bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary Tumors and Adenomatosis Of The Lung In Untreated and In Irradiated Guineá Pigs
Authors: Hoch-Ligeti Cornelia , Congdon Charles C. , Deringer Margaret K. , Strandberg John D. , Sass Bernard , Stewart Harold L. 
Published: September 2009

The morphology of alveologenic tumor, hemangiosarcoma, lymphangioma, intrabronchial papilloma and adenomatosis observed in the lung of guinea pigs is described. Electron micrographs revealed alveologenic tumor to consist of Type II pneumocytes and the lesion of adenomatosis to consist of distended alveoli lined with ciliated bronchial type epithelial cells. A relationship between the dose of gamma or X-ray irradiation received and the frequency of guinea pigs with lung tumors could not be established. In guinea pigs, which survived over 20 months, the frequency of alveologenic tumors in the inbred strains was 23/107 in irradiated and 11/79 in untreated guinea pigs; this difference was statistically not significant. The frequency of tumor bearing inbred males (11/60) was significantly lower than of tumor bearing noninbred males (23/65). In the irradiated guinea pigs alveologenic tumors occurred earlier and tumor nodules in the lung were more numerous than in the untreated guinea pigs. Primary hemangiosarcoma involved the lung of one untreated and one irradiated strain 2 guinea pig. A single lymphangioma was found in an untreated inbred guinea pig. Intrabronchial papillomas were observed twice in irradiated and once in untreated guinea pigs. Adenomatosis was present in the lung of 2 untreated inbred and 5 irradiated noninbred guinea pigs.
Precursor Lesions and Pathogenesis of Spontaneous Mammary Tumors in Mice
Authors: Sass Bernard , Vlahakis George , Heston Walter E. 
Published: September 2009

A histologic study was done on the spontaneously occuring precursor and neoplastic lesions of mammary gland in inbred and hybrid female mice. Hyperplastic alveolar nodules (HAN) are small groups of non-encapsulated mammary acini lined by a single layer of low cubodial epithelial cells. The stroma of HAN often contain macrophages laden with ceroid pigment, which imparts to them a yellow color. Microfoci of carcinoma may be found within HAN, and adenoacanthomas may arise within acini in which there is chronic inflammation. Plaques are pregnancy-dependent lesions which occur in three albino mouse strains: DD, GRS, and RIII. These plaques are disc-shaped, are circumscribed or unencapsulated, have a central myxomatous core, and have acini which exhibit radial symmetry. Plaques can give rise to adenocarcinomas type P, type B (papillary and cystic) and also to the unusual and distinctive pale cell carcinoma. The spontaneous tumors described in this paper are mammary gland adenocarcinomas with sebaceous cell nests, tumors which are papillomas and contain basal epithelial elements and acini derived from mammary, sebaceous glands, or hair follicles.
An Analysis of the Carcinogenesis Testing Experience of the National Cancer Institute
Authors: DVM G. H. Hottendorf , Pachter I. J. 
Published: September 2009

Tabulations of the results of the initial approximately 200 NCI carcinogenesis bioassays conducted in mice and rats were published recently. However, no analysis of the results were provided. Such an analysis is the subject of this report. Ninety eight NCI bioassays were positive for carcinogenicity. Only three bioassays (<2%) were negative in both species and the ratio of positive to negative bioassays was 33:1. The remaining 47% of the bioassays were considered to be suggestive or inconclusive and it is inappropriate to refer to the total positive rate as 50%. The liver was the predominant tumor site and the only tumors produced in either rodent species in 19% of the positive bioassays were in the livers of mice. The high ratio of positive to negative results and the use of the mouse liver as a discriminating target organ raise serious concerns about the carcinogenesis protocol and in the methods of evaluating the results. Several recommendations are offered which may be useful in the current reexamination of bioassay procedures.
Ultrastructure of altered hepatocytes induced by diethylnitrosamine (DENA)
Authors: Zaki F. George 
Published: September 2009

Administration of diethylnitrosamine I.P. at dose level of 2 mg/kg five days a week to young Sprague-Dawley rats induced foci of altered hepatocytes entirely devoid of glucose-6-phosphatase and adenosine triphosphatase activity. Several weeks later, these foci developed hepatocellular carcinoma mostly of the trabecular type. Although these “preneoplastic” altered cells appeared as normal hepatocytes when examined in HE-sections, they were found to exhibit sites of dedifferentiation with ultrastructural features of hepatoma cells. Early morphological changes indicative of neoplastic transformation took place first as excessive storage of glycogen then as marked alterations at the surface membranes of such cells. Striking increase in coated pinocytotic vesicles appeared along the apposing cell membranes associated with loss of sinusoidal microvilli, protrusion of cytoplasmic blebs in the intercellular spaces, reduction or loss of desmosomes and obliteration of bile canaliculi. Subsequent changes were seen as dilation and disruption of the rough endoplasmic reticulum (RER), dispersal of ribosomes, proliferation and clustering of the smooth endoplasmic reticulum (SER), predominance of annulate lamellae, depletion of glycogen, enlargement of the Golgi cisterns and segregation of nucleolar elements. After 20 weeks, rats given DENA at a dose level of 25 mg/kg twice a week developed pronounced cirrhotic nodules in addition to multiple hepatocellular carcinoma. In contrast to the neoplastic nodules, the cirrhotic ones retained normal activity of glucose-6-phosphatase and adenosine triphosphatase and exhibited ultrastructural features typical of normal hepatocytes.
Choline Deficiency, Partial Hepatectomy, and Liver Tumors in Rats and Mice
Authors: Newberne Paul M. , Camargo Joao Lauro V. de , Clark Anthony J. 
Published: September 2009

Choline deficiency (CD) increases susceptability of (he rat liver to a number of hepatocellular carcinogens with a wide diversity of structure and potency. While severe CD results in micronodular cirrhosis and enhanced tumor induction, even a mild deficiency, without cirrhosis is sufficient to result in the increased carcinogenic response. The effects of CD are in part mediated via modulation of microsomal and, possibly, cytosolic enzymes responsible for activation/deactivation of carcinogens. The B6C3F1 hybrid mouse is remarkably sensitive to initiation/promotion of liver tumors by many substances or conditions. Choline deficiency or partial hepatectomy alone, or in concert, markedly enhances liver tumor induction in the absence of any known carcinogen. These data indicate that the liver of this strain of mouse is “initiated” at or shortly after birth and can be promoted by non-carcinogenic substances or conditions.
Proliferative liver lesions and sex steroids in rats
Authors: Schuppler J. , Schulte-Hermann R. , Timmermann-Trosiener I. , Günzel P. 
Published: September 2009

In standard two year tumorigenicity studies some gestagens, alone or in combination with an estrogen have been shown to produce proliferative liver lesions (PLL) in rats. Estrogens in general have not produced PLLs; for ethinyl estradiol the situation is equivocal.The steroids which increase the incidence of PLLs have not been shown to have the characteristics usually associated with classical hepatocarcinogens such as diethylnitrosamine (e.g. negative mutagenicity and cytoxicity, failure to bind covalently to DNA). Therefore, another mechanism must be assumed. A possible explanation is given by the ability demonstrated for a few steroids (mestranol alone or in combination with norethindrone, ethinylestradiol) to promote preneoplastic islands induced by diethylnitrosamine, resulting in an increase in tumor incidence over rats given only the carcinogen. Spontaneous preneoplastic islands in rats occur in various incidence in different strains and we have recently shown that their reaction to steroids—enhanced proliferation—is the same as the effect on preneoplastic islands produced by classical carcinogens. Sex steroids also enhance the growth or normal hepatocytes. It, therefore, seems reasonable to assume that sex steroids produce PLLs by acting on spontaneous preneoplastic lesions and not by the mechanisms usually associated with classical carcinogens.Extrapolating the incidence of PLLs in rats to a risk in humans may be highly misleading because of different pharmacokinetic patterns. Even in rats treated orally for two years with sex steroids dosed as multiples of the human contraceptive dose, resorption and biovailability may vary by a factor of 10 or more. It is, therefore, inappropriate to state that one sex steroid is more active in the production of PLLs than another, unless the data from pharmacokinetic studies are taken into account.Available evidence shows that sex steroids act as tumor promotors and enhance the growth of normal hepatocytes. It is extremely doubtful whether a sex steroid producing PLLs in the rat after two years of oral treatment can be classified as an initiating tumorigen for the rat. Substantial risk for humans cannot be inferred, because of the high incidence of spontaneous preneoplastic lesions in rats, and because of the very high sensitivity of the rat liver to a variety of chemically unrelated compounds including sex steroids.
Hypolipidemics Carcinogenicity and Extrapolation of Experimental Results for Human Safety Assessments
Authors: de la Iglesia Felix A. , Farber Emmanuel 
Published: September 2009

Dyslipoproteinemias represent a group of disorders closely related to alterations of cholesterol and triglycerides. The alterations of these lipids are considered important risk factors in coronary heart disease and indicate the need for clinically effective and safe drugs. Hypolipidemic agent therapy, however, does not appear without risk since the administration of these agents is by necessity, on a long-term basis. In the conduct of animal safety studies with some hypolipidemics, hyperplastic nodules or tumors developed in the liver of rodents. Data from the literature seem to indicate that the tumor response in rodents varies with the type of hypolipidemic drug administered. This paper summarizes the studies with the new lipid-regulating agent gemfibrozil. Aside from conventional long-term studies in rodents, the ultrastructural aspects of the liver were analyzed in several species and genotoxicity assays and short-term tests for hepatocarcinogenicity were conducted. Thus, it was possible to obtain an overview of these biological phenomena in order to allow for safety extrapolations. The biological behavior of these liver nodules showed that gemfibrozil and clofibrate-induced hepatocytes had not undergone malignant transformation. Further, the phenomenon of peroxisome proliferation, a characteristic event that follows hypolipidemic administration in rodents, was not confirmed in primate or human liver. Peroxisome proliferation has been linked to the process of hepatocarcinogenesis in rodents, although genotoxicity assays were negative and initiation/promotion tests failed to elicit tumors or nodules in a system where hepatocarcinogens manifest their activity. Thus, hypolipidemics such as gemfibrozil or clofibrate may possess low tumorigenic potential with low risk due to the lack of correlation between these tests. Nevertheless, these agents are indicated for specific lipoprotein phenotype alteration with the resulting clinical benefits.
Genetic and Environmental Regulation of Aryl Hydrocarbon Hydroxylase in Man: Studies with Liver, Lung, Placenta, and Lymphocytes
Authors: Pelkonen Olavi , Vähäkangas Kirsi , Kärki Niilo T. , Sotaniemi Eero A. 
Published: September 2009

Properties and response smoking of aryl hydrocarbon hydroxylase (AHH) activity in various human tissues are reviewed. In the placenta, induction of AHH by smoking can be demonstrated unequivocally. AHH activity in lung samples is variable, but the relation to current or past smoking is unclear. The effect of cigarette smoking can be readily shown in the rate of antipyrine elimination, although there is no change in AHH activity in liver biopsy samples. The reason for this discrepancy is not known. In peripheral lymphocytes a sort of “memory-effect” of cigarette smoking is retained even after culturing, the nature of this phenomenon remaining unclear. Furthermore, there seem to be many factors affecting AHH induction in peripheral lymphocytes in culture. These data suggest that regulation of AHH activity and induction is tissue-specific, i.e. no systemic regulation is discernible. It is also possible that the P-450 isozyme composition in some tissues masks the induction.Reasons for discrepancies between animal and human data are not clear; however, genuine biological differences and technical difficulties in human studies can be postulated.
Modulatory Mechanisms of Chemical Carcinogenesis: The Role of the NADPH Pool in the Benzo(a)pyrene Activation
Authors: Feo Francesco , Pirisi Lucia , Pascale Rosa , Daino Lucia , Frassetto Serenella , Zanetti Stefania , Garcea Renato 
Published: September 2009

Human lymphocytes and human skin fibroblasts isolated in vitro from subjects carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase (G6PD) exhibit an 86-87% decrease of this enzymatic activity. This is coupled with 51% and 61% decreases of the NADPH/NADP+ ratio in the G6PD-deficient human lymphocytes (HL) and human skin fibroblasts (HSF), respectively. There also occurs a 63-67% decrease of the hexose monophosphate shunt (HMS) in the deficient cells. Incubation with 0.1 mM methylene blue stimulates the HMS of normal HL 15-fold and that of deficient lymphocytes only 2.4-fold. These figures are, respectively, 7 and 2.2 in the case of HSF. This behavior of G6PD-deficient HL and HSF is coupled with an increase of the resistance to the cell death induced by benzo(a)pyrene (BP). This effect is mimicked by the incubation of normal HSF with dehydroepiandrosterone (DEA) which strongly inhibits G6PD. In contrast, no differences between normal and deficient HSF occur as a result of the effect of methylnitrosourea (MNU), a carcinogen that does not need metabolic activation. The NADPH-cytochrome c (P450) reductase of G6PD-deficient HL and HSF homogenates becomes lower than that of controls when endogenous G6PD and exogenous glucose 6-phosphate (G6P) and NADP+ are used as a hydrogen donor system in place of NADPH. Normal and G6PD-deficient HL, having comparable BP-hydroxylating activities, in the presence of exogenous G6P, NADP+, and G6PD, were studied to determine the effect of the absence of exogenous G6PD in the reaction system. When exogenous G6PD is omitted, the deficient HL exhibit a BP hydroxylase activity sharply lower than controls. G6PD-deficient HL and HSF are less prone than controls to produce BP water-soluble metabolites. A decrease in the synthesis of BP metabolites, mutagenic for his– Salmonella typhimurium in G6PD-deficient HL, has also been observed. These results suggest that the decreased susceptibility of G6PD-deficient cells and HSF to the toxic effect of BP and that of deficient HSF to its previously observed transforming effect, could depend on a reduced BP metabolism in the deficient cells.
Detoxification of Genotoxic Compounds as a Threshold Mechanism Limiting Their Carcinogenicity
Authors: De Flora Silvio 
Published: September 2009

In vitro metabolic trends were assessed for 100 genotoxic agents detected in two bacterial test systems, i.e., the Ames reversion test and a liquid DNA-repair test in Escherichia coli. Seventy-five compounds were found to undergo a more or less pronounced decrease of genotoxicity, in at least one of these models, in the presence of rat liver homogenates or in other metabolic systems (up to 40 different preparations, from various sources, for chromium compounds). A number of these deactivable compounds are reported in the literature to yield negative or equivocal results in animal carcinogenicity assays, which may imply the existence of metabolically regulated thresholds in the initiation of cancer. Several examples are provided to support this hypothesis. The in vitro treatment with a pharmacologic agent ( N-acetylcysteine) enhanced detoxification mechanisms, either by stimulating enzyme activities promoting glutathione formation in liver homogenates or by reacting itself with direct-acting mutagens and with the genotoxic metabolites of procarcinogens.
Roles of Gangliosides in the Surface Properties of Normal and Malignant Cells
Authors: Mugnai Gabriele , Tombaccini Donatella , Ruggieri Salvatore 
Published: September 2009

Gangliosides are ubiquitous plasma membrane components whose structural characteristics make it possible to establish multiple interactions with the pericellular microenvironment. Several receptorial activities of gangliosides have already been recognized and the possible involvement of gangliosides in growth control, adhesion, differentiation, and immunologic recognition is at present under study. The study of the role of gangliosides in cell growth control has been approached in our laboratory by investigating whether the ganglioside changes found in SV40-transformed Balb/c3T3 cells (SV3T3 cells) revert to a normal pattern in a variant of SV3T3 cells with growth properties similar to those of normal parental cells, the concanavalin A-selected SV3T3 revertant cells. These latter cells showed the same reduction of the more complex gangliosides as found in SV3T3 cells, while their amount of II3NeuAC-LacCer (GM3) was greatly increased compared to that found in either normal or transformed 3T3 cells. In order to study the role of gangliosides in the adhesion process, we analyzed the ganglioside structure of the so-called substrate-attached material, a cell surface structure involved in the adhesion of cells to substrate, from cultures of Balb/c3T3, SV3T3, and concanavalin A-selected SV3T3 revertant cells and from cultures of a system of transformed cells with different metastatic potential: the nonmetastatic B77-3T3 and the highly metastatic AA6 cells. Compared to normal cells, all the transformed cells contained smaller quantities of gangliosides in their substrate-attached material. In both normal and transformed cell lines, the gangliosides of the substrate-attached material, compared to those of detached cells, were found to be enriched by IV3NeuAC, II3NeuAc-GgOse4Cer (GD1a); the only exception were the AA6 cells which contained rather low levels of GD1a in both detached cells and substrate-attached material. When ganglioside compositions of the substrate-attached material, detached cells, and plasma membranes were compared in Balb/c3T3, SV3T3, and concanavalin A-selected SV3T3 revertant cells, a prevalence of GD1a was noted in the substrate-attached material and not in the plasma membranes. Moreover, the level of GD1a was scarcely modified in the substrate-attached material from cultures of a neuroblastoma cell line after growth in media containing chelating agents, a treatment which is known to modify the composition of cellular gangliosides. The overall indications emerging from these findings suggest a role for GM3 in growth control and a role for complex gangliosides in the adhesion process.
Short- and Long-term Studies on Chemical Carcinogenesis in BALB/Mo Mice
Authors: Chieco-Bianchi Luigi , Aldovini Anna , Ronchese Franca , De Rossi Anita , Majone Franca , Montaldi A. , Levis A. G. 
Published: September 2009

To study the interactions between chemical carcinogens and oncogenic retroviruses, BALB/Mo mice which carry the Moloney murine leukemia virus (M-MuLV) as an endogenous virus, and conventional (M-MuLV-free) BALB/c mice, as well as their Bc1 (M-MuLV+ or M-MuLV−) hybrids were injected neonatally with a single dose of urethane. BALB/Mo and V+ Bc1 mice showed accelerated lymphoma development; similar results were obtained in BALB/Mo mice receiving one or two doses of urethane transplacentally. Lung adenomas developed with shorter latency and higher incidence in BALB/Mo mice given urethane at birth; however, significant differences in the incidence of lung adenomas in BALB/Mo mice were found only in two experiments. Additional short-term experiments were carried out to investigate the mechanism of the higher susceptibility to sister chromatid exchange induction observed in BALB/Mo lymphocytes. It was found that BALB/Mo spleen lymphocytes incubated with cordycepin, an antiviral antibiotic, with or without mitomycin C treatment, showed reduction in both M-MuLV synthesis and sister chromatid exchange frequency, and the latter values were similar to those seen in control cultures. These data suggest that the integration of M-MuLV proviral DNA into the host genome is per se not sufficient to increase the susceptibility to carcinogenic stimuli, but that other events, such as viral gene expression and amplification, are most likely required for the chemical-viral synergistic effect to occur.
2,2,2-Trifluoroethanol-Induced Enteropathy in Rats: Chemically or Bacterially Mediated Effects
Authors: Kim James C. S. , Fraser Joanne M. , Samsonoff William A. , Kaminsky Laurence S. , Shin Sang J. 
Published: September 2009

The lethal effects of the fluorinated ether anesthetic, fluroxene, in rats are a consequence of its metabolism, which is catalyzed by cytochrome P-450 to the toxic metabolite 2,2,2-trifluoroethanol (TFE). The anesthetic or TFE (0.21 g/kg) caused decreased white blood cell counts, necrosis of bone marrow and lymphocytes, and decreased small intestine dry weight and was associated with septicemia. To elucidate the mechanism of TFE toxicity in rats we undertook histopathologic, ultrastructural and bacteriologic studies. TFE produced severe edema of intestinal lamina propria and submucosae, dilatation of crypts, loss of surface epithelium, vacuolation and necrosis of intestinal epithelial cells, and infiltration of polymorphonuclear leukocytes into the edematous lamina propria. Intestinal epithelial villi lost their cellular tissue integrity. Coccobacillary organisms were numerous in the ulcerated intestine. Hemolytic E. coli were isolated from intestinal tissue at a two-log increase in concentration relative to controls. Hemograms from TFE-treated rats exhibited marked leukopenia and morphologic differences. The platelets lost their discoid shape, extended pseudopods, and centralizing granules. Hemoglobin precipitation as Heinz bodies and crystalloid structures was observed in TFE-treated rats. Together the data suggest that TFE-induced enteropathy was most probably due to E. coli precipitated from TFE-mediated alterations in the population of small intestinal microbes.The antibiotics erythromycin, active against gram-positive bacteria, and streptomycin, active against gramnegative bacteria, and the antiendotoxin, polymyxin B, were administered to rats prior to TFE in an effort to differentiate between these mechanisms by altering the intestinal bacteria populations. The results indicate that the TFE-induced small intestinal lesions are initiated by the direct focal necrotic effect of TFE or its metabolites on the small intestinal epithelium. The focal coagulation necrosis produced by TFE predisposes the animals to lethal enteritis and systemic bacteremia.