The mitigating effect of dietary antioxidants on chemically-induced carcinogenesis

The effect of a dietary antioxidant mixture on 3-methylcholanthrene mediated carcinogenesis in hairless mice was investigated. The antioxidant mixture significantly reduced the frequency of premalignant lesions and their subsequent development into tumors. The similarities in response of chemical and UV light-carcinogenesis to these antioxidants suggest some congruity in the mechanisms of the carcinogenic process.     

Les cellules mammotropes et somatotropes de l'antehypophyse chez la souris C3H porteuse de tumeur mammaire spontanée. Etude quantitative au microscope électronique

Summary Pituitaries of mammary tumor-bearing mice (C3H) were examined by quantitative electron microscopy. The results indicate that considerable modifications occur in mammotropic and somatotropic cells. Both types show an increase of the surface of the endoplasmic reticulum and a decrease of the volume of secretory granules (in percent of cytoplasmic volume), suggesting a heightened secretory activity of these cells during mammary carcinogenesis.

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Une partie de ce travail a fait l'objet du mémoire pour le titre d'Assistant étranger de Mlle G. G. Sotiropoulou.

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Avec la collaboration technique dévouée de Mme J. Garaudel et l'aide de l'I.N.S.E.R.M., du C.N.R.S. et de la Ligue Nationale Française contre le Cancer.     

The mitigating effect of dietary antioxidants on chemically-induced carcinogenesis

Summary The effect of a dietary antioxidant mixture on 3-methylcholanthrene mediated carcinogenesis in hairless mice was investigated. The antioxidant mixture significantly reduced the frequency of premalignant lesions and their subsequent development into tumors. The similarities in response of chemical and UV light-carcinogenesis to these antioxidants suggest some congruity in the mechanisms of the carcinogenic process.This investigation was supported by National Research Service Award 1 F32 CA05062, awarded by the National Cancer Institute, DHEW and USPH grant CA13464 from the NCI, DHEW. We thank Dr John I. Thornby for statistical analysis of the data.     

<Emphasis Type="Italic">C</Emphasis>-<Emphasis Type="Italic">Raf</Emphasis> deficiency leads to hearing loss and increased noise susceptibility

The family of RAF kinases transduces extracellular information to the nucleus, and their activation is crucial for cellular regulation on many levels, ranging from embryonic development to carcinogenesis. B-RAF and C-RAF modulate neurogenesis and neuritogenesis during chicken inner ear development. C-RAF deficiency in humans is associated with deafness in the rare genetic insulin-like growth factor 1 (IGF-1), Noonan and Leopard syndromes. In this study, we show that RAF kinases are expressed in the developing inner ear and in adult mouse cochlea. A homozygous C-Raf deletion in mice caused profound deafness with no evident cellular aberrations except for a remarkable reduction of the K⁺ channel Kir4.1 expression, a trait that suffices as a cause of deafness. To explore the role of C-Raf in cellular protection and repair, heterozygous C-Raf ^+/? mice were exposed to noise. A reduced C-RAF level negatively affected hearing preservation in response to noise through mechanisms involving the activation of JNK and an exacerbated apoptotic response. Taken together, these results strongly support a role for C-RAF in hearing protection.     

Influence of presensitization with allogeneic lymphoma cells on the growth and response to therapy of radiation-induced lymphomas in mice

Summary Congenic mice were sensitized with viableH-2-incompatible radiation-induced lymphomas (RIL), challenged with syngeneic RIL and treated with bis-chloroethyl-nitrosourea. Either enhancement or inhibition of RIL was found in presensitized mice, depending on the tumor-host system used.This work was supported by Progetto Finalizzato Virus, CNR (Rome, Italy), Contract No. 770025284/1152505.Acknowledgments. I wish to thank Dr J. Mayo and Mr C.R. Reeder of the Mammalian Genetics and Animal Production Section, Division of Cancer Treatment (DCT), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda (Maryland, 20014, USA) for providing the mice used in this study. I also thank Dr H.B. Wood of the Drug Synthesis and Chemistry Branch, DCT, NCI, NIH, for furnishing the BCNU used.     

Protective effect of Shigyaku-to,a traditional Chinese herbal medicine,on the infection of herpes simplex virus type 1 (HSV-1) in mice

The antiviral activity of Shigyaku-to (TJS-109), a traditional Chinese herbal medicine, was investigated in mice infected with herpes simplex virus type 1 (HSV-1). TJS-109 is a combination of the medicinal plant extracts fromZingiberis siccatum rhizoma,Aconiti tuber andGlycyrrhizae radix in a specific proportion. Mice infected with a 10 LD₅₀ dose of HSV-1 were treated with TJS-109 orally at doses of 1.25 to 20 mg/kg 2 days before, and 1 and 4 days after the infection. The treated groups had 80% (1.25 mg/kg), 40% (5 mg/kg) and 23% (20 mg/kg) mortality rates 25 days after the infection as compared with a 100% mortality rate in control mice treated with saline. When HSV-1 infected mice (recipients) received CD8⁺T cell fractions derived from spleens of mice treated with TJS-109 (donors), 70% of recipients survived, as compared with 0% survivors in the groups of mice treated with saline, B cell fractions, CD4⁺ T cell fractions or macrophage-enriched fractions prepared from the same donors. TJS-109 did not show any virucidal activities against HSV-1 or any virostatic activities on the growth of HSV-1 in Vero cells. These results suggest that TJS-109 protected mice exposed to lethal amounts of HSV-1 through the activation of CD8⁺ T cells.     

Lack of effect of butylated hydroxytoluene on dimethylhydrazine-induced colon carcinogenesis in rats.

Rats were given 6600 ppm of butylated hydroxytoluene (BHT) in the diet along with 10 weekly oral doses of dimethylhydrazine (DMH, 30 MG/KG). The incidence and mean number of colonic tumors produced were similar to that of rats given DMH alone. Thus, BHT did not provide any protective effect against colon carcinogenesis.     

Influences of the submaxillary gland of male mice on the immune response to sheep red blood cells

Summary Removal of the submaxillary gland (SMG) from male but not female mice caused a suppressed immune response to sheep red blood cells. Administration of a SMG saline extract from male mice to SMG-ectomized males restored the suppressed response to control levels. This suggests that the male mouse SMG contains a factor(s), possibly of an endocrine nature, capable of influencing cells involved in an immune response.     

Selenoproteins and oxidative stress-induced inflammatory tumorigenesis in the gut

Selenium is an essential micronutrient that is incorporated into at least 25 selenoproteins encoded by the human genome, many of which serve antioxidant functions. Because patients with inflammatory bowel disease (IBD) demonstrate nutritional deficiencies and are at increased risk for colon cancer due to heightened inflammation and oxidative stress, selenoprotein dysfunction may contribute to disease progression. Over the years, numerous studies have analyzed the effects of selenoprotein loss and shown that they are important mediators of intestinal inflammation and carcinogenesis. In particular, recent work has focused on the role of selenoprotein P (SEPP1), a major selenium transport protein which also has endogenous antioxidant function. These experiments determined SEPP1 loss altered immune and epithelial cellular function in a murine model of colitis-associated carcinoma. Here, we discuss the current knowledge of SEPP1 and selenoprotein function in the setting of IBD, colitis, and inflammatory tumorigenesis.     

Evidence that the establishment of pregnancy requires activation of lipoxygenase and phospholipase-A2

The present work investigates the possibility that lipoxygenase products are involved in the biochemical mechanisms of blastocyst implantation by utilizing nordihydroguaiaretic acid (NDGA) and caffeic acid (CA), inhibitors of lipoxygenase enzymes, and quinacrine (QU), an inhibitor of phospholipase-A2. It has been shown previously that inhibition of cyclooxygenase results in blockade of implantation. The inhibitors were dissolved in a standard medium and 5 microliter of the solutions were micro-injected into the uterine horns of day-4 pregnant mice. The contralateral horns acted as controls and received only vehicle. A sham-operated group provided normal controls. In 14 NDGA-treated mice, the control horns contained 40 implantations while the treated horns contained only 6 small implantations and 8 resorbing sites. These control horns were comparable to the sham controls. In 14 CA-treated mice, treated horns contained 17 small implantations plus 4 resorptions, whereas the control horns contained 26 small implantations and 4 resorptions. Twelve QU-treated mice exhibited 7 small implantations and 4 resorptions in the treated horns, plus 24 small sites and no resorptions in the control horns. Fourteen sham-operated mice had 95 implantation sites and no resorptions in their 28 horns. The results provide evidence for the involvement of the lipoxygenase enzymes and phospholipase-A2 in the initial implantation process and in the subsequent development of early pregnancy.     

Histamine deficiency suppresses murine haptoglobin production and modifies hepatic protein tyrosine phosphorylation

Histidine decarboxylase (HDC) synthesizes endogenous histamine from histidine in mammals. HDC- deficient mice (HDC-/-), if kept on a histamine-free diet, have no histamine in their tissues. HDC-/- mice show multiple phenotypes. In this study we show that both the constitutively expressed and turpentine-induced level of an acute-phase protein, haptoglobin, is significantly lower in the serum of HDC-/- mice compared to that of wild-type animals. This effect was abolished if HDC gene-targeted mice received histamine-rich food. No differences were found when lipopolysaccharide (LPS) was used to induce the acute-phase reaction. Using specific antibodies to phosphorylated tyrosine, we showed that protein tyrosine phosphorylation (Y-P) of ~50- and 26- to 27-kDa liver proteins is significantly decreased in HDC-/- mice, but that the difference was largely diminished if the animals were kept on a histamine-rich diet, suggesting that the phenotype with lower haptoglobin production is diet inducible. Upon in vivo treatment with LPS, Y-P band intensity decreased, regardless of the presence or absence of histamine. Identification of elements of the signalling pathway with decreased phosphorylation may elucidate the molecular background of the effect of endogenous histamine in the hepatic acute-phase reaction. Received 14 February 2001; received after revision 28 March 2001; accepted 4 April 2001     

Deciduogenic effects of mediators of the polyphosphatidylinositol pathway in pseudopregnant mice.

Intraluminal injections (15 microliters) of either concanavalin A (125 micrograms) or ionophore A 23,187 (0.01 mumol) induced a decidual cell reaction (DCR) in the uterus of day 4.5 pseudopregnant mice. However, when these agents were administered in different combinations with each other or with CaCl2 (15 mumol) and phorbol-12-myristate-13-acetate (1.6 nmol), interacting effects occurred to either enhance or inhibit each of the others' independent deciduogenic capacities. The results suggest that the polyphosphatidylinositol pathway and Ca2+ are involved in the induction of the DCR in mice with complex interactions occurring between the active components of the pathway to modulate the outcome of the transformation process.     

CD95-mediated cell signaling in cancer: mutations and post-translational modulations

Apoptosis has emerged as a fundamental process important in tissue homeostasis, immune response, and during development. CD95 (also known as Fas), a member of the tumor necrosis factor receptor (TNF-R) superfamily, has been initially cloned as a death receptor. Its cognate ligand, CD95L, is mainly found at the plasma membrane of activated T-lymphocytes and natural killer cells where it contributes to the elimination of transformed and infected cells. According to its implication in the immune homeostasis and immune surveillance, and since several malignant cells of various histological origins exhibit loss-of-function mutations, which cause resistance towards the CD95-mediated apoptotic signal, CD95 has been classified as a tumor suppressor gene. Nevertheless, this assumption has been recently challenged, as in certain pathophysiological contexts, CD95 engagement transmits non-apoptotic signals that promote inflammation, carcinogenesis or liver/peripheral nerve regeneration. The focus of this review is to discuss these apparent contradictions of the known function(s) of CD95.     

Persistance of endocrine cells in immuno-induced carcinoma of the exocrine pancreas: insulin, glucagon, and somatostatin cells]

In immuno-induced exocrine pancreatic carcinomas, which keep their exocrine secretory specificity through their different evolution stages [(1), (2)], normal B, A and D endocrine cells are still found, demonstrated by immunochemical techniques. They are localized in the islets of Langerhans. B and A cells are scattered in adenomatous pancreatic remains, and in the anaplasic carcinoma; D cells are found in the ductular and adenomatous remains. The three types of endocrine secretion granules are analyzed by electron microscopy at the early and late stages of carcinogenesis. The origin of the persisting endocrine cells and the nature of undifferentiated cells proliferating from the ductular epithelium are discussed.     

Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ ERK1,2 and PI3K/Akt

The E5 oncoprotein of human papillomavirus (HPV) 16 plays an important role in early cervical carcinogenesis. Vascular endothelial growth factor (VEGF) plays a central role in switching on the angiogenic phenotype during early cervical carcinogenesis. However, the relationship between E5 and VEGF has not previously been examined. To clarify the regulatory role of E5 in VEGF expression, we transferred the E5 gene into various cell types. E5 increased VEGF expression. The addition of epidermal growth factor receptor (EGFR) inhibitor significantly suppressed VEGF expression, demonstrating that E5 stimulates VEGF expression through the activation of EGFR. E5-mediated EGFR activation was accompanied by phosphorylation of Akt and ERK1/2, which are also involved in VEGF expression. Furthermore, the mRNA stability of VEGF was not affected by E5, but VEGF promoter activity could be modulated by inhibitors of the EGFR, MEK-ERK1/2 and PI3K/Akt pathways in E5-expressing cells. Collectively, these novel results suggest that HPV 16 E5 increases VEGF expression by activating EGFR, MEK/ERK1/2 and PI3K/Akt. Received 23 November 2005; received after revision 10 January 2006; accepted 9 February 2006     

Verlängerte Überlebenszeit von Hauthomotransplantaten bei Mäusen durch ein Methylhydrazinderivat

Summary Extended survival of skin homografts in mice was obtained by treatment with a methylhydrazine derivative (1-methyl-2-p-(isopropylcarbamoyl)-benzylhydrazine hydrochloride), representative of a new class of cytotoxic agents. Administration of 100 mg/kg prior to and continuously after the transplantation led to similar survival times as when 300 mg/kg was given daily only after the transplantation. In mice, the compound seems to be more effective than most of the drugs so far known to suppress transplantation immunity.