UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multidrug resistance (MDR)-neutralizing and cytotoxic properties of 16 novel tetramethylpiperidine (TMP)-substituted phenazines were compared with those of clofazimine and B669 using a P-glycoprotein (P-gp)-expressing undifferentiated, human leukemia cell line (K562/MMB). Unchlorinated TMP-substituted phenazine molecules were more cytotoxic than their chlorinated counterparts, while the halogenated molecules, especially those with chlorine atoms at position 3 on the aniline and phenyl rings, were less cytotoxic but more effective as chemosensitizing, P-gp-neutralizing agents. One of the TMP-substituted phenazines, B4121, increased the sensitivity of K562/MMB cells to vinblastine by 100-fold. TMP-substituted phenazines are a novel class of pharmacologic anti-cancer agents with both direct cytotoxic, as well as MDR-neutralizing anti-tumor properties.
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PMID:Novel tetramethylpiperidine-substituted phenazines are potent inhibitors of P-glycoprotein activity in a multidrug resistant cancer cell line. 931 48

As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of rebeccamycin, with or without the chlorine atoms on the indole moieties, or modified sugar residues (galactopyranosyl, glucopyranosyl, or fucopyranosyl) linked to the aglycone via a beta- or alpha-N-glycosidic bond. Their inhibitory properties toward protein kinase C, topoisomerase I, and topoisomerase II were examined, and their DNA-binding properties were investigated. Their in vitro antitumor activities against murine B16 melanoma and P388 leukemia cells were determined. Their antimicrobial activities were tested against Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, Gram-negative bacterium Escherichia coli, and yeast Candida albicans. These compounds are inactive toward topoisomerase II but inhibit topoisomerase I. A substitution with a methyl group on the imide nitrogen led to a loss of proteine kinase C inhibition in the maleimide indolocarbazole series but did not prevent topoisomerase I inhibition. Compounds possessing a beta-N-glycosidic bond, which fully intercalated into DNA, were more efficient at inhibiting topoisomerase I than their analogues with an alpha-N-glycosidic bond; however, both were equally toxic toward P388 leukemia cells. Dechlorinated rebeccamycin possessing a methyl group on the imide nitrogen was about 10 times more efficient in terms of cytotoxicity and inhibition of topoisomerase I than the natural metabolite.
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PMID:Syntheses and biological activities (topoisomerase inhibition and antitumor and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group. 934 21

Four groups, each of 50 male and 50 female Sprague-Dawley rats, of the colony used in the Cancer Research Center of Bentivoglio of the Ramazzini Foundation, 12 weeks old at the start of the study, received drinking water containing sodium hypochlorite, resulting in concentrations of active chlorine of 750, 500, and 100 mg/l (treated groups), and tap water (active chlorine < 0.2 mg/l) (control group), respectively, for 104 weeks. Among the female rats of the treated groups, an increased incidence of lymphomas and leukemias has been observed, although this is not clearly dose related. Moreover, sporadic cases of some tumors, the occurrence of which is extremely unusual among the untreated rats of the colony used (historical controls), were detected in chlorine-exposed animals. The results of this study confirm the results of the experiment of the United States National Toxicology Program (1991), which showed an increase of leukemia among female Fischer 344/N rats following the administration of chlorine (in the form of sodium hypochlorite and chloramine) in their drinking water. The data here presented call for further research aimed at quantifying the oncogenic risks related to the chlorination of drinking water, to be used as a basis for consequent public health measures.
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PMID:Results of long-term carcinogenicity studies of chlorine in rats. 947 41

The catalytic mechanism for the enzyme, IMP cyclohydrolase, may involve a reaction intermediate with negative charge in the 2-position of the purine ring (Szabados, E., Hindmarsh, E., Phillips, L., Duggleby, R.G. & Christopherson, R.I. (1994) Biochemistry 33, 14237-14245). Three analogues of IMP have been synthesised where fluorine, chlorine or bromine has been substituted in the 2-position on the purine ring. These analogues with an electronegative substituent may resemble a reaction intermediate for IMP cyclohydrolase; 2-fluoro IMP is a potent inhibitor of the enzyme with a Ki value of 0.19 microM, while 2-chloro IMP has a Ki of 1.9 microM and 2-bromo IMP is not inhibitory. However, IMP cyclohydrolase is not inhibited in human CCRF-CEM leukaemia cells exposed to 2-fluoro inosine although it is toxic to these cells with an IC50 value of 4.9 microM.
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PMID:Inosine-5'-monophosphate analogues as inhibitors of human IMP cyclohydrolase and cellular growth. 955 23

We have synthesized a new compound, 3-bromoacetylamino benzoylurea (3-BAABU), which showed strong cancericidal activity by inducing irreversible mitotic arrest and subsequently apoptosis in human T cell leukemic cells (CEM), human biphenotypic leukemic cells (SP), a human prostate cancer cell line (PC-3), murine melanoma cells (B-16), and murine lymphoma/leukemia cells (EL4) in vitro with an ID50 in the range of 0.013-0.07 microg/ml (0.04-0.22 microM). Treatment of tumor cells for 12-24 h with 3-BAABU resulted in mitotic arrest at prometaphase/metaphase/anaphase, with separation and dispersion of chromosomes and with the absence of mitotic spindle apparatus in cytoplasm. Treatment with 3-BAABU had no cytotoxic and mitotic blocking effect in normal human lymphocytes, proliferating fibroblast cells (3T3), or proliferating myocardial cells (MOT). Cell cycle analyses showed that most treated leukemic cells accumulated at M phase 12 h after treatment. By the end of 48 h of treatment, the cells underwent apoptosis with DNA fragmentation. 3-BAABU inhibited the assembly of microtubules from tubulin but did not interfere with the disassembly of microtubules. The presence and the position of bromine and urea groups on the benzoic ring are the determining factors for its inhibition of microtubule assembly. Replacing bromine with chlorine yielded much less mitotic blocking activity and increased the ID50 40-fold. Substitution of the urea group with ethyl ester abrogated the activity of blocking mitosis but induced apoptosis. Moving the bromoacetylamino group from the 3-position to the 4-position removed blocking activity for mitosis but induced necrosis. These results suggest that 3-BAABU possesses a unique and functional structure and is a potential agent for cancer chemotherapy.
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PMID:Inhibition of microtubule assembly in tumor cells by 3-bromoacetylamino benzoylurea, a new cancericidal compound. 960 56

Inherent resistance of myeloblasts to vincristine (VCR) has been related to the activity of myeloperoxidase (MPO) which can degrade VCR in the presence of hydrogen peroxide (H2O2). We investigated the relationship between VCR degradation and hypochlorous acid (HOCl) generation from the reaction of H2O2 with chlorine (Cl) as catalyzed by MPO. A cell-free system, three human leukemia cell lines (CEM/CCRF, HL-60, U937) and 15 bone marrow samples from children with acute myeloid leukemia (AML) were studied. VCR cytotoxicity was evaluated by MTT assay and by quantitative measurement of apoptosis. In vitro levels of VCR in cell-free systems were measured by high performance liquid chromatography (HPLC), and intracellular HOCl levels by oxidation of 5-thio-2-nitrobenzoic acid with the accompanying decrease in the absorbency at 412 nm. VCR was degraded by increasing concentrations of HOCl in cell-free systems and this activity was inhibited by taurine, which is known to block HOCl activity. This finding was confirmed by the VCR cytotoxicity studies on cell lines. The HOCl-producing myeloblasts from patients were resistant to VCR. In five samples out of eight HOCl was also detected extracellularly. These results suggest that oxidation by HOCl may be the final step in VCR degradation catalyzed by MPO through its action on intracellular H2O2 and Cl. Leukemia (2000) 14, 47-51.
Leukemia 2000 Jan
PMID:Further elucidation of mechanism of resistance to vincristine in myeloid cells: role of hypochlorous acid in degradation of vincristine by myeloperoxidase. 1063 76

Chloride channels on immune cells reportedly play important roles in cell volume regulation, cell proliferation and immune functions, but they are not well characterized at the molecular level. We examined the expression of swelling-and/or pH-regulated chloride channels (ClC-2, 3, 4 and 5) in human leukemic cell lines [Jurkat and Hut-78 (T cells), Raji and Daudi (B cells), K-562 and HL-60 (myeloid cells)] and T cells, B cells and neutrophils from 8 normal subjects to clarify the difference of their expression among different cell types and maturity. Semi-quantitative RT-PCR and Northern blot analysis showed that ClC-3 was most abundantly expressed in all cells regardless of the cell types and maturity, while expression of ClC-2 was weak in these cells. Expression of ClC-4 was observed mainly in leukemic B cell lines, and in B cells and neutrophils from normal subjects. ClC-5 was expressed in all cell lines, while it was observed in only T and B cells but not in neutrophils from normal subjects. Thus, these chloride channels (ClC-2, 3, 4 and 5) showed distinct distribution among human immune cells, suggesting that they have specific roles in these cells. Molecular identification of chloride channels in leukocytes of different types and maturity may provide a new approach for the treatment of leukemia.
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PMID:Expression of swelling- and/or pH-regulated chloride channels (ClC-2, 3, 4 and 5) in human leukemic and normal immune cells. 1188 14

In this paper we describe the synthesis of new copper complexes with alpha-ketoglutaric acid thiosemicarbazone. The crystal structures of the two compounds: [Cu(H(2)ct)Cl](n) [(Cu(H(2)ct)Cl)(2)] (1) and [Cu(Hct)](n).3nH(2)O (2) (H(3)ct=alpha-ketoglutaric acid thiosemicarbazone) have been determined by X-ray and spectroscopic methods. In 1 two independent copper atoms are present. Cu(1), in a nitrogen- and oxygen-bridged polymer, is a six-coordinated (4+2), Cu(2), five coordinated (4+1), is a chlorine-bridged dimer. In 2 the copper atom presents a penta-coordination, polymeric chains form layers and the -CH(2)CH(2)COO(-) groups bridge copper atoms. In 1 a monodentate and in 2 a syn-anti bidentate bridging carboxylate are present. The biological properties of 1 and 2 and also of the free ligand (H(3)ct) were tested in vitro and compared on Friend erythroleukemia cells (FLC) and on human leukemia cell lines K562 and U937. On the FLC cells the free ligand does not inhibit cell growth, but increases the DNA synthesis; complex 1 inhibits cell proliferation and increases the DNA synthesis; complex 2 inhibits cell growth, but induces a decrement of DNA synthesis and increases the reverse transcriptase activity. Regarding the human cell lines, both complexes show proliferation inhibition through an apoptosis mechanism on cell line U937, while they have no effects on the K562 line.
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PMID:Synthesis, characterization and biological activity of two new polymeric copper(II) complexes with alpha-ketoglutaric acid thiosemicarbazone. 1193 61

Chlorine and chloramine are used as disinfectants in water supplies to prevent the spread of waterborne diseases. The U.S. Environmental Protection Agency and the U.S. Congress, through the Safe Drinking Water Acts and Amendments, initiated studies to determine the most effective way to disinfect water supplies and, at the same time, minimize any potential long-term health effects associated with direct chemical exposure or indirect chemical exposure through the formation of byproducts. As part of this evaluation, 2-year studies of chlorinated or chloraminated deionized charcoal-filtered drinking water were conducted in F344/N rats and B6C3F1 mice to determine the potential toxicity and carcinogenicity associated with prolonged exposure and eliminate possible confounding effects of byproducts of chlorination. Chlorinated Water Studies: Water containing 0, 70, 140, or 275 ppm chlorine (based on available atomic chlorine) was provided to groups of 70 F344/N rats or B6C3F1 mice of each sex for up to 2 years. Groups of 10 rats or mice of each sex were predesignated for evaluation at 14 or 15 weeks and 66 weeks. Survival at 2 years of rats and mice receiving chlorinated water was similar to that of the controls. Mean body weights of dosed male rats, high-dose female rats, and dosed mice were slightly lower than those of their respective control groups. There was a dose-related decrease in water consumption by rats and mice. Water consumption by high-dose rats during the second year of the studies was 21% lower than controls for males and 23% lower than controls for females; water consumption by high-dose mice was 31% lower than controls for males and 26% lower than controls for females. The incidence of mononuclear cell leukemia in mid-dose, but not high-dose, female rats was significantly higher than that in controls (control, 8/50; low-dose, 7/50; mid-dose, 19/51; high-dose, 16/50). The proportion of female rats that died of leukemia before the end of the study and the mean time for observation of animals dying with leukemia were similar among all dose groups and controls. Although the marginal increase in leukemia incidence in the mid- and high-dose female rats suggested a possible association with the administration of chlorinated water, the incidence of leukemia was not clearly dose related. There was no indication of reduced latency of leukemia, and the incidence of leukemia in concurrent controls was less than the mean for historical controls; furthermore, there was no supporting evidence of an effect in male rats. Thus, the marginal increase in leukemia incidence in female rats was considered equivocal evidence of carcinogenic activity. There were no neoplasms or nonneoplastic lesions in male rats or in male or female mice that were clearly associated with the consumption of chlorinated water. Chloraminated Water Studies: Water containing 50, 100, or 200 ppm chloramine was provided to groups of 70 F344/N rats or B6C3F1 mice of each sex for up to 2 years. The same control groups were used for the chlorinated water and chloraminated water studies. Groups of 9 or 10 rats or mice of each sex were evaluated at 14 or 15 weeks and 66 weeks. Survival at 2 years of rats and mice receiving chloraminated water was similar to that of the controls. Mean body weights of high-dose rats and dosed mice were lower than those of their respective control groups. There was a dose-related decrease in water consumption by rats and mice. Water consumption during the second year of the studies by high-dose rats was 34% lower than controls for males and 31% lower than controls for females; water consumption by high-dose mice was 42% lower than controls for males and 40% lower than controls for females. Mononuclear cell leukemia occurred with a marginally increased incidence in the mid- and high-dose female rats receiving chloraminated water (control, 8/50; low dose, 11/50; mid dose, 15/50; and high dose, 16/50). As in female rats receiving chlorinated water, the proportion of female rats that died of leukemia before the end of the study and t that died of leukemia before the end of the study and the mean time for observation of animals dying with leukemia were similar among all dose groups and controls. The marginal increase in leukemia incidence in females receiving chloraminated water was considered equivocal evidence of carcinogenic activity for the same reasons given for female rats receiving chlorinated water. There were no neoplasms or nonneoplastic lesions in male rats or in male or female mice that were clearly associated with the consumption of chloraminated water. Conclusions: Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of chlorinated water in male F344/N rats receiving 70, 140, or 275 ppm. There was equivocal evidence of carcinogenic activity of chlorinated water in female F344/N rats based on an increase in the incidence of mononuclear cell leukemia. There was no evidence of carcinogenic activity of chlorinated water in male or female B6C3F1 mice receiving 70, 140, or 275 ppm. Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of chloraminated water in male F344/N rats receiving 50, 100, or 200 ppm. There was equivocal evidence of carcinogenic activity of chloraminated water in female F344/N rats based on an increase in the incidence of mononuclear cell leukemia. There was no evidence of carcinogenic activity of chloraminated water in male or female B6C3F1 mice receiving 50, 100, or 200 ppm.
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PMID:NTP Toxicology and Carcinogenesis Studies of Chlorinated Water (CAS Nos. 7782-50-5 and 7681-52-9) and Chloraminated Water (CAS No. 10599-90-3) (Deionized and Charcoal-Filtered) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). 1263 67

Toxicology and carcinogenesis assessments of chlorinated paraffins (C12, 60% chlorine), a material widely used as a flame retardant and extreme-pressure lubricant, were conducted in male and female F344/N rats and male and female B6C3F1 mice in single-administration, 16-day, 13-week, and 2-year studies. Doses used in the 2-year studies were 0, 312, or 625 mg/kg body weight per day administered by gavage in corn oil five times per week to groups of 70 male and female rats and 0, 125, or 250 mg/kg administered to groups of 50 male and female mice. Ten male and 10 female rats were killed after 6 and 12 months of dosing and examined for toxicity. No chemically related toxicity was observed in single-administration studies in which male and female rats received doses of chlorinated paraffins (C12, 60% chlorine) up to 13,600 mg/kg body weight and male and female up to 27,200 mg/kg. In 16-day studies, deaths did occur in groups of male and female rats given 7,500 mg/kg and in groups of male and female mice given doses of 1,875 mg/kg or higher. In 13-week studies, no chemically related deaths occurred among male and female rats given up to 5,000 mg/kg or mice given up to 2,000 mg/kg. Increased liver weights were noted in dosed rats and mice of each sex in the short-term studies, and dosed male rats showed more severe nephropathy than did vehicle controls. Doses selected for the 2-year studies were those that caused a minimal increase in liver weight in the short-term studies. Liver and kidney weights were increased in dosed rats killed at 6 and 12 months. Morphometric measurements demonstrated hepatocyte hypertrophy in the livers of dosed rats. Lesions of the kidney tubules and interstitial inflammation increased with dose in male and female rats. During the 2-year studies, body weights of high dose male rats were 8%-12% lower than those of vehicle controls after week 20, and body weights of dosed female mice were about 10% lower than those of vehicle controls during the second year. Survival of dosed male rats was lower than that of vehicle controls after about week 85, perhaps due to toxicity to the kidney (final survival: vehicle control, 27/50; low dose, 6/50; high dose, 3/50). Survival of low dose female rats was lower than that of vehicle controls (34/50; 24/50; 29/50). Survival of dosed male mice was not significantly different from that of vehicle controls (34/50; 31/50; 31/50). Survival of high dose female mice was lower than that of vehicle controls after about week 75 (final survival: 36/50; 31/50; 25/50). Chemically related nonneoplastic lesions consisted of hypertrophy and minimal focal necrosis of the liver in rats; erosion, inflammation, and ulceration of the glandular stomach and forestomach a in male rats; and formation ofmultiple cysts in the kidney tubules of male rats. The incidence of nephropathy was also increased in dosed female rats and mice. The maximum tolerated dose may have been exceeded in male and female rats. Neoplastic lesions associated with chlorinated paraffins (C12, 60% chlorine) administration were found in the liver of rats and mice of each sex (see table p. 12 of Technical Report) Dosed male rats showed increased incidences of kidney tubular cell hyperplasia (1/50; 9/50; 12/49) and of tubular cell adenomas (0/50; 7/50; 3/49); two low dose males had tubular cell adenocarcinomas. The incidences of mononuclear cell leukemia were increased in dosed male rats (7/50; 12/50; 14/50) and in low dose female rats (11/50; 22/50; 16/50). Pancreatic acinar cell tumors occurred at increased incidences in low dose male rats (11/50; 22/50; 17/50). Follicular cell adenomas or carcinomas (combined) of the thyroid gland were found at increased incidences in both female rats (0/50; 6/50; 6/50) and female mice (8/50; 12/49; 15/49). Chlorinated paraffins (C12, 60% chlorine) was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley or male Syrian hamster liver S9 when tested according to the preincubational protocol. An ed according to the preincubational protocol. An audit of the experimental data was conducted for these 2-year studies on chlorinated paraffins (C12, 60&percnt; chlorine). No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60&percnt; chlorine) for F344/N rats based on increased incidences of hepatocellular neoplasms (primarily neoplastic nodules) in male and female rats, of adenomas or adenocarcinomas (combined) of the kidney tubular cells in male rats, and of follicular cell adenomas or carcinomas (combined) of the thyroid gland in female rats. Mononuclear cell leukemia in dosed male rats may have been related to administration of chlorinated paraffins (C12, 60&percnt; chlorine). There was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60&percnt; chlorine) for B6C3F1 mice as shown by increased incidences of hepatocellular adenomas and of adenomas or carcinomas (combined) in dosed male and female mice and increased incidences of adenomas and of adenomas or carcinomas (combined) of thyroid gland follicular cells in dosed female mice.
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PMID:NTP Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C12, 60% Chlorine) (CAS No. 108171-26-2*) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 21

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