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Biomedical subjects

J A Kellen

Publications and source records attributed to J A Kellen.

At least 19 recordsLinked to original sources
PubMed2001

Raloxifene.

Efforts to interfere with the initiation and promotion of breast and other cancers by endocrine manipulation are not new. It is of obvious benefit to cancer patients to administer substances that combine minimal general toxicity with maximal oestrogen inhibition. Raloxifene is a relatively recent addition to a group of compounds loosely designated as antioestrogens, which implies their ability to antagonize oestrogen effects via competitive binding to the various receptors. This is a reductionist simplification, since their effect varies and ranges from interaction with lipid transduction cascades, covalent binding to proteins and DNA, regulation of growth factors, erbB2, mdr1 and probably p53 expression, complexing with E-cadherin/catenin to active induction of apoptosis and many other effects on the genome. Also, the action of most antioestrogens is not solely antagonistic and different compounds do exert some agonistic effects in various tissues. Apart from some "pure" antioestrogens, the benzothiophene derivative Raloxifene has been found to combine a high degree of selective oestrogen suppression with several other desirable characteristics, such as reduction of bone demineralisation and antiatherogenic effects without endometrial stimulation. It is well tolerated, has been successfully tested as a chemopreventive agent for breast cancer in certain groups of the population and does not prevent ovulation in women with normal menstrual cycles. Certainly, Raloxifene is only another forerunner of upcoming "designer" oestrogen modulators, but it represents a welcome addition to the therapeutic choices available for the control of some menopausal problems as well as for the prevention and treatment of breast cancer, as outlined in the following brief review.

Breast Neoplasms↗
PubMed1994

Prevalence of serum antibodies against the p53 tumor suppressor gene protein in various cancers.

We have developed 2 new quantitative methods for measuring anti-p53 antibodies in human serum. Using these methods we analyzed 1,392 sera from patients with various malignancies and 230 sera from individuals without malignancy. Highest prevalence of anti-p53 antibodies was associated with ovarian and colon cancers (15%), followed by lung (8%) and breast (5%) cancers. Prevalence in other malignancies was lower (< 4%). In hospitalized patients and apparently healthy individuals, prevalence was very low (< 2 and 1% respectively). Extremely high antibody concentrations (> 10(5) U/L) were found in 5 ovarian, 2 breast, 1 lung and 1 colon cancers. Sequential analysis of 6 positive samples has shown that the p53 antibody test may have potential for patient monitoring. The p53 antibody-positive sera from breast cancer patients were associated with tumors that were steroid hormone receptor-negative (p < 0.002). We propose that the measurement of p53 antibodies is a relatively specific serological test for cancer, which can be performed with easily automatable and quantitative methodologies and may be further exploited for patient monitoring, prognosis, diagnosis and probably screening for selected cancers.

Aged↗
PubMed1988

Characterization of different cell subpopulations derived from an experimental tumor model.

The R3230AC rat mammary adenocarcinoma is a transplantable tumor model, which can be subcultured in vitro and does not metastasize spontaneously. However, when cell suspensions of this tumor are injected intravenously, multiple lung foci develop. These foci were used as source for a cell subpopulation. Prolonged exposure of the original tumor cell line to increasing levels of lectins (concanavalin A and wheat germ agglutinin) resulted in the development of a lectin-resistant subpopulation. Through experimental in vitro exposure to the antiestrogenic compound tamoxifen citrate, a tolerant, karyotypically defined subpopulation was obtained. In the four cell lines studied, heterogeneity was observed in the following parameters: doubling time, steroid receptors, and median chromosome counts. Statistically discernible differences were found. This may represent a model for the effect of selective pressures in the tumor environment, such as endocrine manipulation, leading to the gradual development of resistant cell lines and treatment failure.

Adenocarcinoma↗
PubMed1988

Reversible myocardial damage in gerbil brain ischaemia and its prevention by beta-adrenergic blockade.

Acute cerebral infarction in gerbils, produced by unilateral carotid ligation, was used as a model to investigate secondary myocardial changes. The extent of the myocardial damage revealed by succinic dehydrogenase (SDH) histochemistry and by release of myocardial creatine phosphokinase (MB-CK) was measured in gerbils sacrificed from 3 to 48 h after either carotid ligation, carotid isolation only or skin incision only. For technical reasons dead animals were excluded from analysis. Of surviving ligated animals 74% developed neurological deficits related to brain ischaemia. A significant weight increase in the ipsilateral hemisphere was found at 6-10 h, and maximal histological damage at 16 h, both partially reversible thereafter. Non-ligated animals did not develop neurological changes, and showed neither brain swelling nor cerebral histopathology. Extensive cardiac damage was shown by the SDH method from 3 h postoperatively, and confirmed by the elevated serum levels of MB-CK in the carotid-ligated group. The SDH changes were identical with those described in the hearts of patients with acute intracranial lesions, and appeared to be reversible. The effect of beta-adrenergic blockade was assessed in this model. Metoprolol tartrate injected intraperitoneally 3 h before and 1 h after carotid ligation (10 mg/kg each dose) significantly decreased the extent of myocardial damage as estimated both with SDH histochemistry and MB-CK serum levels. It had no effect on the ischaemic brain changes. These results strongly support the concept of catecholamine mediation of myocardial injury resulting from acute brain lesions.

Animals↗
PubMed1988

Chorionic gonadotropin-induced cell proliferation and polyclonal immunoglobulin synthesis in human mononuclear cells.

Some fetal and placental proteins may play a role in stimulating normal and malignant cell proliferation. We studied the effect of human chorionic gonadotropin (hCG) on the proliferative response of mitogen or alloantigen-activated, human peripheral blood mononuclear cells (PBM). The effect of hCG on polyclonal immunoglobulin synthesis was determined in pokeweed mitogen-activated cultures of PBM. hCG had a statistically discernible, augmenting effect on thymidine uptake in lectin-stimulated mononuclear cell cultures. This effect appeared to be dose-dependent, with an optimal range at 50-150 ng/hCG/ml. Polyclonal IgG and IgM synthesis was also significantly increased, both in PWM-stimulated and PWM-free cultures of PBM. Parallel studies with a rapidly growing EB-virus transformed lymphoblastoid line showed no hCG effect. In contrast to previous reports on the immunosuppressive action of hCG, we conclude that hCG functions, in our experimental conditions, as a mitogen and a stimulator of polyclonal immunoglobulin synthesis.

Adult↗
PubMed1987

Expression of human choriogonadotropin-like material correlates with metastatic phenotype of R3230 AC rat adenocarcinoma.

Human choriogonadotropin (hCG)-like material has been found in variable amounts on the surface of cells of human and animal tumors. Intravenous injection of R3230 AC rat adenocarcinoma cells, one of the models investigated, results in multiple lung foci seeding. We analyzed the phenotypic diversity of this tumor by cloning and culturing two distinct cell subpopulations from a cell culture of this tumor, hereafter called OR or original cell culture. One was obtained after repeated exposure of the OR to increasing concentrations of concanavalin A and wheat germ agglutinin. A single clone was isolated and was named lectin-resistant (LR) cell line. The LR cells did not metastasize but maintained stable tumorigenicity and morphology over at least 10 passages. A second cell line was obtained by repeated passage and injection of cells from a single metastatic node. After repeating the process five times, a single clone of cells was selected from the final variant and was called lung metastatic (LM) cell line. The LM cultured cells maintained stable tumorigenicity, morphology, and metastatic properties for no more than 10 passages. OR, LR, and LM cells were assessed by their doubling time (DT), chromosome counts, and hCG immunocytochemistry. The results demonstrated that the LM cell line had a higher chromosome count than the LR and the OR cell lines, and its DT was the shortest. Immunocytochemistry of the transplanted OR neoplasm showed scattered expression of the hCG-like material. By the same techniques a complete lack of reactivity of the LR cells was found. However, almost all cells of the LM line were strongly positive for hCG-like material. After a few passages, the great majority of the LM cells also became unreactive. Our data demonstrate: (i) the existence of marked heterogeneity of the expression of hCG-like material in the primary tumor cell population; (ii) that the expression of hCG-like material correlates with the metastasizing capacity of the cells; and (iii) that there is a phenotypic instability for the expression of hCG-like material by tumor cells when maintained in vitro.

Adenocarcinoma↗
PubMed1987

Correlation of fibrinolytic activity with invasion and metastasis of R3230 AC rat mammary carcinoma cell lines.

The parent R3230 AC rat mammary carcinoma cell line and the two variant cell lines, R3230 AC MET and R3230 AC LR, differ with respect to their abilities to invade bony matrices and to form lung colonies (experimental metastases). Both the R3230 AC and the R3230 AC MET, a cell line selected in vivo for enhanced metastatic capability, express high potentials for invasiveness and lung colony formation, while the Con A- and WGA-resistant R3230 AC LR cell line grows expansively at the periosseus implantation site and is unable to form lung colonies after intravenous inoculation. The abilities to invade bone and to metastasize to the lung are well correlated with the fibrinolytic activity and the production of urokinase-type plasminogen activators. The contribution of plasminogen activators to invasiveness and metastasis has been ascribed to its role in the fibrinolytic and collagenolytic (i.e., activation of latent collagenase) cascades.

Animals↗
PubMed1986

Lack of immunological analogy between the beta-subunits of cholera toxin and human choriogonadotropin.

A chemical relatedness has been described between the beta-subunit of cholera toxin and that of the four dimeric glycoprotein hormones (hCG, hLH, hFSH and hTSH). However, antibodies induced by cholera toxin did not crossreact, when tested by labeled hCG binding and immunocytochemistry, with the beta-subunit of hCG. It appears that differences in the tertiary structures, as shown in this study, account for distinct epitopes. Similarities in biological activity between these two compounds, such as induction of adenyl cyclase or a protective effect against some tumors, are not based on immunological mechanisms.

Adenylyl Cyclases↗
PubMed1986

3,5,3'-Triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) synthesis in rats hosting the R3230AC mammary tumour.

Generation of T3 and rT3 from T4 was studied in R3230AC mammary tumours grown in Fischer 344 rats as well as in the liver and kidney of these tumour-bearing hosts. The primary objective of this study was to determine if reversion of T3 to rT3 synthesis occurs in this experimental tumour model and in organs remote from the tumour site. Tumours, hepatic and renal homogenates were analyzed 14-16 days following tumour implantation for 5- and 5'-iodothyronine deiodinase activity using thyroxine as substrate. It was observed that similar to the liver and kidney, the mammary tumour was capable of generating both T3 and rT3 from T4; renal synthesis of T3 was significantly greater than that of rT3 in tumour hosts and controls. In contrast, there was no significant difference between T3 and rT3 synthesis in the tumour itself and the livers of normal and tumour-bearing animals. Hepatic and renal T3 synthesis were greater in the tumour-bearing than in the normal rats; no difference in the hepatic and renal rT3 synthesis was observed between the tumour-bearing and the normal animals. Despite the fact that serum T3 was significantly lower in the tumour-bearing than in the normal rats, no difference in the serum rT3 level was observed between the two groups of animals. Our data demonstrate that in this particular animal model there is no evidence of dedifferentiation of iodothyronine deiodinase activity either within the tumour or in remote tissues.

Adenocarcinoma↗
PubMed1985

The presence of glycosylated, biologically active chorionic gonadotropin in human liver.

Whole extracts of normal human liver contain hCG-like material as determined by radioimmunoassay using antibodies to the beta subunit of the hormone. However, the extracts are biologically inactive, when analyzed by the in vitro rat Leydig cell assay for steroidogenesis. When subjected to Concanavalin-A-Sepharose chromatography, the radioimmunoassayable material was entirely lectin-bound. After elution with methyl-alpha-D-glucopyranoside, the lectin-bound fractions now displayed biological activity.

Biological Assay↗
PubMed1984

Plasminogen activator activity in human breast cancer cytosols.

Plasminogen activators are an enzyme complex which first appears in the trophoblast and may contribute to the invasive and metastatic process in neoplastic growth. In this study, 102 cytosols from human breast cancer biopsies were analyzed for PAA (with the chromogenic tripeptide S2251 KABI), steroid receptors (ER and PR), age, nodal and menopausal status. The data were submitted to log (X + 1) transformation and the raw and transformed data were analyzed for distribution. Because of the largely non-normal distribution of the data, Spearman's rank order correlation coefficients were generated to test for relationships between these differentiation markers and the clinical data. Nodal and menstrual status groups were compared for PAA and receptor levels using the Wilcoxon rank sum test. We found significant positive correlations between net PAA and ER (p = 0.0001), net PAA and PR (p = 0.0001), and net PAA and age (p less than 0.05). PAA levels for nodal status groups were found to be significantly different (negative at p less than 0.05). Nodal metastases predict poor prognosis while higher receptor levels indicate a better prognosis. As PAA levels correlate with the above biologic properties of breast tumors, they may provide additional prognostic information, especially in cases in whom auxiliary node status is unknown.

Breast Neoplasms↗
PubMed1983

The effect of experimental rat tumours on progesterone binding in the host liver.

1. The effect of the R3230 AC rat mammary adenocarcinoma on progesterone binding in the liver of female F344 rats has been studied. The growth of the transplanted tumour shows a positive correlation with increased binding of progesterone to the endoplasmic reticulum. 2. Both total binding rate and saturation level in the formation of specific progesterone microsomal receptor complex are increased. 3. This is paralleled by an elevated progesterone content of microsomal membranes. 4. In contrast, nonspecific progesterone binding in the microsomes is reduced. These results may represent a paraneoplastic change.

Adenocarcinoma↗
PubMed1983

Enzymatic determination of oxalates.

An assay for oxalate, based on oxalate oxidase, was studied. It is relatively simple, rapid and reproducible and may be semi-automated and is accurate in the range 10-140 mg/l, has a coefficient of variation of 4.2% in the healthy range (10-19 mg/l serum). Samples may be stored at -20 degrees C for as long as 2 weeks. It cannot be used for the determination of urinary oxalate because of the presence of variable amounts of low molecular weight inhibitor(s).

Autoanalysis↗
PubMed1983

Plasminogen activators as markers of tumor colonization potential.

Cell suspensions from the R 3230 AC rat mammary adenocarcinoma, when injected intravenously into F344 rats, invariably produce multiple lung foci within 10 days. We compared the colonization potential of cultures obtained from these foci and from cell populations exposed to 100 micrograms/ml medium of both concanavalin A and wheat germ agglutinin for 5 passages with the original cell line. Plasminogen activator activity (PAA) was determined in all three cell subpopulations, using S2251 (KABI) as chromogenic substrate. All cell lines retained their ability to grow after subcutaneous implant. The lectin resistant variant was found to have lost its capacity to nidate in the lung completely and also had the lowest PAA. In contrast, the cell population derived from the lung foci ranked highest in PAA.

Adenocarcinoma↗