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PubMedDate not supplied

Inhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonists.

This study was initiated to determine if potential PPAR gamma antagonists could block the inhibition of cell proliferation caused by 4-phenylbutyrate. The action of 4-phenylbutyrate differed from other PPAR gamma ligands examined in that it induces histone acetylation. Proliferation of DS19 mouse erythroleukemia cells was inhibited by PPAR gamma agonists (4-phenylbutyrate, rosiglitazone, ciglitazone and GW1929) and by potential PPAR gamma antagonists: BADGE (Biphenol A diglycidyl ether), GW9662, PD068235 and diclofenac. Combined incubations tended to exhibit additive inhibitory effects. Potential PPAR gamma agonists and antagonists inhibited the incorporation of thymidine into DNA of human prostate (PC3), colon (Caco-2) and breast (T47D) cancer cells but also affected NIH3T3 cells that have little or no expression of PPAR gamma. Lipid accumulation in T47D cells was seen after incubation with 4-phenylbutyrate and both potential PPAR gamma agonists and antagonists. The extent to which the effects of 4-phenylbutyrate on cell proliferation are mediated through PPAR gamma or induction of histone acetylation remains an open question. We conclude that potential PPAR gamma antagonists may fail to reverse the growth inhibitory effect of PPAR gamma ligands and may themselves act as growth inhibitory agents.

Acetylation↗

PubMed1995

Comparison of proliferating cell nuclear antigen versus the more standard measures of rectal mucosal proliferation rates in subjects with a history of colorectal cancer and normal age-matched controls.

Measurement of proliferation rates by the more standard in vitro uptake techniques of [3H]thymidine and 5'-bromo-2'-deoxyuridine (BrdUrd) labeling indices (LIs) were compared to proliferating cell nuclear antigen (PCNA) in rectal mucosal biopsies from 16 subjects with resected colorectal cancer and 14 normal age-matched controls. Correlation coefficients for BrdUrd versus PCNA, [3H]thymidine versus PCNA, and BrdUrd versus [3H]thymidine were 0.691, 0.876, and 0.770, respectively. No significant differences (P > 0.05) were detected in total mean LIs between the LI methods for the normal group. In contrast, total PCNA LIs were found to be significantly different in the resected cancer patients when compared to either BrdUrd (P = 0.005) or [3H]thymidine (P < 0.001). A significant difference (P = 0.010) in total PCNA LI but not in total [3H]thymidine or BrdUrd LIs was also observed between normal controls and resected colorectal cancer subjects. Compartmental analysis of the cancer group versus the normals showed a significant difference in compartments 1 and 3 for PCNA LIs only. The reproducibility of two PCNA LI counts was excellent (r = 0.9). In addition, the reliability of mean LIs were > 0.8 with the exception of [3H]thymidine in the normal group (0.7). These study results demonstrate that PCNA LIs in human rectal mucosal biopsies are correlated highly with other more commonly used cellular proliferation measurements; however, PCNA LIs were found to be significantly higher than the other two methods in the resected colorectal cancer subjects.

Adult↗

PubMed1994

Expression of proliferating cell nuclear antigen in the mouse germ line and surrounding somatic cells suggests both proliferation-dependent and -independent modes of function.

The distribution of proliferating cell nuclear antigen (PCNA) in specific somatic and germ cells of the adult mouse ovary and testis was assessed using immunocytochemical staining and immunoblot analysis and was correlated with cellular proliferation and differentiation. In the adult ovary, immunocytochemical staining for PCNA within follicular cells varied depending on the stage of follicular growth. Since PCNA staining has proven to be a useful indicator of cells involved in DNA synthesis and repair, the pattern of PCNA staining in the ovary was compared to previous studies which used tritiated thymidine labeling as a marker for DNA synthesis. In the testis, PCNA was detected in the mitotically proliferating spermatogonia, but not in spermatocytes which had just entered meiosis. PCNA staining was again observed in spermatogenic cells in later stages of meiotic prophase, in particular zygotene and pachytene spermatocytes. As these cells are undergoing meiotic recombination, the presence of PCNA in these meiotic prophase cells could reflect a second function of PCNA, that of DNA excision repair.

Animals↗

PubMed1994

Analysis of relative proliferation rates of Wilms' tumor components using proliferating cell nuclear antigen and MIB-1 (Ki-67 equivalent antigen) immunostaining and assessment of mitotic index.

BACKGROUND: Flow-cytometric analysis of proliferation index (PI) has potential use in predicting prognosis in malignancy. Its relevance to heterogeneous tumors has not been conclusively studied. In nephroblastoma, where the epithelial components are considered more differentiated than others, potentially different PIs may exist within a single lesion based on the inverse relation between differentiation and proliferation. Proliferating cell nuclear antigen (PCNA) and MIB-1 (Ki-67 equivalent antigen) demonstration in histologic sections by immunoperoxidase methods may allow for determination of PI in relation to tissue type. EXPERIMENTAL DESIGN: A consecutive unselected series of 8 pediatric nephroblastoma patients was used to study the relation between PI and histologic differentiation as established by flow-cytometric analysis of nuclear suspensions prepared from formalin-fixed and paraffin-embedded tissue and by PCNA/MIB1 staining of parallel histologic sections. PI by PCNA/MIB1 was established using 5-microns paraffin sections, immunoperoxidase, and quantification procedures detailed in the literature. The mitotic index (MI) of tissue components was separately assessed using 5-microns hematoxylin and eosin-stained sections and counting procedures detailed in the literature. RESULTS: The 8 lesions showed a PI of 4 to 20% as determined by flow cytometry. Using PCNA staining, the epithelium showed a mean PI of 55.5% (range 40 to 80%), that was significantly higher (p < 0.001, Wilcoxon's two-tailed rank sum test) than blastema (mean PI: 34.1%, range 17.5 to 76.5%) and stroma (mean PI of 14.9%, range 5 to 24%, p < 0.001, Wilcoxon's two-tailed rank sum test). Although, probably due to tissue antigen preservation, acceptable MIB-1 staining was not achieved in all lesions (5 of 8), the results, although generally with lower labeling indices, confirmed the PCNA findings. The relative MI of epithelial components was higher than that of stroma and blastema in keeping with the immunocytochemical findings. In 6 of 8 cases, the PI by flow-cytometric analysis was lower than the lowest value for the PI (labeling index) of an individual tissue type found by PCNA or MIB staining. CONCLUSIONS: The differences found between PI of the different tissue components in nephroblastoma are difficult to understand if the epithelial components (with the highest PI values) are considered as differentiation products from the other components of the lesion. The relation between PIs as determined by PCNA/MIB-1 analysis/mitotic index, for the three components and the PI as established by flow cytometry is not simply explained by the relative volume of the tissue components.

Cell Division↗

PubMed1995

Correlations of morphology, proliferation indices, and oncogene activation in ductal breast carcinoma: nuclear grade, S-phase, proliferating cell nuclear antigen, p53, epidermal growth factor receptor, and c-erb-B-2.

The proliferative capacity of breast carcinomas has prognostic significance as measured by S-phase fraction (SPF), yet the molecular parameters that influence the proliferative capacity of breast carcinomas have not been fully elucidated. Ninety-three cases of invasive ductal breast carcinomas, not otherwise specified, were studied by immunohistochemistry and flow cytometry to determine what correlations exist between nuclear grade (NG), SPF, proliferating cell nuclear antigen and the overexpression of p53, epidermal growth factor receptor (EGFR), and c-erb-B-2 in formalin-fixed tissues by the immunoperoxidase method. NG predicted elevated SPF in 78% of cases and was associated with high proliferating cell nuclear antigen score. The presence of p53 was detectable in 13% of cases, and, in each case, the NG was high (Grade 3), with nine aneuploid tumors and three diploid tumors. The SPFs for all p53-positive cases were markedly elevated, with 77.8% of the cases with SPF > 15%. EGFR was present in 20.4% of all tumors, including 77.8% of tumors positive for p53 and 14% of tumors negative for p53 (P < .001). The mean SPF for p53-positive EGFR-positive tumors was 17.5% versus 21.1% for p53-positive EGFR-negative tumors. The mean SPF for p53-negative tumors was significantly less, regardless of the presence of EGFR. The gene c-erb-B-2 was found in 28% of tumors, all of which were p53 negative. These data clearly show a close relationship between high NG and elevated SPF. As determined by flow cytometry, SPF is more consistent and more reliably related to NG than proliferating cell nuclear antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1995

Proliferation indices of vestibular schwannomas by Ki-67 and proliferating cell nuclear antigen.

Two immunohistologic demonstrations of markers of proliferating cells, Ki-67 and proliferating cell nuclear antigen, were applied to tissues from 10 vestibular schwannomas. Each method demonstrated three distinct rates of positively stained cells (p < .01 and p < .015, respectively, for each method). There was a one-to-one correspondence between the two immunohistologic methods in the assignment of cases to each growth rate category except for two cases (Spearman rank correlation r = 0.76, p < .05). These data support the concept of distinct growth rates in vestibular schwannoma. Tissues were also sampled from different areas of the same tumor within nine samples. The results suggest that tumor growth is not homogeneous within a tumor, but that proliferation may be more active near the surface.

Adult↗

PubMed1998

An evaluation of rectal mucosal proliferation measure variability sources in the polyp prevention trial: can we detect informative differences among individuals' proliferation measures amid the noise?

We assessed components of total variability of bromodeoxyuridine (BrdUrd) and proliferating cell nuclear antigen (PCNA) assays of rectal mucosal proliferation in a subset of 390 participants from the U. S. National Cancer Institute's multicenter Polyp Prevention Trial. Biopsies were blindly double-scored by two technicians. For those participants for whom at least one evaluable biopsy was obtained, a mean of 2.0 and 2.6 biopsies, and 6.2 and 8.7 crypts/biopsy were evaluated, respectively, with the BrdUrd and PCNA assays. Factors such as clinical center, scorer, and month of biopsy collection significantly affected the observed values of the labeling index (LI) and proliferative height (PH). Therefore, it is essential to control or adjust for these variables in proliferation studies. Sources of random variation for LI and PH measures remaining after the aforementioned factors include between-participant variation and several sources of within-participant variation, including variation over time, between biopsies, and between multiple measurements on the same biopsy. Both LI and PH measurements exhibited substantial variability over time, between biopsies, and from reading-to-reading of the same biopsy. When other sources of variability have been accounted for, the PCNA LI seems to have little between-participant variation. This brings into question its utility as a marker in colorectal cancer studies. The PCNA PH showed significant between-participant variability and may hold some promise as a useful marker in colorectal cancer studies. Results for BrdUrd were less conclusive. The BrdUrd LI showed marginally significant between-participant variation, whereas the corresponding variation for PH was nonsignificant.

Adult↗

PubMed1991

Variations in the occurrence of silver-staining nucleolar organizer regions (AgNORs) in non-proliferating and proliferating tissues.

Previous studies on the subject of silver-staining nucleolar organizer regions (AgNORs) as indicators of precise proliferative status of tissues have sometimes resulted in ambiguity. The studies, however, have most frequently addressed themselves to the prognosis of neoplasias, with the aim of using AgNORs principally to distinguish between benign and malignant tumours. This investigation was to determine a base-line relationship of AgNOR clusters to proliferation and thus concentrated on normally proliferative tissues and conditionally renewing tissues after appropriate stimulation. Two murine transplantable tumours were also examined as examples of frank malignancy. As an example of the former, variations in AgNOR clusters were noted in the small intestine of man, mouse, and rat. The conditionally renewing systems of liver, prostate, and salivary glands were stimulated into proliferation by two-thirds partial hepatectomy, castration followed by treatment with testosterone, and isoproterenol treatment, respectively, in rat models; the murine sarcoma SaF and carcinoma CaNT provided relatively simple malignant tumours for AgNOR investigation. Proliferation was monitored by noting labelling indices after injection with bromodeoxyuridine (BrdUrd) in vivo followed by immunocytochemical visualization of S-phase cells. In all tissues, an increase in the size of AgNOR clusters rather than their number correlated positively with elevated labelling, particularly with the emergence of silver-staining regions of 2-3 microns visible diameter. Thus, increased AgNOR cluster size (diameter) as representative of AgNOR cluster/nucleolus volume was found to be dependent on proliferative activity in a range of normal and neoplastic tissues.

Animals↗

PubMed1993

Studies of the relationship between cell proliferation and cell death. III. AP-1 DNA-binding activity during concanavalin A-induced proliferation or dexamethasone-induced apoptosis of rat thymocytes.

In previous papers we started to investigate the possible relationship existing between cell proliferation and cell death. We reported that in rat thymocytes, undergoing cell proliferation upon stimulation with Concanavalin A or cell death following dexamethasone treatment, an induction of c-fos and c-jun occurs with different but partially overlapping kinetics (Grassilli et al., BBRC, 1992, 188, 1261-1266). To test the hypothesis that, in both processes, the early induction of these nuclear oncogenes is necessary to allow the induction of later-expressed genes regulated at the transcriptional level by AP-1 complex, AP-1 DNA-binding activity was investigated in the aforementioned model. Indeed, we found that AP-1 is activated not only in proliferating but also in apoptotic cells, with a kinetics in accord with our data about c-fos and c-jun mRNA accumulation in the same experimental model. Moreover, our findings suggest that an interaction between AP-1 and glucocorticoid receptor also occurs in our model of dexamethasone-mediated apoptosis.

Animals↗

PubMed1995

Expression and biological activities of bovine interleukin 4: effects of recombinant bovine interleukin 4 on T cell proliferation and B cell differentiation and proliferation in vitro.

Interleukin 4 (IL-4) is a pleotropic cytokine affecting a wide range of cell types in both the mouse and the human. These activities include regulation of the growth and differentiation of both T and B lymphocytes. The activities of IL-4 in nonprimate, nonmurine systems are not well established. Herein, we demonstrate in the bovine system that IL-4 upregulates production of IgM, IgG1, and IgE in the presence of a variety of costimulators including anti-IgM, Staphylococcus aureus cowan strain I, and pokeweed mitogen. IgE responses are potentiated by the addition of IL-2 to IL-4. Culture of bovine B lymphocytes with IL-4 in the absence of additional costimulators resulted in the increased surface expression of CD23 (low-affinity Fc epsilon RII), IgM, IL-2R, and MHC class II in a dose-dependent manner. IL-4 alone increased basal levels of proliferation of bulk peripheral blood mononuclear cells but in the presence of Con A inhibited proliferation. In contrast to the activities of IL-4 in the murine system, proliferation of TH1- and TH2-like clones was inhibited in a dose-dependent manner as assessed by antigen-or IL-2-driven in vitro proliferative responses. These observations are consistent with the role of IL-4 as a key player in regulation of both T and B cell responses.

Animals↗

PubMed1988

The intestinal diamine oxidase activity under the influence of adaptive proliferation of the intestinal mucosa--a proliferation terminating principle?

Under clinical conditions, intestinal mucosal hyperproliferation together with a reduced diamine oxidase (DAO) activity was found in inflammatory and neoplastic diseases. Therefore, we studied the influence on DAO activity of a regulated mucosal proliferation as obtained following partial small bowel resection in a rat model. A statistically significant, more than 4-fold elevation of the enzymic activity was observed during the first days after partial resection. At the peak of mucosal proliferation (8th. postoperative day) the DAO activity was significantly reduced by about 50% of the initial value. We suggest that the DAO may be involved in a negative feed-back control mechanism of mucosal proliferation.

Adaptation, Physiological↗

PubMedDate not supplied

CYP4A1 gene transfection studies and the peroxisome proliferator-activated receptor: development of a high-throughput assay to detect peroxisome proliferators.

An in vitro reporter gene assay has been established to examine cytochrome P4504A1 (CYP4A1) induction. A response element from the upstream region of the rat CYP4A1 gene containing a peroxisome proliferator response element (PPRE) has been linked to the chloramphenicol acetyl-transferase (CAT) gene in a reporter vector (1). This CYP4A1 reporter construct has been co-transfected into human HepG2 cells in the presence and absence of expression vectors encoding the transcription factors PPAR alpha and RXR alpha. The assay employs calcium phosphate-DNA co-precipitate mediated transfection. Reporter gene products have been quantitated using chemiluminescent based assays. We have shown that, in the presence of PPAR alpha, the above CYP4A1 construct is transcriptionally activated by a range of structurally different peroxisome proliferators including Wy-14,643, ciprofibrate, clofibric acid and nafenopin. Our future efforts will focus on the establishment of a high-throughput assay for the detection of peroxisome proliferators. Such an assay would provide an invaluable in vitro test for the screening of developmental drug candidates prior to in vivo studies.

Animals↗

PubMed1986

Colorimetric B cell proliferation assay based on alkaline phosphatase activity. Selective measurement of B cell proliferation in the presence of other cell types.

In this study we show that a rapid colorimetric determination of alkaline phosphatase (APase) activity can be used in conjunction with a multiwell scanning photometer to quantitatively measure lymphokine-dependent B cell proliferation. Despite the fact that only activated but not resting B cells exhibit APase activity, i.e., that APase expression in B cells is variable, the results obtained by monitoring the enzyme activity were very similar to those obtained by measuring thymidine incorporation in two murine B cell systems. With regard to a potential application to the screening of the effects of hybridoma supernatants on B cells, it is relevant that HAT medium has practically no influence on the colorimetric B cell proliferation assay. Another advantage of the method is that since T cells and macrophages lack APase activity, one can detect the proliferation of B cells even in the presence of a high number of such cells, for example, in studying a T cell-dependent response.

Alkaline Phosphatase↗

PubMed1992

Repair of DNA damage induced by oxygen radicals in human non-proliferating and proliferating lymphocytes.

Repair of DNA lesions induced by oxygen radicals, generated by xanthine/xanthine oxidase (X/XO), was studied in human peripheral blood lymphocytes and in PHA-stimulated proliferating lymphocytes from 4 healthy subjects. The lesions included DNA-strand breaks (SSB) and other lesions that are converted to SSB under alkaline conditions. The frequencies of SSB were estimated by fluorometric analysis of DNA unwinding. Maximum production of SSB occurred within 10 min of incubation with X/XO at 22 degrees C; with 0.5 mM or higher concentrations of xanthine; and with 0.1-0.5 units/ml of xanthine oxidase. Proliferating lymphocytes repaired X/XO-induced SSB about 4 times more rapidly than lymphocytes. Lymphocytes repaired X/XO-induced SSB more slowly than SSB caused by gamma-radiation. These findings are consistent with the evidence that a number of DNA-repair enzymes have greater activity in proliferating cells than in resting cells. These findings also support the view that there are differences between the DNA damage due to oxygen radicals and that due to ionizing radiation.

DNA↗

PubMed2003

Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands as bifunctional regulators of cell proliferation.

Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the ligand-activated nuclear receptor superfamily, plays a key role in mediating differentiation of adipocytes and regulating fat metabolism. PPARgamma has been implicated in the pathophysiology of atherosclerosis, inflammation, obesity, diabetes, immune response, and ageing. Recently, it has been shown that activation of PPARgamma by J(2) series cyclopentenone prostaglandins (cyPGs), especially 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or synthetic agents, such as antidiabetic thiazolidinediones, causes anti-proliferation, apoptosis, differentiation, and anti-inflammation of certain types of cancer cells. The anti-proliferative effects of PPARgamma activators are associated with de novo synthesis of proteins involved in regulating the cell cycle and cell survival/death. Anti-inflammatory effects of 15d-PGJ(2) are associated with interruption of nuclear factor-kappaB and subsequent blockade of inflammatory gene expression. Furthermore, 15d-PGJ(2) at nontoxic doses induce expression of phase II detoxification or stress-responding enzymes, which may confer cellular resistance or adaptation to oxidative stress. The presence of a reactive alpha,beta-unsaturated carbonyl moiety in the cyclopentenone ring of 15d-PGJ(2) is important for part of biological functions this cyPG has. Recently, attention has been focused on the anti-proliferative activity of nonsteroidal anti-inflammatory drugs (NSAIDs) in cancerous or transformed cells, which is mediated through interaction with PPARgamma irrespective of their ability to inhibit COX-2. Despite the fact that abnormally elevated COX-2 is associated with resistance to cell death, induction of apoptosis by certain NSAIDs is accompanied by up-regulation of COX-2 expression. This commentary focuses on dual effects of the typical PPARgamma agonist 15d-PGJ(2) on cell proliferation and growth, and its possible involvement in the NSAID-induced COX-2 expression and apoptosis.

Animals↗

PubMed2000

Peroxisome proliferator-activated receptor (PPAR)-gamma expression in human vascular smooth muscle cells: inhibition of growth, migration, and c-fos expression by the peroxisome proliferator-activated receptor (PPAR)-gamma activator troglitazone.

This study was conducted to determine whether cultured human coronary artery and aorta vascular smooth muscle (VSM) cells express the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma); whether the thiazolidinedione troglitazone, a ligand for PPARgamma, would inhibit c-fos expression by these cells; and whether troglitazone would inhibit proliferation and migration induced in these cells by mitogenic growth factors. Using immunoblotting and reverse-transcriptase polymerase chain reaction (RT-PCR) techniques, we show that both human aorta and coronary artery VSM cell lines expressed PPARgamma protein and mRNA for both PPARgamma isoforms, PPARgamma1 and PPARgamma2. Immunocytochemical staining localized the PPARgamma protein primarily within the nucleus. Troglitazone inhibited basic fibroblast growth factor and platelet-derived growth factor-BB induced DNA synthesis in a dose-dependent manner and downregulated the growth-factor-induced expression of c-fos. Troglitazone also inhibited the migration of coronary artery VSM cells along a platelet-derived growth factor-BB concentration gradient. These findings demonstrate for the first time the expression and nuclear localization of PPARgamma in human coronary artery and aorta VSM cells. The data also suggest that the downregulation of c-fos expression, growth-factor-induced proliferation, and migration by VSM may, in part, be mediated by activation of the PPARgamma receptor.

Blotting, Northern↗

PubMed1978

Responses of proliferating and non-proliferating Chinese hamster cells to cytotoxic agents.

The effects of various cytotoxic chemicals, as measured by viable cell counts, colony-forming ability and proliferative capacity, have been studied using Chinese hamster cells in exponential and plateau (stationary) phases of growth. The proliferating cells were altogether more sensitive to the action of the drugs than non-proliferating cells. However, imuran (azathioprine) a purine antimetabolite, was more effective against the plateau-phase cells. The observed response of cells to imuran could be detected at a wide range of concentrations (1-100 microgram/ml). These findings are discussed in view of the possible ability of imuran to interfere with active metabolic processes in non-proliferating cells.

Antineoplastic Agents↗

PubMed2000

Captopril inhibits in vitro and in vivo the proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation.

Angiotensin I-converting enzyme (ACE) has been shown to be involved in the catabolism of the tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP). As AcSDKP is a physiological inhibitor of haematopoietic stem cell proliferation, we investigated the in vitro and in vivo effects of captopril, one of the specific inhibitors of ACE, on the proliferation of primitive haematopoietic cells. Regenerating bone marrow cells obtained from mice given one injection of cytosine arabinoside (100 mg/kg) as well as SA2 myeloid leukaemia cells were incubated in vitro for 24 h with 10-6 M captopril. Captopril significantly reduced the proportion of high proliferative potential colony-forming cells (HPP-CFC-1) in S-phase, whereas it had no effect on the proportion of SA2 leukaemic colony-forming cells in S-phase. When given in vivo to mice 1 h after 2 Gy gamma-irradiation or cytosine arabinoside (AraC) injection, captopril (100 mg/kg) was shown to prevent HPP-CFC-1 entry into S-phase induced by these cytotoxic treatments. The observed effects correlated with a reduction in ACE degradative activity and an increase in the level of endogenous AcSDKP both in the supernatants of captopril-treated bone marrow cells and in plasma of treated animals. The present findings suggest that AcSDKP might mediate the observed in vitro and in vivo inhibitory effects of captopril on primitive haematopoietic cell proliferation.

Angiotensin-Converting Enzyme Inhibitors↗