Humoral and cellular immunity to paternal antigens in trophoblastic neoplasia.
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Antibodies, Neoplasm↗
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Different profiles of neuroendocrine cell differentiation evolve in the PC-310 human prostate cancer model during long-term androgen deprivation.
BACKGROUND: Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating peptide hormones via a regulated secretory pathway (RSP). We studied NE differentiation after long-term androgen withdrawal in the androgen-dependent human prostate cancer xenograft PC-310. METHODS: Tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, 21, 47, 84, and 154 days after castration. The half-life of the PC-310 tumor was 10 days, with a stable residual tumor volume of 30--40% after 21 days and longer periods of androgen deprivation. RESULTS: Proliferative activity and prostate-specific antigen serum levels decreased to zero after castration, whereas cell-cycle arrest was manifested by increased p27(kip1) expression. A temporary downregulation of androgen receptor (AR) expression was noted after androgen deprivation. The expression of chromogranin A, secretogranin III, and secretogranin V (7B2) increased 5 days after castration and later. Subsequently, pro-hormone convertase 1 and peptidyl alpha--amidating monooxygenase as well as vascular endothelial growth factor were expressed from 7 days after castration on. Finally, such growth factors as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days after castration, but strong expression was induced late during androgen deprivation, that is, 84 and 154 days after castration, respectively. CONCLUSIONS: Androgen deprivation of the NE-differentiated PC-310 model induced the formation of NE-differentiated AR(minus sign) and non-NE AR(+) tumor residues. The NE-differentiated cells actively produced growth factors via an RSP that may lead to hormone-refractory disease. The dormant non-NE AR(+) tumor cells were shown to remain androgen sensitive even after long-term androgen deprivation. In the PC-310 xenograft, time-dependent NE differentiation and subsequent maturation were induced after androgen depletion. The androgen-dependent PC-310 xenograft model constitutes an excellent model for studying the role of NE cells in the progression of clinical prostate cancer.
Androgens↗
Immune response to murine neuroblastoma: effects of in vitro culture of the tumor.
The humoral and cellular immune response of neuroblastoma (NB)-bearing mice has been investigated and shown to be dependent on the treatment of the NB tumor cells before implantation. Established lines and clones derived from the original tumor, as well as C1300 cells passaged in vitro, provoke an immune reaction which differs markedly from the one induced by the original C1300 tumor. Indeed, only the latter induces the formation of high amounts of circulating immune complexes (CIC), is able to trigger peritoneal macrophages in the host and to induce suppression, as shown in mixed lymphocyte cultures. After subculture of the tumor cells in vitro, none of these effects were observed. The pattern of immune response produced by tumor cells grown in vitro can be converted into the original type of response by repeated passaging of the tumor cells in vivo.
Animals↗
Multiple forms of peptidyl alpha-amidating enzyme: purification from rat medullary thyroid carcinoma CA-77 cell-conditioned medium.
Conditioned medium from cultures of rat medullary thyroid carcinoma CA-77 cells was used as a source for purification of the secreted forms of peptidyl alpha-amidating enzyme. The alpha-amidating enzyme activity was partially purified using a combination of weak anion exchange and gel filtration chromatography. Subsequent strong anion exchange chromatography at pH 6.0 resolved this partially pure enzyme into four distinct peaks of activity, termed Ia, Ib, II, and III. Peaks Ia and Ib exhibited broad pH optima between pH 6.0-8.5, whereas peaks II and III both exhibited pH optima at approximately pH 5.0. The peak III activity was further purified to electrophoretic homogeneity using hydrophobic interactive chromatography followed by strong anion exchange chromatography at pH 8.0. The enzyme exhibited an apparent molecular mass of 75K, a pH optimum of approximately pH 5.0, and a maximal turnover number of 580 min-1 in the presence of L-ascorbate. Kinetic studies demonstrated that the enzyme probably functions through a ping-pong mechanism with respect to the binding of the glycine-extended peptide substrate and the L-ascorbate cofactor. The peak III enzyme exhibits several distinctive characteristics compared to amidating enzymes isolated and characterized by other laboratories.
Animals↗
The efficacy of large volume plasma exchange in chemotherapy resistant malignancies.
Chemotherapy resistance in cancer patients may be due to serum blocking factors, which can be diminished or eliminated by large volume plasma exchange (PE). This procedure was performed with the IBM blood cell separator in 69 patients resistant to chemotherapy. Immediately after PE the chemotherapy was given but it was reinstituted, if clinical evaluation revealed partial remission, minor response or no change. 37 out of 69 patients (53.6%) responded again, 32 (46.4%) did not. Response duration ranged from 2 to 45 weeks. Best clinical results were obtained in patients with colorectal cancer, 15 out of 23 showed improvement between 4 to 45 weeks. Serum blocking activity was measured using a modified mixed lymphocyte culture assay (MLC). There was a 80% positive correlation between clinical course of patients and MLC levels, if basic activity before the first PE was compared to MLC inhibition before the following PE's.
Adult↗
Mixed connective tissue disease, Sjögren's syndrome, and abdominal pseudolymphoma.
A young female with mixed connective tissue disease (MCTD) presented with the unusual occurrence of abdominal pseudolymphoma. Although the pseudolymphoma could be related to concomitant sicca complex, some data suggest that MCTD, as such, could carry a high incidence of malignancy.
Abdominal Neoplasms↗
Mixed leucocyte culture blocking factor activity in the plasma of patients with cancer.
Plasma samples obtained from 74 patients with malignant disease were assayed for their ability to suppress or block the mixed lymphocyte reactivity of random normal donors. 24 of the 74 patients investigated had evidence of mixed lymphocyte culture blocking factoractivity (MLC-BFA). 19 of 33 patients with disseminated disease had evidence of MLD-BFA whereas in only 5 of 41 patients with localized disease was evidence of BFA found. There was a relationship between a history of previous blood transfusion inthe 6-month period prior to study and the presence of MLC-BFA in patients' plasma. Excluding this group of patients, where previous transfusion might have been responsible for MLC-BFA and excluding, too, that group of patients with a history of past pregnancy,there remained still 11 patients with evidence of BFA in their plasma. Nine of these11 had widely disseminated and progressiv disease. MLC-BFA was found in both IgM and IgG fractions of plasma. Plasma with MLC-BFA was found to suppress normalin vitro lymphocyte responses to mitogens PWM and PHA. The MLC-BFA assay utilized in this work may provide the means of monitoring cancer patients in order to detect 'blocking' antibody.
Antigen-Antibody Complex↗
Secretion and regulation of two biosynthetic enzyme activities, peptidyl-glycine alpha-amidating monooxygenase and a carboxypeptidase, by mouse pituitary corticotropic tumor cells.
Secretion of peptidyl-glycine alpha-amidating monooxygenase (PAM) activity and enkephalin convertase (a carboxypeptidase B-like enzyme) activity from AtT-20 mouse corticotrope tumor cells was compared with secretion of pro-ACTH/endorphin-derived peptides. Upon stimulation of secretion by corticotropin-releasing factor, a beta-adrenergic agonist, or barium ions, secretion of PAM activity, enkephalin convertase activity, and immunoactive hormone rose in parallel. During inhibition of stimulated secretion with glucocorticoids or cobalt ions, secretion of PAM activity, enkephalin convertase activity, and immunoactive hormone fell in parallel. No measurable secretion of cytosolic, mitochondrial, or lysosomal marker enzymes was detected, indicating that the secretion of PAM activity and enkephalin convertase activity was specific and not a result of cell damage or lysis. The kinetic characteristics, apparent mol wt, and enzymatic properties determined for the secreted enzymes were similar to those for the enzymes from secretory granules. In AtT-20 cells treated with glucocorticoids for up to 8 days, cellular levels of immunoactive ACTH/endorphin-related peptides decreased to one third of control levels. Levels of PAM activity in cell extracts declined in parallel with levels of hormone. In contrast, levels of enkephalin convertase activity, cell protein, lactate dehydrogenase, fumarase, and lysosomal carboxypeptidase did not decline in response to chronic glucocorticoid exposure.
Animals↗
Ascorbate transport by AtT20 mouse pituitary corticotropic tumor cells: uptake and secretion studies.
Ascorbate is an important cofactor in the biosynthesis of alpha-amidated endocrine and neural peptides. Peptidylglycine alpha-amidating monooxygenase (PAM) is the enzyme responsible for the generation of mature COOH-terminal alpha-amidated peptides from COOH-terminal glycine-extended peptides, and this enzyme requires ascorbate for full activity in vitro. Also, cultured intermediate pituitary lobe cells contain PAM and require ascorbate for the COOH-terminal alpha-amidation of alpha MSH. Since pituitary cells are not capable of synthesizing ascorbate, the ability of the cells to accumulate the cofactor must play an important role in the biosynthesis of alpha-amidated peptides. The AtT20 corticotropic pituitary tumor cell line also contains PAM and a potential site for COOH-terminal alpha-amidation of the pro-ACTH/endorphin-derived hinge peptide and was, thus, used for the study of cellular ascorbate transport. Radiolabeled L-[1-14C]ascorbate ([1-14C]ascorbate) was incubated with the cells under various conditions, and the accumulation of radioactivity by the cells was followed. Reverse phase HPLC was used to identify the integrity of the labeled ascorbate, both intra- and extracellular, during the course of the experiments. The uptake of [1-14C]ascorbate was saturable (Km = 31.5 microM), sodium and temperature dependent, and stereoselective. The products of ascorbate autooxidation, dehydroascorbate and 2,3-diketogulonic acid, did not inhibit [1-14C]ascorbate uptake. To study the presence of ascorbate in the secretory granules, cells were incubated with [1-14C]ascorbate and then induced to secrete with isoproterenol or 8-bromo-cAMP. A 2- to 6-fold stimulation of ACTH secretion over the basal secretion rate was observed; however, the secretion of intracellular [1-14C]ascorbate did not change significantly with stimulation, suggesting that very little of the cellular ascorbate was contained within secretory granules.
2,3-Diketogulonic Acid↗
Suppression of cytochrome P450 1A1 and 4A1 gene expression in renal carcinomas of TSC2 gene mutant (Eker) rats.
In the kidney, cytochrome P450 (CYP) is involved in arachidonic acid metabolism and the maintenance of homeostasis, but only scarce information is available as to how CYP expression is altered in rodent renal carcinomas (RCs). TSC2 gene mutant (Eker) rat RCs are an example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. In the present study, the expression of CYP in Eker RCs was studied. In the normal kidney, CYP 1A1 and 4A1 mRNAs were expressed, but this expression was suppressed in spontaneously-induced Eker RCs and in cell line Lk9dL and Lk9dR. In Lk9dL and Lk9dR, Ah receptor nuclear translocator and haemoxygenase-1 mRNAs were expressed, but this expression was inconsistent in spontaneously-induced Eker RCs. The present results showed the suppression of CYP 1A1 and 4A1 mRNA expression in spontaneously-induced Eker RCs and this suppression indicates altered metabolic conditions in Eker RCs.
Animals↗
Inhibition of peptide amidation by disulfiram and diethyldithiocarbamate.
Peptidylglycine alpha-amidating monooxygenase is a copper- and ascorbate-dependent enzyme that converts peptides with COOH-terminal glycine residues into the corresponding alpha-amidated product peptides. The relatively selective copper chelator N,N-diethyldithiocarbamate (DDC) and its disulfide dimer, disulfiram (Antabuse), were used to determine whether the availability of copper affects the production of two alpha-amidated pro-ACTH/endorphin-derived peptides, alpha-melanotropin (alpha MSH) and joining peptide. When mouse pituitary corticotropic tumor cells (AtT-20) were grown in medium containing micromolar concentrations of disulfiram or DDC, alpha-amidation of newly synthesized joining peptide was specifically inhibited in a dose-dependent manner. In rats injected twice with disulfiram or DDC, the ability of the intermediate pituitary to alpha-amidate newly synthesized alpha MSH and joining peptide was inhibited in a dose-dependent manner; at disulfiram doses equivalent to those used in alcohol abuse therapy (4 mg/kg/day), only about 10% of the newly synthesized peptides were correctly alpha-amidated. Chronic treatment of rats with DDC or disulfiram produced a dose-dependent increase in the pituitary content of glycine-extended alpha MSH and joining peptide; the total amount of pro-ACTH/endorphin-related material was unaltered. After 11 days of treatment with 4 mg/kg/day disulfiram, about one-third of the pituitary alpha MSH and joining peptide were present in the glycine-extended rather than the alpha-amidated form; pituitary extracts normally contain almost entirely alpha-amidated peptides.
Animals↗
[Antitumor activity of mixed cis-complexes of platinum(II) with ammonia and cycloalkylamines].
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Animals↗
Emerging tumor entities and variants of CNS neoplasms.
Since the appearance in 2000 of the World Health Organization (WHO) classification for central nervous system (CNS) neoplasms, numerous descriptions of new entities or variants have appeared in the literature. In the group of neuronal and mixed glioneuronal neoplasms are lesions with distinctive morphological features that are still not included in a precise classification, including extraventricular neurocytoma, papillary glioneuronal tumor, rosette-forming glioneuronal of the fourth ventricle, glioneuronal with neuropil-like rosette, and DNT-like tumor of the septum pellucidum. The glioneuronal tumor with neuropil-like rosette and oligodendroglioma with neurocytic differentiation represent morphological variants of genetically proven diffuse gliomas. The lipoastrocytoma and the pilomixoid astrocytoma enlarge the group of astrocytic lesions. Rare, low-grade gliomas of the spinal cord with extensive leptomeningeal dissemination associated with unusual neuroimaging are described. The chordoid glioma of the third ventricle and the papillary tumor of the pineal region seem to be correlated by a common histogenesis from the specialized ependyma of the subcommissural organ. An embryonal tumor with neuropil and true rosettes combining features of neuroblastoma and ependymoblastoma is discussed. These new, recently described lesions indicate that the complex morphologic spectrum of CNS tumors is far from being completely delineated.
Central Nervous System Neoplasms↗
Purification of a peptidylglycine alpha-amidating enzyme from transplantable rat medullary thyroid carcinomas.
A peptidyl glycine alpha-amidating activity has been isolated from total tissue extracts of rat medullary thyroid carcinoma (MTC). Purification of the activity by ammonium sulfate fractionation, Sephacryl S-300 chromatography, and strong anion-exchange chromatography at pH 6.0 has resolved at least four peaks of activity. The activity associated with peak III has been further purified to apparent homogeneity by strong anion-exchange chromatography at pH 8.0. The purified peak III enzyme has an apparent molecular mass of 75,000 Da as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The identity of the 75,000-Da band as the alpha-amidating enzyme has been confirmed by recovery of activity from a nondenaturing polyacrylamide gel. The enzyme is catalytically active as a monomer, exhibits a pH optimum between 5.0 and 5.5, and has a turnover number of 300 min-1 for N-dansyl-Tyr-Val-Gly amidation at pH 5.5. The larger size, more acidic pH optimum, and higher specific activity distinguish the purified peak III rat MTC enzyme from the enzymes isolated from bovine and porcine pituitary or from frog skin.
Animals↗
The swine leucocyte antigen (SLA) complex and Sinclair swine cutaneous malignant melanoma.
Cutaneous malignant melanoma of Sinclair swine (SSCM) is an inherited neoplasm present at birth in a majority of affected animals. We have characterized the swine leucocyte antigen (SLA) complex of the Sinclair herd at Texas A & M University using a one-way mixed lymphocyte test and found that one particular haplotype, arbitrarily identified as haplotype B, is associated with the expression of SSCM. Only a single dose of the B haplotype is required for a dominant allele at a 'tumour initiator' locus to be fully penetrant. In addition, swine homozygous for haplotype B develop more primary tumours between birth and weaning than those heterozygous for the B haplotype. Taken together, these findings indicate that tumour initiation, in utero, and expression between birth and weaning may involve different mechanisms.
Animals↗
Peptide substrate specificity of the alpha-amidating enzyme isolated from rat medullary thyroid CA-77 cells.
The kinetic parameters were obtained for enzymatic alpha-amidation of peptides of the form N-dansyl-(Gly)4-X-Gly-OH, in which the amino acid at position X was substituted with each of the 20 natural amino acids. The enzyme used in these studies was a highly enriched preparation of alpha-amidating enzyme secreted by a clonal (CA-77) cell line which actively expresses mature alpha-amidated peptides. A 130-fold and 11-fold variation respectively in apparent Km and Vmax values was observed. The effect of the amino acid side chain at position X in stabilization of the enzyme-substrate complex decreased through the series X = planar aromatic or sulfur containing greater than neutral aliphatic greater than polar and basic greater than cyclic aliphatic or acidic.
Animals↗
Tissue-specific regulation of peptidyl-glycine alpha-amidating monooxygenase expression.
Peptidyl-glycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) is present in a variety of tissues, where it plays a vital role in the processing of numerous peptide substrates, often conferring bioactivity. PAM is present in high amounts in heart atrial myocytes and the pituitary gland, where activity is present in both soluble and membrane forms. We used AtT-20 cells, a mouse corticotrope tumor cell line, and primary heart atrial cultures to establish the occurrence of tissue-specific regulation of PAM expression. In the AtT-20 cells, PAM expression is regulated in parallel with the source of its peptide substrate, pro-ACTH/endorphin. PAM mRNA levels are increased to 132 +/- 5% of control values by treatment with (Bu)2-cAMP and decreased to 55 +/- 7% of control values by treatment with dexamethasone. Treatment with (Bu)2cAMP decreases PAM specific activity in the AtT-20 cells to 68 +/- 4% of the control value, presumably due to secretion of enzyme from the cells; dexamethasone treatment decreases PAM specific activity to 57 +/- 1% of the control value. In contrast, in heart atrial cultures, dexamethasone stimulates PAM expression. In atrial cultures exposed to dexamethasone for 48 h, PAM mRNA and PAM specific activity are elevated to 230 +/- 50% and 220 +/- 20% of control values, respectively; secretion of PAM activity is increased to 230% of the control value. As for AtT-20 cells, treatment of atrial cultures with (Bu)2cAMP increases PAM mRNA levels. Thus, PAM expression is regulated in a tissue-specific manner by dexamethasone in the two tissues examined. In AtT-20 cells, time-course studies and studies with cycloheximide indicate that dexamethasone exerts its effects on PAM mRNA levels by an indirect mechanism involving protein synthesis.
Animals↗
Host age and H-2 tolerance in chimeric mice: mixed lymphocyte reactivity, cell-mediated lympholysis and responses to hapten-modified self.
In order to further our understanding of the reasons for the increased susceptibility of aged animals to autoimmunity, neoplasms and infectious diseases, experiments were performed to determine the ability of an aged environment to induce and support tolerance to major histocompatibility complex (MHC) determinants as well as to support the development of a specific immune response to modified self-determinants. The degree and mechanisms of tolerance to host and donor histocompatibility antigens were studied in bone marrow chimeras of the type (C57B1/6 X CBA)F1 leads to (C57B1/6 X DBA/2)F1 (BCF1 and BDF1, respectively). BCF1 bone marrow donors were 6 weeks old and BDF1 hosts were 18 months old at the time of chimerization. Four to ten months later, chimeras were found to fully tolerant to all three parental haplotyes and competent to respond to fourth-party strains as assessed in both mixed lymphocyte reactions and cell-mediated lympholysis. Tolerance to parental haplotypes could not be attributed to active suppression of reactivity. The aged host environment proved incapable of supporting the development of anti-modified self-reactivity as attested by the fact that neither the senescent BDF1 mice nor the BCF1 leads to BDF1 chimeras established in aged hosts could respond to trinitrophenol-modified autologous parental cells. In contrast, young BDF1 mice and BCF 1 leads to BDF1 chimeras established in young adult hosts were competent to respond to trinitrophenol-modified autologous and parental cells in an MHC restricted fashion. The significance of these results to the susceptibility of aged animals to intracellular parasitic infections and neoplasia is discussed.
Aging↗