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This report focuses on the use of freshly isolated primary mammalian cells from different tissues and organs of the rat for the rapid and efficient analysis of toxic and genotoxic chemicals. The cells are either treated in vitro or they are isolated from treated animals. Viability by trypan blue exclusion and DNA damage as single-strand breaks are monitored in either case. Therefore, it is possible to compare in vitro and in vivo results directly. N-nitrosamines with unique organ-specific modes in carcinogenesis were studied in vitro using hepatocytes derived from three species (rat, hamster, and pig) and in rat lung and kidney cells. The sensitive detection of all carcinogenic nitrosamines was achieved, although a pattern of cell-specific activation was not observable. The new modification of the in vivo approach allowed the sensitive detection of NDMA genotoxicity in hepatic and in extrahepatic tissues. It is important to point out that the method is an efficient tool for toxicokinetic studies with genotoxic carcinogens in vivo.
Environ Mol Mutagen 1990
PMID:Employment of adult mammalian primary cells in toxicology: in vivo and in vitro genotoxic effects of environmentally significant N-nitrosodialkylamines in cells of the liver, lung, and kidney. 229 98

The ACI rat constitutes a unique model for human prostatic carcinogenesis. A high percentage of these animals spontaneously develop prostatic carcinomas in the ventral lobe as they age. The light microscopic appearance of these tumors is similar to the cribriform pattern of adenocarcinoma in human prostate. In order to further characterize this useful model, we carried out light and electron microscopy studies of the morphology of carcinomatous lesions developing in these animals. Sixteen rats ranging in age from 25 to 43 months were examined histologically, and ultrastructural studies were performed on eight of these cases. The neoplastic cells showed features of well-developed secretory epithelium including prominent Golgi apparatus, abundant rough endoplasmic reticulum, and numerous secretory vacuoles. Microvilli were numerous in some cells and focal apocrine secretory activity was present. Intraluminal crystals similar to those associated with human prostate carcinoma were observed in one of our cases. Prostate carcinomas developing in the ACI rat share many of the ultrastructural features of human prostatic carcinoma.
Exp Mol Pathol 1990 Apr
PMID:Morphologic characterization of early prostatic carcinomas in the ACI rat: a light and electron microscopic study. 233 37

Melanins, pigments of photoprotection and camouflage, are very photoreactive and can both absorb and emit active oxygen species. Nevertheless, black skinned individuals rarely develop skin cancer and melanin is assumed to act as a solar screen. Since DNA is the target for solar carcinogenesis, the effect of melanin on Ultraviolet (UV)-induced thymine lesions was examined in mouse melanoma and carcinoma cells that varied in melanin content. Cells prelabeled with 14C-dThd were irradiated with UVC; DNA was isolated, purified, degraded to bases by acid hydrolysis and analyzed by HPLC. Thymine dimers were detected in all of the extracts of irradiated cells. Melanotic and hypomelanotic but not mammary carcinoma cell DNA from irradiated cells contained hydrophilic thymine derivatives. The quantity of these damaged bases was a function of both the UVC dose and the cellular melanin content. One such derivative was identified by gas chromatography-mass spectroscopy as thymine glycol. The other appears to be derived from thymine glycol by further oxidation during acid hydrolysis of the DNA. The finding of oxidative DNA damage in melanin-containing cells suggests that melanin may be implicated in the etiology of caucasian skin cancer, particularly melanoma. Furthermore, the projected decrease in stratospheric ozone could impact in an unanticipated deleterious manner on dark-skinned individuals.
Environ Mol Mutagen 1990
PMID:Melanin photosensitizes ultraviolet light (UVC) DNA damage in pigmented cells. 237 74

C3H 10T1/2 mouse embryo fibroblasts were exposed to 3 microM 5-azacytidine for 24 h and then serially passaged in the absence of 5-azacytidine and examined for subsequent changes in growth properties. The treated cells showed changes in morphology, saturation density, growth rate, and serum dependence. By the 5th passage they acquired the ability to grow in 0.3% agarose, and by the 30th passage they gave rise to fully transformed foci that grew in agarose, in agar, and in liquid suspension. This progression was rapidly accelerated if the cultures derived from 5-azacytidine-treated cells were exposed for 48 h to the carcinogen benzo[a]pyrene. Results of these studies provide evidence that aberrations in DNA methylation may be one of a series of critical events during the course of multistage carcinogenesis and thus enhance the evolution of tumor cells.
Mol Cell Biol 1985 Jul
PMID:Effects of 5-azacytidine on the progressive nature of cell transformation. 241 Jul 74

A number of closely related post-transcriptional facets of RNA metabolism show nuclear compartmentation, including capping, methylation, splicing reactions, and packaging in ribonucleoprotein particles (RNP). These nuclear 'processing' events are followed by the translocation of the finished product across the nuclear envelope. Due to the inherent complexity of these interrelated events, in vitro systems have been designed to examine the processes separately, particularly so with regard to translocation. A few studies have utilized nuclear transplantation/microinjection techniques and specialized systems to show that RNA transport occurs as a regulated phenomenon. While isolated nuclei swell in aqueous media and dramatic loss of nuclear protein is associated with this swelling, loss of RNA is not substantial, and most studies on RNA translocation have employed isolated nuclei. The quantity of RNA transported from isolated nuclei is related to hydrolysis of high-energy phosphate bonds in nucleotide additives. The RNA is released predominantly in RNP: messenger-like RNA is released in RNP which have buoyant density and polypeptide composition similar to cytoplasmic messenger RNP, but which have distinctly different composition from those in heterogeneous nuclear RNP. Mature 18 and 28S ribosomal RNA is released in 40 and 60S RNP which represent mature ribosomal subunits. RNA transport proceeds with characteristics of an energy-requiring process, and proceeds independently of the presence or state of fluidity of nuclear membranes. The energy for transport appears to be utilized by a nucleoside triphosphatase (NTPase) which is distributed mainly within heterochromatin at the peripheral lamina. Photoaffinity labeling has identified the pertinent NTPase as a 46 kD polypeptide which is associated with nuclear envelope and matrix preparations. The NTPase does not appear to be modulated via direct phosphorylation or to reflect kinase-phosphatase activities. A large number of additives (including RNA and insulin) produce parallel effects upon RNA transport and nuclear envelope NTPase, strengthening the correlative relationship between these activities. Of particular interest has been the finding that carcinogens induce specific, long-lasting increases in nuclear envelope (and matrix) NTPase; this derangement may underlie the alterations in RNA transport associated with cancer and carcinogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Cell Biochem 1985 Jul
PMID:Nucleocytoplasmic RNA transport. 241 44

The hamster cheek pouch is an excellent target tissue for the experimental study of oral carcinogenesis. In the course of searching for molecular alterations during the malignant transformation process, the necessity for a molecular marker for cellular proliferation became apparent. In this report, we show that the cellular level of the histone H3 mRNA is valid as a molecular index of proliferation for cycling cell populations. H3 is known to be proliferation dependent for its expression in cultured animal cells. This study shows that H3 retains its cell-cycle-dependent expression in chemically transformed oral keratinocytes. The onset of H3 mRNA synthesis couples to the onset of DNA synthesis (S-phase). The cellular level of H3 mRNA therefore is proportional to the fraction of cells in the S-phase of the cell cycle. This conveniently allows us to correlate, in asynchronized cell populations, the expression of cellular genes to their proliferation rates. We demonstrate the usefulness of this proliferation marker by presenting data that different chemically induced oral carcinomas, but not normal cheek pouch tissues, contain readily detectable levels of c-Ki-ras proto-oncogene mRNA. Probing the same RNA blot to quantitate H3 mRNA levels allowed us to conclude that the high levels of c-Ki-ras mRNA in tumor tissues was likely due to the increased growth rate of the tumor tissues and not due to the deregulated expression of this cellular-proto-oncogene.
Exp Mol Pathol 1988 Oct
PMID:Histone gene (H3) expression in chemically transformed oral keratinocytes. 245 60

The nature and significance of so-called dark keratinocytes in the epidermis during chemical carcinogenesis is still a matter of concern and debate. Based on ultrastructural observations it has been suggested that dark cells most often are shrunken cells. Reports on skin carcinogenesis, however, claim that dark cells are a sign of ongoing tumor promotion and represent those stem cells in the epidermis from which the tumors originate. It is therefore important to find out whether these cells are simply injured and shrunken cells, or vital cells of great importance for carcinogenesis. Dark cells are assumed to be rich in ribosomes. There is evidence, however, that the observed number of dark cells is highly dependent on tissue fixation. In the present ultrastructural study, morphometric methods were used to compare the effects of two different fixation procedures on the amount of cytoplasmic ribosomes in dark cells from both untreated and carcinogen-treated hairless mouse epidermis. The results show that the ultrastructural features of both dark and clear cells vary considerably with different fixation procedures. In acetone-treated controls typical dark cells are only observed when the fixative has a lower osmotic activity than the plasma. With iso-osmolal fixation typical dark cells are not observed. After an abortive two-stage carcinogenesis treatment, in which a single application of 9,10-dimethyl-1,2-benzanthracene (DMBA) in acetone was followed by a single application of 12-O-tetradecanoyl-13-acetate (TPA) in acetone, signs of cell injury could be found after both fixation procedures. With DMBA/TPA and hypo-osmolal fixation the number of dark cells seemed to increase, whereas only signs of cell injury with occurrence of some heavily altered "clear cells" dominated the picture with iso-osmolal fixation. Morphometry showed that both the numerical and the volumetric densities of cytoplasmic ribosomes in basal keratinocytes varied most significantly with the fixation procedure used. The cytoplasmic volumes did not vary in a way that could explain these differences. One might therefore assume that the number of ribosomes depends on the fixative. Large swelling artifacts occurred when a fixative with low osmotic activity was used, leading to compression of neighboring cells. Hence, an increased ribosomal density reported previously in dark cells is probably related to such cell volume artifacts and does not reflect an actually increased quantity of ribosomes.(ABSTRACT TRUNCATED AT 400 WORDS)
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:The influence of fixation on the relative amount of cytoplasmic ribosomes in mouse epidermal basal keratinocytes. A morphometric study of so-called "dark cells" and their putative role in epidermal carcinogenesis. 246 50

We recently developed rat fibroblast cell lines that stably overproduce high levels of the beta 1 form of protein kinase C (PKC). These cells display several disorders in growth control and form small microscopic colonies in agar. In the present study we demonstrate that one of these cell lines, R6-PKC3, is extremely susceptible to transformation by an activated human bladder cancer c-H-ras oncogene (T24). Compared with control cell line R6-C1, T24-transfected R6-PKC3 cells yielded a 10-fold increase in the formation of large colonies in agar. Cell lines established from these colonies displayed a highly transformed morphology, expressed the T24-encoded p21 ras protein, continued to express high levels of PKC, and were highly tumorigenic in nude mice. These results provide genetic evidence that PKC mediates some of the effects of the c-H-ras oncogene on cell transformation. Data are also presented suggesting that optimum synergistic effects between c-H-ras and PKC require critical levels of their respective activities. These findings may be relevant to the process of multistage carcinogenesis in tissues containing cells with an activated c-H-ras oncogene.
Mol Cell Biol 1989 Jun
PMID:Cells that overproduce protein kinase C are more susceptible to transformation by an activated H-ras oncogene. 247 57

Expression of four oncogenes and two keratin genes was determined in rat tracheal epithelial cell lines derived from tracheal implants exposed in vivo to 7,12-dimethylbenz[a]anthracene. Cell lines were grouped into four stages of neoplastic progression based on phenotypic markers in order to correlate oncogene expression with stage of malignancy. Northern analysis of RNA revealed a significantly enhanced expression of the c-myc oncogene in the most tumorigenic or tumor-derived cell lines, whereas preneoplastic cells expressed approximately five-fold less transcript. Southern analysis of tracheal cell DNA did not demonstrate amplification of the c-myc gene in any of the positive cell lines. In contrast to c-myc, other oncogenes such as ras and fos were expressed in all cell lines, as well as in control cell cultures, to a similar extent. Patterns of differentiation were examined in these epithelial cell lines by determining the expression of two distinct keratin genes, KA-1 and KB-2. Both malignant and preneoplastic cells expressed the KB-2 gene at variably high levels, whereas the expression of the KA-1 keratin was barely detectable in any of the cell lines. The stage-specific expression of the c-myc oncogene in these tracheal cell lines suggests a correlation between the regulation of certain oncogenes and neoplastic progression in this model of respiratory carcinogenesis.
Mol Carcinog 1989
PMID:Oncogene expression in cell lines derived from rat tracheal implants exposed in vivo to 7,12-dimethylbenz[a]anthracene. 248 55

Recent years of cancer research have defined the role of key regulatory genes in oncogenesis. Oncogenes and suppressor genes are affected in the process of carcinogenesis either by mutations within the coding region, promoter mutations, or gene amplification. This review describes our studies on gene amplification in mammalian cells, with emphasis on the initiating events induced by carcinogenic chemicals and various types of radiation. The influence of genomic instability, cell dedifferentiation, and the malignant potential of a cell on their capacity to amplify genes is demonstrated by molecular biologic and cytogenetic studies on human and rodent cells. Cells that contain amplified DNA are at risk for chromosomal aberrations, sister chromatid exchanges, and rearrangements. Surviving cells show such cancer-prone genetic consequences.
Mol Toxicol
PMID:Review: gene amplification--a cellular response to genotoxic stress. 249 Sep 79


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