Biomedical subjects

J Bergh

Publications and source records attributed to J Bergh.

At least 163 records · Page 9Linked to original sources

PubMed1985

Neurone specific enolase: a useful diagnostic serum marker for small cell carcinoma of the lung.

Among lung cancers small cell carcinoma is the most sensitive to chemotherapy and radiation. This has emphasised the importance of an accurate diagnosis of this cell type, and the present study examined the use of serum neurone specific enolase (NSE) as a diagnostic marker for small cell carcinoma. NSE was measured in pretreatment sera from 103 patients with small cell carcinoma and in sera from relevant controls, including patients with other lung cancers, non-malignant lung diseases, and healthy adults. Serum NSE concentration was raised (greater than 25 ng/ml) in 72% of patients with small cell carcinoma. Ninety one per cent of patients with extensive disease and 50% of patients with limited disease were serum NSE positive. Patients with extensive disease in general had higher serum NSE concentrations than patients with limited disease. No definite difference in serum NSE positivity could be shown between oat cell and intermediate cell subtypes. Out of 51 patients with other lung cancers, four (8%) had a raised serum concentration, whereas all patients with non-malignant diseases and healthy individuals had normal serum NSE concentrations. Serum NSE determination seems to be a valuable tool for the diagnosis of small cell carcinoma.

Adult↗

PubMed1985

Amplification of the c-myc oncogene in a subpopulation of human small cell lung cancer.

We have examined a panel of human lung cancer cell lines for amplification and expression of the c-myc, N-myc, and c-myb oncogenes. The cell lines analyzed represent various histopathological types of lung cancer: small cell carcinoma with neuroendocrine properties; squamous cell carcinoma with epithelial markers; and large cell carcinoma with a mixed neuroendocrine-epithelial phenotype. Two of six cell lines, both of which were small cell carcinomas, showed about a 20-fold amplification of the c-myc oncogene. In both cell lines, the amplification is accompanied by an enhanced expression of c-myc. The N-myc or c-myb genes were not amplified in any of the cell lines, nor were they expressed in detectable amounts. The results confirm and extend earlier findings on c-myc amplification in small cell lung cancer.

Carcinoma, Small Cell↗

PubMed1984

Neuron-specific enolase as a marker for neuroblastoma and small-cell carcinoma of the lung.

The use of neuron-specific enolase (NSE, E.C. 4.2.1.11) as a clinical marker for neuroblastoma and small-cell carcinoma of lung (SCCL) is presented. Both tumors have a high content of NSE as demonstrated enzymatically or by immunocytochemistry. Other retroperitoneal tumors in children and other lung tumors had insignificant NSE concentrations. NSE can thus be used in the differential diagnosis of neuroblastoma and SCCL. 73% of patients with SCCL had elevated serum NSE levels. The corresponding figure for patients with other types of lung cancer was 3%. There was a good correlation between serum NSE levels and the clinical course of patients with SCCL.

Adult↗

PubMed1984

Expression of intermediate filaments in established human lung cancer cell lines. An indicator of differentiation and derivation.

A panel of established human pulmonary cancer cell lines, representing the major histopathologic groups according to the World Health Organization (WHO) classification (WHO 1, squamous cell carcinoma; WHO 2, small cell carcinoma; WHO 3, adenocarcinoma; WHO 4, large cell carcinoma) were examined for their expression of various types of intermediate filaments in order to determine their phenotypic differences and to attempt to disclose their histogenetic origin. The cells were investigated with antibodies specific for cytokeratin, vimentin, and neurofilament polypeptides with both immunofluorescence microscopy and immunoblotting techniques. Squamous cell carcinoma and adenocarcinomas expressed cytokeratin in accordance with the epithelial nature of these tumors but not neurofilament polypeptides. Small cell carcinomas, on the other hand, were positive for neurofilaments but negative for keratin. In contrast to small cell carcinoma, adenocarcinoma, and squamous cell carcinoma, one cell line derived from large cell carcinoma appeared to express both neurofilaments and keratin. All cell lines studied also contained variable amounts of vimentin, a phenotypic characteristic obtained by many cells under in vitro conditions. The results demonstrate, in accordance with our earlier observations in vivo, a distinctly divergent expression of intermediate filament proteins in different types of lung cancers. The persistence of this phenotypic heterogeneity in vitro consolidates the use of cell cultures as useful models to study the biologic behavior and interrelationships of lung cancers. Based on the present studies, and taking into account the occurrence of mixed forms of lung cancers, we present a hypothetical scheme of the histogenetic derivation of different types of lung cancers.

Adenocarcinoma↗

PubMed1983

Formation and growth of multicellular spheroids of human origin.

Different types of human cells which normally grow as monolayers or suspension cultures were tested for their capacity to form and grow as spheroids. Sixteen out of the 27 tested tumour cell lines formed spheroids. Nearly all of these spheroids also grew. With only two exceptions the doubling times were longer when the tumour cells grew as spheroids than when they grew in conventional mass culture. Eleven out of 13 tested human non-tumour cells formed small spheroids but of these only the spheroids of lymphoid origin could grow. These lymphoid cells grew faster when aggregated to spheroids than when in single-cell suspension culture. None of the other non-tumour cells, which normally grew as monolayers, could grow as spheroids. The normally monolayer-cultured tumour cells formed symmetrical spheroids with smooth surfaces while the normally suspension-cultured cells formed irregular spheroids with rough surfaces. All large spheroids had a necrotic centre surrounded by a shell of viable cells. The thickness of the viable cell layer varied depending on cell type. The shape and organization of cells within the spheroids also varied largely. The results show that many types of human cells can be cultured as spheroids and that a wide spectrum of morphological appearances and growth rates can be obtained.

Cell Aggregation↗

PubMed1983

Cell surface glycoprotein patterns of cell lines derived from human small cell carcinoma of the lung.

The expression of major cell surface glycoproteins (sgp) of seven established human pulmonary small cell carcinoma (SCC) cell lines and two autologous non-neoplastic lymphoblastoid and fibroblastic cell lines were studied by the galactose oxidase tritiated sodiumborohydride labelling technique. The general sgp pattern of SCC cell lines was different from that of the autologous non-malignant cell lines and the various other normal and malignant hematopoietic cells, gliomas and melanomas previously studied by the same technique, thus confirming that the sgp pattern seems to represent a molecular "fingerprint" of various human cell types. The SCC cell lines could be subdivided into two major subgroups with respect to expression of characteristic sgps. One group of lines was characterized by having prominent sgp 52000 (52 K) Dalton (D), 50 KD, 40 KD, 34 KD and 10 KD. In the other group the major sgps had apparent molecular weights of 110 KD, 75 KD and 10 KD, respectively. In addition to these common basic "group specific" sgps each SCC line expressed individually distinct sgps.

Bone Marrow Cells↗

PubMed1982

Establishment and characterization of two neoplastic cell lines (U-1285 and U-1568) derived from small cell carcinoma of the lung.

Two human cell lines have been established in vitro from patients with small cell carcinoma of the lung (SCC). The U-1285 line was derived from the classical small cell type of SCC while the U-1568 originated from a larger cell variant. The cell lines grow as suspension cultures and have been passaged continuously in vitro for 3 years (U-1285) and 2 years (U-1568), respectively. The malignant nature of the lines is suggested by their infinite growth potential, their capacity to form colonies in agarose and their aneuploidy. Both cell lines contain cytoplasmic electron dense particles indistinguishable from classical neurosecretory granules but only in U-1568 has hormone production (human chorion gonadotropin (alpha-HCG)) been proven. The U-1568 line produces carcino-embryonic antigen (CEA) while both U-1285 and U-1568 produce alpha-feto-protein (AFP). Chromosome analysis reveal aneuploidy of both lines. Among structural aberrations, involvement of chromosome 14 in U-1285 and chromosomes 1, 7 and 12 in U-1568 is interesting since alterations of these chromosomes have been described previously in other malignant conditions.

Carcinoma, Small Cell↗

PubMed1981

Establishment and characterization of a continuous lung squamous cell carcinoma cell line (U-1752).

A continuous cell line, U-1752, was established from a lung tumor originally diagnosed as a small cell carcinoma. The cell line has been in continuous in vitro passage for 29 months. The epithelial, rather than small cell nature of the U-1752 cells was demonstrated by the presence of desmosomes, prominent tonofilament bundles, by the reactivity with an anti-keratin antiserum and by the expression of cell surface receptors for epidermal growth factor (EGF). The U-1752 cells grow as monolayer cultures and have a population doubling time of around 36 hours at optimal growth in 20% calf serum. The most important neoplastic features of U-1752 were its aneuploidy, its capacity for colony formation in agarose and its tumorigenic potential subcutaneously in nude mice.

Adult↗

PubMedDate not supplied

Use of TPS and CA 15-3 assays for monitoring chemotherapy in metastatic breast cancer patients.

TPS and CA 15-3 have been applied for monitoring treatment in patients with advanced breast cancer and the relationship between the initial marker levels and the changes of the markers during chemotherapy has been established. Both markers have demonstrated high sensitivity for detecting visceral and bone metastases in the patients (90-95%) compared to soft tissues and locally advanced disease (45-50%). The marker combination, TPS and CA15-3, showed the highest sensitivity for detecting bone/visceral metastases (98%) and soft tissue/locally advanced metastases (75%). TPS showed a more frequent decrease in marker level (> 50%) compared to CA 15-3 as well as the highest correlation (68%) to the clinically confirmed events CR, PR compared to CA 15-3 (54%). In the subgroup of metastatic breast cancer patients, demonstrating increased marker levels (> 25%) during follow-up, TPS showed the highest correlation compared to the clinically confirmed progressive disease. In the subgroup of patients with clinically confirmed progression, contemporary measurements of the marker values resulted in correlation with the clinical findings in 78% for TPS and 58% for CA 15-3. TPS appears to be superior to CA 15-3 for follow-up of metastatic breast cancer patients. TPS and CA 15-3 marker increase preceded the clinical and/or radiological signs of distant metastases in most of the patients; 1.5 and 1.1 months, respectively. The time elapsed between tumor marker increase and clinically confirmed progression was very short, which is also related to the frequent follow-up visits for metastatic breast cancer patients receiving chemotherapy. TPS appears to indicate the changes in the disease state earlier than clinical criteria or than the established tumor burden markers. The simultaneous determination of TPS and CA 15-3 provided additive information in advanced breast cancer patients and might guide management decisions in the individual patients.

Adult↗

PubMedDate not supplied

Cytotoxic action of cyclosporins on human tumor cell lines is not dependent on immunosuppressive activity.

The cytotoxic activity of cyclosporin A (CsA) and the three non-immuno-suppressive CsA analogues B3-243, WO-039 and B3-665 were studied in tumor cell lines representing both classical and atypical forms of multidrug resistance (MDR): T-ALL GM3639 L100 cells selected for vincristine (vcr) resistance and displaying characteristics of classical MDR, including P-glycoprotein (pgp) expression and increased drug efflux which can be inhibited by pgp blockers (e.g. verapamil), and U-1285/ADR, a small cell lung cancer (SCLC) cell line selected for doxorubicin resistance which lacks pgp, is insensitive to pgp-blockers and shows cross resistance to cis-platinum. At 1 micrograms/ml CsA was the most active agent in reversing Vcr resistance in L100 cells followed by B3-243 and WO-039, with no effect of B3-665. Parental LO cells were only marginally sensitized to Vcr by these agents. No reversing effect of any cyclosporin was observed in the U-1285/ADR or its parental cell line. Compared to LO cells, L100 cells showed a marked hypersensitivity to CsA > B3-243 > WO-039 with B3-665 being inactive. No collateral sensitivity was observed for cyclosporins in U-1285/ADR cells. Although of different magnitude, the pattern of cytotoxic activity for the different cyclosporins alone closely parallelled that of L100 cells for U-1285, U1285/ADR and LO cells. The results indicate that not only the collateral sensitivity in classical MDR but also the cytotoxic actions of cyclosporins per se on tumor cells alone are independent of immunosuppressive activity. The results also suggest a structure-activity relationship for cyclosporin-induced cytotoxicity similar to, but independent of, MDR reversing activity.

Antineoplastic Agents↗

PubMedDate not supplied

Combination of cyclosporin A and buthionine sulfoximine (BSO) as a pharmacological strategy for circumvention of multidrug resistance in small cell lung cancer cell lines selected for resistance to doxorubicin.

The small cell lung cancer (SCLC) cell lines U-1285 and U-1690 were adapted to growth in continuous presence of doxorubicin (Dox). The resulting cell lines U-1285R and U-1690R were investigated with respect to sensitivity to the glutathione (GSH) depleting agent buthionine sulfoximine (BSO) and the immunosuppressant cyclosporin A (CsA) as well as the Dox resistance modifying ability of these agents. The parental U-1285 cells were more sensitive to BSO compared to parental U-1690 and the multidrug resistant (MDR) sublines, whereas no difference in sensitivity to CsA was observed between parental and MDR lines. BSO (10 microM) or CsA (1 microgram/ml) alone were able to partially reverse Dox resistance in the MDR cell lines, CsA being only marginally active in U-1285R cells. However, the combination of these two drugs at the same concentrations completely reversed Dox resistance in the MDR U-1690R cells whereas the combination was less effective in the U-1285R cells. The results demonstrate that a combination of low concentrations of BSO and CsA, only partially active by themselves in modifying Dox resistance, may be used as a pharmacological strategy to increase Dox sensitivity in some MDR SCLC cells.

Antimetabolites↗

PubMedDate not supplied

In vivo imaging and treatment of human brain tumours utilizing the radiolabelled monoclonal antibody MUC 2-63.

The monoclonal antibody MUC 2-63 identifies a glycoprotein antigen with a molecular weight of 32,000 Dalton present on human malignant gliomas but not detected on normal nerve and brain tissues. This was the prerequisite for these clinical studies with 111In-MUC 2-63 for imaging and 90Y-MC 2-63 for treatment. Seven patients with malignant gliomas, 6 with astrocytomas grade III-IV and 1 with a relapsing astrocytoma grade I-11 received the 111In labelled monoclonal antibody MUC 2-63 for in vivo diagnosis. Six patients had an uptake in the tumour of 0.01 to 0.05% of the MUC 2-63- 111In monoclonal antibody. The patient with the relapsing astrocytoma grade I-II had a negative scan due to a radical operation before the diagnostic dose. All patients received treatment with 90Y-MUC 2-63 intravenously in doses ranging from 146 to 830 MBq. Two patients with relapsing grade III-IV astrocytomas demonstrated clinical improvements and CT changes interpreted as necroses. No serious side-effects were observed in the 5 patients who only received one dose. The two patients who received up to 4 doses experienced grade 3 to 4 leukocyte and thrombocyte toxicity, most likely related to the bone-marrow toxicity by 90Yttrium. These data indicate the potential usefulness of the MUC 2-63 monoclonal antibody for in vivo image on humans with brain tumours and for adjunct treatment after operation and external radiotherapy.

Adult↗

PubMedDate not supplied

Neuron-specific enolase in small-cell carcinoma of the lung: the value of combined immunocytochemistry and serum determination.

The value of neuron-specific enolase (NSE) as a marker for small-cell carcinoma of the lung has been the subject of several reports. Taken together, about 70 per cent of patients with small-cell carcinoma had a raised serum concentration of NSE, and in a majority of patients NSE could be detected immunocytochemically in tumor biopsy speciments. This study examined the diagnostic value of combined immunocytochemical detection and serum determination of NSE in 96 unselected patients with small-cell carcinoma. Seventy-one patients had raised serum concentrations and in 69 a positive immunoreaction for NSE was demonstrated in the biopsy cells. However, for 87 (91%) of the patients, both or either of the NSE assays were positive. The combined use of immunocytochemistry and serum determinations thus gave better information on tumor NSE expression than either method alone. When patients with small or mechanically maltreated biopsy specimens were excluded, the accuracy of the combined assays was even higher (47/49, 96%). We therefore conclude that NSE, although not a specific marker for small-cell carcinoma of the lung, is useful as a complement to conventional diagnostic procedures and, when assayed both in biopsy material and in patient sera, tumor NSE expression can be demonstrated with a high precision.

Biomarkers, Tumor↗

PubMedDate not supplied

Surface-glycoprotein patterns of established human lung cancer cell lines and primary cultures.

The cell surface glycoprotein (GP) profiles of cell lines representing the four major histopathological lung cancer entities, squamous cell (SQC)-, small cell (SCC)-, adeno (ADC)-, and large cell carcinoma (LCC), and two primary cultures of SCC and LCC, respectively, have been examined by the galactose-oxidase tritiated sodium-borohydride cell surface labelling method, The SCC specimens (five cell lines and one biopsy) had a characteristic pattern of major surface GPs, with common GPs at apparent molecular weights (MWs) of 54 -kilo (k) Daltons (D) and 88 kD, which was discriminative from the group of non-SCC (SQC, ADC and LCC). The non-SCC group constantly expressed GPs at apparent MWs of 80 kD and 110 kD, both as established cell lines and in the primary LCC culture. The GP patterns of the SCC cell lines and the LCC cell line were retained in comparison to corresponding primary biopsy material. The propagation of an established SCC cell line without supplementation of serum did not alter the GP expression at the cell surface. Taken together, the surface GP patterns for SCC versus non-SCC appear to be reliable and reproducible markers for these tumor entities, both in biopsy material and in established cell lines.

Adenocarcinoma↗

PubMedDate not supplied

Characterization of four doxorubicin adapted human breast cancer cell lines with respect to chemotherapeutic drug sensitivity, drug resistance associated membrane proteins and glutathione transferases.

Four human breast cancer cell lines with or without estrogen and progesterone receptors were adapted to growth in the continuous presence of doxorubicin (Dox) at 10 (Zr-75-1), 15 (HTB-122), or 50 (MDA-MB-231 and Hs578T) ng/ml. The sublines of Zr-75-1, MDA-MB-231 and Hs578T showed 5-10-fold Dox resistance and also cross-resistance to vincristine (VCR) and etoposide (VP16). The sublines of Zr-75-1, MDA-MB-231 and Hs578T showed 5-10-fold Dox resistance and also cross-resistance to vincristine (VCR) and etoposide (VP16). The sublines maintained or slightly increased their cis-platinum (CDDP) sensitivity. The sublines of HTB-122 showed resistance only to VP16 combined with a paradoxical increased sensitivity to VCR. The phenotypic alteration in the sublines with respect to Dox sensitivity was maintained for at least two months in the absence of Dox. The glutathione depletor buthionine sulfoximine (BSO) and the calcium channel blocker verapamil (Ver) increased the Dox sensitivity slightly only in the MDA-MB-231 and Hs578T sublines, respectively. Ver also tended to protect some of the sublines from CDDP. The sublines of Zr-75-1 and Hs578T showed increased expression of the 170-kDa permeability glycoprotein (P-gp), whereas expression of a 85-kDa membrane protein determined by the MRK20 antibody was increased in the sublines of Zr-75-1, and HTB-122. Class pi glutathione transferase (GST) levels varied greatly between the cell lines but increased during Dox selection only in the subline of Zr-75-1. Class mu GST was detectable in the MDA-MB-231, Hs578T and HTB-122 cell lines, whereas class alpha GST was detectable in these sublines but undetectable in their parental cell lines. The Zr-75-1 subline showed a 5-fold increase in the class alpha concentration. Except for a correlation between increased P-gp expression and resistance to Dox, VCR and VP16, no obvious correlations between receptor status, increased P-gp expression, membrane proteins, GST levels and acquired drug resistance were found. Thus, except for a possible role for P-gp in multidrug-resistance, these findings indicate a pronounced mechanistic heterogeneity responsible for cytotoxic drug sensitivity also in cells with a common histologic origin and exposed to the same drug.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Expression of the CD44 glycoprotein (lymphocyte-homing receptor) in untreated human breast cancer and its relationship to prognostic markers.

CD44 is a cell surface glycoprotein which has been suggested to be associated with aggressive histological features in breast cancer (BC). It has also been implicated in conferring metastatic potential to rat carcinoma cells. The aim of this study was to determine the potential value of CD44 as a prognostic/metastatic marker in BC by means of immunohistochemistry. The expression of the CD44 glycoprotein was investigated in tumours from 52 untreated female patients with BC, using the monoclonal antibody A3D8. 10 samples of normal breast tissue were randomly obtained and also investigated with respect to CD44 expression. DNA ploidy, the S-phase fraction (SPF) and oestrogen-(OR) and progesterone-receptor (PgR) contents in the tumours were determined and together with the prognostic markers of age, tumour size, tumour grade and lymph node status, correlated with CD44 expression in BC. Also, the distribution of CD44 tumour cell expression was compared with expression of the permeability drug resistance glycoprotein (P-gp) in this material. Expression of CD44 on carcinoma cells was observed in 21/52 cases (40%). Capillary endothelial reactivity of the tumours occurred in 42 cases (80%). Non-neoplastic epithelial breast tissue was positive in 2/10 (20%) samples and capillary vessels in 7/10 (70%). Carcinoma CD44 cell expression was not associated with age, tumour size, tumour grade, DNA ploidy, SPF, hormone-receptor contents or lymph node metastases. There was a statistical correlation between CD44 and P-gp expression in breast carcinoma cells which may suggest a connection between adhesion molecules and drug resistance. These findings do not support an association between CD44 expression and adverse prognostic features or lymph node metastases in BC. Capillary CD44 staining was a common feature in BC. There appeared to be an upward regulation in CD44 expression in BC compared with the normal breast tissue.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Characterisation of the G1/S cell cycle checkpoint defect in lung carcinoma cells with different intrinsic radiosensitivities.

Cell cycle perturbations in three lung carcinoma cell lines (U-1285,U1906 and U-1810) with different intrinsic radiosensitivities (SF2 U-1285 = 0.25, SF2 U-1906 = 0.45, SF2 U-1810 = 0.88) were investigated following x-irradiation. Cell cycle flow calculations showed that the G1-->S-phase transit was accelerated in irradiated compared with untreated U-1285 cells, up to 24 hours postirradiation. In U-1810 cells and U-1906 cells the postirradiation G1-->S transit decreased compared with controls. All three cell lines showed no postirradiation induction of p53 and p21CIP1 proteins. Cyclin E was overexpressed and cyclin E-dependent kinase activity was substantially induced by irradiation in U-1285 cells compared with U-1906 and U1810 cells while p27KIP1 was detected at the highest intensity in U-1810 cells and lowest in U-1285 cells. We hypothesise that the accelerated postirradiation G1-->S transit in U-1285 cells is associated with induction of cyclin E-dependent kinase activity and may account for increased radiosensitivity in these cells.

Carcinoma, Non-Small-Cell Lung↗

PubMedDate not supplied

Spontaneous and radiation-induced apoptosis in lung carcinoma cells with different intrinsic radiosensitivities.

Spontaneous and radiation-induced apoptosis in three lung carcinoma cell lines (U-1285, U-1906 and U-1810) with previously characterised intrinsic radiosensitivities (RS) was assessed by TUNEL-staining, detection of DNA laddering and cleavage of poly-(ADP-ribose) polymerase (PARP). Spontaneous apoptosis was detected at a high level in the radiosensitive U-1285, at an intermediate level in U-1906 and not detected in the radioresistant U-1810 cell line. Radiation-induced apoptosis, assessed by TUNEL assay, was present in U-1285 and U-1906 cells but not in U-1810 cells. To explain these findings, expression of Bcl-2, Bax, c-Myc and RB protein and mutations of the p53 gene were analysed. The ratio Bcl-2/Bax was higher in U-1810 cells compared with U-1285 and U-1906 cells. Overexpression of c-Myc and loss of RB was found in U-1285 cells whereas both U-1906 and U-1810 cells expressed RB and showed lower c-Myc expression. Analysis with sequencing of all p53 exons disclosed mutations in all three cell lines. Thus, apoptosis was a p53 independent process in U-1285 and U-1906 cells. RB loss and overexpression of c-Myc may enhance apoptosis in U-1285 cells. Our data suggest that spontaneous apoptosis may correlate with RS in SCLC.

Apoptosis↗