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[Effect of thymosine on oxidative phosphorylation in mitochondria of mouse liver in the dynamics of chemical carcinogenesis].

Oxidative phosphorylation in the mice liver mitochondria with chemical carcinogenesis was studied as affected by thymosine. It is found that under chemical carcinogenesis the energy metabolism (fraction III) lowered and administration of thymosine in the early periods of carcinogenesis favoured an increase in the indices up to the control level. In the late period of carcinogenesis the mentioned effect was not observed. The favourable effect of thymosine on the oxidative phosphorylation was associated with an increase in the immunological indices in the animals under experiment. It is supposed that the activity of thymosine as a hormonal factor includes participation in the energy metabolism regulation.

Animals↗
PubMed1979

Dose response problems in carcinogenesis.

The estimation of risks from exposure to carcinogens is an important problem from the viewpoint of protection of human health. It also poses some very difficult dose-response problems. Two dose-response models may fit experimental data about equally well and yet predict responses that differ by many orders of magnitude at low doses. Mechanisms of carcinogenesis are not sufficiently understood so that the shape of the dose-response curve at low doses can be satisfactorily predicted. Mathematical theories of carcinogenesis and statistical procedures can be of use with dose-reponse problems such as this and, in addition, can lead to a better understanding of the mechanisms of carcinogenesis. In this paper, mathematical dose-response models of carcinogenesis are considered as well as various proposed dose-response procedures for estimating carcinogenic risks at low doses. Areas are suggested in which further work may be useful. These areas include experimental design problems, statistical procedures for use with time-to-occurrence data, and mathematical models that incorporate such biological features as pharmacokinetics of carcinogens, synergistic effects, DNA repair, susceptible subpopulations, and immune reactions.

Animals↗
PubMed1977

Comparison of the mode of immunopotentiating action of BCG and wax D. II. Effect on the methylcholanthrene carcinogenesis.

The effects of BCG and wax D on methylcholanthrene (MCA) carcinogenesis in mice were studied. BCG given 8 weeks after MCA administration conferred a significant protection against carcinogenesis. When given either on the same day as MCA injection or 4 weeks after MCA, BCG slightly increased tumor incidence. Wax D provided a marked protection against tumor development when given 4 weeks after MCA. An enhanced tumor development was obtained, when wax D was administered either on the day of MCA injection or 8 weeks after MCA. These results indicated that the effects of BCG and wax D on MCA carcinogenesis varied with the timing of administration. When BCG and wax D increased the level of delayed type hypersensitivity (DTH) at the initiating time of tumor development, a protection against carcinogenesis was obtained. On the other hand, BCG and wax D enhanced tumor development, when it increased antibody formation at the time of initiation of tumor development.

Animals↗
PubMed2024

Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach.

Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.

Kidney Neoplasms↗
PubMed1977

Releasing carcinogenesis test results: timing and extent of reporting.

A carcinogenic in an animal bioassay is usually characterized by gradaul accumulation of a tumor incidence significantly in excess in the treated versus the control animals. In some cases, a definite response is realized relatively early, prior to planned sacrifice. In others, positive results are found at termination. In both cases, a long delay may occur before the information is ready to reach the public due to the time needed to complete pathology, data analysis, publication of a report. Since the finding that a chemical is carcinogenic may have serious implications for public health and technology, reports of carcinogenesis bioassays should be thoroughly and critically reviewed before being issued. A delicate ethical dilemma confronts scientists in selecting the proper timing and extent for the release of carcinogenesis test results. Early findings may not be confirmed and may cause technological and economic problems and unnecessary anxiety. On the other hand, delaying public notification of highly suspicious findings until a final, detailed report is published, may delay preventive actions that could protect exposed populations from unnecessary risks. To meet differing requirements in regard to timing and extent of reporting, procedures were developed to issue reports on National Cancer Institute (NCI) carcinogenesis bioassays when the findings are clearly identified and well documented in the following forms: a) reports of preliminary findings, when the evidence is strongly suggestive; b) summary reports of completed bioassays; and c) detailed technical reports. Availability of such reports, particularly for preliminary findings, will be announced in the Federal Register and in a press release. The reports will be submitted for publication in the scientific literature.

Animals↗
PubMed1979

Ureterosigmoidostomy in rats: a model for the study of bladder tumour carcinogenesis and cocarcinogenesis.

A modified Coffey I ureterosigmoidostomy has been developed in rats as a model of urinary diversion for studying bladder carcinogenesis and co-carcinogenesis. Diverted and sham-operated animals were killed at 1, 3 and 6 months. Excretory urograms revealed minimal hydroureteronephrosis in most diverted animals. Upper tract bacterial colonisation was 9 times more frequent in diverted animals. Approximately one-third of the diverted animals had focal cortical scarring; however, renal function was normal in all groups as assessed by serum creatinine and electrolytes. These studies indicate that ureterosigmoidostomy in rats is a satisfactory model of urinary diversion for studying carcinogenesis.

Animals↗
PubMed1979

Relation of adenomatous hyperplasia of the gastric mucosa to carcinogenesis.

Experimental studies of stomach carcinogenesis were carried out in two series of Wistar rats (66 and 174 animals). In both series submucosal foci of adenomatous hyperplasia were observed either without atypia, or with atypia at different, gradually increasing degrees. The number of these focal lesions in the submucosa (87 in the first series) was smaller than that of focal dysplastic changes with varying grades of atypia within the mucosa. On the basis of different degrees of atypia observed in these adenomatous hyperplasias, we have to assume that a phase shifting occurs in those areas that show lower grades or absence of atypia. In the framework of carcinogenesis this kind of adenomatous hyperplasia is interpreted as an incomplete or incompletely persisting carcinogenesis. In analogy to our experimental findings we found identical lesions in three human cases where different grades of atypia were observed distant from the primary stomach cancer. These results are discussed with reference to the animal experiments and to the literature.

Adenoma↗
PubMed1977

Two-stage carcinogenesis with rat embryo cells in tissue culture.

Transformation of rat embryo fibroblasts in vitro has been investigated using initiation with either benzo(a)pyrene (BaP), 7,12-dimethylbena(a)anthracent (DMBA) or benzo(e)pyrene (BeP) and promotion with either phorbol ester (TPA) or croton oil (Cr.Oil). The criteria used to assess in vitro transformation were (a) the efficiency of cloning in liquid medium, (b) abnormal cellular morphology and (c) the development of malignant tumours following s.c. inoculation of newborn rats. The results show that the cloning efficiency, which remained low in the control cells, was increased to a variable extent in the treated groups. Transformation occurred in all groups, but occurred earliest in cells that were initiated and promoted. Initiation with DMBA or BaP and promotion with TPA or Cr.Oil led to the earliest acquisition of malignancy. Correlations were found between the transformation of cells in vitro and the acquisition of malignant potential, and between the carcinogenic action of the compounds in vitro and their action in vivo, but cloning efficiency was not a reliable indicator of in vitro transformation or of malignancy. In most cases in vitro transformation appeared to precede the acquisition of malignancy, but in two cases it occurred later. The studies also show that BeP, which is a tumour initiator in vivo, also acts in this way in vitro. The conclusion drawn from a discussion of these results and of two-stage carcinogenesis in vivo is that two-stage carcinogenesis can be reproduced in tissue culture; this model may be useful in studies of those mechanisms of chemical carcinogenesis that involve the processes of initiation and promotion.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1977

Relationship between differentiation and carcinogenesis.

Carcinomas are caricatures of the normal process of tissue renerwal. Malignant stem cells proliferate, and some of their progeny differentiati and form benign functional cells. In teratocarcinoma, it has been demonstrated that the stem cells are the target in carcinogenesis and become malignant stem cells. The normal and malignant stem cells are equally differentiated. Normal stem cells of breast and colon are no more differentiated than their counterparts. If they are the target in carcinogenesis, then the concept of dedifferentiation is bypassed as an explanation for the undifferentiated appearance of tumors. While the focus of this meeting has been on mutation as an explanation for carcinogenesis, in this paper emphasis is placed on electrophilic carcinogens acting on cytoplasmic molecules that control gene expression. A type of gene control in addition to the operon is postulated.

Animals↗
PubMed1978

Changes in polyamine levels and protein synthesis rate during rat liver carcinogenesis induced by 4-dimethylaminoazobenzene.

The concentrations of putrescine, spermidine, and spermine in liver of rats fed on 4-dimethylaminoazobenzene and in the resultant hepatomas were found to be significantly higher than were those observed in normal liver from rats of the same strain, sex, and age. These modifications were due to the carcinogen and not to the special low-riboflavin diet used to obtain the carcinogenic effect of 4-dimethylaminoazobenzene. The first change observed during liver carcinogenesis was the early increase in the putrescine level, followed by an increase of spermidine and spermine, which reached maximum levels in growing hepatomas. A significant increase of urinary polyamines was also observed in tumor-bearing rats. Experiments on leucine incorporation into proteins of tissue slices, which were obtained from the same tissues on which polyamine determinations were carried out, showed that in rat liver carcinogenesis the rate of protein synthesis was well correlated with the polyamine levels. These results suggest that polyamines may play a role in the process of carcinogenesis and in tumor protein synthesis in vivo.

Animals↗
PubMed1978

Hormonal induction of mammary tumor viruses and its implications for carcinogenesis.

The purpose of this study was to evaluate the possibility that hormones and mouse mammary tumor virus (MuMTV) are cocarcinogenic for mammary epithelium. Results of our investigations in vivo and in vitro suggest: (a) Hormones promote mammary carcinogenesis in BALB/c females whether MuMTV is germinally (BALB/c) or horizontally (BALB/cfC3H) transmitted; the rate of carcinogenesis in BALB/cfC3H females is substantially faster than it is in BALB/c, but the final mammary carcinoma incidence is approximately the same. The rate-limiting step in malignant transformation in BALB/c, which infectious MuMTV overcomes, is in premalignant transformation from normal. (b) One characteristic of horizontal MuMTV transmission in BALB/c that is not observed in germinal transmission is integration of new MuMTV sequences in mammary cell DNA. Integration is mammary cell specific and constant at 2 to 3 copies/cell from tumor to tumor. (c) MuMTV expression is changed in mammary epithelial cells during hormonal carcinogenesis. The nature of the change is qualitatively similar in both BALB/c and BALB/cfC3H. Expression of envelope glycopeptides (glycoprotein with a molecular weight of 52,000) is induced, which correlates with amplification of MuMTV RNA sequence content. Quantitative differences exist in induced levels in BALB/c and BALB/cfC3H. (d) MuMTV RNA and a glycoprotein with a molecular weight of 52,000 were not inducible with dexamethasone in normal mammary epithelial cells in culture. These structural components were induced in both premalignant (BALB/cfC3H) and malignant (BALB/c and BALB/cfC3H) cells. MuMTV RNA was induced by dexamethasone in normal cells pretreated with 5-iodo-2'-deoxyuridine. (e) Both premalignant and malignant cells have altered (vis-à-vis normal) surfaces, discernible by differences in reactivity with concanavalin A in hemadsorption assays. Indirect evidence suggests that the alteration includes membrane incorporation of MuMTV-related determinants of a glycoprotein with a molecular weight of 52,000. (f) Malignant cells exhibit enhanced sensitivity to insulin for reinitiation of DNA synthesis and mitosis in contact-inhibited homotypical monolayers. These findings have been organized into a hormonal cocarcinogenesis hypothesis in which expression of germinally transmitted MuMTV genes is the proximal cause of neoplastic transformation.

Animals↗
PubMed1979

Sequential analysis of hepatic carcinogenesis: a comparative study of the ultrastructure of preneoplastic, malignant, prenatal, postnatal, and regenerating liver.

The objective of this study was to compare the fine structure of presumptive preneoplastic hepatocytes at various times during liver carcinogenesis with that of normal, developing, and regenerating liver and of hepatocellular carcinomas, using transmission and scanning electron microscopy. A new model of liver carcinogenesis was used in which several of the early steps are quite well synchronized. A single initiating dose of diethylnitrosamine induced isolated islands of altered hepatocytes. The cells were characterized by persistence of glycogen despite starvation, increase in smooth endoplasmic reticulum, and hypertrophic nucleoli. Following intense selection of the altered hepatocytes by dietary 2-acetylaminofluorene plus partial hepatectomy, the affected hepatocytes proliferated rapidly to produce basophilic foci. These early hyperplastic lesions revealed stellate-shaped dilated bile canaliculi lined by blebs and abnormally thick elongated microvilli, a decreased number of microvilli on the sinusoidal surface, a marked increase in smooth endoplasmic reticulum, large nucleoli, and bundles of pericanalicular microfilaments. A majority of the proliferating lesions reacquired a normal organizational pattern within several weeks after partial hepatectomy and could not be distinguished from normal liver. A small number continued to grow and become typical persistent hyperplastic nodules. These showed significant widening of intercellular spaces between hepatocytes, elongated microvilli over large regions of the cell surface, many invaginations of the cell membrane, and irregularly shaped bile canaliculi. Sequential changes in focal hyperplastic hepatocytes during carcinogenesis could be distinguished from normal, developing, and regenerating liver. The major differences involved the cell surfaces and cytoplasmic organelles. The findings are compatible with the hypothesis that a carcinogen may act by inducing alterations in a small number of hepatocytes and that hepatocellular carcinomas arise through stepwise evolutional changes in these cells.

Animals↗
PubMed1979

Current status of experimental chemical carcinogenesis and its applications to human cancer risk.

The history of chemical carcinogenesis is a record of the observations of physicians and epidemiologists of the relation between the occurrence of uncommon cancers in humans and the exposures of those people to certain chemical agents. In parallel with some of these findings, experimental animal models were developed to imitate the findings in humans. From these experimental studies has been obtained most of the information we have about the mechanisms of chemical carcinogenesis. Many of the biochemical studies have focused on liver cancer which might be an inappropriate general model for chemically induced cancer, liver cancer being comparatively rare in humans. It is not known to what extent exposures to any particular chemical carcinogens are responsible for the major human cancers, and the agents responsible for most of them are not known. It is probable that many noncarcinogenic chemicals act as promotors of carcinogenesis, and among these alcohol can be included as in important contributor.

Alcoholism↗
PubMed1979

Effect of trichloropropene oxide and benzoflavone on polycyclic hydrocarbon carcinogenesis in C3H/He and DBA/2 mice.

Effect of 1,1,1-trichloropropene 2,3-oxide and 7,8-benzoflavone on benzo[a]-pyrene and 3-methylcholanthrene carcinogenesis in the subcutaneous tissues of C3H/He and DBA/2 mice was examined. By a single application of the carcinogen, the incidence of fibrosarcoma was higher and the latency of tumorigenesis was shorter in C3H/He mice than in DBA/2 mice. Treatment with 1,1,1-trichloropropene 2,3-oxide increased the incidence of fibrosarcoma in DBA/2 mice, but decreased the rate in C3H/He mice, when benzo[a]pyrene was used as a carcinogen. On the other hand, in 3-methylcholanthrene carcinogenesis, no effect of the oxide on the tumor incidence was observed. By the simultaneous application of 7,8-benzoflavone with benzo[a]pyrene, the tumor incidence increased, but not so significantly in DBA/2 mice, compared to that treated with benzo[a]pyrene alone, and no appreciable effect was observed in C3H/He mice treated with benzo[a]pyrene, and in both strains of mice with 3-methylcholanthrene. The relationship between the activity of arylhydrocarbon hydroxylase and the change in polycyclic hydrocarbon carcinogenesis is briefly discussed.

Animals↗
PubMed1979

[State of the erythrocyte surface (echinocytosis) in experimental carcinogenesis].

Characteristic red cell deformation, echinocytosis peculiar to mammary tumour susceptible C3H mice, were revealed by a comparative study of erythrocytes in animals with a different natural resistance to spontaneous carcinogenesis. 58.6% of spiny red cells was found at the early latent period (at the age of 3-4 months) and reached 91.1% at the late latent period (at the age of 11-12 months). In the blood of intact C57BL/6 mice resistant to mammary carcinogenesis, at the same ages the echinocyte count ranged from 16.0 to 18.7%. The tumour growth (spontaneous tumour in C3H mice and transplantable Ehrlich adenocarcinoma in C57BL/6 mice was accompanied by an increase in the echynocyte count and in the expression of echinocytosis (up to 96.6 and 65.3%, respectively). Possible pathogenetic mechanisms of echinocytosis in carcinogenesis are discussed.

Animals↗
PubMed1977

Reduction of N-nitrosodiethylamine carcinogenesis in rats by lipotrope or amino acid supplementation of a marginally deficient diet.

In studies in this and other laboratories, induction of hepatocardinoma by several different chemical carcinogens was enhanced in rats fed diets deficient in lipotropes (choline, methionine, folic acid), amino acids, and niacin, and high in fat. In some cases, specific supplementation with lipotropes blocked carcinogenesis. In studies reported here, specific supplementation of a marginally deficient diet that enhanced carcinogenesis in rats, with the amino acids or lipotropes in which it was deficient, significantly decreased induction of hepatocarcinoma by N-nitrosodiethylamine. Niacin supplementation decreased hepatocarcinoma incidence only slight; the addition of beef fat to an adequate diet did not enhance tumor induction. Rats fed the amino acid- or lipotrope-supplemented diets had an increased incidence of hepatic hemangioendothelial sarcomas, compared to deficient rats or to rats fed the adequate control diet. Methionine was contained in both the amino acid and the lipotrope supplement and probably was responsible for reducing hepatocarcinoma incidence. Methionine has been found to have an anticarcinogenic effect in other studies and also to block the depletion of hepatic folate stores that is induced by N-nitrosodiethylamine. Interactions between carcinogens, S-adenosylmethionine, and folate may be significant in hepatic or other tissue carcinogenesis. One of more hepatic microsomal oxidases were depressed in rats fed any of the high-fat diets but were not correlated with tumor incidence.

Amino Acids↗
PubMed1978

Effects of diet on colon carcinogenesis and the immune system in rats treated with 1,2-dimethylhydrazine.

The effects of different types of diets on colon carcinogenesis by 1,2-dimethylhydrazine and on the immune system were studied in W/Fu rats. Six different types of diets were used in two sets of experiments. Rats in each group were fed the respective diets immediately upon weaning. 1,2-Dimethylhydrazine dihydrochloride was administered s.c. at a dosage of 15 mg/kg weekly in two divided doses. The rats were followed by sequential laparotomies for the development of gastrointestinal (GI) tumors until death. Tumors appeared earlier, and the total number of GI tumors, particularly those of the colon, was higher in rats fed diet enriched with fat from animal sources. In these rats the GI tumors metastasized more frequently, and their survival, after appearance of the first GI tumor, was significantly shortened. The diet low in animal fat and enriched with carbohydrate reduced the number of GI tumors and delayed their appearance. Semisynthetic elemental diet accelerated the appearance of colon tumors without increasing the total number of GI tumors over the life span of the animals. Serum cholesterol levels evaluated during carcinogenesis suggest a correlation between serum cholesterol levels and the increased frequency of colonic tumors. The alterations in serum immunoglobulin G levels, lymphocyte counts, and surface immunoglobulin-bearing lymphocytes evaluated at different times during carcinogenesis suggested a biphasic ("M type") immune response. Rats fed low residue diets and/or diets containing fat from animal sources had depressed serum immunoglobulin G levels. However, the pattern of immune response was similar in groups of rats fed different types of diets.

Animals↗
PubMed1978

Effect of azathiopurine and OK-432 on urinary bladder carcinogenesis in rats.

The effect of azathiopurine and OK-432 on bladder carcinogenesis in rats was evaluated using the carcinogens, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT). Azathiopurine did not affect FANFT bladder carcinogenesis in any treatment. By contrast, when azathiopurine was fed simultaneously with BBN there was a significant increase in the incidence of bladder tumors, although it had no effect if administered before or after BBN. Short-term administration (8 weeks) of OK-432 subcutaneously before, during, or after BBN did not affect bladder carcinogenesis, but if OK-432 was begun after BBN and continued until the end of the experiment, the incidence of BBN-induced bladder tumor was significantly reduced. No bladder lesions were observed in control rats or in rats receiving only azathiopurine or OK-432.

Animals↗