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J Hansson

Publications and source records attributed to J Hansson.

At least 91 records · Page 5Linked to original sources
PubMed1993

Contribution of glutathione transferase M3-3 to 1,3-bis(2-chloroethyl)-1-nitrosourea resistance in a human non-small cell lung cancer cell line.

The glutathione transferase (GST) isoenzyme profile was determined in two human tumor cell lines, U1690 derived from a small cell lung cancer and U1810 derived from a non-small cell lung cancer. U1810 cells are 3.2-fold more resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) than are U1690 cells, a finding ascribable in part to the expression of O6-alkylguanine-DNA alkyltransferase activity in the U1810 cells. GST P1-1 and GST A1-1 were determined quantitatively by enzyme-linked immunoassay and were found to be 1.3- and 15-fold higher in the cytosol fraction of U1690 cells as compared to U1810 cells, respectively. The higher BCNU resistance in U1810 cells can, therefore, not be correlated with the expression of these isoenzymes. However, sodium dodecyl sulfate/polyacrylamide gel electrophoresis in combination with immunoblot analysis demonstrated a class Mu GST, which was identified as GST M3-3 on the basis of electrophoretic mobility and cross-reaction with anti-rat GST 3-3 antibodies. This isoenzyme was detectable in U1810 cells but not in U1690 cells. Studies with purified human GST A1-1, GST M1-1, GST M3-3, and GST P1-1 demonstrated that GST M3-3, but not the other isoenzymes, catalyzed the denitrosation of BCNU. Such inactivation of BCNU has previously been demonstrated with rat class Mu GSTs (M. T. Smith et al., Cancer Res., 49: 2621-2625, 1989) but not with any human GST. These findings suggest that GST M3-3 contributes to BCNU resistance in the U1810 cells.

Carcinoma, Non-Small-Cell Lung↗
PubMed1992

In vivo induced allo-reactive natural killer cells.

We have previously shown that rat allo-selective cells of the CD2+CD5- phenotype were generated in Brown Norway (BN) rats after immunization with allogeneic Wistar/Furth (WF) cells, whereas immunization with semi-allogeneic F1 (WF/BN) cells generated CD2+CD5+ effector T cells. We now report that the allo-selective CD2+CD5- lymphocytes lacked expression of intact CD3 complexes and expressed NKR-P1 molecules although lower as compared to classical NK cells, implicating that these lymphocytes constitute a subset of NK cells. The CD5+ T cells were not cytolytically active in BN rats immunized with WF cells indicating an intersubset regulation with mutually exclusive activation of either allo-selective T cells or allo-selective NK cells. Cold target inhibition showed that lysis of both allogeneic target cells and NK-sensitive target cells was mediated by the same NKR-P1 intermediate effector cells. These NK cells lysed WF but not allogeneic Fischer 344 or autologous BN target cells, indicating selective recognition of an allogeneic determinant. Semiallogeneic F1 (WF/BN) target cells were not lysed. Furthermore, target cells from F1 (WF/BN) x WF back-cross hybrids lacking expression of RT1n (self-MHC class I) were susceptible to lysis, whereas back-cross hybrids expressing RT1n were protected from lysis, indicating that self-MHC molecules conferred protection from lysis. These findings implicate the existence of NKR-P1intermediate and NKR-P1high NK cell subsets with different regulation and function in vivo.

Animals↗
PubMed1992

Locally superantigen-activated peritoneal cytolytic T lymphocytes belong to the CD8+ CD45RC- subset and lyse MHC class II+ tumor cells.

Bacterial encoded superantigens (SA) are capable of activating and targeting cytolytic human and mouse T lymphocytes (CTL) to lyse major histocompatibility complex class II positive (MHC class II+) target cells. In this study both in vitro and in vivo activated rat CTL were directed against MHC II+ tumor targets by bacterial encoded SA. Polyclonal in vitro activation of rat peripheral blood T lymphocytes generated CTL capable of killing MHC class II+ human BSM cells coated by staphylococcal enterotoxin (SE) -A, -E, -D, and TSST-1 but not by SEB or SEC1-3. Allo selective peritoneal CTL generated by intraperitoneal stimulation with allogeneic spleen cells were directed against BSM cells by SEA, -D, and -E but not by SEB, SEC1-3 or TSST-1. Based on the above observations, and in order to locally activate CTL, SEA was chosen for in vivo priming of rats by intraperitoneal inoculation of the toxin. SEA injection generated highly cytolytic CTL, and maximum cytolytic responses were seen at 50-250 micrograms SEA per animal with a peak in response 48-72 hours after injection of the toxin. The cytolytic activity of peritoneal SEA reactive effector cells was confined to the TCR alpha beta+ CD4- CD8+ CD45RC- cell population. MHC class II- colon carcinoma cells were insensitive to lysis by SEA reactive CTL but colon carcinoma cells induced to express MHC class II by interferon-gamma (IFN-gamma) treatment were efficiently lysed in the presence of SEA. Comparison of rat and human MHC II+ colon carcinomas revealed a peak in sensitivity to lysis at 10-100 ng SEA/ml for both tumor targets. These findings suggest that superantigens can be used in local immunotherapy of peritoneal tumors such as ovarian and colorectal carcinomatosis, with inducible or constitutive expression of MHC class II.

Animals↗
PubMed1992

Inherited defects in DNA repair and susceptibility to DNA-damaging agents.

Since all organisms are continuously exposed to exogenous and endogenous DNA damaging agents, mechanisms of repair of DNA lesions are necessary to maintain the integrity of the genome. Studies of the cellular defects in human inherited diseases with deficiencies in DNA repair have given new insights into these processes. Nucleotide excision repair is an important DNA repair pathway in which several types of DNA lesions are removed by a multi-step enzymatic process. This repair mechanism is deficient in the rare disease xeroderma pigmentosum (XP), which results in extreme sensitivity to ultraviolet light (UV) and development of UV-induced skin tumors at an early age. There are several genetic complementation groups of XP. The genes that are mutated in some of the XP complementation groups have been cloned and the functions of the encoded proteins are being characterised. Several types of DNA lesions are removed more rapidly from active genes than from other regions of DNA. This preferential repair of active genes is deficient in Cockayne's syndrome, which is characterised by developmental abnormalities and UV-sensitivity but no marked increase in cancer incidence. Other syndromes associated with increased sensitivity to certain DNA damaging agents where no defect in DNA repair has been defined include Fanconi's anemia (sensitivity to DNA cross-linking agents), hereditary dysplastic nevus syndrome (sensitivity to UV) and ataxia-telangiectasia (sensitivity to ionizing radiation).

Ataxia Telangiectasia↗
PubMed1992

Fosfomycin/metronidazole compared with doxycycline/metronidazole for the prophylaxis of infection after elective colorectal surgery. A randomised double-blind multicentre trial in 517 patients.

OBJECTIVE: To find out if fosfomycin together with metronidazole was any better than doxycycline with metronidazole for the prophylaxis of infection before elective colorectal operations. DESIGN: Multicentre, double blind, random control trial. SETTING: Nine Swedish hospitals. SUBJECTS-559 patients admitted for elective colorectal operations. INTERVENTIONS: Fosfomycin 8 g and metronidazole 1 g before operation and fosfomycin 8 g eight hours afterwards, or doxycycline 400 mg and metronidazole 1 g before operation, and placebo eight hours afterwards. MAIN OUTCOME MEASURES: Incidence of all types of infection, mortality, and side effects. RESULTS: There were no significant differences between the groups for any of the outcome measures studied, the overall abdominal infection rates (wound, deep, and septicaemia) being 4.6% and 7.4%, and the remote infection rates (pneumonia, urinary tract, and central venous line) 15.1% and 12.8%, respectively. Of the predictors studied, only duration of operation was significantly related to risk of infection. CONCLUSION: The combination of fosfomycin and metronidazole was as safe and effective as that of doxycycline and metronidazole in preventing infections after elective colorectal operations.

Aged↗
PubMed1991

Induction of interleukin-1 in human monocytes by the superantigen staphylococcal enterotoxin A requires the participation of T cells.

Nanogram quantities of the bacterial superantigen Staphylococcal Enterotoxin A (SEA) induced significant amounts of extracellular IL-1 alpha and IL-1 beta in human peripheral blood mononuclear cells. Induction of maximal IL-1 alpha and IL-1 beta levels by lipopolysaccharide (LPS) required microgram quantities. LPS induced detectable extracellular IL-1 content within 3-6 hr and maximal levels were detected already after 12 hr. Induction of IL-1 production by SEA showed a delayed release with peak values after 24-48 hr. IL-1 beta was the major species of IL-1 seen in both SEA- and LPS-stimulated culture supernatants. SEA was in general a relatively stronger inducer of extracellular IL-1 alpha than LPS. SEA-induced extracellular IL-1 production in human monocytes was entirely dependent on the presence of T cells, whereas addition of T cells to LPS-stimulated purified human monocytes only marginally enhanced the extracellular IL-1 production. The capacity to induce extracellular IL-1 production in monocytes in response to SEA was high in the CD4+ 45RO+ memory T cell subset, whereas CD4+ 45RA+ naive T cells and CD8+ T cells had lower IL-1-inducing capacity. The T cell help for IL-1 production could not be replaced by a panel of T cell-derived recombinant lymphokines added to SEA-stimulated monocytes, including IFN-gamma and TNF, indicating the participation of cell membrane-bound ligands or hitherto unidentified soluble mediators.

Antigens, Bacterial↗
PubMed1991

DNA excision repair in cell extracts from human cell lines exhibiting hypersensitivity to DNA-damaging agents.

Whole cell extracts from human lymphoid cell lines can perform in vitro DNA repair synthesis in plasmids damaged by agents including UV or cis-diamminedichloroplatinum(II) (cis-DDP). Extracts from xeroderma pigmentosum (XP) cells are defective in repair synthesis. We have now studied in vitro DNA repair synthesis using extracts from lymphoblastoid cell lines representing four human hereditary syndromes with increased sensitivity to DNA-damaging agents. Extracts of cell lines from individuals with the sunlight-sensitive disorders dysplastic nevus syndrome or Cockayne's syndrome (complementation groups A and B) showed normal DNA repair synthesis in plasmids with UV photoproducts. This is consistent with in vivo measurements of the overall DNA repair capacity in such cell lines. A number of extracts were prepared from two cell lines representing the variant form of XP (XP-V). Half of the extracts prepared showed normal levels of in vitro DNA repair synthesis in plasmids containing UV lesions, but the remainder of the extracts from the same cell lines showed deficient repair synthesis, suggesting the possibility of an unusually labile excision repair protein in XP-V. Fanconi's anemia (FA) cells show cellular hypersensitivity to cross-linking agents including cis-DDP. Extracts from cell lines belonging to two different complementation groups of FA showed normal DNA repair synthesis in plasmids containing cis-DDP or UV adducts. Thus, there does not appear to be an overall excision repair defect in FA, but the data do not exclude a defect in the repair of interstrand DNA cross-links.

Cells, Cultured↗
PubMed1991

Sensitization of human melanoma cells to the cytotoxic effect of melphalan by the glutathione transferase inhibitor ethacrynic acid.

Glutathione transferases are enzymes implied in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We have investigated the effect of the glutathione transferase inhibitor by ethacrynic acid on the cytotoxicity of melphalan to a human melanoma cell line (RPMI 8322) with a high level of glutathione transferase activity. Using 1-chloro-2,4-dinitrobenzene as substrate, ethacrynic acid was shown to inhibit the activity of purified human glutathione transferases, with 50% inhibition values of 1, 10, and 15 microM for transferase mu (class mu), transferase epsilon (class alpha) and transferase pi (class pi), respectively, all of which occur in RPMI 8322 cells. Ethacrynic acid at a concentration of 20 microM, which by itself was noncytotoxic, increased the cytotoxicity of melphalan to RPMI 8322 human melanoma cells approximately 2-fold. The induction of DNA interstrand cross-links by 40 microM melphalan was increased 1.4-fold by 30 microM ethacrynic acid. These results indicate that a potentiation of the cytotoxic effect of bifunctional alkylating agents can be achieved by inhibition of glutathione transferase and that the enhanced cytotoxicity may be caused at least in part by increased formation of drug-DNA adducts.

Cell Survival↗
PubMed1991

In vivo induction of gamma/delta T cells with highly potent and selective anti-tumor cytotoxicity.

High frequencies of CD5+TcR alpha/beta- T cells were induced in the peritoneal cavity of rats immunized with syngeneic W439 lymphoma cells. These TcR alpha/beta- cells expressed TcR delta mRNA as analyzed by the polymerase chain reaction technique. The delta + (TcR gamma/delta +) T cells were of the CD2+, CD3+, CD4-, CD8+, CD45RB+ phenotype and showed stronger anti-tumor cytotoxicity compared to the TcR alpha/beta + T cells. The cytotoxic effects of both alpha/beta and gamma/delta T cells were selective for the W439 lymphoma cells and were not directed to other syngeneic tumors, natural killer targets and syngeneic or allogeneic normal cells. T cells, including both alpha/beta and gamma/delta cells, were induced when WF rats were immunized with allogeneic BN spleen cells. In this case the gamma/delta T cells showed allo-selective cytotoxicity, although weaker compared to the TcR alpha/beta + T cells. The gamma/delta T cells, induced by immunization with either W439 cells or BN spleen cells, were selective for the immunogen used and had no effect on irrelevant target cells, indicating that these effector cells were not activated by a shared gamma/delta T cell-related superantigen. Since highly potent tumor-selective gamma/delta cytotoxic T lymphocytes could be induced by syngeneic lymphoma cells, we suggest a role for gamma/delta T cells in the defense against certain types of tumors.

Animals↗
PubMed1991

Comparative study of two human melanoma cell lines with different sensitivities to mustine and cisplatin.

The cytotoxic effects of the bifunctional DNA-reactive drugs cisplatin, mustine and melphalan were studied in two human melanoma cell lines, RPMI 8322 and A 375. A 375 cells were 3.0 times more sensitive to cisplatin and 1.5 times more sensitive to mustine than RPMI 8322 cells. In contrast, A 375 cells were less sensitive to melphalan than RPMI 8322 cells. The increased sensitivity of A 375 cells was parallelled by an increased induction of DNA interstrand crosslinks following exposure to cisplatin and mustine. After cisplatin exposure A 375 cells also showed higher levels of platinum-DNA intrastrand adducts than RPMI 8322 cells. The increased effect of cisplatin in A 375 cells was not due to an increased drug accumulation in these cells. The higher sensitivity of A 375 cells to cisplatin may be related to lower intranuclear levels of glutathione, compared to RPMI 8322 cell nuclei, while the sensitivity to mustine may depend on lower overall levels of glutathione than in RPMI 8322 cells.

Cell Line↗
PubMed1991

Carmustine-induced toxicity, DNA crosslinking and O6-methylguanine-DNA methyltransferase activity in two human lung cancer cell lines.

O6-methylguanine-DNA methyltransferase (O6-MT) probably plays an important role in the repair of chloroethylnitrosourea-induced DNA damage. O6-MT was studied as a possible drug resistance factor in two human lung cancer cell lines, one small cell lung cancer (U1690) and one non-small cell lung cancer (U1810), with different sensitivities to carmustine. The U1810 cell line was 3.4-fold more resistant to carmustine than U1690 cells, although the two cell lines were equally sensitive to mustine, melphalan and cisplatin. A 23-fold higher level of DNA interstrand crosslinks was observed following exposure of U1690 cells to carmustine compared with U1810 cells. The O6-MT activity of U1810 cells was 11 times higher than that of U1690 cells. The O6-MT activity in the U1810 cells showed a dose-dependent decrease after exposure to carmustine. These results show a correlation between increased O6-MT activity, decreased drug induced DNA interstrand crosslinking and cellular resistance to carmustine.

Carcinoma, Non-Small-Cell Lung↗
PubMed1990

Production of TNF-alpha and TNF-beta by staphylococcal enterotoxin A activated human T cells.

Staphylococcal enterotoxin at concentrations of less than 1 pg/ml induces significant TNF activity in human peripheral blood T cells and monocytes. Maximal TNF activity is routinely detected after 48 to 72 h of culture. IL-2 and IL-4 were both growth promoting for human T cells but only IL-2 could efficiently induce TNF production. The production of TNF-alpha and TNF-beta differed greatly in kinetics. An early intracytoplasmatic production of TNF-alpha after 6 h was detected in both monocytes and T cells whereas a late production of TNF-beta (lymphotoxin) after 48 h, occurred in the T cell population. Induction of TNF-alpha and TNF-beta production by Staphylococcal enterotoxin requires the presence of both monocytes and T cells. The CD4+45R- but not CD4+45R+ and CD8+ cells supported TNF-alpha production in monocytes. The main lytic component from Staphylococcal enterotoxin-activated mononuclear cells is TNF-beta. CD4+ and CD8+ T cells produced about equal amounts of biologically active TNF into the culture supernatants but a fourfold higher frequency of TNF-beta producing cells was demonstrated among CD4+ vs CD8+ cells. The CD4+45R- T cell subset was an efficient producer of TNF-beta and IFN-gamma whereas the CD4+45R+ T cell subset produced significant amounts of TNF-beta but only marginal amounts of IFN-gamma.

Antigen-Presenting Cells↗
PubMed1990

Complementation of the xeroderma pigmentosum DNA repair synthesis defect with Escherichia coli UvrABC proteins in a cell-free system.

A newly developed cell-free system was used to study DNA repair synthesis carried out by extracts from human cell lines in vitro. Extracts from a normal human lymphoid cell line and from cell lines established from individuals with hereditary dysplastic nevus syndrome perform damage-dependent repair synthesis in plasmid DNA treated with cis- or trans-diamminedichloro-platinum(II) or irradiated with ultraviolet light. Cell extracts of xeroderma pigmentosum origin (complementation groups A, C, D, and G) are deficient in DNA repair synthesis. When damaged plasmid DNA was pretreated with purified Escherichia coli UvrABC proteins, xeroderma pigmentosum cell extracts were able to carry out DNA repair synthesis. The ability of E. coli UvrABC proteins to complement xeroderma pigmentosum cell extracts indicates that the extracts are deficient in incision, but can carry out later steps of repair. Thus the in vitro system provides results that are in agreement with the incision defect found from studies of xeroderma pigmentosum cells.

Cell-Free System↗
PubMed1990

Tumor-selective cytolysis is executed exclusively by CD45R+ CTL whereas allo-specific cytotoxicity can be executed also by CD45R- CTL.

Naive and memory CD4+ T helper cells can be distinguished on the basis of expression of the CD45R molecule. Whether this dichotomy applies also to CD8+ T cells has not yet been established. In the present investigation the cytolytic activity of peritoneal CD8+CD45R+ and CD8+CD45R- T cells from tumor- and allo-immunized rats has been studied. More than 90% of the CD8+ peripheral blood T lymphocytes expressed the CD45R molecule, whereas in the peritoneal cavity about 60% of the CD8+ T cells displayed the CD45R+ phenotype. Analysis of cytotoxicity of sorted peritoneal cells of W439 tumor-immunized donors demonstrated selective cytolytic activity of the CD5+CD4-CD8+CD45R+ subpopulation to W439 lymphoma target cells but no effect of CD5+CD4-CD8+CD45R- lymphocytes. None of these lymphocyte populations exhibited cytolytic activity to the NK-sensitive cell line YAC-1, whereas the CD5-CD45R+ population showed strong cytotoxicity to YAC-1 cells. In allo-immunized rats both CD5+CD4- CD8+CD45R+ and CD5+CD4-CD8+CD45R- peritoneal cells exhibited strong allo-specific cytolytic activity, but no activity to YAC-1 cells. Both CD5+CD4-CD8+CD45R+ and CD5+CD4-CD8+CD45R- cells from tumor-immunized rats proliferated in response to Con A and rIL-2. This is the first study demonstrating that tumor-selective cytolytic CD8+ T cells express the CD45R molecule and that allo-specific cytolytic CD8+ T cells are found in both the CD45R+ and CD45R- populations.

Animals↗
PubMed1990

Dacarbazine-vindesine-cisplatin in disseminated malignant melanoma. A phase I-II trial.

Dacarbazine-vindesine-cisplatin treatment was evaluated in a phase II study of patients with disseminated malignant melanoma after the dose of cisplatin had been determined in a phase I study. Dose of dacarbazine was 250 mg/m2 X V every 4 weeks, vindesine 3 mg/m2 once every week, and cisplatin 100 mg/m2 every 4 weeks. Forty patients with advanced disseminated malignant melanoma are available for response. Complete remissions were obtained in three patients (8%) and partial remissions in 12 patients (30%). The total response rate was 38%. Median response duration was 4 months. Toxicity was unacceptable in five cases (nephrotoxicity, one patient; ototoxicity, two patients; hypotonia, one patient; gastrointestinal toxicity, one patient). The conclusion is that the combination dacarbazine-vindesine-cisplatin gives rise to a high response rate in patients with advanced disseminated malignant melanoma. Despite its considerable toxicity, the regimen should be tested on patients with a limited tumor burden.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Localization of DNA repair synthesis by human cell extracts to a short region at the site of a lesion.

Double-stranded bacteriophage M13 DNA molecules were constructed containing a single specifically placed 2-(acetylamino)fluorene adduct or a single 4'-hydroxymethyl-4,5',8-trimethylpsoralen monoadduct. These circular DNA molecules were used to analyze in vitro DNA repair synthesis by cell extracts from normal human lymphoid cell lines. Both types of lesions stimulate DNA repair synthesis at the site of the adduct. DNA repair synthesis induced by the 2-(acetyl-amino)fluorene adduct took place in the damaged strand and was confined to a region within a 31-base pair restriction fragment around the adduct.

2-Acetylaminofluorene↗
PubMed1989

Repair synthesis by human cell extracts in DNA damaged by cis- and trans-diamminedichloroplatinum(II).

DNA damage was induced in closed circular plasmid DNA by treatment with cis- or trans-diamminedichloroplatinum(II). These plasmids were used as substrates in reactions to give quantitative measurements of DNA repair synthesis mediated by cell free extracts from human lymphoid cell lines. Adducts induced by both drugs stimulated repair synthesis in a dose dependent manner by an ATP-requiring process. Measurements by an isopycnic gradient sedimentation method gave an upper limit for the average patch sizes in this in vitro system of around 140 nucleotides. It was estimated that up to 3% of the drug adducts induce the synthesis of a repair patch. The repair synthesis is due to repair of a small fraction of frequent drug adducts, rather than extensive repair of a rare subclass of lesions. Nonspecific DNA synthesis in undamaged plasmids, caused by exonucleolytic degradation and resynthesis, was reduced by repeated purification of intact circular forms. An extract made from cells belonging to xeroderma pigmentosum complementation group A was deficient in repair synthesis in response to the presence of cis- or trans-diamminedichloroplatinum(II) adducts in DNA.

Antineoplastic Agents↗