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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The modifying effects of 22-oxa-calcitriol (OCT), a synthetic analog of 1 alpha,25-dihydroxyvitamin D3, were assessed in a multi-organ carcinogenesis model using male F344 rats initially treated with five kinds of carcinogens. In experiment 1 the rats were given OCT intraperitoneally at doses of 30 micrograms/kg (25 rats) or 3 micrograms/kg (25 rats), three times a week for 24 weeks after initial carcinogen exposure over 4 weeks and a 2 week non-treatment period. Twenty-two rats received the five carcinogens and were given the vehicle intraperitoneally as a control. A further group of 10 rats was given the 30 micrograms/kg dose of OCT without prior carcinogen application. At the end of the total observation period of 30 weeks the carcinoma incidence in the small intestine of rats given 30 micrograms/kg OCT after carcinogen treatment was 0%. This incidence was significantly smaller when compared with the control group. The incidence of large intestine carcinomas in the 30 micrograms/kg OCT group showed a tendency to decrease. The numbers of small and large intestinal carcinomas per rat were also significantly lower in the group given 30 micrograms/kg OCT than after 3 micrograms/kg OCT or carcinogens alone. Attention was, therefore, focused on colon carcinogenesis and in experiment 2 30 micrograms/kg OCT administered six times a week to rats for 8 weeks after the last injection of N,N'-dimethylhydrazine (DMH) exposure. OCT significantly reduced the formation of DMH-induced aberrant crypt foci, considered to be putative preneoplastic lesions. In experiment 3 30 micrograms/kg OCT was administered six times a week to rats for 4 weeks without prior carcinogen treatment. The proliferating cell nuclear antigen labeling index for the colonic epithelium of rats given 30 micrograms/kg OCT was decreased. Ornithine decarboxylase and spermidine/spermine N1-acetyltransferase activities in colonic epithelium, assayed as indicators of cell proliferation, were not significantly decreased as compared with control group values. Furthermore, vitamin D receptors in colonic epithelium were not significantly increased. Thus the present study indicates that OCT can exert inhibitory effects on tumor development in the small and large intestines, although the mechanism is unclear.
Carcinogenesis 1995 Sep
PMID:Inhibition of intestinal tumor development in rat multi-organ carcinogenesis and aberrant crypt foci in rat colon carcinogenesis by 22-oxa-calcitriol, a synthetic analogue of 1 alpha, 25-dihydroxyvitamin D3. 755 59

Dysregulation of cyclin expression has been reported for several human malignancies, including breast cancer. To further investigate the role of cyclin genes in mammary tumorigenesis we analyzed the expression of cyclins D1, E and A and other cell cycle-related proteins in a series of nine N-methyl-N-nitrosourea-induced primary rat mammary tumors. Western blot analysis revealed a 10- to 15-fold increase in the level of cyclin D1 protein in most (7/9) of the tumors, when compared with normal rat mammary gland. The two tumors that did not show this increase also displayed negligible levels of the retinoblastoma protein. A moderate increase, 1.5- to 2-fold, in the level of cyclin E was observed in four tumors and three tumors displayed abnormal low molecular weight cyclin E-related proteins. None of the tumors showed amplification of the cyclin D1 or E genes when studied by Southern blot analysis. All nine tumors showed a 2- to 6-fold increase in the level of cyclin A protein. Most of the tumors also displayed a marked increase in levels of the CDK2 and CDK4 proteins. These changes did not appear to be simply a consequence of increased cell proliferation, as assessed by proliferating cell nuclear antigen analysis. Thus, aberrant expression of cyclins and other cyclin-related genes occurs frequently in mammary tumorigenesis in both rodents and humans.
Carcinogenesis 1995 Sep
PMID:Deregulated expression of cyclin D1 and other cell cycle-related genes in carcinogen-induced rat mammary tumors. 755 74

Mirex, a halogenated hydrocarbon, is a potent skin tumor promoter in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. In the present study retinoic acid (RA) and fluocinolone acetonide (FA), classical inhibitors of phorbol ester- and non-phorbol ester-type skin tumor promoters, were examined for their ability to inhibit mirex tumor promotion. Female CD-1 mice were initiated with 200 nmol DMBA and promoted with equipotent promoting doses of either 5 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) or 200 nmol mirex twice weekly for 25 weeks and RA (2(1 or 5 nmol), FA (0.5 or 2 nmol) or acetone were applied 30 min prior to each TPA or mirex dose. TPA-promoted papilloma formation was strongly inhibited by > 70% with both doses of RA and by > 90% with both doses of FA. In contrast, mirex-promoted papilloma formation was not inhibited by either dose of RA or 0.5 nmol FA and 2 nmol FA weakly inhibited mirex-promoted papillomas by only 32%. TPA- and mirex-promoted papillomas that were refractory to RA and FA demonstrated the same incidence of Ha-ras mutation as TPA- or mirex-promoted papillomas without RA and FA treatment, further indicating that the inhibitory activity of RA and FA is promoter-dependent and not solely dependent on mutant Ha-ras. FA (2 nmol) treatment completely abolished TPA-induced epidermal hyperplasia and proliferating cell nuclear antigen (PCNA) S phase-positive cells, however, FA had no inhibitory effect on the weak proliferative response induced by mirex. Collectively, these results indicate that the promotional activity of mirex, as well as its weak proliferative response, result from a distinct promoter mechanism and/or that mirex promotes a unique population of epidermal cells that are insensitive to FA and RA and cannot be distinguished by their mutant Ha-ras genotype.
Carcinogenesis 1995 Sep
PMID:Lack of effect of retinoic acid and fluocinolone acetonide on mirex tumor promotion indicates a novel mirex mechanism. 755 75

The present study was undertaken to examine the effects of cyclic administration of low-dose progestogen on endometrial carcinogenesis in mice. A total of 115 female ICR mice, 10 weeks of age, were divided into four experimental and control groups. Mice in groups 1-3 received laparotomy and were injected with N-methyl-N-nitrosourea (MNU) solution at a dose of 1 mg/100 g body weight to the left uterine tube and with normal saline to the right uterine tube. From one week after the MNU exposure, groups 1 and 2 were given 5 ppm 17 beta-estradiol (E2)-containing diet throughout the experiment. Mice in group 1 received 5 s.c. injections of medroxyprogesterone acetate (MPA) (2 mg/mouse) at intervals of 4 weeks from week 7. Group 3 was treated with MNU/normal saline alone. Group 4 consisted of mice treated with MPA alone. At the termination of the experiment (week 30), all animals were killed and autopsied for pathological examinations. It was found that adenocarcinomas and preneoplastic lesions developed in the bilateral uterine corpora in mice of groups 1-3. MPA treatment significantly decreased the weight of the uterine corpus (P < 0.05) and the incidences of endometrial adenocarcinoma and atypical or adenomatous (P < 0.001) but not cystic glandular hyperplasias in the MNU/E2-treated groups. Additionally, MPA treatment tended to decrease the proliferating cell nuclear antigen-labeling index in endometrial glandular cells. These data indicate that MPA, even at low dose, has an inhibitory effect on mouse endometrial carcinogenesis induced by MNU and E2.
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PMID:Inhibitory effects of medroxyprogesterone acetate on mouse endometrial carcinogenesis. 755 94

The modifying effect of dietary administration of protocatechuic acid (PCA) during the initiation and postinitiation phases on N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder carcinogenesis was investigated in male F344 rats. Animals were divided into nine groups and groups 1-7 were given 0.05% BBN in drinking water for 6 weeks to induce bladder neoplasms. Rats in groups 2, 3 and 4 were fed diets containing 500, 1000 and 2000 p.p.m. PCA respectively for 8 weeks, starting 1 week before BBN exposure. Groups 5, 6 and 7 were fed the PCA-containing diets at three dose levels for 33 weeks. Group 8 was fed the diet containing 2000 p.p.m. PCA alone throughout the study. Group 9 was given tap water without BBN and the basal diet without PCA and served as an untreated control. At 41 weeks after the start, all animals were killed. The incidence of bladder tumors and preneoplastic lesions, and cell proliferation activity estimated by the numbers of silver-stained nucleolar organizer regions proteins (AgNORs) and proliferating cell nuclear antigen (PCNA)-immunoreactive cells were compared among the groups. PCA administration at 1000 and 2000 p.p.m. during the initiation and postinitiation phases significantly decreased the carcinoma incidence in a dose-dependent manner. Also, PCA at all doses given during either initiation or postinitiation phases reduced the development of the preneoplastic lesions. PCA feeding significantly reduced the numbers of AgNORs and PCNA-positive cells in the non-lesional transitional epithelium, preneoplasms, and neoplasms in the urinary bladder of rats treated with BBN. These results indicate that dietary administration of PCA is quite effective in preventing BBN-induced bladder carcinogenesis.
Carcinogenesis 1995 Oct
PMID:Chemoprevention of urinary bladder carcinogenesis by the natural phenolic compound protocatechuic acid in rats. 758 32

Intense research using animal models has indicated that chemically-induced rat liver cancer proceeds through multiple, distinct stages that can be characterised morphologically and biochemically. Primary human liver cancer, with hepatitis B and other environmental factors such as poor nutrition and food contaminating mycotoxins as contributing etiological factors, is one of the major causes of cancer deaths in African, Asian and some Western countries. Recent advances in surgical and diagnostic techniques have also allowed the identification of potential morphological precursors of primary human liver cancer, and suggested a model consistent with the concepts of initiation--promotion--progression as in the rat. The expression of proliferating cell nuclear antigen (PCNA), silver-staining nucleolar organiser regions (AgNOR), oncogenes and the tumor suppressor gene p53 in preneoplastic and neoplastic lesions of rat and human livers is presently reviewed. This undertaking is an attempt to evaluate whether the current knowledge regarding molecular mechanisms of carcinogenesis is sufficient to permit the use of these molecular parameters as 'intermediate' markers in studies of risk assessment and cancer prevention, without having to resort to tumor appearance as an end-point.
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PMID:The potential for the use of cell proliferation and oncogene expression as intermediate markers during liver carcinogenesis. 760 May 46

Male Sprague-Dawley rats received the hepatocarcinogen N-nitrosomorpholine (NNM) in the drinking water at low dose levels ranging from 6 mg/l to 60 mg/l for 6 and 12 weeks, respectively. Foci of altered hepatocytes (FAH) were demonstrated histochemically using changes in the activities of glucose-6-phosphate dehydrogenase and glycogen phosphorylase, and in the glycogen content as markers. Proliferating cells were detected by the immunohistochemical reaction for proliferating cell nuclear antigen (PCNA). The number and size of foci of altered hepatocytes increased in a time and dose-related manner. The dose-effect curves were non-linear with a slight positive slope at the low doses and a markedly increased slope at higher doses. The number of PCNA positive hepatocytes showed a dose-dependent increase. In addition to the granular distribution of PCNA in the nuclei, hepatocyte nuclei with homogeneously distributed PCNA occurred in animals exposed to 60 mg/l NNM. It is proposed that these cells are related to the occurrence of hepatocytes with higher ploidy induced by NNM and may be regarded as cells in the G2 phase of the cell cycle. The non-linear shape of the dose-response-curve of the FAH suggests that some mechanisms contribute to carcinogenesis over the whole dose range, whereas other mechanisms enhance carcinogenesis only at higher doses. The relevance of the non-linear dose-effect curve for the risk assessment of carcinogens is discussed.
Carcinogenesis 1995 Jul
PMID:Effects of low doses of N-nitrosomorpholine on the development of early stages of hepatocarcinogenesis. 761 84

Induction of c-fos protooncogene expression following exposure of mammalian skin to UV irradiation suggests an involvement in UV-induced alterations of epidermal cell proliferation and viability. In the present study we have investigated whether topically administered c-fos antisense oligodeoxynucleotides (ODNs) inhibit c-fos activation in the UV-exposed rat skin and thereby modulate the delayed increase in cellular proliferative activity. The accumulation of c-Fos immunolabeled nuclei in the epidermis was almost completely blocked 18 h post-irradiation by topical treatment with the c-fos antisense ODN. The co-expression of c-Jun was not affected and a random sequence control ODN was ineffective. Epicutaneous application of fluorescein-labeled ODNs revealed penetration into the underlying epidermis. The appearance of nuclear immunoreactivity for proliferating cell nuclear antigen (PCNA) 18 h after UV exposure was significantly suppressed in the epidermis treated with c-fos antisense ODNs. In vitro PCNA is involved in both DNA repair synthesis and DNA replication, and the expression of PCNA mRNA is increased after UV irradiation. Thus, it may be speculated that UV-induced c-Fos transcription factor may be linked to repair of photodamaged DNA and/or cell cycle progression by trans-activating PCNA gene expression.
Carcinogenesis 1995 Aug
PMID:Inhibition of c-Fos expression in the UV-irradiated epidermis by topical application of antisense oligodeoxynucleotides suppresses activation of proliferating cell nuclear antigen. 763 14

The effect of Helicobacter mustelae infection on gastric epithelial proliferation was studied in ferrets colonized with H.mustelae and specific pathogen-free (SPF) ferrets not infected with H.mustelae. Thirteen H. mustelae-infected ferrets between the ages of 13 and 32 months and 16 SPF ferrets between 6 and 18 months were analyzed. Bacterial cultures, urease tests and Warthin-Starry stains were used to identify H.mustelae. Tissues obtained from the antrum and the body regions of the stomach were assayed by proliferating cell nuclear antigen (PCNA) immunohistochemistry and measured using a computerized color image analysis system. PCNA-expressing gastric epithelia in the antrum and the body regions were significantly increased in the H.mustelae-infected ferrets versus the SPF ferrets (P < 0.001). PCNA positivity in the antrum regions of both the H.mustelae-infected ferrets and SPF ferrets was significantly higher than that of the body regions (P < 0.001). Comparison of the histopathology of infected ferrets indicated that PCNA positivity correlated with the histological severity of gastritis. This study suggests that cell proliferation in ferret gastric mucosa increases with H.mustelae infection and provides evidence that PCNA is a useful biomarker for studying the changes in cell kinetics in the ferret stomach. The data also further support the use of the H.mustelae-infected ferret as an animal model for studying the pathogenesis of Helicobacter pylori-induced gastric diseases of humans.
Carcinogenesis 1995 Aug
PMID:Effect of Helicobacter mustelae infection on ferret gastric epithelial cell proliferation. 763 23

Human papillomaviruses (HPVs) have been recognized as likely viral agents responsible for anogenital precancer lesions and squamous cell cancers in both men and women. Nevertheless their role in carcinogenesis is not entirely clear. There are many other agents, both viral and non-viral, which might act synergistically or separately with HPV in a multistep tumorigenic process. Among non-viral factors, protooncogene and tumor suppressor gene alterations may be a major step towards the malignant transformation of an HPV-infected cell. The induction of unscheduled DNA synthesis and cell proliferation by human papillomaviruses would provide the basis for the potential of these viruses to contribute to the formation of tumors in vivo. Thus, we studied by in situ hybridization (ISH) the cyclin A gene expression in HPV-induced condylomatous and dysplastic lesions of the anogenital tract, and in inflammatory squamous intraepithelial tissues. We observed a high level of cyclin A gene expression in low grade squamous intraepithelial lesions infected by HPV type 6/11. Cyclin A induction was surprisingly more important in the upper third layers of differentiated cells together with large amounts of HPV DNA, than in proliferating basal and parabasal cells. An identical pattern was also shown in some low grade squamous intraepithelial lesions infected with potential oncogenic HPV. In contrast, there was evidence of low abundance cyclin A mRNA in most high grade squamous intraepithelial lesions induced by high risk HPV. In the inflammatory tissues, an ISH signal was sometimes detected in the basal cells. As for proliferating cell nuclear antigen (PCNA), these results observed in vivo reveal that viral oncoproteins are able to reactivate cellular DNA replication machinery to support papillomavirus DNA replication in normally differentiated, non-cycling cells. The induction of cyclin A gene expression appears to correlate with the proliferative rather than the transforming properties of these cells.
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PMID:[Detection of cyclin A mRNA in intra-epithelial lesions of the anogenital tract induced by papillomavirus]. 764 62


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