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Biomedical subjects

M R Berger

Publications and source records attributed to M R Berger.

At least 127 records · Page 7Linked to original sources
PubMed1986

Comparison of DNA damage in various tissues, myelosuppression and serum levels of transaminases and bilirubin in tumor-bearing female Sprague-Dawley rats treated with 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (HECNU).

Female Sprague-Dawley rats bearing methylnitrosourea-induced mammary carcinomas were treated with 100 mumol 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (HECNU)/kg to investigate the time course of DNA-DNA interstrand cross-linking (DNA-XL) as measured by alkaline elution in tumor, bone marrow and liver cells. The inhibition of bone marrow stem cell colony formation in culture (CFU-C) and in spleens of lethally irradiated mice (CFU-S), serum transaminase levels and total bilirubin were concomitantly determined. All parameters were evaluated at different times from 4 to 72 h after treatment. The highest amounts of DNA-XL were found in tumor cells, peaking at 24 h after treatment. A parallel increase was observed in bone marrow cells up to 16 h with a subsequent rapid decrease to about one-third of DNA-XL in tumor cells after 72 h. Concomitantly, CFU-C and CFU-S were suppressed, the nadir being at 24 h after treatment. In liver cells, however, constant low levels of DNA-XL were found, which had disappeared after 48 h. In accordance with this observation, serum transaminase levels were only slightly elevated.

Animals↗
PubMed1986

Effect of interleukin-2 on the manifestation and growth of acetoxymethyl-methylnitrosamine-induced colorectal rat adenocarcinoma.

The effect of highly purified human interleukin-2 (IL-2) was assessed on acetoxymethyl-methylnitrosamine(AMMN)-induced colorectal Sprague-Dawley rat adenocarcinoma. Treatment was given for 5 weeks and started 5 weeks after a period of 10 weeks intrarectal administration of 2 mg/kg of AMMN once a week. Animals which showed no evidence of tumors by endoscopical examination of the gut were given 10,000 units/kg of IL-2 s.c. into the dorsal region 5 days a week. Blood samples were analyzed from half of the animals before and 72 h after the end of the treatment. The median tumor volume and the median tumor number per rat were lower in the treated group than in the control. A significant decrease in response to two mitogens (PHA, Con-A) was seen in tumor-bearing rats concomitantly with the tumor growth. The immunological suppression was not restored by treatment with IL-2. No differences in natural killer activity or interferon levels were detected between the control and the treated group. These data indicate some antitumor effect of IL-2 given before the manifestation of tumors in AMMN-induced colorectal rat adenocarcinoma.

Adenocarcinoma↗
PubMed1986

Estrogen-linked 2-chloroethylnitrosoureas: anticancer efficacy in MNU-induced rat mammary carcinoma, uterine activity in mice and receptor interactions.

A series of estradiol-linked N-(2-chloroethyl)-N-nitrosocarbamoyl(CNC)-L-alanines attached in various positions (positions 3, 6 alpha, 17, 3 + 17 of estradiol) have been synthesized and tested in hormone-dependent MNU-induced rat mammary carcinoma. Compounds were given i.p. on day 1, 8, 22 and 29 after randomization in equimolar dosage. Equimolar mixtures of unlinked agents were tested in comparison. The results show that the 17-linked derivative was significantly superior to the other congeners and to the unlinked equimolar mixture. The 6 alpha-linked analogue unexpectedly was highly toxic and ineffective. Binding affinities to cytosolic estrogen receptors cannot fully explain the findings of the chemotherapy experiments. Especially the 3-linked derivative we found to exhibit much higher values for relative binding affinity than the 17-analogue, which was a distinctly more effective antineoplastic agent. Estradiol liberation by facile cleavage of the phenolic 3-ester bond might be responsible. Estradiol receptor contents in tumours were diminished or disappeared completely during treatment with individual analogues, progestin receptor contents behaved differently. After a single dose of CNC-L-alanine-estradiol-17-ester, a long-lasting disappearance of estradiol-receptors, measured for up to 192 hr, and a strong induction of progesterone receptors was observed with a maximal value reached at 16 hr, and return back to normal at 192 hr. In the Dorfman uterine weight test in mice, all compounds exhibited distinct uterotrophic activity with no clearcut differences. The relevance of estradiol receptor contents in tumours for antineoplastic activity of the most effective analogue, the 17-ester, became evident from the observed reduced responsiveness of MNU-induced rat tumours after ovariectomy. In these hormone-independent tumours the linked compound revealed only the same antitumour efficacy as CNC-L-alanine alone.

Animals↗
PubMed1986

Protection by the alkyllysophospholipid, 1-octadecyl-2-methoxy-rac-glycero-3-phosphocholine, but not by the retinoid etretinate against leukemia development in DMBA-treated Long-Evans rats.

The antileukemic potency of the alkyllysophospholipid, 1-octadecyl-2-methoxy-rac-glycero-3-phosphocholine (Et-18-OCH3) and of the retinoid etretinate was examined alone and in combination in 7,12-dimethylbenz-anthracene(DMBA)-induced Long-Evans (LE) rats. Lifelong administration of Et-18-OCH3 at a dose of 20 mg/kg per day slightly but significantly reduced the incidence of leukemias and thereby significantly prolonged the life span of animals. The best effect was seen when treatment started at day 58 of life, i.e. 1 day after the third of 4 DMBA injections (P = 0.0001). Administration of etretinate, however, at a dose of 5 mg/kg did not show any efficacy against leukemia development. The combination of both agents reduced the incidence of mammary neoplasias only (P = 0.04).

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Influence of the application mode of N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide on the localization of its carcinogenic expression in female NMRI-mice.

The administration of N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide FANFT) by gavage to female NMRI-mice resulted in a high incidence of neoplasms of the forestomach. From 117 effective animals which were pooled from 3 dosed groups, 30 squamous cell carcinomas and 26/117 papillomas of the forestomach were diagnosed. Only 5/117 neoplasms of the urinary bladder occurred. The average cumulative dose administered was 1180 mg/mouse, and the mean latent period for the induction of forestomach tumours was 574 days. The mode of application seems to be an important factor in the carcinogenicity of FANFT.

Adenocarcinoma↗
PubMed1986

Delayed development of bladder cancer in male SD rats induced with N-nitroso-N-butyl-N-(4-hydroxybutyl)amine following concomitant administration of sodium 2-mercaptoethane sulfonate.

This study describes the prolonged survival of male SD-rats that bear bladder carcinomas induced either with 44 mg/kg or 28 mg/kg of N-nitroso-N-butyl-N-(4-hydroxybutyl)amine (BBNOH), when daily doses of 350 mg/kg of sodium-2-mercaptoethane sulfonate (mesna) were administered concomitantly. The difference to carcinogen-treated positive controls was highly significant (P = 0.0009 and 0.0013, respectively). Tumor volumes at time of death (P less than 0.005) and frequency of metastases were also reduced in rats that received both compounds in comparison to BBNOH-treated animals.

Animals↗
PubMed1986

Drug design: nitrosoureas.

Attempts to develop more effective and less toxic antineoplastic nitrosoureas are summarized. Previous research resulted in the synthesis and extensive preclinical testing of new, short-chain, water-soluble, but lipophilic compounds--1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)urea (HECNU) and 1-(2-chloroethyl)-1-nitroso-3-(methylene carboxamido)urea. Molecular mechanisms of reactions with biomolecules are discussed with regard to DNA alkylation and cross-linking, carbamoylation of glutathione and glutathione reductase inhibition. Results of a clinical phase-II study show that HECNU, as predicted from preclinical tests, exhibits outstanding activity in brain tumours. Future development concentrates on the use of carrier molecules for nitrosoureas. Results of an extensive structure-activity study with oestradiol-linked analogues show that an oestradiol-17 ester derivative is much more active than other analogues.

Alkylating Agents↗
PubMed1986

Autochthonous, acetoxymethylmethylnitrosamine-induced colorectal cancer in rats: a useful tool in selecting new active antineoplastic compounds?

Acetoxymethylmethylnitrosamine (AMMN)-induced autochthonous colorectal rat adenocarcinomas are an interesting model for the secondary evaluation of new antineoplastic compounds aimed at predicting clinical activity. These orthotopic tumors mimic the human situation closer than conventionally used transplanted systems with respect to their relatively slow growth, their genuine histology, their original tumor-host interaction and their low chemosensitivity to clinically used drugs. 4-Amino-N-(2' aminophenyl) benzamide, 4-Oxo-2-phenyl-4H-1-benzopyran-8-acetic acid, dichloro-bis(1-phenyl-1,3-butanedionato)titanium(IV) and diethoxy-bis(1-phenyl-1,3-butanedionato)titanium(IV) are four new agents, which have shown promising anticancer activity in this model, but which failed to show high activity in fast-growing transplanted systems. Clinical studies on these agents are highly warranted. A comparison of predicted and actual clinical anticancer activity will finally point to the appropriate means of drug selection.

Adenocarcinoma↗
PubMed1986

More than additive toxicity of the combination of 1-methyl-1-nitrosourea plus 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat.

The combination toxicity index of 1-methyl-1-nitrosourea plus 1,3-bis (2-chloroethyl)-1-nitrosourea determined in the rat was 0.32. This overadditive combination toxicity appears mainly to be due to severe damage of the intestinal mucosa as diagnosed by histological examination and to damage of pluripotent stem cells in the bone marrow as could be assessed by the spleen colony technique. The molar ratio of 1-methyl-1-nitrosourea to 1,3-bis(2-chloroethyl)-1-nitrosourea resulting in maximum mortality was about 6. Concomitantly measured DNA interstrand cross-linking in bone marrow cells revealed a slight increase in DNA interstrand cross-linking following both drugs compared to 1, 3-bis(2-chloroethyl)-1-nitrosourea alone.

Animals↗
PubMed1986

Long-term toxicology effects of prednimustine in comparison with chlorambucil, prednisolone, and chlorambucil plus prednisolone in Sprague-Dawley rats.

Chlorambucil was linked to prednisolone to improve the therapeutic and toxic properties of this potent alkylating agent, which is known to induce second tumors in humans. To compare the carcinogenic potency of the linked compound with that of the respective individual agents and of their unlinked mixture, prednimustine (I), chlorambucil (II), prednisolone (III), chlorambucil plus prednisolone (IV), or vehicle were administered to groups of 120 female Sprague-Dawley rats for 18 months. The following doses were administered nine, four, five, two times, or once a month per subgroup of 30 rats: I, 12 mg/kg; II, 3 mg/kg; III, 3 mg/kg; IV, 3 mg/kg. After natural death of animals, median survival times were analyzed, and percentages of malignant tumors were recorded. An increased tumor risk was found in the following organs compared with those of vehicle-treated controls: I, external auditory canal (EAC); II, mammary gland (MG), central and peripheral nervous tissue (CPNT), hematopoietic and lymphatic tissue (HLT), and EAC; III, none; and IV, MG, CPNT, and EAC. There is evidence of carcinogenic activity of prednimustine compared with untreated controls, but the cancer-inducing potential of the linked compound is distinctly lower than that of the unlinked mixture of chlorambucil plus prednisolone or that of chlorambucil.

Animals↗
PubMed1985

Effects of diazoxide-induced reversible diabetes on chemically induced autochthonous mammary carcinomas in Sprague-Dawley rats.

The effect of oral administration of diazoxide on rats bearing mammary carcinomas induced by dimethylbenzanthracene (7,12-DMBA) or methylnitrosourea (MNU) was investigated. Administration of 300 mg/kg diazoxide caused mild reversible diabetes with maximum glucose levels of 305 +/- 74 (control: 119 +/- 12) mg/dl and related insulin levels of 15 +/- 5 (control: 24 +/- 11) microU/ml after 4 hr in tumor-bearing animals. Following the same dose of diazoxide a more than 90% inhibition of tumor growth was observed in 7,12-DMBA- and MNU-induced autochthonous rat mammary carcinomas as well as remission of the median total tumor volume per group in 7,12-DMBA-induced lesions. Frequently, onset of remissions and median remission duration proved to be dose-dependent in 7,12-DMBA-induced mammary carcinoma and, with the exception of the median remission duration, in MNU-induced tumors too. After cessation of diazoxide application, 30% rebound responses were observed in 7,12-DMBA-induced tumors of animals that had had a first remission due to diazoxide. Application of insulin (2 IU per rat) together with diazoxide (300 mg/kg) reversed the tumor-inhibiting effect of diazoxide in MNU-induced tumors. The diazoxide effect might in part be due to a decrease in the percentage of proliferating cells caused by insulin depletion as indicated by a lower amount of cells in S-phase, as measured by DNA-flow cytometry. Marked toxicity was observed after effective doses of diazoxide; the experiments indicate that induction of reversible diabetes might be a useful tool in the treatment of hormone-dependent mammary carcinoma.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Relationship between DNA damage and the inhibition of stem cells in murine bone marrow after single and repeated administration of BCNU and HECNU.

The effects of dose and schedule of administration of either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (HECNU) were compared in terms of induction of DNA damage in the bone marrow of male C6B3F1 mice or in the inhibition of two stem cell lines contained therein. At equimolar doses HECNU induced a 3- to 40-fold deeper nadir of proliferation of both stem cell lines compared to BCNU, but subsequently a 2- to 30-fold quicker recovery of these lines was observed. An enhancement of myelotoxicity was only found following injections with intervals of 1 week. Myelosuppression was almost twice as great, when six instead of three weekly injections of 50 mumol/kg were given. When, however, sufficient time was allowed for recovery, doubling the number of significantly larger doses of drug was tolerated at the level of the bone marrow stem cell. The maximum inhibition of pluripotent- and granulocyte-committed stem cells following HECNU was paralleled by higher amounts of DNA-DNA interstrand crosslinks in the entire bone marrow compared to BCNU. During the initial stages, the degree of myelosuppression did, to some extent, parallel the number of DNA-DNA interstrand crosslinks induced in the bone marrow as a whole, but this relation was lost after the initial period.

Animals↗
PubMed1985

The inhibitory effect of 4-chloro-2-(2,6-dichloro-4-hydroxyphenyl)-1-ethyl-6-hydroxyindole (D 15413) on estrogen-dependent mammary tumors.

The antineoplastic activity of 4-chloro-2-(2,6-dichloro-4-hydroxyphenyl)-1-ethyl-6-hydroxyindole (D 15413) was determined in several estrogen-dependent mammary tumor models. The growth of DMBA-induced rat mammary carcinomas was inhibited by doses ranging from 2 to 18 mg/kg. A dose of 6 X 12 mg/kg per week p.o. reduced the tumor area by 82% (control + 192%). D 15413 was also active against MNU-induced rat mammary tumors and transplanted MXT tumors of the mouse. In vitro, the growth of estrogen receptor positive MCF-7 breast cancer cells was inhibited by D 15413 (10(-8) - 10(-5) M). A mode of action considering endocrine and cytotoxic effects is discussed.

Animals↗
PubMed1985

Influence of experimental diets on hepatic glutathione levels in rats with methylnitrosourea-induced mammary carcinoma.

Mammary tumor development induced by methylnitrosourea in female Sprague-Dawley rats had no significant effect on hepatic glutathione levels. If the diets of methylnitrosourea-treated animals were supplemented with vitamin A and E an increased hepatic glutathione level was observed initially. A high fat diet (21% per weight) supplemented with the two vitamins led to a decreased hepatic glutathione level 2 months after tumor induction. Advanced tumor development under any of the diets tested had no effect on hepatic glutathione.

Animals↗
PubMed1985

Synthesis, toxicity, and therapeutic efficacy of 4-amino-N-(2'-aminophenyl)-benzamide: a new compound preferentially active in slowly growing tumors.

The present paper describes 4-amino-N-(2'-aminophenyl)benzamide (GOE1734) with regard to synthesis; toxicity in mice, rats, and dogs; and differential therapeutic efficacy in slowly and rapidly proliferating rat tumors. GOE1734, an analog of a group of compounds known for other than antitumor effects with relatively simple N-acyl-O-phenylenediamine structure, is characterized by a low bacterial mutagenic potential after in vitro metabolic activation and DNA-DNA crosslinking activity after in vivo treatment. Maximum tolerated doses in rats and dogs amount to 4 and 1 mg/kg, respectively. High growth-inhibiting efficacy was obtained in intratibially implanted osteosarcoma, in methylnitrosourea-induced primary mammary carcinoma, and in acetoxymethyl-methylnitrosamine-induced colorectal adenocarcinoma. GOE1734 proved to be ineffective in transplanted Yoshida sarcoma and Walker 256 carcinosarcoma when single or multiple doses were administered at dose levels that were moderately toxic or not toxic. Some antitumor effects were observed in L5222 leukemia after ip transplantation, but no effect could be observed after ic implantation or in vitro incubation and subsequent retransplantation of these cells. Since the latter three rat tumors are characterized by relatively short tumor volume doubling times (0.5-2 days), whereas the first three grow slower (tumor volume doubling time, 11-19 days), the remarkable differential antitumor activity of GOE1734 in fast and slowly growing malignancies is striking.

Animals↗
PubMed1985

Comparative carcinogenic activity of prednimustine, chlorambucil, prednisolone and chlorambucil plus prednisolone in Sprague-Dawley rats.

This study compares long term toxic effects of equivalent doses of prednimustine (12 mg/kg) chlorambucil (3 mg/kg), prednisolone (3 mg/kg) and chlorambucil plus prednisolone (3 mg/kg each) in comparison to vehicle treated controls after regular administration over a period of 18 months to 600 female Sprague Dawley rats. Frequency of administration to subgroups (30 rats each) varied between 9 (a), 4.5 (b), 2 (c) times or once (d) a month. When comparing organ specific, age-adjusted expected versus observed incidences after natural death of animals an increased tumor risk was found in organ systems of all treatment modalities but prednisolone. Prednimustine-administration was related to an elevated risk of developing squamous-cell carcinomas of the external auditory canal only (alpha = 0.013), whereas simultaneous application of chlorambucil plus prednisolone induced significantly higher rates of adenocarcinomas of the mammary gland, of malignant tumors of the central and peripheral nervous tissue and of squamous cell carcinomas of the external auditory canal (alpha less than 0.01 for each tissue). Chlorambucil alone caused a significantly higher rate of malignancies of the hematopoietic and lymphatic tissue (alpha less than 0.01) additionally to effects observed after the unlinked mixture of chlorambucil plus prednisolone. There is evidence of carcinogenic activity of prednimustine compared to untreated controls, but the cancer-inducing potential of the linked compound is distinctly lower than that of the unlinked mixture of chlorambucil plus prednisolone or of chlorambucilalone.

Animals↗