Inhibitory Effect of Filipendula ulmaria on Mammary Carcinogenesis Induced by Local Administration of Methylnitrosourea to Target Organ in Rats.

BACKGROUND: The meadowsweet (Filipendula ulmaria (L.) Maxim.) may have a cancer prophylactic activity, since its extracts exhibit antioxidant, anti-inflammatory and other effects. We investigated the ability of a meadowsweet decoction to inhibit mammary carcinogenesis induced by intramammary injections of Methylnitrosourea (MNU) to the target organ in rats. MATERIALS AND METHODS: The chemical composition of meadowsweet extracts was studied by traditional methods. In animal experiments, adult outbred female rats received single injections of MNU at a dose 1mg directly into the tissue of each mammary gland. After carcinogenic exposure one group (MNU) of rats continued to receive standard feed and tap water throughout life. In another group (MNU+meadowsweet), rats were given daily a decoction of the meadowsweet instead of drinking water and standard feed. RESULTS: Meadowsweet extracts showed a sufficiently high content of flavonoids and tannins and also some individual phenolic compounds. In rats after injections of MNU the overall incidence of tumors was 90% with tumor multiplicity of 3.1. The majority of rats (86%) developed multiple malignant tumors of the mammary gland (most often adenocarcinomas). In rats from the group MNU+meadowsweet, there was a statistically significant decrease of the overall tumor multiplicity-by 1.5 times, and the incidence and multiplicity of breast tumors-by 1.6 and 2.2 times, respectively. CONCLUSIONS: Meadowsweet extract can be considered an effective inhibitor of breast carcinogenesis.

Evaluation of the immunological cellular response of Cebus apella exposed to the carcinogen N-methyl-N-nitrosourea and treated with CANOVA®.

The immune response modifier Canova® is a homeopathic remedy indicated for patients with depressed immune system, since this drug appears to increase adaptive immunity and induce an immune response against multiple and severe pathological conditions, including cancer. We evaluated the pattern of immune cellular response in non-human primates of the species Cebus apella exposed to N-methyl-N-nitrosourea (MNU) with and without Canova®. Twelve animals were divided into four groups, with three animals each: negative control and three experimental groups, MNU-alone (35 days); MNU (35 days)-plus-Canova® (3 days) and Canova®-alone (3 days). The animals received MNU orally and Canova® by three intravenous injections. Evaluation of the cellular immune response was performed by immunophenotyping of T-lymphocytes (CD4(+), CD8(+)), B-lymphocytes and natural killer cells. Analysis was also performed of the cell cycle. Our results suggest an increase of T-lymphocytes (CD4(+)CD3(+)) only in the Canova® group, while in the MNU-plus-Canova® group only B-lymphocytes increased.

Dehydroepiandrosterone inhibits the progression phase of mammary carcinogenesis by inducing cellular senescence via a p16-dependent but p53-independent mechanism.

INTRODUCTION: Dehydroepiandrosterone (DHEA), an adrenal 17-ketosteroid, is a precursor of testosterone and 17beta-estradiol. Studies have shown that DHEA inhibits carcinogenesis in mammary gland and prostate as well as other organs, a process that is not hormone dependent. Little is known about the molecular mechanisms of DHEA-mediated inhibition of the neoplastic process. Here we examine whether DHEA and its analog DHEA 8354 can suppress the progression of hyperplastic and premalignant (carcinoma in situ) lesions in mammary gland toward malignant tumors and the cellular mechanisms involved. METHODS: Rats were treated with N-nitroso-N-methylurea and allowed to develop mammary hyperplastic and premalignant lesions with a maximum frequency 6 weeks after carcinogen administration. The animals were then given DHEA or DHEA 8354 in the diet at 125 or 1,000 mg/kg diet for 6 weeks. The effect of these agents on induction of apoptosis, senescence, cell proliferation, tumor burden and various effectors of cellular signaling were determined. RESULTS: Both agents induced a dose-dependent decrease in tumor multiplicity and in tumor burden. In addition they induced a senescent phenotype in tumor cells, inhibited cell proliferation and increased the number of apoptotic cells. The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action. CONCLUSION: We provide evidence that DHEA and DHEA 8354 can suppress mammary carcinogenesis by altering various cellular functions, inducing cellular senescence, in tumor cells with the potential involvement of p16 and p21 in mediating these effects.

Antitumoral effect of recombinant mistletoe lectin on chemically induced urinary bladder carcinogenesis in a rat model.

BACKGROUND: The objective of this study was to determine the effect of intravesically applied, recombinant, galactoside specific mistletoe lectin (rML) on chemically induced tumor development in the urinary bladder of rats. METHODS: For tumor induction, rats were treated with four biweekly 1.5 mg doses of N-methyl-N-nitrosourea (NMU) intravesically (Weeks 0, 2, 4, and 6). The control group (n = 39 + 17 rats) received no other treatment. The four therapy groups also received rML twice weekly according to one of the following instillation regimens: 1) 30 ng rML per instillation from Week 8 to Week 13 (Group a: n = 14 rats), 2) 150 ng rML per instillation from Week 8 to Week 13 (Group b: n = 23 + 15 rats), 3) 30 ng rML per instillation from Week 14 to Week 19 (Group c: n = 22 rats), and 4) 150 ng rML per instillation from Week 14 to Week 19 (Group d: n = 19 rats). After the rats were asphyxiated at Week 21, the urinary bladders were excised in toto and examined histopathologically. To study the immunomodulatory effects of intravesically applied rML, 17 animals from the control group and 15 animals from Group b were asphyxiated at Week 13, and urinary bladder tissue was analyzed by semiquantitative reverse transcriptase-polymerase chain reaction analysis for mRNA expression of interferon-gamma, interleukin-10, and Fas ligand. RESULTS: By Week 21, atypical hyperplasia and neoplastic transformation were found in 82% of the animals in the control group. In contrast, in all four cohorts that were treated with rML, significantly lower rates of atypical hyperplasia and neoplastic transformation were found (Group a, 50%; Group b, 52%; Group c, 45%; and Group d, 42%). By Week 13, in the bladder tissue of 15 rML-treated animals from Group b, lower expression of interleukin-10 mRNA was measured, whereas the expression levels of interferon-gamma mRNA and Fas ligand mRNA were comparable to those of 17 animals from the control group. CONCLUSIONS: The current data provide evidence for an inhibitory effect of rML on experimental urothelial carcinogenesis that does not seem to be due to interferon-gamma and/or interleukin-10 dependent mechanisms.

Lack of chemoprevention effects of the monoterpene d-limonene in a rat multi-organ carcinogenesis model.

Modifying effects of dietary administration of the monoterpene d-limonene were examined using a multi-organ carcinogenesis model. Groups of twenty F344 male rats were treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), 1,2-dimethylhydrazine (DMH, s.c.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, in drinking water) and dihydroxy-di-N-propylnitrosamine (DHPN, in drinking water) during the first 4 weeks (DMBDD treatment), and then d-limonene was administered in the diet, at the dose of 2.0, 1.0 or 0.5%. The maximal tolerable dose was 2.0% under the present conditions. Further groups were treated with DMBDD or 2.0% d-limonene alone as controls. All surviving animals were killed at week 28, and major organs were examined histopathologically for development of preneoplastic and neoplastic lesions. The incidences and/or multiplicities of renal atypical tubules and adenomas were increased in animals fed 2.0% d-limonene. The immunohistochemical reactivity for alpha2u-globulin in the proximal tubules was greater in rats fed d-limonene than in the carcinogen alone group. No enhancing or inhibitory effect was noted for tumor development in other organs. The present results indicate a lack of any chemopreventive effect of d-limonene in any organ of male rats under the present experimental conditions.

[Comparative evaluation of the antitumor, cytogenetic and immunodepressive effects of dimetinur when used perorally and parenterally]. / Sravnitel'naia otsenka protivoopukholevogo, tsitogeneticheskogo i immunodepressivnogo éffektov dimetinura pri peroral'nom i parenteral'nom primenenii.

The dimethylnitrosourea action after oral and parenteral administration was comparatively evaluated on the basis of criteria for the antitumour and cytogenetic activity, as well as for the immune (T-cell) reactivity of tumour-bearing and intact animals. A considerable antitumour effect and the induction of the overload chromosomal aberrations in tumour cells with the complete preservation of bone marrow cells were observed during the oral drug application. Dimethyl nitrosourea-induced T-cell depression in murine spleen was transitory and reversible. Thus the oral administration of the drug was shown to be optimal for realization of its therapeutical activity with the least toxic side effect on the host normal hemopoietic and immunocompetent cells.

[Effectiveness of nitrosomethylurea derivatives in the combined chemotherapy of experimental tumors]. / Effektivnost' proizvodnykh nitrozometilmocheviny v kombinirovannoi khimioterapii éksperimental'nykh opukholei.

An antitumour activity of combined application of two nitrosomethylurea derivatives--dimethylnitrosourea and ADEKO with cytostatics of various groups was studied in transplanted tumours of La and L 1210 leukemias and Lewis lung carcinoma. A combined treatment by ADEKO with cyclophosphamide, methotrexate and dibunol resulted in therapeutic synergism evaluated by the tumour growth inhibition activity (kappa *) and by life span (delta tau) increase of tumour-bearing animals. An additive antitumour effect was established in case of a combined application of ADEKO with ftorafur, vincristine, prednisolone and dimethylnitrosourea with methotrexate.