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 synthesis of four mononuclear palladium complexes of general formula [Pd(en)Cl(L)]NO3 (en = ethylenediamine; L = pyridine (I), 4-methylpyridine (II), 4-hydroxypyridine (III) or 4-aminopyridine (IV) has been achieved. The structure of these compounds was studied by elemental analysis, IR, far-IR and 1H NMR; complex I was analyzed by X-ray diffraction. The crystal of [Pd(en)(pyridine)Cl]NO3 is monoclinic, space group P21/c (a = 7.990(2), b = 16.058(3), c = 9.846(2) A, beta = 103.81(3) degrees, Z = 4, R = 0.067, Rw = 0.066). The Pd(II) atom exhibits an approximately square planar coordination with bond lengths in the range 2.017-2.042 A for Pd-N and 2.320 A for Pd-Cl. In order to determine the donor strength of the aromatic pyridine ligands, the stability constants of binary complex ML2+ (M = [Pd(en) (H2O)2]2+; L = pyridine, 4-Me-pyridine, 4-OH-pyridine and 4-NH2-pyridine) were determined by potentiometric pH titration in aqueous solution (T = 25 degrees C, I = 0.1 mol l-1 NaNO3). The results show that the stability constants of the binary complexes systematically increase with increasing pKa of the pyridines. The above four palladium complexes, [Pt(en)(pyridine)Cl]NO3 and cis-diamminedichloroplatinum (II) (cis-DDP) were assayed for cytotoxicity in vitro against the human leukemia cell line HL-60, and compounds I, II, III and cis-DDP show significant cytotoxic activity against HL-60.
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PMID:Ethylenediamine-palladium(II) complexes with pyridine and its derivatives: synthesis, molecular structure and initial antitumor studies. 1033 Dec 44

New platinum(II) complexes of cyclopentanecarboxylic acid hydrazide (cpcah) were prepared, characterized by elemental analysis, IR and 1H NMR spectra, and evaluated for in vitro cytotoxicity in Friend leukemia (FL) and A2780 ovarian tumor cells, induction of apoptosis in FL cells, as well as for in vivo antitumor activity toward murine L1210 leukemia and Lewis lung carcinoma. The spectral analyses indicated a cis-square planar structure of the complexes with hydrazide ligand coordinated via the NH2 group. The compounds exerted significantly lower in vitro and in vivo toxicities as compared with those of cisplatin (cis-diamminedichloroplatinum(II), DDP). On the other hand, the complex [Pt(NH3)(cpcah)Cl2] exhibited antitumor activity against L1210 leukemia in mice comparable to that of cisplatin, resulting at a dose of 42 mg/kg (administered 3 times) in a T/C (mean survival time) of 280%. This compound displayed an in vitro macromolecular synthesis inhibition pattern similar to that of DDP. At concentrations close to the cytostatic ones (10-20 microM) this complex, as well as DDP, was able to induce apoptosis in FL cells as shown by neutral comet assay and morphological analysis. We concluded that there is a correlation between the ability of platinum complexes to induce apoptosis and their antitumor activity.
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PMID:Synthesis, cytotoxicity and antitumor activity of platinum(II) complexes of cyclopentanecarboxylic acid hydrazide. 1061 21

The production of peptide hormones by skeletal muscle tissue is a promising area of gene therapy. Skeletal muscle myogenesis can be induced in vitro, resulting in the fusion of mononucleate myoblasts to form multinucleate myotubes, and delivery vectors are first tested in vitro. C2C12 myoblasts transfected with pcDNA3-GH, which used the human cytomegalovirus (CMV) promoter, secreted immunoreactive GH with comparable biological activity to pituitary GH. Mouse myeloid leukaemia cells, which express the mouse GH receptor were used for the bioassay, and activation of these cells by GH was measured by a colorimetric microculture tetrazolium assay. Cells were incubated with a tetrazolium salt (MTS) and an intermediate electron acceptor (phenazine methosulphate, PMS), and formazan production was measured as optical density (O.D.) at 490 nm. The efficiencies of several plasmid expression vectors were compared in differentiated and non-differentiated muscle cells, as a function of bioactive GH secreted by the transfected cells. Ten-day differentiated C2C12 myotubes transfected with pcDNA3E-GH, which used the CMV promoter and a rat myosin light chain enhancer element, secreted significantly more biologically active GH than myotubes transfected with pcDNA3-GH (0.82 O.D. units+/-0.06 vs 0.57+/-0.05 respectively, P<0.001). This was consistent with reduced CMV promoter activity in myotubes. Myoblasts transfected with pcDNA3-GH secreted more bioactive GH than 10-day transfected myotubes (1.1+/-0. 1 vs 0.77+/-0.07 respectively). However, the responses were indistinguishable (both 1.0+/-0.09) if both the myotubes and myoblasts had been transfected with pcDNA3E-GH. Substitution of the vector pMHLC-GH, which used a muscle-specific truncated rabbit myosin heavy chain promoter, and the myosin enhancer resulted in a marked decrease in the responses to the conditioned medium from fused myotubes compared with the vectors pcDNA3-GH and pcDNA3E-GH (0. 24+/-0.02 vs 0.57+/-0.05 vs 0.82+/-0.06 respectively). We concluded that the combination of CMV promoter and myosin light chain enhancer in pcDNA3E-GH had the greatest expression efficiency of the several plasmid vectors which we investigated.
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PMID:Optimisation of growth hormone production by muscle cells using plasmid DNA. 1081 Feb 97

Multiple myeloma (MM) is a clonal neoplasm of plasma cells which offers an excellent model to study multistep molecular oncogenesis. In 20-25% of primary tumors and cell lines examined, cyclin D1 is overexpressed due to the translocation t(11;14)(q13;q32). We have characterized cyclin-dependent kinase inhibitor p15 (CDKN2B), p16 (CDKN2A) and p18 (CDKN2C) deletions in cyclin D1-expressing and non-expressing MM cell lines. p18 was found to be frequently deleted (38%); in some cases p18 deletions coexisted with hemizygous p16 deletion. To examine the function of p18 as a putative tumor suppressor in myeloma cells, a zinc-inducible p18 construct was stably transfected into KMS12, a MM cell line with biallelic p18 and monoallelic p16 deletions as well as cyclin D1 overexpression. Ectopic expression of p18 caused 40-45% growth suppression as determined by trypan blue exclusion and MTS assays. p18 induction also resulted in apoptosis, suggesting that inhibition of the cyclin D1/CDK/pRb pathway in these tumor cells could be a crucial step toward the induction of tumor regression via apoptotic cell death. This cell cycle pathway is thus frequently mutated and provides a potentially novel target for gene therapeutic or pharmacologic approaches to human myeloma.
Leukemia 2002 Jan
PMID:Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis. 1184 Feb 72

The inhibitory activities of Schiff bases of hydroxysemicarbazide (HSC) against eight human and murine tumor cell lines and one non-cancer cell line were studied using MTS/PES microculture tetrazolium and methylene blue assays. Compounds 1 (1-[9-(10-methylanthryl)methylene]-4-HSC), 2 (1-[2-hydroxy-3,5-dibromobenzylidene]-4-HSC) and 3 (1-[2,3,4-trihydroxybenzylidene]-4-HSC), which have been shown to be active against murine leukemia L1210 cells in our laboratories, inhibited human leukemia CCRF-CEM cells with similar IC50s ranging from 2.7 to 7.0 microM. Of the compounds tested against attached tumor cell lines (B16, CHO, HT29, ZR75) at 50 microM concentration, compound 1 showed the strongest inhibition, followed by 4 (1-[2-(5-nitrothienyl)methylene]-4-HSC), 2 and 5 (1-[2-hydroxy-3,5-diiodobenzylidene]-4-HSC) with more than 50% inhibition. The IC50s of compound 1 were found to range from 2.7 to 12 microM against the attached tumor cell lines examined. As compared with hydroxyurea, compound 1 had more favorable selectivity against tumor cells. Further more, compound 1 was found to have IC50s of 2.8 and 6.5 microM against hydroxyurea-resistant and gemcitabine-resistant KB cells, respectively, but had no cross-resistance with hydroxyurea and gemcitabine (two known ribonucleotide reductase inhibitors acting at different sites of the same enzyme). In conclusion, several Schiff bases of HSC showed inhibition of tumor cell growth at micromolar concentration and had no cross-resistance with hydroxyurea-resistant KB cells.
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PMID:Inhibition of tumor cell growth by Schiff bases of hydroxysemicarbazide. 1184 7

Two cationic multinuclear platinum complexes linked with the 4,4'-dipyrazolylmethane (dpzm) ligand, trans-[[Pt(NH3)2Cl]2-mu-dpzm]Cl2 (di-Pt) and trans-[trans-[Pt(NH3)2Cl]2[trans-[Pt(NH3)2(mu-dpzm)2]]]Cl4 (tri-Pt), have been synthesized. Both complexes show activity in the murine leukaemia cell line L1210 (IC50 = 3.8 and 2.5 microm, respectively) and the cisplatin-resistant subline L1210/DDP (8.8 and 3.6 microM), and in the human ovarian carcinoma 2008 (2.5 and 17.8 microM) and its cisplatin-resistant subline C13*5 (20.9 and 37.7 microM). Both complexes show high levels of uptake into 2008 cells, when administered at 100 microM, but significantly reduced uptake in the cisplatin-resistant cell line C13*5 (di-Pt, 66% decrease; tri-Pt, 42%; cisplatin, 86%). Both complexes form very high levels of DNA interstrand cross-links in vitro, with 50% interstrand cross-linking observed at far lower concentrations (di-Pt, 12 nM; tri-Pt, 22 nM) than cisplatin (450 nM). It is proposed that the higher extent of interstrand cross-linking may be due to the rigid nature of the dpzm linking ligand, which prevents the complexes from forming short-range intrastrand adducts, like the GpG adduct formed by cisplatin. The results of this study indicate the importance of the flexibility of the linking ligand for the cytotoxicity of di- and trinuclear platinum anti-cancer complexes.
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PMID:Synthesis, cytotoxicity, cell uptake and DNA interstrand cross-linking of 4,4'-dipyrazolylmethane-linked multinuclear platinum anti-cancer complexes. 1196 17

New platinum(II) complexes of 3-aminocyclohexanespiro-5-hydantoin (achsh) were prepared and characterized. Ab initio calculation of the structure and the measurements of IR and NMR spectra of [Pt(NH(3))(achsh)Cl(2)] were also performed. Quantum-chemical and spectroscopic studies indicated a cis-square planar structure with a hydantoin ligand coordinated via the NH(2) group. The complexes were evaluated for in vitro cytotoxicity in murine erythroleukemia (MEL) cells, clone F4N, as well as for in vivo antitumor activity toward murine L1210 leukemia. The complexes exerted significantly lower in vitro and in vivo toxicities compared with those of cisplatin (cis-diamminedichloroplatinum(II), DDP). The complex [Pt(NH(3))(achsh)Cl(2)] exhibited antitumor activity against L1210 leukemia, comparable to that of cisplatin, resulting at a dose of 72 mg/kg in a %T/C (increased survival time) of 191%. This complex, as well as cisplatin, induced apoptosis in F4N cells, and exerted antibacterial activity as assessed in 10 bacterial strains.
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PMID:Synthesis, cytotoxicity, antibacterial and antitumor activity of platinum(II) complexes of 3-aminocyclohexanespiro-5-hydantoin. 1206 24

Imatinib mesylate (STI571, Glivec, Gleevec) is a powerful inhibitor of the tyrosine kinase activity of Bcr-Abl, the oncoprotein responsible for chronic myeloid leukemia (CML). The drug shows great efficacy in chronic phase, but is less effective in maintaining hematologic remissions in blast crisis patients. Our group has previously described several cell lines made resistant to imatinib. We now examine the question of cross-resistance to other chemotherapeutic drugs used in CML. Four paired imatinib-sensitive/resistant CML cell lines were assessed by caspase-3 and MTS assays for their proliferative response to cytosine arabinoside (Ara-C), daunorubicin (DNR), homoharringtonine (HHT) and hydroxyurea (HU), either alone or in combination with imatinib. Primary blasts from advanced-stage CML patients refractory to imatinib therapy were studied by semi-solid media clonogenic assays. We found that these drugs are generally capable of major inhibition of proliferation of the CML cell lines, although differential responses to DNR and HHT were noted between some sensitive and resistant cell line pairs, implying that resistance to imatinib may confer a growth advantage under such conditions. The four drugs were also effective in preventing the formation of progenitor cell colonies from CML patients both before treatment with imatinib, and after relapse on the drug. Isobolographic analysis implied that these drugs will generally combine well with imatinib, and in some cases will be synergistic. We conclude that Ara-C, DNR or HHT, either alone or in combination with imatinib, are likely to be the best therapeutic alternatives in the management of patients who become resistant to imatinib monotherapy.
Leukemia 2002 Dec
PMID:Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs. 1245 39

The aim of this work was to test the effect of p16 on the proliferation of leukemic cells and its potential in gene therapy for leukemia. The full-length p16 cDNA was transfered by recombinant retrovirus vector into leukemia cell line K562, which is homozygous p16 deletion and retains functional retinoblastoma (RB) protein. The cell proliferation was tested in liquid and in soft agar culture after transduction of p16 retrovirus. The results showed a strong inhibition of cell proliferation. Phosphorylation of RB protein was also inhibited. The findings demonstrated that p16 (MTS/CDKN2) inactivation is a significant factor in the genesis and progression of leukemia and p16 could be a candidate gene for gene therapy in leukemia.
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PMID:[p16 (CDKN2) Gene Transfer Mediated by Retrovirus Vector Inhibits Proliferation of Leukemia Cell Line K562] 1257 99

Two potentially hydrophilic platinum (II) complexes 10 and 11 bound to the minor groove binder stallimycin (distamycin A, CAS 636-47-5) by L-cysteine and D,L-2,3-diaminopropionic acid have been synthesized. The in vitro cytotoxicity of both these complexes was evaluated against several cell lines. None of the synthesized platinum complexes showed greater activity than that of cisplatin (cis-DDP, 1) (CAS 15663-27-1). Interestingly, the free ligands 6 and 9 were more active than the related platinum complexes 10 and 11, respectively, with respect to RAJI, CCRF-CEM and MOLT-4 human leukaemia cell lines.
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PMID:Design, synthesis and in vitro cytotoxicity of a cis-dichloroplatinum (II) complex linked to the minor groove binder stallimycin. 1264 66


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