Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibition of [14C]thymidine incorporation into DNA of tumor and normal tissues of L1210-leukemia-bearing mice by single doses of cis-diamminedichloroplatinum (II) (cisplatin, cis-DDP) and two newly synthesized platinum (II) complexes containing as ligands dimethyl aminomethylphosphine oxide (complex I) and methyl bis(aminomethyl)phosphine oxide (complex II) was studied and used as an indication of drug toxicity. All three complexes caused selective inhibition of precursor incorporation in L1210 cells as compared to host tissue cells. cis-DDP caused a complete block of incorporated thymidine in tumor cells during more than 48 h, whereas in intestinal mucosa and bone marrow reverse inhibition was observed. In spleen, liver and kidney the inhibition was about 50% and endured up to 96 h without reversal. Complex I treatment of L1210 cells resulted in an earlier recovery of thymidine incorporation into DNA in comparison with cis-DDP. Towards all other normal tissues compound I was less toxic than cis-DDP. Unlike cis-DDP and complex I, complex II was less active against L1210 cells and most toxic against bone marrow and kidney.
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PMID:Inhibition of DNA synthesis in different tissues of L1210-leukemia-bearing mice by new platinum (II) complexes. 844 64

Some platinum complexes contain 1,2-diaminocyclohexane (DACH) as a stable carrier ligand, which can exist as the R,R-, S,S- and cis-isomers. Tetraplatin, for instance, is a mixture of R,R- and S,S-DACH-Cl4-Pt(IV). We have examined each of the three individual isomers of DACH-Cl4-Pt(IV) with respect to cytotoxicity, uptake of platinum and total DNA-platinum in three murine leukemia L1210 (cisplatin-sensitive L1210/0, 50-fold cisplatin-resistant L1210/DDP and 36-fold tetraplatin-resistant L1210/DACH) and human ovarian carcinoma A2780 (cisplatin-sensitive) and A2780cp (8-fold cisplatin-resistant) cell lines. Against A2780, A2780cp and L1210/DDP cell lines, the R,R-isomer was the most potent followed by the S,S-isomer and then the cis-isomer. However, the three isomers demonstrated similar IC50 values against the L1210/0 and L1210/DACH cell lines. The cis-isomer demonstrated cross-resistance (9- to 20-fold) to cisplatin in L1210/DDP and A2780cp cell lines. On the other hand, R,R- and S,S-isomers demonstrated minimal (2- to 4-fold) cross-resistance against these tumor models. Intracellular platinum accumulation over a 2 h period at 40 microM drug concentration was significantly (p < 0.05) greater for the R,R-isomer than the cis-isomer in L1210/0 (122 versus 101 ng Pt/mg protein) and L1210/DDP (73 versus 50) cell lines, while no difference was observed in L1210/DACH cells (55 versus 56). In L1210/DDP cells, total DNA-bound platinum was significantly (p < 0.05) greater for the R,R-isomer compared with the cis-isomer (10.3 versus 7.5 ng Pt/mg DNA).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential cytotoxicity, uptake and DNA binding of tetraplatin and analogous isomers in sensitive and resistant cancer cell lines. 849 Feb 3

Intracellular glutathione (GSH) content was measured by flow cytometry using monochlorobimane (mBCl) and by the enzymatic assay in a set of 6 sublines of murine L1210 leukemia cells made resistant to DNA-interacting agents having distinct mechanisms of action: L-phenylalanine mustard (L-PAM), 1,3-bis(2-chloroethyl)-I-nitrosourea (BCNU), cisplatin (DDP), N-deformyl-N-(4-N,N-bis(2-chloroethylamino) benzoyl) distamycin A (FCE 24517), doxorubicin (DX) and 3'-deamino-3' (2-methoxy-4-morpholinyl)-doxorubicin (FCE 23762). A significant correlation was demonstrated between the mean intracellular mBCl fluorescence values measured by flow cytometry and levels of GSH measured by the classical enzymatic assay, despite the possible influence of glutathione-S-transferases and of other thiols on the mBCl fluorescence. Although less specific, the flow cytometric method is more informative than the enzymatic assay, allowing detection of fluorescence distributions, which we proved to be characteristic of each subline. In order to assess a procedure enabling a quantitative analysis to be made of intercellular GSH heterogeneity, we propose the use of appropriate thresholds and parameters of the mBCl flow cytometric distribution. By use of this analysis procedure, distinct types of alterations, with respect to the heterogeneity distribution of the parental L1210 cell line, have been evidenced in resistant cells. A uniform increase in mBCl fluorescence was observed among cells of the sublines resistant to L-PAM and FCE-24517. The mean mBCl fluorescence increase in sublines resistant to DX and DDP was due to a higher number of cells with fairly high mBCl fluorescence, but still within the range spanned by the parental cell line. A less heterogeneous mBCl fluorescence distribution was found in the L1210 subline resistant to FCE 23762, which was, however, similar to a cloned sensitive line. Though GSH was linked to the principal cause of drug resistance only in the L-PAM-resistant cell line, alterations in heterogeneity, as detected by mBCl fluorescence distributions, were found in 5 out of 6 resistant lines.
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PMID:Intracellular glutathione heterogeneity in L1210 murine leukemia sublines made resistant to DNA-interacting anti-neoplastic agents. 850 18

The biological activity of cis and trans complexes of formula [PtCl2(HN = C(OMe)Me)2] has been investigated. The iminoether ligands can have either E or Z configuration about the C = N double bond, therefore EE, EZ and ZZ isomers are obtainable. Substitution of iminoether with EE configuration for amine leads to unexpectedly high antitumor activity for the complex with trans geometry which turns out to be more active than the cis congener in the P388 leukaemia system. The same trans-EE complex shows an activity comparable to that of cisplatin in reducing the primary tumour mass and lung metastases in mice bearing Lewis lung carcinoma, thus representing a trans platinum complex active on both limphoproliferative and solid metastasizing murine tumours. Also the cytotoxicity, the inhibition of DNA synthesis and the mutagenic activity, which are greater for the cis- with respect to the trans-isomer in the amine complexes, are instead greater for the trans- than for the cis- isomer in the case of iminoether compounds. Binding to calf thymus DNA is slower for iminoether complexes than it is for amine complexes, however after 24 h reaction time the level of binding is similar for both types of complexes. Trans-EE, like trans-DDP, does not give the DNA conformational alterations (terbium fluorescence) typical of antitumour-active cis- platinum compounds, but, under strictly analogous experimental conditions, shows a greatly reduced DNA interstrand cross-linking ability (heat denaturation/renaturation assay) with respect to either trans-DDP or cis-EE and cis-DDP. The data in hand point to a new trans platinum antitumour complex with a mechanism of action different from that of cis-DDP and classical analogues.
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PMID:Platinum(II) complexes containing iminoethers: a trans platinum antitumour agent. 854 63

We report a murine leukemia cell variant (L1210/DDP), selected for cisplatin (DDP) resistance, to be cross-resistant to methotrexate (MTX). Cross-resistance of L1210 cells to DDP and MTX has been observed by others, and has also been recorded in P388 murine leukemia and SSC-25 human squamous carcinoma cells. We demonstrated that MTX resistance is not due to dihydrofolate reductase (DHFR) gene amplification, increased DHFR enzyme activity or decreased MTX binding to the target enzyme. Of the mechanisms commonly proposed for MTX resistance, only differences in transport were observed when comparing sensitive (L1210/0) and resistant (L1210/DDP) cells. Our results suggest that MTX resistance in L1210/DDP cells is due to altered methotrexate uptake.
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PMID:Investigations on the mechanisms of methotrexate resistance in a cisplatin-resistant L1210 murine leukemia cell subline. 854 79

Collateral resistance to cisplatin and methotrexate has been reported in several cell lines. A murine leukemia cell line (L1210/DDP) selected for cisplatin resistance also has been shown to be highly resistant to methotrexate. Of the mechanisms proposed for methotrexate resistance, only changes in methotrexate transport into the cells were found in an earlier report. Methotrexate enters mammalian cells via an active transport system. In the present study, we demonstrated that the transport into the cell may be impaired in the resistant cells due to altered tyrosine phosphorylation of a membrane protein with a molecular mass of 66 kDa. This alteration was manifested by altered tyrosine phosphorylation of the 66 kDa protein and may be an underlying modification that renders the cells resistant to methotrexate. These results suggest involvement of tyrosine phosphorylation in folate transport and methotrexate resistant in L1210/DDP cells.
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PMID:Correlation of altered tyrosine phosphorylation with methotrexate resistance in a cisplatin-resistant subline of L1210 cells. 861 93

It has been recently reported that a number of anticancer drugs, including cisplatin, may exert their toxicity by inducing apoptosis. In order to investigate whether an alteration in the mechanisms involved in the process of apoptosis could contribute to cellular resistance, induction of apoptosis was studied in a cisplatin-resistant cell line (L1210/DDP) derived from a L1210 murine leukemia cell line (L1210/0). We first established that the mutant cell line resisted 5-azacytidine, a drug to which it was never exposed and which is known to have a very different mechanism of action from that of cisplatin. We then showed that these cells did not exhibit any DNA fragmentation or morphological changes typical of apoptosis, when exposed to toxic concentrations of either cisplatin or 5-azacytidine. The failure of these cells to undergo typical apoptosis upon cisplatin or 5-azacytidine exposure was correlated with the lack of a nuclear endonuclease activity present in wild type cell nuclei. However, staurosporine, a potent protein kinase C inhibitor, which exerted the same toxicity on both cell lines, induced the internucleosomal DNA fragmentation and morphological features of apoptosis in both of them. This indicates that a functional pathway for apoptosis is preserved in the resistant cells. The induction of this pathway can be correlated with the presence of a cytoplamic endonuclease activity whose specificity seems different from that operating in L1210/0 cells. In conclusion, our data indicate that the mechanisms which control activation of apoptosis in L1210/0 cells differ from those which operate in L1210/DDP cells. One of the differences concerns the nature and the subcellular localization of the endonuclease activity possibly involved in the internucleosomal DNA cleavage.
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PMID:[Cisplatin resistance in a murine leukemia cell line associated with defect of apoptosis]. 868 89

The thymic stroma has long been implicated in AKR thymic leukaemia. In this study an extensive panel of monoclonal antibodies was used to investigate changes in the AKR thymic microenvironment, in parallel with thymocyte differentiation of normal (2 month), preleukaemic (5-7 month) and leukaemic (> 7 month) mice. We found select alterations in the thymic stroma, including a loss of isolated medullary antigens and changes in MTS 32, a mAb detecting an antigen on both thymocytes and stroma in the thymic cortex. Stromal alterations were accompanied by shifts in thymocyte differentiation and the appearance of the leukaemogenic mink cell focus-forming (MCF) murine leukaemia virus.
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PMID:Characterization of the AKR thymic microenvironment and its influence on thymocyte differentiation and lymphoma development. 896 Jan 10

A series of novel platinum(IV) complexes of the type DACH-PtIV-trans-(Y)2-cis-X (where DACH = trans-(1R,2R)-, trans-(1S,2S)-, or cis-1,2-diaminocyclohexane; X = diacetate, oxalate, malonate, methylmalonate, cyclobutanecarboxylate (CBCA), or 1,1-cyclobutanedicarboxylate (CB-DCA); and Y = acetate or trifluoroacetate) has been synthesized and characterized by elemental analysis, IR, and 195Pt-NMR spectroscopy. The compounds have been tested against cisplatin-sensitive L1210/0 leukemia, cisplatin-resistant L1210/DDP leukemia, and M5076 reticulosarcoma cell lines in vivo. Most of these analogs displayed reasonable activity against L1210/0 cells (%T/C = 135 to > 700). There were no gross differences in activity between analogs containing isomers of DACH. Selected compounds were evaluated against L1210/DDP tumor models in which they demonstrated reduced but significant activity compared with activity in the L1210/0 model. Interestingly, complex 20, PtIV(trans-1R,2R-DACH)-trans-(acetate)2-methylmalonate, was highly active against M5076, although it had no activity against the L1210 lines. The results demonstrate that specific combinations of axial and equatorial carboxylate ligands, together with the DACH carrier ligand, can favorably modulate the antitumor properties of platinum complexes and enhance circumvention of cisplatin resistance.
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PMID:Chemical and biological studies on a series of novel (trans-(1R,2R)-, trans-(1S,2S)-, and cis-1,2-diaminocyclohexane)platinum(IV) carboxylate complexes. 901 35

Several lichen species have been used traditionally as medicinal plants. It has previously been shown that two low-molecular-weight lichen metabolites, lobaric acid isolated from Stereocaulon alpinum Laur. and protolichesterinic acid isolated from Cetraria islandica L. (Ach.), have in-vitro inhibitory effects on arachidonate 5-lipoxygenase. We have studied the effects of these compounds on cultured cells from man, including three malignant cell-lines (T-47D and ZR-75-1 from breast carcinomas and K-562 from erythro-leukaemia), as well as normal skin fibroblasts and peripheral blood lymphocytes. Both test substances caused a significant reduction in DNA synthesis, as measured by thymidine uptake, in all three malignant cell-lines; the dose inducing 50% of maximum inhibition (ED50) was between 1.1 and 24.6 microg mL(-1) for protolichesterinic acid and between 14.5 and 44.7 microg mL(-1) for lobaric acid. The breast-cancer cell-lines were more sensitive than K-562. The proliferative response of mitogen-stimulated lymphocytes was inhibited with a mean ED50 of 8.4 microg mL(-1) and 24.5 microg mL(-1) for protolichesterinic acid and lobaric acid, respectively. These concentrations are of the same order of magnitude as the IC50 values in the 5-lipoxygenase assay. Significant cell death (assessed by the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-( 4-sulfophenyl)-2H-tetrazolium) assay and trypan blue exclusion) occurred in the three malignant cell-lines at protolichesterinic acid and lobaric acid concentrations above 20 and 30 microg mL(-1), respectively. In K-562 morphological changes consistent with apoptosis were detected. Up to 38% cell death was observed at 20 microg mL(-1) for protolichesterinic acid and 15 microg mL(-1) for lobaric acid in mitogen-stimulated lymphocytes but unstimulated lymphocytes were clearly less sensitive. In contrast, the DNA synthesis, proliferation and survival of normal skin fibroblasts were not affected at doses up to 20 microg mL(-1) for protolichesterinic acid and 30 microg mL(-1) for lobaric acid. We conclude that the anti-proliferative and cytotoxic effects observed might be related to the 5-lipoxygenase inhibitory activity of protolichesterinic acid and lobaric acid. These results open up the opportunity for future studies of these lichen metabolites with regard to their anti-tumour and anti-inflammatory properties.
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PMID:Anti-proliferative effects of lichen-derived inhibitors of 5-lipoxygenase on malignant cell-lines and mitogen-stimulated lymphocytes. 950 41


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