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Biomedical subjects

M R Berger

Publications and source records attributed to M R Berger.

At least 91 records · Page 5Linked to original sources
PubMed1989

Nitrosoureas. Modes of action and perspectives in the use of hormone receptor affinity carrier molecules.

Mechanisms of DNA adduct formation by antineoplastic 2-chloroethyl-N-nitrosoureas (CNUs) and of DNA damage induced by these compounds are discussed. CNUs are alkylating agents that form DNA-DNA cross-links as well as 2-chloroethylated and 2-hydroxyethylated adducts, the N-7-position of guanine being the predominantly alkylated site. A close correlation exists between the potential of a given compound to induce DNA-DNA cross-links and its antineoplastic effectiveness. However, levels of DNA-DNA cross-linking in bone marrow and extent of myelosuppression as measured in rodents are also closely correlated. The design of new cross-linking analogues capable of directing the antineoplastically relevant activity predominantly to the target tumour appears therefore to be of great promise. Cross-linking agents have been attached to a variety of steroid hormone carrier molecules and the conjugates have been tested in structure-activity studies using hormone-receptor containing animal tumours. These studies have revealed that some hormone-linked antineoplastic agents are highly effective in receptor positive experimental tumours and are superior to mixtures of unlinked alkylating agents with hormones. Indications for a relative enrichment of DNA damaging effects in the tumour tissue and for reduced myelotoxicity have been obtained with specific hormone conjugates.

Animals↗
PubMed1989

Evaluation of spin labeled TEPA and CCNU analogs against osteosarcoma and MNU-induced mammary carcinoma of the SD-rat.

The effectiveness to reduce tumor growth by 1-(2-chloroethyl)-3-(1-oxyl-2,2,6,6-tetramethylpiperidinyl)- 1-nitrosourea (SLCNU) and N,N,N,'N'- bis(1,2-ethanediyl)-N"-(1-oxyl-2,2,6,6-tetramethyl- 2-piperidinylaminocarbonyl)-phosphoric triamide (SLDU) was studied in osteosarcoma and MNU-induced mammary carcinoma in the SD-rat. Both compounds elicited neither an inhibitory effect on these tumors nor an increase in the mean/median life span as compared to the control group.

Animals↗
PubMed1988

Study on the long-term toxic efficacy of cytosine-arabinoside in Sprague-Dawley rats.

This study describes the development of neoplasms and the suppression of bone marrow stem cells following chronic administration of cytosine-arabinoside (ara-C) in Sprague-Dawley rats. Ara-C was administered i.p. either at daily dosages of 5 mg/kg and 25 mg/kg or at pulse doses of three times 500 mg/kg within 1 week followed by a time interval of 11 weeks. The total doses of the higher daily dose and of the pulse dose were chosen to be equally high. No significant carcinogenic activity of ara-C could be assessed following either of these dose schedules. With regard to general toxicity, as expressed by body weight gain and long-term bone marrow toxicity, high pulse doses of ara-C were better or at least equally tolerated as were the equivalent daily low doses.

Animals↗
PubMed1988

Comparison of in vivo and in vitro activity of estrogen-linked nitrosoureas in methylnitrosourea-induced rat mammary carcinoma.

The anticancer activity of estradiol-linked 2-chloroethylnitrosoureas in methylnitrosourea-induced rat mammary carcinoma was investigated using the short-term assay and the bilayer soft agar system after in vitro exposure as well as the monolayer methylcellulose assay following in vivo treatment. The aim was to evaluate to what extent previous in vivo findings are paralleled by the results of two in vitro test systems and the monolayer culture technique ex vivo. From the test systems investigated and under the conditions used, the results of the short-term test and the monolayer methylcellulose assay did not show a correlation with previous in vivo findings. Only the results of the bilayer clonogenic assay paralleled therapeutic parameters in vivo, although the degree of activity obtained in vivo was not reflected in vitro.

Animals↗
PubMed1988

In vitro evaluation of an estradiol-linked nitrosourea in mammary carcinomas of mouse, rat and man.

In vitro activity of 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine-estradiol-17-ester (CNC-ala-17-E2) at three concentrations in transplanted MXT mammary carcinoma in B6D2F1 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 per cent of MXT tumors showed a more than 70% inhibition of colony formation following CNC-ala-17-E2. In the MNU-induced model this high degree of inhibition was not observed: only 5% of individual tumors showed an inhibition up to 70%, but a superiority of the hormone-linked agent over the unlinked single agents was nevertheless discernible. In contrast, in human breast carcinomas a response at this sensitivity level could not be assessed. Thus, in the MXT mammary carcinoma the in vitro results paralleled previous findings in vivo, whereas in the MNU-induced autochthonous tumor 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.

Adult↗
PubMed1988

Characterization of the antitumor activity of hexadecylphosphocholine (D 18506).

Hexadecylphosphocholine (HPC) differs from ether lipids with known antitumor activity by its lack of the glycerol part. In the experiments described here HPC revealed outstanding antitumor activity in dimethylbenzanthracene (DMBA)-induced rat mammary tumors. A dose-response relationship was seen after daily oral treatment with complete suppression of tumor growth at doses of 46.4 mg/kg/day. There was no schedule dependence and the therapeutic efficacy was independent of the tumor weight at the initiation of therapy. Another autochthonous tumor, the benzo[a]pyrene-induced sarcoma of the rat did not respond to HPC treatment, indicating a highly selective spectrum of activity of the test compound. In comparison to an optimal single dose of cyclophosphamide, a single high dose of HPC was considerably more active against the DMBA tumor. At therapeutic dose levels no major toxicity of HPC was observed. Bone marrow suppression was not encountered, on the contrary, at high doses leukocytosis became apparent. The available pharmacological and toxicological data suggest that HPC may be useful in the treatment of human cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Carcinogenicity of 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)-3- nitrosoureahydrochloride and three related N-nitroso derivatives following repeated intravenous administration to male Wistar rats.

Long-term toxic evaluation of 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3- (2-chloroethyl)-3-nitrosoureahydrochloride (ACNU), 1-(2-chloroethyl)-1-nitroso-3-(methylene-2-pyridylium)-urea- hydrochloride (CNMPU), 1-(2-chloroethyl)-1-nitroso-3-(4-thiomorpholino)-urea (CNTMU) and 4-[N-(2-chloroethyl)-N-nitrosocarbamoyl]-morpholine (CNCM) which were administered each at five dosages, adapted to the clinical situation, revealed significantly increased tumor risks for the first three agents in the lung and the adrenal gland. Additionally, CNTMU and ACNU induced a significant rise in the tumor load of the neurogenic tissue; the latter compound, being in clinical use, was associated with a significantly increased number of mammary tumors as well. CNCM, however, did not exhibit significantly elevated carcinogenic activity, although the overall tumor load was up to 2.4-fold increased compared to controls. The results indicate no advantage of the newly developed ACNU with respect to its inherent carcinogenic risk as compared to clinically established 2-chloroethyl-N-nitroso derivatives.

Animals↗
PubMed1988

Technique for long-term infusion into the inferior mesenteric artery of unrestrained rats.

A technique for long-term infusion into the inferior mesenteric artery was developed which allows simple and reliable regional infusion into the colorectal segment of unrestrained rats. The cannulation system consists of an injection port 'In Stoppers' as a flow swivel, connected to an injection needle, which is inserted into a polyethylene tube protected by a steel spiral. During infusion the animals are free to move in the cage with access to food and water ad libitum. The method is suitable for regional chemotherapy as well as for studies of colorectal tumours in rats. In this study 73% of the cannulae remained functional for continuous infusion over a 15 day period.

Animals↗
PubMed1988

First experiments with locoregional chemotherapy in the treatment of autochthonous rat hepatoma.

The aim of this study was to establish the efficacy of treating chemically induced, autochthonous liver cancer by locoregional administration of cytostatics. Hepatomas were induced by p.o. application of diethylnitrosamine (15 mg/kg/week X 25 weeks) in female SD-rats and were staged macroscopically at four weeks after the end of the induction period. For treatment, catheters were inserted into the proper hepatic artery (i.a.) or the vena cava (i.v.) and tumor-bearing rats received a course of either mitomycin C (1 mg/kg i.a. within 24 hours), of mafosfamide (40 mg/kg i.a. within 4 hours) alone or in combination with sarcosinedithiocarbamate (300 mg/kg i.v. within 4 hours) or of triglycidylurazol (40 mg/kg i.a. or 20 mg/kg i.a. within 4 hours). At 14 days later no spontaneous repression of hepatomas were observed in the control animals, but 27% to 78% of treated animals showed a positive response. This response, however, was shortlived and did not lead to a significant prolongation of the animals life span in comparison to sham-treated controls.

Animals↗
PubMed1988

Interaction of nicotine with anticancer treatment.

Investigations on the in vivo interaction of nicotine and antineoplastic agents were prompted by the observation that nicotine lowered the carcinogenicity of the alkylating agent methylnitrosourea (MNU) in rats. Since alkylating agents play an important role as antitumor drugs, nicotine may influence the anticancer activity of anticancer drugs, especially alkylating agents. Two tumor models were selected: (a) autochthonous, MNU-induced mammary carcinoma and (b) transplanted rat leukemia L5222. The antitumor drugs investigated were cyclophosphamide (CPA) and 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea (HECNU). Nicotine was administered continuously by Alzet-osmotic minipumps, at a dose of 2.5 and 5 mg/kg daily. Under these conditions the observed nicotine and cotinine plasma levels approximated levels measured in heavy smokers (nicotine peak level, 47 ng/ml; cotinine peak level, 635 ng/ml). In MNU-induced autochthonous mammary carcinoma, a solid hormone-dependent tumor, the combination of HECNU and nicotine yielded greater tumor inhibition than HECNU alone. The anticancer activity of CPA on transplanted L5222-leukemia, on the other hand, was decreased by continuous infusion of nicotine. The interpretation of both results has to take into account the following possibilities of nicotine action: influence on (a) microcirculation, (b) cell proliferation, (c) membrane transport, (d) metabolism of cytotoxic drugs, and (e) hormonal milieu. The results demonstrate that nicotine is able to influence the outcome of antitumor treatment. The mechanism of interaction needs clarification. Additionally, further combination studies with other classes of cytotoxic drugs are warranted.

Animals↗
PubMed1988

Development of more selective anti-cancer nitrosoureas.

2-Chloroethyl-N-nitrosoureas are highly active anti-neoplastic drugs in clinical use for many years. Therapy with these DNA cross-linking agents is limited by their toxic side effects, cumulative and delayed bone marrow toxicity being the main dose-limiting one. Since the intrinsic anti-tumour activity of the nitrosourea group is very high, coupling to appropriate carrier molecules represents a challenge for target-orientated chemotherapy. Many human tumours contain receptors for steroid hormones. Therefore, 2-chloroethyl-N-nitroso-carbamoyl(CNC)-amino acid derivatives have been developed that are linked to steroid hormones. In the series of oestradiol (E2)-linked analogues CNC-L-alanine-E2-17-ester was significantly superior to other E2-linked congeners and to the unlinked equimolar mixture when tested against hormone-dependent N-methyl-N-nitrosourea-induced mammary carcinoma of the rat. Relevance of E2 receptor contents for therapy with E2-linked drugs is evidenced by loss of superiority of this analogue in hormone-independent mammary carcinomas. Some androgen-linked CNC-amino acids showed substantial affinity to the androgen receptor and in part also to the progesterone receptor. A preliminary study in rat leukaemia L5222 revealed the CNC-L-alanine-dihydrotestosterone-17-ester to be highly active. Studies with hormone-dependent tumour models are under way.

Androgens↗
PubMed1988

[Chemotherapeutic characterization of new nitrosourea compounds].

The development of new nitrosoureas is described using selected examples. Results obtained with water-soluble analogs and with compounds linked to biomolecules as for instance amino acids, oligopeptides and steroids, are presented. The pronounced antineoplastic effect of some water-soluble analogs is paralleled by an increased rate of DNA-interstrand cross-links and by an increased suppression of hematopoietic stem cells. The suppression of bone marrow stem cells is followed by their rapid regeneration. Water-soluble nitrosoureas induce significant less inhibition of glutathione reductase as compared with established compounds. With regard to long-term toxicity and carcinogenicity water-soluble are superior to established compounds as for instance BCNU. Linking of the nitrosourea moiety to amino acids and oligopeptides led to some analogs with outstanding therapeutic ratio. Out of a group of steroid-linked nitrosoureas, CNC-L-alanine-estradiol-17-ester (CNC-ala-17-E2) is chosen to demonstrate the possibility of reducing bone marrow toxicity despite unchanged or increased therapeutic activity by attachment of the nitrosourea moiety to a steroid. Results of a comparative interspecies in vitro evaluation of CNC-ala-17-E2 in transplanted MXT mammary carcinoma of the mouse, MNU-induced autochthonous rat mammary carcinoma and primary human mammary carcinomas are presented and the question is discussed to what extent in vitro activity of such receptor agents using the tumor stem cell assay reflects their in vivo activity.

Animals↗
PubMed1987

Comparison between the effects of dietary fat level and of calorie intake on methylnitrosourea-induced mammary carcinogenesis in female SD rats.

The aim of this study was to separate the effects of calorie intake on tumorigenesis from those of fat content and fat composition in an animal model. Our principal observations were the following. Decreasing the calorie level by 30% significantly inhibited tumor development in any observed parameter of tumorigenesis, independently of the level of fat. The fat content of semi-synthetic diets, although varying by 44.4%, did not significantly influence mammary tumorigenesis; in fact, carcinogenic expression was discontinuously related to the fat level. A plateau of tumor incidence was observed at the level of 35 energy percentage of fat. Fat composition did not influence tumorigenesis or body weight gain. The role of caloric restriction is thus stressed in relation to possible dietary prevention of cancer.

Animals↗
PubMed1987

Comparative antitumor activity of ruthenium derivatives with 5'-deoxy-5-fluorouridine in chemically induced colorectal tumors in SD rats.

The activity of the newly synthesized ruthenium derivative imidazolium-bis(imidazole)tetrachlororuthenate (III) [ImH(RuIm2Cl4)] was compared with that of 5'-deoxy-5-fluorouridine (5'dFUR) in autochthonous acetoxy-methyl-methylnitrosamine (AMMN)-induced colorectal cancer in SD rats. Following coloscopic diagnosis of colorectal tumors treatment was administered twice weekly for a 10-week period. ImH(RuIm2Cl4) exhibited considerable antitumoral efficacy compared with 5'dFUR (20 T/C % and 60 T/C %, respectively) against the growth of AMMN-induced colorectal adenocarcinoma in SD rats. The mortality rates with ImH(RuIm2Cl4) were dose-related, but its efficacy did not vary in all doses administered.

Adenocarcinoma↗
PubMed1987

Feasible model for locoregional and systemic longterm administration of drugs and concomitant blood sampling in Sprague-Dawley rats.

This methodological study describes three surgical procedures for locoregional and systemic drug administration, which are based on a similar experimental design. Cannulation of the arterial and portal access to the liver in comparison to the general venous system, and arterial access to the large intestine through a permanently implantable system, suitable for serial bolus injections and infusions in unrestrained rats, is presented (experiment I). Furthermore, an infusion system for longterm administration (experiment II) and a method for blood sampling during locoregional or systemic infusion procedures (experiment III) have been developed. The positioning and free flow of the catheters were checked by means of scintigraphy, administration of fluorescein under UV light and angiography in animals of experimental series I. After 7 days, no obstruction was detected. On day 15 and 30 following implantation 73.3% and 58.3% of the animals, respectively, showed unimpeded flow through the catheter system. The methods described here were well tolerated by the animals without alteration of their general condition and are currently in use in a series of chemotherapeutic and pharmacokinetic investigations.

Animals↗
PubMed1987

Therapeutic ratio of mono or combination bacterial lipopolysaccharide therapy in methylnitrosourea-induced rat mammary carcinoma.

Four experiments investigating the antitumor activity of bacterial lipopolysaccharide (LPS) against the autochthonous methylnitrosourea-induced mammary carcinoma are summarized. Administration of LPS alone i.v. caused distinct regression of small tumors following its first injection. This therapeutic effect, however, was short-lived and could not be maintained by administering a second dose. The observed antineoplastic activity of LPS was dose-related, whereas no dose-response relationship was observed with respect to its toxicity. A series of experiments in which LPS was combined with other compounds to possibly exploit its activity while reducing the toxicity were performed. Neither the combination with cytotoxic drugs such as 4'-(9-acridinylamino)-methansulfone-m-aniside or cyclophosphamide nor that with 1-octadecyl-2-methoxy-rac-glycero-3-phosphocholine or hexadecylphosphocholine showed sufficient anticancer activity at acceptable toxicity. In all experiments promising efficacy was observed at high dosages but also high toxicity. When the dosages were reduced, diminished antineoplastic activity was found together with overproportionally high mortality. It might therefore be concluded that the active dose range of LPS cannot be reached clinically because of its inherent toxicity.

Animals↗
PubMed1987

Efficacy of beta-diketonato complexes of titanium, zirconium, and hafnium against chemically induced autochthonous colonic tumors in rats.

Bis-beta-diketonato complexes of titanium, zirconium, and hafnium were tested against autochthonous colorectal tumors in rats. The model was found to reflect the clinical situation most closely. Of the compounds tested, budotitane was the most effective in terms of decrease in tumor weight and number and in increasing the lifespan of the treated animals. The therapeutic efficiency was superior to that of 5-fluorouracil, which so far has been the drug with the best activity in patients suffering from colon cancer.

Animals↗