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M A Lea

Publications and source records attributed to M A Lea.

At least 55 records · Page 3Linked to original sources
PubMed1983

Decreased sensitivity to colchicine-mediated inhibition of metabolite uptake in isolated hepatoma cells.

The effects of colchicine on the incorporation of [3H]-leucine and [3H]thymidine were studied in inbred BUF rats bearing Morris hepatomas and in isolated hepatoma cells and hepatocytes. The results confirmed previous work by other investigators that uptake of amino acids in hepatomas can be inhibited by colchicine (250 micrograms/100 body wt) under conditions in which uptake is not impeded in host liver. Uptake and incorporation of [3H]thymidine in hepatomas were also more sensitive to inhibition by colchicine. Evidence was obtained that these inhibitory effects on incorporation were diminished in isolated cells and were similar for isolated hepatoma cells and hepatocytes. The data did not exclude alternative mechanisms, but they were compatible with a previous suggestion that an effect of colchicine on circulation in hepatomas may be a factor in the inhibitory action on metabolite uptake.

Animals↗
PubMed1982

Effects of nicotinamide, isonicotinamide, and bleomycin on DNA synthesis and repair in rat hepatocytes and hepatoma cells.

Because inhibitors of poly (ADP-ribose) synthetase have been found to influence DNA synthesis in some systems, the possibility that nicotinamide or isonicotinamide might potentiate the effect of bleomycin on DNA replication and repair was examined. After a 30-minute incubation with bleomycin (200 micrograms/ml), tritiated thymidine ([3H]dThd) incorporation into DNA was stimulated during a subsequent 30-minute incubation with hepatocytes of inbred BUF rats but was decreased in HTC cells of BUF rats. When unscheduled DNA synthesis was measured in the presence of 10 mM hydroxyurea, bleomycin (200 micrograms/ml) increased [3H]dThd incorporation in both cell types. A dose of 20 mM nicotinamide and isonicotinamide caused an approximately 50% inhibition of total [3H]dThd incorporation in HTC cells. Significant inhibitory effects of 20 mM nicotinamide and isonicotinamide on unscheduled DNA synthesis were observed after preincubation of hepatocytes and HTC cells with bleomycin. When the effects of bleomycin on DNA structure were assessed fluorometrically with ethidium bromide after mild alkaline incubation, nicotinamide and isonicotinamide did not significantly affect the damage revealed with bleomycin alone. When HTC cells were incubated for 48 hours with bleomycin (20 micrograms/ml), the increase in cell numbers was about 50% of that in control cultures. Nicotinamide and isonicotinamide also inhibited the proliferation of HTC cells, but the effects were not additive with the effect of bleomycin.

Animals↗
PubMed1981

Colchicine affects the distribution of isotope-labeled H2O and extracellular markers in rat liver and hepatomas.

Treatment of hepatoma-bearing rats with colchicine (175 or 250 micrograms/100 g body wt) greatly diminished the radioactivity in tumors when measured 10 min after subcutaneous injection of 3H2O. There were relatively small effects of colchicine treatment on the level of radioactivity in blood and little change in the ratio of radioactivity in blood and liver. Inhibitory effects of colchicine were also observed for the distribution in hepatomas of the extracellular markers [3H] methoxy-inulin and [14C] sucrose. An effect of colchicine on circulation in hepatomas may be a factor in the previously reported inhibitory action on metabolite uptake.

Animals↗
PubMed1981

Uptake of 14C-labeled dicarboxylic amino acids in hepatocytes and hepatoma cells.

In previous studies, we observed decreased uptake of 14C-labeled L-aspartate and L-glutamate in s.c. transplants of several rapidly growing hepatomas relative to that in normal liver. The present report extends these observations to isolated cells and indicates that circulation differences cannot be the major factor. Mean net uptakes for the two dicarboxylic amino acids in cells from the rapidly growing Morris Hepatomas 7288ctc and 7777 were 5 to 26% of corresponding values for normal hepatocytes. Rates for net uptake in Hepatoma 7787 cells were intermediate between those of the rapidly growing hepatomas and hepatocytes, while the rates for Hepatoma 5123C cells and hepatocytes were similar. The contribution of sodium-dependent uptake to the mean total net uptake of [14C]aspartate and [14C]glutamate tended to be higher in hepatoma cells than in hepatocytes. Studies with isolated hepatocytes and Hepatoma 5123C cells showed no significant effect on uptake by 10 mM alpha-(methylamino)isobutyric acid and 10 mM 2-amino-2-carboxybicyclo[2.2.1]heptane. On the other hand, L-cysteic acid, L-alanosine, and N-phosphonacetyl-L-aspartic acid were shown to be effective inhibitors of sodium-dependent uptake in Hepatoma 5123C cells. The data suggest that the A and L systems are not major contributors to the uptake of dicarboxylic amino acids in hepatic cells. It was concluded that decreased uptake of dicarboxylic amino acids in rapidly growing hepatomas may accompany decreased metabolism of these dietary nonessential amino acids.

Alanine↗
PubMed1981

X-irradiation and the incorporation of precursors for salvage and de novo synthesis of DNA in hepatomas and liver.

The effect of X-irradiation 15 Gy (1500 rad) on precursor incorporation into DNA was studied in transplanted Morris hepatomas and liver of the tumor-bearing rats. Precursors were studied which are utilized by salvage mechanisms ([3H] thymidine and [3H]deoxyuridine) or in de novo synthesis of DNA ([14C]aspartate and [14C]formate). The data suggested that salvage mechanisms are more sensitive to inhibition by X-irradiation and that DNA repair activity is greater in liver than hepatomas.

Animals↗
PubMed1981

Effects of cyanate on the distribution of isotope-labeled H2O and extracellular markers in rat liver and tumors.

Previous work has shown that administration of sodium cyanate inhibits the uptake of several metabolites in tumors under conditions in which there is generally no inhibition in normal tissues of the rat. In the present work, it was found that cyanate treatment inhibits the distribution of 3H2O, [3H]methoxyinulin, and [14C]sucrose in rats with greater effects in the tumors than the normal tissues examined. Tumor-bearing rats received i.p. injections of sodium cyanate (250 mg/kg body weight). After 60 min, the rats received s.c. injections of 3H2O. Treatment with cyanate decreased the radioactivity in blood and liver, but greater effects were seen in five transplanted tumors (LK1 colon tumor and Morris hepatomas 5123C, 7288CTC, 7777, and 9618A2). At 10 min after injection of 3H2O, the mean radioactivities in tumors of cyanate-treated rats were 11 to 23% of control values and in some tumors were still less than in controls at 60 min after isotope injection. Evidence was obtained that the action of cyanate was not due to osmotic effects or loss of water from the tissues. The distribution of the extracellular markers [3H]methoxyinulin and [14C]sucrose was also decreased in hepatomas in cyanate-treated rats. The data do not exclude effects on membrane permeability but suggested that cyanate decreased circulation in the tumors.

Animals↗
PubMed1980

Decreased uptake of 14C-labeled dicarboxylic amino acids in rapidly growing hepatomas.

In contrast to the increased uptake of amino acids which has been found in many neoplastic cells, we have observed a decrease in the net uptake of [14C]aspartate and [14C]glutamate in rapidly growing hepatomas relative to rat host liver. When measured 10 min after s.c. injection, the radioactivity from 14C-labeled dicarboxylic amino acids was greater in liver than in all other tissues examined (blood, skeletal, muscle, heart, spleen, lung, and brain) except kidney, where there was an approximately 2-fold greater uptake of aspartate and 10-fold greater uptake of glutamate. Mean uptakes in the rapidly growing Morris hepatomas 7288CTC and 7777 were 19 to 26% of corresponding values for the host livers. Comparison with uptake of 3H2O indicated that these low values were not solely due to differences in circulation. Decreased uptake was not accompanied by equivalent decreases in the concentration of aspartate and glutamate in the tumors. There were small changes in the net uptake of these amino acids in the slowly growing hepatoma 7787 and no significant differences in regenerating liver and hepatoma 5123C, a tumor of intermediate growth rate. The net uptake of [14C]arginine and [14C]lysine in the hepatomas was similar to that in host livers, except for a 250% increase in uptake of [14C]lysine in hepatoma 5123C. A decreased uptake of the magnitude seen with dicarboxylic amino acids in rapidly growing hepatomas has not been observed with other amino acids.

Amino Acids, Dicarboxylic↗
PubMed1979

Selective effects of two chloromethyl ketones on amino acid and phosphate uptake in rat liver and tumors.

Injection of L-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK) at a level of 10 mg/100 g body weight inhibited the incorporation of 3H-labeled amino acids into protein in Morris hepatomas 7777and 9618A2. The degree of inhibition was similar in cytoplasmic proteins and in histone and nonhistone nuclear protein fractions. There was no inhibitory effect on 3H-labeled amino acid incorporation in the livers of the tumor-bearing rats. The inhibitory effect of N-tosyl-L-lysine chloromethyl ketone (TLCK) on incorporation of 3H-labeled amino acids was observed in both the slowly growing hepatoma 7787 and the rapidly growing hepatoma 7777. In hepatoma 7777, TLCK (2.5 mg/100 g body wt) exerted a greater inhibitory effect on incorporation when administered 60 minutes before [3H]leucine injection than when injected simultaneously. Studies on tissue uptake of amino acids, thymidine, and phosphate indicated that inhibitory effects of TPCK and TLCK on active transport may be a major factor in the action of these drugs on macromolecular synthesis. The inhibitory effects of TPCK and TLCK seen in transplanted hepatomas and a colon tumor were not generally seen in normal tissues of the tumor-bearing rats.

Amino Acid Chloromethyl Ketones↗
PubMed1979

Effects of cyanate, thiocyanate, and amygdalin on metabolite uptake in normal and neoplastic tissues of the rat.

Thiocyanate was found to resemble cyanate in its inhibitory effects on [3H]thymidine incorporation and the uptake of [32P]phosphate and [3H]amino acids in transplanted tumors of the BUF rat. The capacity to inhibit metabolite uptake in hepatomas and a colon tumor under conditions in which uptake was unchanged or increased in host liver was concluded to be a common feature of the action of cyanate and thiocyanate. Inhibition of [32P]phosphate uptake and [3H]thymidine incorporation into DNA of tumors was also observed after treatment of rats with amygdalin. With this drug, however, the action on tumors and livers of host rats was similar.

Amino Acids↗
PubMed1979

Spermine-induced variations in the adenosine 5'-diphosphate ribosylation patterns of nuclear proteins from rat liver and hepatoma.

Rat liver and hepatoma nuclei were incubated in vitro with [3H]nicotinamide adenine dinucleotide to allow synthesis of a polymer of adenosine diphosphoribose subunits joined in an 1',2' ribose-ribose linkage. The addition of 1 mM spermine altered the adenosine 5'-diphosphate (ADP) ribosylation patterns of nuclear proteins in hepatoma, host liver, and regenerating liver. Spermine-treated nuclei showed a greater incorporation of ADP-ribose into H1 histones and nonhistone nuclear proteins with isoelectric points between pH 3.0 and 6.0 when separated on polyacrylamide gels. Conversely, a large reduction in ADP ribosylation was seen in core histones (H2A, H2B, and H3) from the same nuclei. The proportion of ADP-ribose incorporated into histones was reduced in the nuclei from proliferating cells relative to their respective control livers. These results imply that polyamines, which are higher in concentration in rapidly dividing cells, may elicit a regulatory function by causing the preferential ADP ribosylation of H1 histones, as well as the more acidic of the nuclear proteins.

Adenosine Diphosphate Sugars↗
PubMed1979

Soluble factors from liver and hepatomas which inhibit [3H]thymidine incorporation into DNA of Novikoff hepatoma cells.

The nature of soluble factors from liver and hepatomas which inhibit [3H]thymidine incorporation into DNA was studied in Novikoff hepatoma cells. The decreased activity in hepatoma preparations was due to loss of a high-molecular-weight heat-labile factor. Although this factor cochromatographed with arginase activity on Sephadex G-150, it does not appear to result from this activity as judged by the failure of arginine to prevent the inhibitory effect on [3H]thymidine incorporation. Both liver and hepatomas contained a heat-stable factor with inhibitory activity. Studies with ethanol-soluble material suggested that the action was not solely attributable to the presence of unlabeled thymidine, since the apparent molecular weight was too high and since the factor(s) inhibited [3H]leucine incorporation into protein in addition to inhibiting [3H]thymidine incorporation in DNA.

Animals↗