotoxic efficacy of CPA reduced its carcinogenicity at the higher dosage.

Animals↗