Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the effects of mitoxantrone in combination with other anticancer agents, a human T-cell leukemia cell line, MOLT-3, was incubated for 3 days in the presence of two drugs (mitoxantrone and the combined drug) and cell growth inhibition was determined by assay with 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazonium bromide. The effects of drug combinations at doses giving 80% inhibition (ID80) were analyzed by an improved isobologram method. A supra-additive (synergistic) effect was observed for mitoxantrone in combination with amsacrine, cisplatin, or cytosine arabinoside. An additive effect was observed for its combination with bleomycin, doxorubicin, etoposide, 5-fluorouracil, mitomycin C, 6-mercaptopurine, or vincristine. A sub-additive (antagonistic) effect was observed for its combination with methotrexate. These data suggest that mitoxantrone, administered simultaneously with any one of a majority of anticancer agents we studied, is advantageous for cytokilling. Of the anticancer agents tested, amsacrine, cisplatin, and cytosine arabinoside are the most suitable for combination with mitoxantrone, and these combinations are worthy of clinical investigation. Methotrexate in our system is inappropriate for simultaneous administration with mitoxantrone. These data should provide useful information for the establishment of clinical protocols involving mitoxantrone.
Leukemia 1992 May
PMID:Effects of mitoxantrone in combination with other anticancer agents on a human leukemia cell line. 159 9

We report on the individual and combined effects of adriamycin (ADR) and hyperthermia (HYP) on the sedimentation behavior of L1210 mouse leukemia cell nucleoids in neutral sucrose gradients. Nucleoid sedimentation profiles obtained from cells incubated with ADR (1-10 microM; 30 min; 37 degrees C) exhibited an increased sedimentation rate associated with an increased protein content of these subnuclear units. Exposure of cells to HYP (1-3 h; 42 degrees C) produced similar results. Simultaneous exposure of L1210 cells to conditions of HYP and ADR which resulted in minimal changes in nucleoid sedimentation when used singly, produced an enhanced effect. A similar enhancement was observed with other intercalating antineoplastic agents believed to exert their effect, at least partially, via free radicals (daunorubicin, amsacrine, bisantrene, mitoxantrone). However, enhancement with HYP was not observed with (a) the classic intercalating agent, ethidium bromide; (b) non-intercalating DNA-breaking agents (bleomycin, lithocholic acid, etoposide); (c) inhibitors of poly (ADP-ribose) polymerase (m-methoxybenzamide, benzamide); or (d) non-intercalating antineoplastic agents capable of causing free radical formation (bleomycin). The results suggest that DNA intercalating agents capable of initiating free radical processes may show an enhanced toxicity with simultaneous HYP treatment, and that the nucleoid assay may be a means of screening agents with these biological properties for potential clinical usefulness in combination with HYP.
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PMID:Effect of adriamycin and hyperthermia on the sedimentation of nucleoids from L1210 cells. 325 52

The kinetics of the reaction of a series of cis-platinum(II) compounds with DNA in vitro has been studied using their ability to disturb the secondary structure of the macromolecule. The complexation modifies the stacking of the base pairs and causes an inhibition of the intercalation of ethidium bromide which is correlated with the number of platinum atoms bound per nucleotide. The compounds fall into three groups which react in a few minutes, in a few hours or in several days. The inhibition of the complexation by chloride and carboxylato ions indicates that the interaction occurs through hydrolysed species and that hydrolysis is the rate limiting step. In addition the results indicate that the carboxylato entities are able to react with DNA in vitro without enzymatic activation and that there is no correlation between the antitumoral activity of these compounds against L1210 Leukemia cells and their in vitro reactivity towards DNA.
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PMID:Kinetics of the reaction of cis-platinum compounds with DNA in vitro. 407 75

9,10-Anthracenedicarboxyaldehyde bis[(4,5-dihydro-1H-imidazol-2yl)hydrazone] dihydrochloride (Cl 216,942) is a new anthracene bishydrazone derivative which has shown antitumor activity in Phase I trials against both hematological cancers and solid tumors. The effects of Cl 216,942 on L1210 mouse leukemia cells were studied with the nucleoid sedimentation and alkaline elution assays. Evidence for Cl 216,942 intercalation into cellular DNA was obtained in exponentially growing cells by comparing the L1210 nucleoid sedimentation behavior in neutral sucrose gradients of ethidium bromide with nucleoids from Cl 216,942-treated cells. A 1-hr treatment of exponentially growing L1210 cells with Cl 216,942 induced both protein-associated DNA single-strand breaks and DNA-protein crosslinks as detected by the alkaline elution assay. The DNA strand break and DNA-protein cross-link frequencies were found to be within a factor of 2 of each other over a range of Cl 216,942 concentrations. The dose response for the induction of DNA damage showed a linear decrease up to 10 micrograms/ml, but this was followed by a decrease in damage at dose levels greater than 10 micrograms/ml. The biphasic dose response could not be explained by changes in the cellular uptake of Cl 216,942. The kinetics of Cl 216,942 induction of DNA damage after a 1-hr treatment showed that at the dose which gave maximum damage the degree of damage (10 micrograms/ml) decreased with further incubation, but at a higher dose (20 micrograms/ml) DNA damage increased with postincubation at 37 degrees. The cytotoxicity produced by Cl 216,942 at a given frequency of protein-associated strand breaks was low. Cl 216,942 thus appeared to belong to a low-toxicity group of DNA intercalators.
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PMID:Molecular pharmacology of the anthracycline drug 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1 H-imidazol-2-yl)hydrazone] dihydrochloride (Cl 216,942). 708 58

The title compounds were prepared by Koenigs-Knorr condensation of 3,4,6-tri-O-acetyl-2-deoxy-2-[(trifluoroacetyl)amino]-alpha-D-glucopyranosyl bromide with daunomycinone or a side-chain protected adraimycinone, followed by selective hydrolysis of blocking groups. Despite poor complexation with DNA and weak growth-inhibitory properties in vitro, the glucosaminyl analogues of the antitumor antibiotics daunorubicin and adriamycin, at their optimal (highest nontoxic) doses, exhibited antileukemic activity equivalent to that of adriamycin against a usually drug-refractory mouse leukemia model system (L1210) in vivo. These findings, together with other data from these laboratories, continue to support the hypothesis that the mechanism of action of adriamycin and related agents cannot be due exclusively to DNA binding, as has earlier been believed.
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PMID:Adriamycin analogues. Preparation and antitumor evaluation of 7-O-(beta-D-glucosaminyl)daunomycinone and 7-O-(beta-D-glucosaminyl)adriamycinone and their N-trifluoroacetyl derivatives. 708 17

The cyanogen bromide method was applied to the assay of vitamin B12-dependent methyltetrahydrofolate:homocysteine methyltransferase activity in normal and leukemic human hematopoietic cells. Normal peripheral lymphocytes and leukemia cells of lymphoid origin wuch as CLL and ALL, contained higher levels of enzyme activity than did normal human bone marrow cells. Normal granulocytes and leukemia cells of myeloid origin, such as CML in the chronic phase and AML, contained lower enzyme activity. Leukemia cells of CML in blast crisis showed higher mean activity than in the chronic phase of the disease.
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PMID:Vitamin B12-dependent methyltetrahydrofolate: homocysteine methyltransferase activity in normal and leukemic human hematopoietic cells. 747 90

Lymphoblasts were separated from the peripheral blood or bone marrow of 19 children (age 1-15, median 4 years) and 13 adults (age 18-59, median 47 years) with acute lymphoblastic leukaemia (ALL). Twenty-one samples were examined at presentation (16 from children and five from adults) and 13 at relapse (three children and ten adults). Glutathione (GSH) levels in leukaemic blasts were compared with in vitro sensitivity to a variety of cytotoxic drugs assessed using 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) as an indicator of cell viability. There was a statistically significant positive correlation between GSH levels and in vitro sensitivity to daunorubicin (Spearman's rank correlation coefficient rs = 0.38, p < 0.04), melphalan (rs = 0.39, p < 0.04) and prednisolone (rs = 0.48, p < 0.01), but not mitozantrone, etoposide or 6-thioguanine. There was no statistically significant difference in median GSH levels between blasts from children and adults or between samples taken at presentation or relapse. The sample median GSH levels in blasts from patients who responded to therapy (n = 21) and those who did not (n = 7) were 1.05 fmol/cell (97.3% confidence interval (CI) 0.78-1.52) and 2.66 fmol/cell (98.4% CI 0.53-5) respectively, and this difference was statistically significant (p < 0.02, Mann-Whitney U test). In two patients for whom paired samples were available, GSH levels in blasts on relapse were greater than 2-fold higher than on presentation. These results provide evidence that elevation of GSH in leukaemic blasts may be associated with resistance to drugs used in the treatment of children and adults with ALL.
Leukemia 1994 Sep
PMID:Raised intracellular glutathione levels correlate with in vitro resistance to cytotoxic drugs in leukaemic cells from patients with acute lymphoblastic leukemia. 809 28

Topoisomerase II (topo II) is a target for many cytotoxic agents. Two observations, however, warrant caution in their therapeutic use: first, these agents can inhibit differentiation and second, perturbations in function render the enzyme error-prone. Illegitimate recombination events occurring at sites where topo II acts in differentiation could be particularly important in the development of secondary malignancies (relatively frequent after therapy with agents that target topo II). Topo II inhibitors are heterogeneous in mechanisms of action; in site-specificity of cleavable complex 'entrapment' (where present) and in the relative potency against the two topo II isoforms, all potentially influencing the site of maximum DNA damage. The object of this study was to examine the effect of topo II inhibitors on human haemopoietic precursor cells, to determine which have most impact on differentiation. We selected two which act via cleavable complex entrapment, but with different site preferences (m-AMSA and VP-16), and two acting via other mechanisms (merbarone and fostriecin). VP-16 and m-AMSA showed similar patterns with low dose stimulation of granulocyte-macrophage colony formation and high dose inhibition of all colony types. The stimulation was accompanied by an increase in colony size and blast content, consistent with a low dose inhibition of differentiation. Forstriecin, in contrast, stimulated predominantly mixed and erythroid colonies. Merbarone failed to increase colony formation. Neither produced substantial inhibition of colony formation. The effects on granulocyte-macrophage progenitors were confirmed using 7-day suspension cultures, using nitroblue tetrazolium (NBT) reduction and 3-4,5,dimethylthiazol 2,5-diphenyl tetrazolium bromide (MTT) assays for differentiated cells and total cell mass, respectively. These results demonstrate that the effects of topo II inhibitors on haemopoietic cell proliferation and differentiation are agent-specific and can involve lineage-restricted partial inhibition of differentiation.
Leukemia 1994 Jan
PMID:Effects of DNA topoisomerase II inhibitors on human bone marrow progenitor cells. 828 77

A Ca(2+)-calmodulin dependent histone 3 kinase was partially purified from a low salt (150 mM NaCl) nuclear extract of mouse leukemia cells by calmodulin-Sepharose affinity chromatography. In vitro, the kinase activity transferred gamma-phosphate from ATP to histone 3 to form an acid-labile and alkaline-stable linkage. Under the assay conditions 1.8 mol of phosphate are incorporated per mol of histone 3. Upon modification of arginine residues with phenylglyoxal prior to phosphorylation, a considerable decrease in the amount of phosphate transferred to histone 3 was observed. Amino acid analysis revealed that H3 was phosphorylated on arginine residues. To identify the phosphorylated peptide(s), histone 3 was cleaved with cyanogen bromide prior to phosphorylation. The phosphorylated mixture was then separated by gel filtration high-performance liquid chromatography under denaturing conditions. Fragments I (N-terminal 10.3-kDa peptide) and III (C-terminal 1.7-kDa peptide) were both phosphorylated. Amino acid sequencing further revealed that the molar yields of 3 of the 4 arginines present in the phosphorylated cyanogen bromide fragment III were reduced by a factor of about 10 compared with the corresponding arginines from the unphosphorylated fragment. In the case of fragment I, 25 cycles of Edman degradation revealed that the recovery of only arginine 2 was reduced by a factor of 20. The putative phosphorylation sites are arginines 2, 128, 129, and 131. The sequence information offered an indirect evidence that these arginines were the sites of phosphorylation. The kinase described in this report represents a first member of a potentially important new class of kinases which are Ca(2+)-calmodulin dependent and which phosphorylate arginine.
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PMID:Ca(2+)-calmodulin-dependent phosphorylation of arginine in histone 3 by a nuclear kinase from mouse leukemia cells. 830 Jun 3

We have analyzed ten APL patients using reverse transcription polymerase chain reaction (RT-PCR) technique to detect PML/RAR alpha fused mRNA. All patients in this study had PML/RAR alpha fused mRNA (three cases of the short type and seven cases of the long type), although the chromosomal translocation t(15;17) was not detected in one patient. After ethidium bromide staining, two-thirds of the short type and all cases of the long type were found to have multiple PCR products (192 and 93 base pair (bp) bands in the short type and 666, 522, 263, and 164 bp in the long type). A total of six distinct fused mRNAs were sequenced (P1R1, P1R2, P3R1, P2R1, and P2R2). Southern hybridization analysis showed only one rearranged band in each of the patients. These results suggest that the longest mRNAs in each type are the authentic fused mRNAs and the other smaller mRNAs are generated through splicing events. In RAR alpha, a novel fusion point (R2) was identified within the fourth exon. This uncommon splicing may be caused by the instability of the splicing mechanism of the rearranged PML/RAR alpha gene. Among the ten APL patients, no correlation was observed between the type of fused mRNA and the clinical characteristics examined.
Leukemia 1993 Aug
PMID:Unexpected heterogeneity of PML/RAR alpha fused mRNA detected by nested polymerase chain reaction in acute promyelocytic leukemia. 839 80


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