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At least 19 recordsLinked to original sources
PubMed1988

The significance of free radicals and free radical scavengers in L1210 leukemia.

L1210 leukemia is a murine leukemia which is associated with anemia and marked neutrophilia. In order to determine the significance of free radicals (FR) in this disorder, we determined the presence and localization of free radical scavengers (FRS) and scavenger-like systems in L1210 leukemia cells obtained in vivo and from in vitro cultures. FR are metabolized or detoxified by certain FRS such as glutathione (GSH and GSSG), superoxide dismutase (SOD) and enzymes such as epoxide hydrolase (EH). In all cases specific fractions of L1210 cells, bone marrow and liver were examined for FR/FRS levels. Reduced (GSH) and oxidized (GSSG) glutathione were measured fluorometerically using o-opthalaldehyde (OPT). SOD was determined colorimetrically utilizing pyrogallol by substrate autolysis inhibition, and EH was determined by utilizing [3H] styrene oxide as a substrate. Ratios of GSH/GSSG in fractions prepared from in vivo and in vitro L1210 cells showed a predominance of GSH-reductase with the highest activity in mitochondria (ratio = 15 vs. 10). Normal liver showed a similar pattern whereas, leukemic liver showed altered GSH/GSSG ratios in mitochrondria and microsomes. Leukemic bone marrow showed a predominance of GSH-reductase in all fractions. EH activity was highest in microsomal fractions obtained from L1210 cells grown in vitro and found to become increased in both the mitrochondrial (100%) and microsomal (200%) fractions when cells were exposed to retinoic acid (RA) in culture. SOD activity in the cytosolic (21.2 U SOD/mg) and mitochondrial (12 U SOD/mg) fractions whereas, leukemic liver showed a significant decrease in activity in all fractions compared to normals. SOD was determined in fractions taken from L1210 cells in vivo and in vitro. Results demonstrated detectable but reduced SOD activity in the L1210 cell fractions as contrasted with liver activity. Results from these studies indicate that certain FRS systems are functional in L1210 leukemic animals. Furthermore, variations in the ratios or levels may be of significance in the leukemic and hematological states.

Animals↗
PubMed1992

Antileukemic effects of recombinant human tumor necrosis factor alpha (rh-TNF alpha) with cyclophosphamide or methotrexate on leukemia L1210 and leukemia P388 in mice.

We investigated the influence of recombinant human tumor necrosis factor alpha (rh-TNF alpha) administered as a single agent or in combination with cyclophosphamide (CY) or methotrexate (MTX) on the survival time of mice inoculated with lymphoblastic leukemia L1210 or lymphatic leukemia P388. The median survival time of leukemia L1210 bearing mice treated with rh-TNF alpha at doses ranging from 200 to 275 g/kg in daily i.p. injections was longer than that of control animals. Groups of mice with leukemia L1210 receiving rh-TNF alpha combined with either MTX or CY lived longer than animals treated with these agents individually. We observed only slight prolongation of life of animals inoculated with this tumor and treated with rh-TNF alpha at dose of 800 micrograms/kg in four injections on 2, 4, 6 and 8 day of experiment, and no effect when rh-TNF alpha was administered at dose of 200 or 400 micrograms/kg at the same treatment regime. In contrast no significant differences in lifetime were obtained from either simultaneous or sequential treatment of mice bearing leukemia P388. Groups of mice with this tumor treated with rh-TNF alpha in conjunction with either MTX or CY lived longer than controls, or rh-TNF alpha singly treated mice, but their survivals were not significantly prolonged compared with mice receiving cytostatics alone.

Animals↗
PubMed1986

Influence of rate of heating on thermosensitivity of L1210 leukemia: membrane lipids and Mr 70,000 heat shock protein.

We examined the effect of rate of temperature rise on the thermosensitivity of a murine lymphoblastic leukemia. L1210 cells suspended in RPMI 1630 medium:5% fetal bovine serum at pH 7.4 were heated from 37 degrees C-42 degrees C, or 44 degrees C over variable times (immediately, 30, 60, 120, 180 min) in a circulating water bath controlled by an electronic temperature programmer. Survival of the cells using a soft agar clonogenic assay was plotted against the time at final temperature so that a Do (min of heat required to reduce survival by 63% on the exponential portion of the survival curve) could be calculated as an estimate of thermosensitivity. Cells heated from 37 degrees C-42 degrees C over a time period of 30 min (10 degrees C/h) were less thermosensitive (Do 62.7 +/- 12.5 min) as compared to those exposed immediately to 42 degrees C (Do 38.5 +/- 2.2 min). Cells heated over a period of 180 min (1.6 degrees C/h) showed almost no death even after 4 h at 42 degrees C. Thermosensitivity of cells heated to several other high temperatures was also a function of rate of heating. This relative thermal resistance induced by slow heating was not a result of a change in membrane cholesterol content or fatty acid composition. Similarly, there was no difference between cells heated at slow and fast rates in cell cycle distribution or in cellular protein concentration. The major heat shock protein of Mr 70,000, which was induced by immediate heating, was not synthesized at the same high rate 1-12 h after heat treatment by the cells made thermotolerant with slow heating. We conclude that the thermosensitivity of this neoplastic cell can be altered considerably by the rate of heating. This alteration is not due to a change in membrane lipids. Furthermore, the heat shock protein at Mr 70,000 which was synthesized after immediate heating could not be demonstrated in the gradually heated L1210 leukemia cells.

Animals↗
PubMed1984

[Disruption of DNA synthesis and structure of mouse L1210 leukemia cells, sensitive and resistant to 1-methyl-1 nitrosourea and 1,3-bis(2-chloroethyl)-1-nitrosourea in vivo].

Leukemia L1210 cells with acquired resistance to 1-methyl-1-nitrosourea (MNU) (L1210/MNU) and 1.3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (L1210/BCNU) were developed from leukemia L1210 cells sensitive to these drugs (L1210/0). The modal chromosome number of leukemia L1210/MNU and L1210/BCNU cells increases from 40 (L1210/0) to 41. It was shown that in leukemia L1210/MNU cells the inhibition of DNA synthesis after MNU administration in a therapeutic dose (80 mg/kg) is lasted within 24 hours, while that in leukemia L1210/0 cell--within 96 hours. After administration of BCNU (20 mg/kg) inhibition of DNA synthesis in leukemia L1210/BCNU cells reached of 50% of control in comparison with practically complete inhibition of DNA synthesis in leukemia L1210/0 cells. Centrifugation on alkaline sucrose density gradients revealed no differences in the rate of sedimentation of leukemia L1210/0, L1210/MNU and L1210/BCNU cell lysates. After 1 hour treatment with MNU of mice bearing L1210/MNU and L1210/0 leukemia cells single-strand breaks in DNA were determined. After 4 hours these strand-breaks retained in leukemia L1210/0 cells, but were eliminated in leukemia L1210/MNU cells. Administration of BCNU to mice with leukemia L1210/0 and L1210/BCNU cells resulted in both cases in the production of DNA aggregates. There is no complete cross-resistance between MNU and BCNU which allows a substitution of these drugs providing for the increase in their therapeutic efficiency.

Animals↗
PubMed1983

Differential selectivity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in cultured human B lymphocytes and mouse L1210 leukemia.

The role of differential metabolic activation of a 5-fluorouracil (FU) prodrug, 5'-deoxy-5-fluorouridine (dFUR), in achieving selective cytotoxicity was investigated in cultured human (dFUR), in achieving selective cytotoxocity was investigated in cultured human B lymphocytes and murine leukemia L1210 cells. B cells were cross-sensitive to FU and dFUR. On the other hand, leukemia L1210 cells were sensitive to FU but resistant to dFUR. The difference in the biological activities of FU and dFUR in B and L1210 cells correlated with (a) the metabolism of dFUR to FU by intact B (60% conversion) and L1210 (no conversion) cells, and (b) the phosphorylase activity of B (660 nmoles converted in 2 hr per mg protein) and L1210 (undetectable) cells. The intracellular metabolism of FU and dFUR was studied using a reversed-phase ion-pair high pressure liquid chromatographic assay. FU and dFUR shared similar metabolic pathways in B cells; their anabolites included FU ribose and deoxyribose nucleosides and nucleotides. In L1210 cells, FU was anabolized to 5-fluorouridine triphosphate and 5-fluorodeoxyuridine monophosphate, whereas dFUR was present mainly as the unchanged drug. Further metabolism studies using dFUR with tritium label in either the FU moiety or the altered sugar moiety established that the metabolic pathway of dFUR to cytotoxic FU anabolites in the B cells was via phosphorolysis to FU. These data indicate that, on a cellular level, an FU prodrug such as dFUR, which is activated by cytosolic enzyme, has a different selectivity from that of FU, and that the basis of differential selectivity is the initial phosphorolysis to FU.

Animals↗
PubMed1981

[Protective effect of P40 fraction of C. granulosum against leukemia L1210 in mice].

Administration of glutaraldehyde treated L1210 leukemia cells, either alone or coupled with tetanus toxoid by means of glutaraldehyde as well as L1210 cells inactivated by mitomycin, did not induce appreciable protection against a tumorigenic dose of L1210 cells. On the other hand, injection of P40 fraction of C. granulosum induced non-specific resistance to L1210 leukemia and increased the efficiency of specific immunization by either glutaraldehyde treated L1210 cells or cells coupled with tetanus toxoid. Injection of Freund's complete adjuvant resulted in increase of rate of mortality after challenge with L1210 cells.

Adjuvants, Immunologic↗
PubMed2003

Effects of flavonoids on cisplatin-induced apoptosis of HL-60 and L1210 leukemia cells.

Effects of three flavonoids, quercetin (QU), galangin (GA), and chrysin (ChR) on cisplatin (cis-Pt)-induced apoptosis of human promyelocytic leukemia HL-60 cells and murine leukemia L1210 cells were investigated. The quantitative analysis of apoptotic DNA fragmentation was used to show that preincubation of cells with flavonoids can influence cis-Pt-induced apoptosis in different way. ChR had no effect, QU enhanced, and GA reduced apoptotic DNA fragmentation. It is also shown that combined treatment with QU and cis-Pt showed synergistic effect, however, GA combined with cis-Pt exhibited antagonism on cytotoxicity in L1210 murine leukemia cells. We assume that tested flavonoids affect the important biological activities connected with cancer chemotherapy and chemoprevention as they differently modulated the sensitivity of cells to cis-Pt treatment. QU is presented as pro-apoptotic agent and GA as agent with anti-apoptotic potential.

Animals↗
PubMed1978

[Selective treatment of leukemia L1210 with combination of deoxycytidine and lethal doses of cytosine arabinoside].

Oral administration of deoxycytidine simultaneously with intraperitoneal injections of toxic doses of cytosine arabinosidetomice with advanced L1210 leukemia diminished the toxic effects preventing drug death of these mice. They developed a marked antitumor effect. The mean survival time of these mice was considerably extended as compared to that of untreated animals or those given one of these drugs alone. At the optimum schedule of treatment about 23% of the mice survived over 60 days. Deoxycytidine protection reduced the antileukemic effect of cytosine arabinoside administered in nontoxic doses. The deoxycytidine plus cytosine arabinose combination was ineffective in the treatment of transplantable myeloid leukemia in mice.

Administration, Oral↗
PubMed1989

In vivo DNA cross-linking by cyclophosphamide: comparison of human chronic lymphatic leukemia cells with mouse L1210 leukemia and normal bone marrow cells.

Alkaline elution was done on a variety of cells following cyclophosphamide (CY) treatment in vivo. Cells used were L1210 leukemia, normal mouse bone marrow, and peripheral blood cells obtained from a patient with chronic lymphatic leukemia (CLL). Endpoints used were determination of single strand breaks, DNA-DNA interstrand and DNA-protein cross-links. After treatment of mice with CY (4 mg/mouse), low levels of single strand breaks were observed in both L1210 leukemia and CDF1 normal bone marrow. When a patient with CLL was treated with CY (750 mg/m2), no evidence of single strand breaks could be demonstrated. Maximum levels of DNA-DNA interstrand cross-links were observed in mice 2 h after injection of CY for the L1210 leukemia cells [175 +/- 25 rad-equivalents (req)] and at 4 h for the CDF1 normal bone marrow cells (47 +/- 9 req). In human CLL, maximum levels were observed 12 h after injection of CY. Peak levels of DNA-DNA interstrand cross-links were approximately 4-fold lower in CDF1 normal bone marrow cells than in L1210 leukemia. The frequencies measured in human CLL cells were relatively low at any timepoint (mean at 12 h = 36 req). Maximum levels of DNA-protein cross-links were observed 4 h after injection of CY (4 mg/mouse) for both L1210 leukemia [123 req (mean)] and normal bone marrow cells [50 req (mean)]. DNA-protein cross-links were measurable in CLL at timepoints later than 4 h after the start of injection of CY. In order to obtain equitoxicity between L1210 leukemia and CDF1 normal bone marrow cells, about 18-fold higher doses of CY had to be given than in the case of the normal bone marrow cells. In contrast, only 4-fold higher doses had to be given to the normal bone marrow to obtain equivalent peak levels of DNA-DNA interstrand cross-links.

Animals↗
PubMed1987

Glutathione depletion reverses cisplatin resistance in murine L1210 leukemia cells.

Little is understood about the mechanism of acquired resistance to the widely used antineoplastic drug, cisplatin. The cisplatin-resistant murine leukemia L1210 cell line L1210/PAM has an elevated cellular glutathione content, as compared to its sensitive parent cell line, L1210/*. Exposure to D,L-buthionine-S,R-sulfoximine reduced L1210/PAM cells' glutathione content to nearly that of L1210/* cells and abrogated the resistance to cisplatin.

Animals↗
PubMed1980

Deoxycytidine kinase-mediated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine L1210 leukemia in vivo.

An inherited deficiency of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) produces selective lymphopenia and immunodeficiency disease in humans. Previous experiments have suggested that lymphospecific toxicity in this condition might result from the selective accumulation of toxic deoxyadenosine nucleotides by lymphocytes with high deoxycytidine kinase, levels and low deoxynucleotide dephosphorylating activity. The present experiments were designed to determine if deoxyadenosine analogs which are not substrates for adenosine deaminase might similarly be toxic toward lymphocytes and lymphoid tumors. Two such compounds, 2-chlorodeoxyadenosine and 2-fluorodeoxyadenosine, at concentrations of 3 nM and 0.15 microM, respectively, inhibited by 50% the growth of human CCRF-CEM malignant lymphoblasts in vitro. Each was phosphorylated in intact cells by deoxycytidine kinase accumulated as the nucleoside triphosphate, and inhibited DNA synthesis more than RNA synthesis. Both deoxynucleosides had significant chemotherapeutic activity against lymphoid leukemia L1210 in mice.

Adenosine Deaminase↗
PubMed1986

Evaluation of cis-diamminedichloroplatinum(II) combined with metoclopramide or sodium thiosulfate on L1210 leukemia in vitro and in vivo.

A microtiter assay was developed to monitor cytotoxic activity of drugs alone and in combination at varying ratios on a single plate. Combinations of metoclopramide or sodium thiosulfate with cis-diamminedichloroplatinum(II) (cisplatin) were evaluated in vitro and in vivo for cisplatin cytotoxicity to murine leukemia L1210. The in vitro assay indicated that metoclopramide did not interfere with cisplatin-induced cytotoxicity and confirmed previously reported inhibition of cisplatin activity by sodium thiosulfate. The drug combinations were also evaluated in vivo for antitumor activity and the results of these studies corroborated the in vitro results.

Animals↗
PubMedDate not supplied

Cytochemical characterization of mouse L1210 leukemia.

Mouse lymphatic leukemia L1210 cells were characterized with polyclonal and monoclonal antibodies and lectins. The cells were found to have the phenotype IgG-, Thy-1.2-, Lyt-1-, Lyt-2-, asialo-GM1-, TL-, I-Ad-, IL-2R+, peanut agglutinin+, and Helix pomatia lectin +/-. They retained expression of H-2Kd and H-2Dd. Thus, these cells resemble "null" cells.

Animals↗
PubMed1981

Cell kill kinetics of several nogalamycin analogs and adriamycin for Chinese hamster ovary, L1210 leukemia, and B16 melanoma cells in culture.

Nogalamycin is an anthracycline antibiotic which was markedly cytotoxic in vitro and was active against several tumor systems in vivo. We compare here the lethality of several nogalamycin analogs against Chinese hamster ovary (CHO), mouse leukemia (L1210), and mouse melanoma (B16) cells in culture. 7-con-O-Methylnogarol (7-con-OMEN) was the most lethal of all the analogs tested. Thus, for CHO cells exposed for two hr to the drug, the 50% lethal doses of 7-con-OMEN, nogalamycin, and dis-nogamycin were 0.25, 2.7, and 5.8 micrograms/ml, respectively. In general, CHO cells were less sensitive than B16 or L1210 cells to most compounds. All compounds gave dose-survival curves which consisted of a shoulder region followed by a region of exponential decline in survival. The nogalamycin analogs nogalamycin, dis-nogamycin, 7-con-O-methylnogalarol, and 7-con-OMEN were selected for further study because of their greater lethality in vitro and antitumor activity in vivo. The lethality of these compounds was compared to that of Adriamycin. 7-con-OMEN was more toxic to CHO cells than was Adriamycin but was less toxic to B16 and L1210 cells. All of these compounds (except 7-con-O-methylnogalarol which was not tested) were more lethal to exponentially growing cells than to plateau-phase cells. The survival response after different periods of exposure to these drugs was compared. In order to make valid comparisons of the time-survival response to different drugs, the drug concentrations chosen were such that they were equitoxic after a two-hr exposure. Under these conditions, the order of lethality after long-term exposure (8 hr to 24 hr) was nogalamycin > dis-nogamycin > 7-con-OMEN, Adriamycin > 7-con-O-methylnogalarol. With all the drugs, the rate of cell death increased with increasing drug concentrations.

Animals↗
PubMed1987

Topoisomerase II-mediated DNA breaks and cytotoxicity in relation to cell proliferation and the cell cycle in NIH 3T3 fibroblasts and L1210 leukemia cells.

The DNA intercalator, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and the nonintercalator, etoposide (VP-16) produce topoisomerase II-mediated protein-linked DNA strand breaks. This function of topoisomerase II was investigated in relation to cell proliferation and cell cycle. Mouse fibroblasts NIH 3T3 and mouse leukemia L1210 cells stop proliferation when they reach a certain density. Nuclei were isolated from proliferative or quiescent cells and then treated with drug for 30 min. DNA modifications were assayed by alkaline elution. We found that the frequencies of m-AMSA- or VP-16-induced DNA-protein links were higher in nuclei from exponentially growing than in those from quiescent cells in both the 3T3 and the L1210 lines. Drug-induced protein-associated DNA breaks were also studied as a function of the cell cycle in 3T3 cells that had been arrested by contact inhibition in medium containing 1% calf serum and then stimulated to proliferate by raplating at a lower cell density in medium containing 10% serum. In these synchronized cells, a large peak of [3H]thymidine incorporation occurred 18-30 h after replating. The yield of DNA-protein cross-links produced by 30-min drug treatments of nuclei isolated at various times after growth initiation increased concomitantly with the peak of the DNA synthesis. The topoisomerase II activity of nuclear extracts, as measured by kinetoplast DNA decatenation followed a similar pattern. Using colony-forming assays, we also observed that m-AMSA and VP-16 were most cytotoxic in proliferative cells and during DNA synthesis. These results suggest that alkaline elution measurement of m-AMSA- or VP-16-induced protein-linked DNA breaks reflects the association of topoisomerase II with DNA. This association is increased during DNA replication, making the cells more vulnerable to m-AMSA and VP-16 at this time.

Amsacrine↗
PubMed1993

Establishment of L1210 leukemia cells resistant to the distamycin-A derivative (FCE 24517): characterization and cross-resistance studies.

N-deformyl-N-[4-N,N-bis(2-chloroethylamino)benzoyl] distamycin-A (FCE 24517) is a new cytotoxic anti-tumor agent in phase-1 clinical trials. We have isolated stable FCE-24517-resistant cell sublines from murine leukemia L1210 cells by in vitro exposure to the drug. FCE 24517 selects a mixed population of resistant cells: the L1210/24517(1) cell line in vitro was in fact resistant to the selecting agent (RI 48.3), as well as to L-PAM (RI 5.4) and DX (RI 8.6) and over-expressed the mdr-I gene. When L1210/24517(1) cells were implanted in vivo and evaluated for sensitivity to the same agents, resistance was observed only to FCE 24517 and partially to L-PAM, whereas DX had the same anti-tumor efficacy as on the sensitive line. The clone derived from the above subline (L1210/24517(2)) was resistant to FCE 24517, distamycin-A and other cytotoxic compounds bearing the distamycin-A skeleton, and fully sensitive to DX and other anti-tumor compounds involved in the multi-drug resistance mechanisms, with a complete disappearance of the mdr phenotype. L1210/24517(2) cell line is partially cross-resistant to L-PAM, this resistance being accounted for by higher GSH intracellular levels, which however do not influence the resistance to FCE 24517. In fact, BSO treatment was capable of significantly modifying only the cytotoxicity of L-PAM. Our data suggest that L1210/24517(2) cells present a mechanism of resistance specific for FCE 24517 and related molecules.

Animals↗
PubMed1985

Rapid determination of thymidylate synthase activity and its inhibition in intact L1210 leukemia cells in vitro.

A rapid and convenient tritium release assay for measuring thymidylate (dTMP) synthase activity and its inhibition within intact mammalian cells is described in detail. Short-term incubation of murine leukemia L1210 cells with an appropriately labeled substrate precursor, either deoxyuridine ([5-3H]dUrd) or deoxycytidine ([5-3H]dCyd), allowed for: (1) uptake and intracellular conversion to the substrate deoxyuridylate ([5-3H]dUMP); and (2) the obligatory displacement of tritium from [5-3H]-dUMP during the dTMP synthase catalyzed reaction. Tritium released into the aqueous environment was quantitated after a quick one-step separation of tritiated H2O from other radiolabeled materials and cell debris. The amount of tritium released was evaluated as a function of a number of variables, including the concentration of labeled substrate precursors, cell number, and incubation time. Tritium from [5-3H]dCyd was released significantly faster than from [5-3H]dUrd under a variety of conditions. Both 5-fluorodeoxyuridine (1 microM) and methotrexate (10 microM), which effectively block intracellular dTMP synthesis, completely inhibited the release of tritium from either [5-3H]dCyd or [5-3H]dUrd demonstrating that the release of tritium is mediated exclusively by the dTMP synthase catalyzed reaction. In addition, there was a good correlation between tritium release, cellular uptake, and incorporation of [2-14C]dUrd into DNA. The inhibitory effects of antifolates such as methotrexate were independent of the type of labeled precursor used. In contrast, preferential interference with the release of tritium from [5-3H]-dCyd by dCyd derivatives and from [5-3H]dUrd by dUrd derivatives was observed, suggesting that competition for uptake and/or phosphorylation may contribute to the overall effects of certain nucleoside analogues on cellular dTMP synthase activity measured using the tritium release assay.

Animals↗