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K Linnainmaa

Publications and source records attributed to K Linnainmaa.

At least 55 records · Page 3Linked to original sources
PubMed1992

Interferon-alpha and -gamma in combination with chemotherapeutic drugs: in vitro sensitivity studies in four human mesothelioma cell lines.

Mesothelioma is a tumor of the serous surfaces in the thorax and abdomen. This tumor has proved to be exceptionally resistant to treatment, although a variety of multi-modality therapies have been tried. We have used four human mesothelioma cell lines, originating from diffuse asbestos-related malignant (pleural) mesothelioma, to assess in vitro sensitivity to five chemotherapeutic drugs, to recombinant human interferon (IFN)-alpha and -gamma and to combined immuno-chemotherapy. The cytotoxic effects were assayed by vital dye exclusion. The drugs tested were etoposide, cisplatin, mitoxantrone, 4-epirubicin and vindesine. The combinations tested were etoposide+cisplatin, and etoposide+cisplatin+mitoxantrone. All the drugs and combinations were also tested with recombinant human (rHu) IFN-alpha 2C (rHuIFN-alpha), rHuIFN-gamma, and rHuIFN-alpha+rHuIFN-gamma. The cell lines were most sensitive to mitoxantrone, 4-epirubicin and vindesine (TC50 < or = 0.001 micrograms/ml), and least sensitive to etoposide and cisplatin (TC50 > or = 0.1 micrograms/ml) used singly. There was no improvement in sensitivity when the drugs were combined. To further investigate the lack of response to cisplatin treatment, we examined the binding of cisplatin to the mesothelioma cell DNA. The tumor cell DNA bound markedly less cisplatin than human fetal fibroblast DNA. Three cell lines were tested with rHuIFN-alpha and rHuIFN-gamma on their own or rHuIFN-alpha+rHuIFN-gamma. They were consistently sensitive to rHuIFN-alpha, but the sensitivity to rHuIFN-gamma varied with the cell lines. Finally, we tested two cell lines with the drugs singly and in combination, together with 0.01 micrograms/ml each of rHuIFN-alpha and rHuIFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1991

Malignant mesothelioma: the antiproliferative effect of cytokine combinations on three human mesothelioma cell lines.

Tumour necrosis factor (TNF) combined with gamma-interferon (IFN gamma) is known to have antiproliferative effects on many tumour cells, both in vitro and in vivo. We investigated whether human mesothelioma cells would respond in a similar way. Mesothelioma cell lines established from primary tumours did not respond significantly in vitro to either TNF or IFN gamma alone but were inhibited by combinations of TNF and IFN gamma at concentrations as low as 5 ng/ml. In contrast, a mesothelioma cell line established from a metastatic tumour was sensitive to IFN gamma both alone and in combination with TNF but not to TNF alone. We also looked at the responses of one primary tumour cell line and the metastatic tumour cell line to alpha-interferon (IFN alpha) both alone and in combination with TNF. Both cell lines were sensitive to IFN alpha but were more sensitive to the THF/IFN alpha combination. We conclude that these low dose combinations of cytokines are worth further investigation in the development of mesothelioma therapy.

Cell Line↗
PubMed1990

An inter-Nordic prospective study on cytogenetic endpoints and cancer risk. Nordic Study Group on the Health Risk of Chromosome Damage.

To investigate whether high rates of chromosomal aberrations (CAs), sister chromatid exchange (SCE), or micronuclei(MN) in peripheral lymphocytes indicate an increased risk for subsequent cancer, a prospective cohort study of 2,969 subjects cytogenetically examined between 1970 and 1988 in four Swedish, two Finnish, and two Norwegian laboratories was initiated. To standardize for the interlaboratory variation, the results of the three cytogenetic endpoints were trichotomized for each laboratory into "low" (1st to 33rd percentile), "medium" (34th to 66th percentile), and "high" (67th to 100th percentile]. Thirty-four cancers had been diagnosed in the cohort during the observation period (1970 to 1985). The point-estimates of the standardized morbidity ratio (SMR) in the three CA strata were 90, 92, and 180, respectively. This trend for a positive association was not statistically significant (p = 0.06). There was no significant trend between SMR and the trichotomized rates of SCE. In the subcohort examined for MN only two cases of cancer had been diagnosed until now. If subjects with "high" frequencies of CA or SCE have a two-fold (or greater) risk of developing cancer as compared with individuals who have "medium" or "low" frequencies, we estimate that there is a likelihood of 80% and 70%, respectively, that this will be detectable as significant (p less than or equal to 0.05) differences after a further follow-up period of 5 years. Weaker associations between cancer risk and the cytogenetic endpoints would not be possible to evaluate until even later follow-ups.

Chromosome Aberrations↗
PubMed1989

Effects of commercial chlorophenolate, 2,3,7,8-TCDD, and pure phenoxyacetic acids on hepatic peroxisome proliferation, xenobiotic metabolism and sister chromatid exchange in the rat.

The induction of hepatic peroxisome proliferation and drug metabolizing enzymes and of sister chromatid exchange (SCE) in lymphocytes was studied in male Han/Wistar rats after exposing them for 2 weeks to a commercial chlorophenolate formulation (Ky-5) (100 mg/kg/day), to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; 0.05-5 micrograms/kg/wk) and to the pure phenoxyacetic acids, 2,4-dichlorophenoxyacetic acid (2,4-D; 100 mg/kg/day) and 2-chloro-4-methylphenoxyacetic acid (MCPA; 100 mg/kg/day). The chlorophenolate formulation and pure 2,4-D and MCPA caused significant increases in the number of peroxisomes in liver cells, although the average size of peroxisomes was not affected, whereas the effect of even the highest dose of 2,3,7,8-TCDD remained small. This finding indicates that dioxin impurities do not account for the peroxisome proliferation induced by chlorophenolate. The relative weight of the liver increased significantly in rats treated with the chlorophenolate formulation and with 2,3,7,8-TCDD (5.0 and 0.5 micrograms/kg). The pattern of induction of xenobiotic metabolizing enzymes showed some differences between chlorophenolate treatment and 2,3,7,8-TCDD treatment. Furthermore, the effects of pure phenoxyacetic acids were different from that seen with chlorophenolate and 2,3,7,8-TCDD. The highest dose of 2,3,7,8-TCDD increased the frequency of SCE in circulating lymphocytes slightly, but significantly.

Animals↗
PubMed1987

Heterogeneity of intercellular adhesion in rat liver cells in culture.

The intercellular homotypic adhesive properties of 14 clones derived from a nontumorigenic rat liver epithelial cell line (LEC), derived from neonatal Fischer rats, were examined and compared to those of the hepatoma H4-II-E cell line. Each clone was assayed also for the degree of chromosomal aneuploidy and the ability to grow in soft agar. Over 100-fold differences in adhesive properties were observed among the clones, but no correlation was observed between the degree of aneuploidy in the clones and intercellular adhesive properties. The parent LEC cell line and the clones derived from it were unable to grow in soft agar. The H4-II-E cells showed negligible capacity to reaggregate after dissociation into single cells and these cells readily formed colonies in soft agar. Many of the LEC clones were similar to the H4-II-E cells in their adhesive properties, which suggests that reduced cell-to-cell adhesiveness per se is not a necessary prerequisite of epithelial cells to be able to grow independent of anchorage. Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) of concanavalin A (Con A)-binding glycoproteins in the "most adhesive" clone 67 and the "least adhesive" clone 201 showed markedly elevated amounts of acidic 105 and 67-kDa glycoproteins in clone 67. Proteins with similar migration patterns in 2D-PAGE have previously been reported to participate in specific homotypic intercellular adhesion of liver cells. The Con A-binding glycoprotein pattern in H4-II-E cells was markedly different from that of LEC cells with a set of six proteins missing and nine proteins appearing new in the H4-II-E cells. It is suggested that, in addition to identifying known epithelial cell polypeptides, systematic screening of cell surface-associated glycoproteins in normal and transformed epithelial cells in vitro and in vivo may lead to identification of novel polypeptides intimately associated with the transformed phenotype.

Aneuploidy↗
PubMed1986

Fecapentaene-12 causes DNA damage and mutations in human cells.

Fecapentaenes are mutagens found in human feces and may play a role in the pathogenesis of colon carcinoma. However, the genotoxic effects of fecapentaenes have not been previously studied in mammalian cells. We now report that fecapentaene-12 (fec-12), a prototype for these compounds, causes DNA single strand breaks, sister chromatid exchanges and mutations in cultured human fibroblasts. These results indicate that fec-12 is a potent genotoxic agent in human cells.

Cells, Cultured↗
PubMed1986

Effects of phenoxyacetic acids on the induction of chromosome aberrations in vitro and in vivo.

The effects of phenoxyacetic acid herbicides were investigated on the induction of chromosome aberrations in human peripheral lymphocyte cultures in vitro and in lymphocytes of exposed workers in vivo. Pure 2,4-dichlorophenoxyacetic acid (2,4-D; 0.125, 0.150, 0.200 and 0.350 mM) did not increase the number of aberrations, whereas the commercial 2,4-D formulation (0.125, 0.250, 0.500, 1.000 and 1.250 mM, with respect to phenoxyacetic acid concentration) significantly increased the number of chromosome aberrations in vitro (without exogenous metabolic activation). The phenoxy acid levels in the breathing zone of the workers varied between 0.3 and 0.4 mg/m3, and the concentrations of phenoxyacetic acids in the urine of the workers after exposure varied from 0.000 to 0.055 mmol/l. There were no increases in chromosome aberrations in peripheral lymphocytes of the exposed subjects.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1985

Enhanced peroxisomal beta-oxidation of fatty acids and glutathione metabolism in rats exposed to phenoxyacetic acids.

Peroxisomal beta-oxidation of fatty acids and the activities of glutathione-metabolizing enzymes in rat liver were measured after administration of 2,4-dichlorophenoxyacetic acid (2,4-D), 4-chloro-2-methylphenoxyacetic acid (MCPA), clofibrate [ethyl], 2-(p-chlorophenoxy)-2-methylpropionate], glyphosate (N-phosphonomethyl glycine, a herbicide not structurally related to phenoxy acids) or saline for 14 days. beta-Oxidation increased by 6-fold in the group given clofibrate, 3-fold in the 2,4-D-treated group, and 2-fold in the MCPA-treated group over the level in the controls (saline-treated). Glyphosate did not increase beta-oxidation. No significant change in reduced glutathione content from that in controls was found in any of the treated groups. Glutathione reductase activity increased by about 40% after administration of either 2,4-D or MCPA, and glutathione peroxidase activity increased by 30% in animals given MCPA. A slight decrease in glutathione S-transferase activity was found in the group treated with clofibrate. The marked increases in peroxisomal beta-oxidation of fatty acids were accompanied by only minor changes in the activities of enzymes involved in glutathione-dependent inactivation of organic hydroperoxides and other oxygen-centred reactive agents.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1984

Induction of sister chromatid exchanges by the peroxisome proliferators 2,4-D, MCPA, and clofibrate in vivo and in vitro.

Phenoxy acid herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxyacetic acid (MCPA) have been found to induce proliferation of peroxisomes in the liver cells of rodents in the same manner as the hypolipidemic drug clofibrate. Both phenoxy acid herbicides and clofibrate (ethyl-alpha-p- chlorophenoxyisobutyrate ) are suspected carcinogens. The present study reports the effect of these agents on the induction of sister chromatid exchange (SCE) in the blood lymphocytes of exposed rats (100 mg/kg with 2,4-D and MCPA, 200 mg/kg with clofibrate for 2 weeks in one intragastric dose/day), in the bone marrow cells of exposed Chinese hamsters (100 mg/kg, treatments as above), and in Chinese hamster ovary (CHO) cells in vitro (10(-5), 10(-4), and 10(-3) M, for 1 h). In the experiments in vitro, the effects of purified 2,4-D and MCPA phenoxy acids were studied, in addition to those of the commercial herbicide formulations and clofibrate. No increase of SCE frequency was observed in the blood lymphocytes of the exposed rats in comparison with the controls. In the bone marrow cells of the exposed Chinese hamsters, a slight increase of SCE was found in the group treated with MCPA but not in the groups treated with 2,4-D or clofibrate. A slight increase in the number of SCEs was characteristic of all the treated CHO cell cultures, both with and without a rat liver microsomal activation system (S9 mix). No clear dose-related effects, however, could be discerned with any of the compounds, and no differences in the SCE induction were observed between the commercial herbicide products and the purified phenoxy acetic acids. The present results support the data which indicate that 2,4-D, MCPA, and clofibrate do not act as direct DNA-damaging agents.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1983

Hypolipidemia and peroxisome proliferation induced by phenoxyacetic acid herbicides in rats.

Male Wistar rats were treated daily by gavage with two phenoxy herbicides, 2,4-dichlorophenoxyacetic acid (2,4-D)(100-200 mg/kg body wt) and 4-chloro-2-methylphenoxyacetic acid (MCPA) (100-200 mg/kg body wt), and with the chemically different glyphosate N-phosphonomethyl glycine (300 mg/kg body wt) 5 days per week for 2 weeks. A hypolipidemic drug, clofibrate [ethyl-2-(4-chlorophenoxy)-2-methylpropionate], which is structurally related to phenoxy acids, was used as a positive control (200 mg/kg body wt). 2,4-D and MCPA had several effects similar to those of clofibrate: all three compounds induced proliferation of hepatic peroxisomes, decreased serum lipid levels, and increased hepatic carnitine acetyltransferase and catalase activities. 2,4-D and MCPA, but not clofibrate, decreased lipoprotein lipase activity in the adipose tissue to about a third of the control value but did not change the lipoprotein lipase activity in the heart muscle. The data suggest that these compounds cause hypolipidemia not by enhancing the storage of peripheral lipids in adipose tissue but by preferentially increasing lipid utilization in the liver. Glyphosate caused no peroxisome proliferation or hypolipidemia, suggesting that these effects are associated with the structural similarity between phenoxy acid herbicides and clofibrate.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1983

Sister chromatid exchanges among workers occupationally exposed to phenoxy acid herbicides 2,4-D and MCPA.

The induction of sister chromatid exchanges (SCEs) was studied in the peripheral lymphocytes of workers spraying foliage in forestry with phenoxy acid herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-methyl-4-chlorophenoxyacetic acid (MCPA) or their mixtures. In order to follow possible exposure-related changes in the frequencies of SCEs, three successive blood samples were taken from 50 male sprayers during the spraying season of July-October, 1981. In addition, 15 control subjects not working with herbicides were included in the study. The actual exposure levels of the exposed subjects were estimated by measuring the concentrations of 2,4-D and MCPA in the urine of the sprayers. Enough cells for the SCE analysis were obtained from 35 herbicide workers and 15 control subjects. The concentrations of 2,4-D and MCPA in the urine samples after exposure varied from 0.00 to 10.99 mg/l. No significant differences in the frequencies of SCEs were observed in samples taken before, during, or after the exposure. Furthermore, the means of SCEs in a nonexposed control group of 15 subjects fell in the same range as those of the exposed subjects. A difference in the means of SCEs was observed between nonsmokers and smokers, smokers having significantly higher mean values than nonsmokers. The results of the present study add support to the earlier data indicating that 2,4-D and MCPA do not act as direct DNA-damaging agents.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1983

Reactivity, SCE induction and mutagenicity of benzyl chloride derivatives.

Benzyl chloride, benzyl bromide, p-methylbenzyl chloride, and p-nitrobenzyl chloride were used to study chemical reactivity with 4-(p-nitrobenzyl)-pyridine (NBP), and with guanosine in vitro, in relation to mutagenic potency in S. typhimurium and sister chromatid exchange (SCE) induction in CHO cells. Benzyl bromide was found to be the most reactive compound, followed by p-methylbenzyl chloride, benzyl chloride and p-nitrobenzyl chloride. The order of mutagenicity was p-nitrobenzyl chloride much greater than benzyl bromide greater than benzyl chloride approximately equal to p-methylbenzyl chloride. The compounds tested caused base-pair mutations only. The order of SCE-inducing ability decreased as follows: benzyl bromide greater than benzyl chloride approximately equal to p-nitrobenzyl chloride approximately equal to p-methylbenzyl chloride. The particularly high mutagenicity of p-nitrobenzyl chloride in bacteria may be due to reactions other than direct aralkylation, or it may react particularly actively with DNA. Among the other compounds, benzyl bromide was the most active aralkylating compound, mutagen and SCE inducer. The results suggested that reaction of N2 of guanine, as compared with N-7 of guanine, failed to show any remarkable mutagenicity or SCE induction, since p-methylbenzyl chloride, reacting preferentially at N2 of guanosine, failed to show unexceptional potency.

Animals↗
PubMed1983

Effects of phenoxyherbicides and glyphosate on the hepatic and intestinal biotransformation activities in the rat.

The effects of phenoxyacid herbicides 2,4-D (2,4-dichlorophenoxyacetic acid) and MCPA (4-chloro-2-methylphenoxyacetic acid), clofibrate, and glyphosate on hepatic and intestinal drug metabolizing enzyme activities were studied in rats intragastrically exposed for 2 weeks. The hepatic ethoxycoumarin O-deethylase activity increased about 2-fold with MCPA. Both 2,4-D and MCPA increased the hepatic epoxide hydrolase activity and decreased the hepatic glutathione S-transferase activity. MCPA also increased the intestinal activities of ethoxycoumarin O-deethylase and epoxide hydrolase. Glyphosate decreased the hepatic level of cytochrome P-450 and monooxygenase activities and the intestinal activity of aryl hydrocarbon hydroxylase. Clofibrate decreased the hepatic activities of UDPglucuronosyltransferase with p-nitrophenol or methylumbelliferone as the substrate. Also 2,4-D decreased the hepatic activity of UDPglucuronosyltransferase with p-nitrophenol as the substrate. MCPA decreased the intestinal activities of UDPglucuronosyltransferase with either p-nitrophenol or methylumbelliferone as the substrate. The results indicate that phenoxyacetic acids, especially MCPA, may have potent effects on the metabolism of xenobiotics. Glyphosate, not chemically related to phenoxyacids, seems to inhibit monooxygenases. Whether these changes are related to the toxicity of these xenobiotics remains to be clarified in further experiments.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1982

Sister chromatid exchange induced by short-lived monoadducts produced by the bifunctional agents mitomycin C and 8-methoxypsoralen.

To see if DNA crosslinks are involved in the induction of sister chromatid exchange (SCE), Chinese hamster ovary cells were exposed to two bifunctional alkylating agents, mitomycin C and 8-methoxypsoralen, and their monofunctional derivatives, decarbamoyl mitomycin C and angelicin. The data indicate that monoadducts, rather than crosslinks, are responsible for SCE formation. Furthermore, all agents but angelicin produced short-lived lesions that led to SCEs in the first period of DNA replication after treatment (twin SCEs), but not in the second (single SCEs). In contrast, angelicin, like methyl methanesulfonate and N-acetoxyacetylaminofluorene, produced lesions that lasted more than one cycle, indicating that several different types of DNA lesions are capable of SCE induction.

Animals↗
PubMed1982

Phenoxy acid herbicides cause peroxisome proliferation in Chinese hamsters.

An increase in either the size or amount of peroxisomes was obtained in the liver cells of Chinese hamsters after the animals were exposed to the phenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) or 4-chloro-2-methylphenoxyacetic acid (MCPA). At the dose level studied, 2,4-D was found to be more potent than MCPA in increasing the number of peroxisomes. A phenoxy acid derivative, clofibrate, one of the peroxisome proliferators known to possess carcinogenic properties in rodents, appeared to be still more potent in inducing peroxisome proliferation than either of the herbicides studied. Further investigations are warranted to clarify the significance of peroxisome proliferation to the toxicity of phenoxy herbicides.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1978

Cytogenetic effects of styrene and styrene oxide.

Styrene and styrene oxide induce various cytogenetic effects, similar in both human lymphocytes in vitro and onion root-tip cells in vivo. Styrene appears to cause chromosome breakage in both systems, and in Allium it shows a strong c-mitotic effect. Styrene oxide, on the other hand, seems to destroy the tertiary folding of the chromatin. Cytotoxicity of styrene oxide is very high (complete mitotic inhibition occurs on 0.03% v/v) in human lymphocytes, whereas, in Allium, styrene is slightly more toxic than styrene oxide. Styrene glycol, a further metabolite of styrene oxide, does not cause mitotic inhibition.

Cells, Cultured↗