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 compound 8,11-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]- 6-methoxy-1,2,3,4-tetrahydro-7,12-benz[a]-anthraquinone (7) was synthesized from 3,6-dimethoxyphthalic anhydride and 6-methoxy-1,2,3,4-tetrahydronaphthalene by a Friedel-Crafts reaction, cyclization to form a dihydroxyanthraquinone, and conversion into the amino-substituted derivative by reaction with 2-[(2-hydroxyethyl)amino]ethylamine. The new compound, a ring D analogue of mitoxantrone, showed growth inhibition, at micromolar concentrations, of murine leukemia 1210, human lung H125, human breast MCF7, human ovary 121, and human colon WiDr and increased the life span of leukemic mice by 38%.
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PMID:Antitumor properties of tetrahydrobenz[a]anthraquinone derivatives. 229 18

The rates of incorporation of 2-14C-thymidine into DNA of leukemia P388, bone marrow, gastrointestinal mucosa and spleen cells at various time after administration of 3,4-disuccinyldianhydrogalactitol (DisuDAG), 1-methyl-1-nitrosourea (MNU), 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (HECNU) and their combinations at different doses to mice with leukemia P388 (solid form) were studied. DisuDAG (80 mg/kg) induced the deep and the stable inhibition in DNA synthesis of leukemia P388, bone marrow and spleen cells. The combination of DisuDAG and HECNU at small doses induced the deep and the stable suppression of DNA synthesis in tumor cells, however DNA synthesis in normal dividing cells was shown to recover more rapidly than in leukemia P388 cells. Administration of the combination of DisuDAG with MNU to tumor-bearing mice induced more stable inhibition of DNA synthesis in tumor cells in comparison with MNU and DisuDAG. In vivo inhibition of DNA synthesis in leukemia P388 cells with DisuDAG and HECNU was not due to damage in pool of precursors (TCA soluble fraction).
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PMID:[The effect of 3,4-disuccinyldianhydrogalactitol, N-nitrosourea and their combination on DNA synthesis in normal and mouse P388 tumor cells]. 279 30

Mitozantrone (MTZ; Novantrone), 1,4-dihydroxy-5,8-bis-[(2-[(2-hydroxyethyl)amino]ethyl]amino)-9,10- anthracenedione dihydrochloride (NSC 302739), is a synthetic anthracenedione with intercalating properties. Activity has been shown in preclinical studies in mice bearing intraperitoneal P388 and L1210 leukaemias and a variety of solid tumours. Three sequential studies to examine the activity, toxicity and scheduling of MTZ in acute leukaemia or chronic granulocytic leukaemia in myeloid transformation were undertaken in relapsed and/or refractory disease in patients up to the age of 70. Single-dose treatment up to 32 mg/m2 showed little activity but in a 5-day schedule (10 mg/m2/day) MTZ gave a 24% complete remission rate in relapsed and/or resistant acute leukaemia. In a phase III study in which MTZ was given in a similar schedule combined with a 7-day infusion of cytosine arabinoside (Ara-C; 100 mg/m2/day), 68% of patients were rendered leukaemia-free. In studies from other centres, similar very encouraging results have been obtained where MTZ has been combined with high-dose Ara-C or VP16/213.
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PMID:The role of mitozantrone in the treatment of acute leukaemia. 312 36

Investigations on the in vivo interaction of nicotine and antineoplastic agents were prompted by the observation that nicotine lowered the carcinogenicity of the alkylating agent methylnitrosourea (MNU) in rats. Since alkylating agents play an important role as antitumor drugs, nicotine may influence the anticancer activity of anticancer drugs, especially alkylating agents. Two tumor models were selected: (a) autochthonous, MNU-induced mammary carcinoma and (b) transplanted rat leukemia L5222. The antitumor drugs investigated were cyclophosphamide (CPA) and 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea (HECNU). Nicotine was administered continuously by Alzet-osmotic minipumps, at a dose of 2.5 and 5 mg/kg daily. Under these conditions the observed nicotine and cotinine plasma levels approximated levels measured in heavy smokers (nicotine peak level, 47 ng/ml; cotinine peak level, 635 ng/ml). In MNU-induced autochthonous mammary carcinoma, a solid hormone-dependent tumor, the combination of HECNU and nicotine yielded greater tumor inhibition than HECNU alone. The anticancer activity of CPA on transplanted L5222-leukemia, on the other hand, was decreased by continuous infusion of nicotine. The interpretation of both results has to take into account the following possibilities of nicotine action: influence on (a) microcirculation, (b) cell proliferation, (c) membrane transport, (d) metabolism of cytotoxic drugs, and (e) hormonal milieu. The results demonstrate that nicotine is able to influence the outcome of antitumor treatment. The mechanism of interaction needs clarification. Additionally, further combination studies with other classes of cytotoxic drugs are warranted.
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PMID:Interaction of nicotine with anticancer treatment. 318 71

A previous report was made on the carcinogenicity of 1-(2-hydroxyethyl)-1-nitrosourea [(HENU) CAS: 13743-07-2] in rats. Because the cyclic nitrosocarbamate 3-nitroso-2-oxazolidinone (NOZ) is readily produced during the synthesis of HENU and can be confused with HENU, HENU was retested and NOZ was tested for carcinogenicity. Improved syntheses of both compounds are described. They were administered in drinking water to male MRC-Wistar rats for 1 year, starting at 3 or 9 weeks of age. The HENU-treated rats showed incidences of 48% for bone tumors, 32% for intestinal tumors (mostly duodenal adenocarcinomas), and 53% for lymphoma-leukemia. Of the bone tumors, which were evaluated microscopically and radiologically, 68% were osteosarcomas and 32% were osteoblastomas. The skeletal distribution of these tumors was similar to that of human osteosarcoma, with the tumors occurring most frequently in the lower limbs near the knees. Of the hematopoietic tumors, the majority were lymphoblastic lymphoma-leukemia, which showed a diffuse organ distribution resembling human B-cell (Burkitt's-like) lymphoblastic lymphoma-leukemia, and differed from the usual type of convoluted T-cell lymphoma-leukemia induced by other nitrosoureas in rats and mice. NOZ induced intestinal tumors (mostly duodenal adenocarcinomas) in 80% and liver tumors (mostly hepatocellular adenomas) in 53% of the rats.
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PMID:Carcinogenicity of 1-(2-hydroxyethyl)-1-nitrosourea and 3-nitroso-2-oxazolidinone administered in drinking water to male MRC-Wistar rats: induction of bone, hematopoietic, intestinal, and liver tumors. 346

A number of chloro-substituted [(aminoalkyl)amino]anthraquinones were synthesized and evaluated for their antineoplastic and cytotoxic activity. Treatment of 5,8-dichloroquinizarin with substituted amines in pyridine resulted in the replacement of one halogen atom by the amino group to yield mainly 1-chloro-5,8-dihydroxy-4-(substituted amino)anthraquinones. On the other hand, reaction between the dichloroquinizarin and the amines in butanol gave predominantly 1,4-dichloro-5-hydroxy-8-(substituted amino)anthraquinones. Other compounds in this series were prepared by displacement of chloro, nitro, or tosyl functions of the appropriate anthraquinone derivatives with various amines by conventional methods. 1,4-Dichloro-5-hydroxy-8-[[2-[(2-hydroxyethyl)amino]ethyl]amino] anthraquinone (6b) possesses the highest inhibitory activity against P388 leukemia. Its inhibitory action against B16 melanoma and against the in vitro L1210 screen is also significant. Several other chloro- and hydroxy-substituted aminoanthraquinones (5a, 5b, and 6a) also showed noticeable activity against P388 in vivo and L1210 in vitro. Structure-activity-relationship examination indicated that the hydroxyl group may contribute to the binding of certain chloroaminoanthraquinones for their biological activity and that the [2-[(2-hydroxyethyl)amino]ethyl]amino side chain seems to be the preferred substituent over other amino side chains.
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PMID:Structural modification study of mitoxantrone (DHAQ). Chloro-substituted mono- and bis[(aminoalkyl)amino]anthraquinones. 362 13

Ametantrone acetate is an antineoplastic drug chemically described as 1,4-bis [[2-[(2-hydroxyethyl)-amino] ethyl]amino] -9,10-anthracenedione diacetate salt. The drug has activity against leukemia and solid tumors in animal models. The purpose of this study was to investigate the teratogenic potential in pregnant rats and rabbits when administered during the critical period of organogenesis. Daily doses of 1.5, 3.0, and 6.0 mk/kg were administered IP to pregnant rats on days 6 through 15 of gestation, and 0.2, 0.4, and 0.8 mg/kg to rabbits on days 6 through 18. Dose-related weight loss occurred in both species during treatment as well as in the entire gestation period. Maternal and fetal parameters were evaluated upon uterotomies in rats on gestation day 20 and rabbits on day 28. In both species, there was dose-related blue discoloration of abdominal viscerae and of skin at injection sites. In rats, fetal malformations and developmental variations were comparable between treated and control fetuses. However, the incidence of fetal malformations was increased in rabbits given 0.4 and 0.8 mg/kg but not at 0.2 mg/kg. Based on these data, ametantrone was considered teratogenic at dose levels of 0.4 mg/kg and above in rabbits.
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PMID:Teratology studies of ametantrone acetate in rats and rabbits. 379 63

Mitoxantrone (Novantrone; 1, 4-dihydroxy-5, 8-bis [[2-[(2-hydroxyethyl) amino]ethyl]amino-] 9, 10 anthracenedione dihydrochloride (NSC 301739] is a synthetic anthracenedione with intercalating properties. Activity has been shown in preclinical studies in mice bearing intraperitoneal P388 and L1210 leukaemias, ADJ-Pc6 plasmacytoma and a variety of solid tumours. In a phase I/II collaborative study fourteen consecutive patients with relapsed or primarily refractory acute leukaemia received a single infusion of mitoxantrone (20-32 mg/m2) at fourteen-day intervals. Antileukaemic activity was seen but there were no complete remissions and toxicity was minimal. Mitoxantrone was subsequently given in a five-day schedule at a dose of 10mg/m2 daily to twenty-one patients with relapsed or refractory acute leukaemia or chronic myeloid leukaemia in blast crisis (CML-BC). Four of five patients in first relapse of acute non-lymphoblastic leukaemia (ANLL) achieved a complete remission (CR). The overall response rate (CR + partial remission (PR] was 48%. In an ongoing phase III study the same (5-day) mitoxantrone treatment has been given in conjunction with a 7-day continuous infusion of cytosine arabinoside (Ara-C) in a kinetically designed schedule based upon the preclinical studies of the Mount Sinai group.
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PMID:Sequential studies on the role of mitoxantrone in the treatment of acute leukemia. 389 80

Mitoxantrone (1,4-dihydroxy-5,8-bis[(2-[(2-hydroxyethyl)-amino]-ethyl) amino]-9,10-anthracenedione dihydrochloride) is a representative of a new class of chemical compounds with antineoplastic activity. It was one of a number of polycyclic aromatic compounds tested at the American Cyanamid Laboratories and was the most effective and potent derivative synthesized. Mitoxantrone produced significant increases in life span and long-term survivors when tested against P388 and L1210 leukemias, B16 melanoma, and colon tumor 26 transplanted into mice. In comparative animal trials, it proved more effective than most of the other agents tested, including doxorubicin, cyclophosphamide, methotrexate, cytarabine, and 5-fluorouracil. It was also active against intravenously implanted L1210 leukemia, in contrast to doxorubicin, though this is considered to have a similar mode of action. Mitoxantrone also demonstrated moderate activity against sublines of the mouse leukemias, which were resistant to anthracyclines. Significant therapeutic synergism against P388 leukemia was observed when mitoxantrone was administered on the same day as methotrexate and cytarabine or in sequence with cyclophosphamide, cisplatin, or vincristine sulfate. Mitoxantrone is active intraperitoneally, intramuscularly, subcutaneously, and intravenously, but oral activity has not been demonstrated. Although dose schedule did not appear critical, treatment every 4 days X 3 appeared to be the most effective. The mechanism of action of mitoxantrone has not been fully elucidated, but it is known to inhibit DNA and RNA synthesis. In cell culture, mitoxantrone induces nuclear aberrations with chromosomal scattering and morphologic alterations similar to those induced by doxorubicin. Drug-induced cell kill was not phase specific. Experiments with a resistant human colon carcinoma cell line (WiDr) indicated that resistance may be due to alterations of the cell membrane with decreased uptake. Mitoxantrone has markedly less cardiotoxicity than doxorubicin, and this may be linked to the fact that the drug does not induce free radical formation but inhibits lipid peroxidation.
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PMID:Biologic and biochemical effects of mitoxantrone. 648 79

Treatment of Friend leukemia cells for 18 hours with 9,10-anthracenedione, 1,4-bis[[(2-hydroxyethyl)amino]ethyl]amino]-, diacetate (ANT) at concentrations up to 1.0 microgram/ml induced significant changes in cell metabolism and structure. Alterations in cell nucleic acid content were detected in cells stained with acridine orange under conditions such that DNA and RNA contents could be measured simultaneously by flow cytometry. Cells treated for 18 hours with ANT at concentrations of 0.05-0.1 microgram/ml became partially blocked at the G2 phase. In addition, about 30% of the cells became polyploid and demonstrated diplochromosomes at the 8C level of mitosis. The nuclear chromatin of blocked cells had an altered structure as reflected by a change in sensitivity of DNA in situ to denaturation induced by low pH. All viable cells treated with ANT for 18 hours at concentrations of 0.4-1.0 microgram/ml were blocked in G2 phase. These cells had significantly more RNA than did untreated cells. Transmission electron microscopic observations of thin-sectioned cells suggested that this increased RNA content in ANT-treated cells was mostly due to an approximately 50% increased cell diameter and partly due to a disproportionate increase in nucleolar size. In addition, electron microscopy revealed that ANT caused increased chromatin condensation and granulation. The drug had no apparent effect on production of the endogenous Friend murine leukemia virus.
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PMID:Effects of 9,10-anthracenedione, 1,4-bis[[2-[(2-hydroxyethyl)amino]-ethyl]amino]-, diacetate on cell morphology and nucleic acids of friend leukemia cells. 692 97


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