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 unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones bearing one "mitoxantrone side arm" and another (aminoalkyl)amino moiety has been described. These unsymmetrical anthracene-9,10-diones exhibit cytotoxic activity against L1210 leukemia cells and antitumor activity against P388 leukemia in mice.
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PMID:Synthesis of unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones as potential antileukemic agents. 275 97

DBA/2 mice carry a single endogenous ecotropic murine leukemia provirus designated Emv-3. Although this provirus appears to be nondefective by genomic restriction enzyme mapping, weanling mice do not produce virus and only about one-third of adult mice ever express virus. 5-Iododeoxyuridine and 5-azacytidine, two potent inducers of ecotropic virus expression, are relatively ineffective at inducing Emv-3 expression. However, the chemical carcinogen 7,12-dimethylbenz(a)anthracene can induce ecotropic virus expression in approximately 95% of treated DBA/2 mice. Previous experiments involving DNA transfection and marker rescue analysis of molecularly cloned Emv-3 DNA suggested that Emv-3 carries a small defect(s) in the gag gene, not detectable by restriction enzyme mapping, that inhibits virus expression in vivo and in vitro. Using a combination of approaches, including DNA sequencing, peptide mapping, and metabolic labeling of cells with [3H]myristate, we have demonstrated that the defect in Emv-3 most likely results from a single nucleotide substitution within the gene for p15gag that inhibits myristylation of the Pr65gag N terminus. Myristylation of Pr65gag is thought to be required for this protein to associate with the plasma membrane and is essential for virus particle formation. These results provide a conceptual framework for understanding how Emv-3 expression is regulated during development and after chemical induction.
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PMID:Poorly expressed endogenous ecotropic provirus of DBA/2 mice encodes a mutant Pr65gag protein that is not myristylated. 282 10

The antileukemic potency of the alkyllysophospholipid, 1-octadecyl-2-methoxy-rac-glycero-3-phosphocholine (Et-18-OCH3) and of the retinoid etretinate was examined alone and in combination in 7,12-dimethylbenz-anthracene(DMBA)-induced Long-Evans (LE) rats. Lifelong administration of Et-18-OCH3 at a dose of 20 mg/kg per day slightly but significantly reduced the incidence of leukemias and thereby significantly prolonged the life span of animals. The best effect was seen when treatment started at day 58 of life, i.e. 1 day after the third of 4 DMBA injections (P = 0.0001). Administration of etretinate, however, at a dose of 5 mg/kg did not show any efficacy against leukemia development. The combination of both agents reduced the incidence of mammary neoplasias only (P = 0.04).
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PMID:Protection by the alkyllysophospholipid, 1-octadecyl-2-methoxy-rac-glycero-3-phosphocholine, but not by the retinoid etretinate against leukemia development in DMBA-treated Long-Evans rats. 308 Feb 26

The potential carcinogenicity of 3 azabenz(a)anthracenes was determined in vitro. The 3 compounds tested were 1-, 2-, and 9-azabenz(a)anthracene. The initial assay was chemical carcinogen-induced enhancement of anchorage-independent survival of Rauscher leukemia virus-infected Fischer rat embryo cells, 2FR(4)50 (2FR4). Cells treated with 2- and 9-azabenz(a)anthracene showed dose-dependent increased survival. After continued subculturing, the surviving cells from 2- and 9-azabenz(a)anthracene-treated cultures displayed morphological transformation and ability to grow in semi-solid medium. Mock-treated controls and I-azabenz(a)anthracene-treated cultures did not show either of these properties. These data suggest that certain azabenz(a)anthracenes are potential carcinogens.
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PMID:Potential carcinogenicity of aza-aromatic hydrocarbons: azabenz(a)anthracenes. 308 72

Male Wistar rats received repeated pulse doses of 7,12-dimethylbenz(a)anthracene (DMBA), known to elicit myelodysplasia followed by acute, mostly erythroblastic, leukemia at 10-day intervals. The recovery of spleen colony forming hemopoietic stem cells (CFU-s) surviving the cytocidal action of DMBA was examined between pulses. Recovery after a pulse of 35 mg/kg body weight varied with the organ source of the CFU-s (femoral bone marrow or spleen) and the number of preceding DMBA pulses. After a single DMBA pulse bone marrow CFU-s initially recovered faster than reported for normal bone marrow CFU-s transplanted into chemically conditioned rats. But recovery was followed by regeneration arrest. Population doubling times of marrow CFU-s increased with the number of DMBA pulses. Recovery of splenic CFU-s was slower after a single DMBA pulse than reported for normal spleen CFU-s transplanted into chemically conditioned rats. The CFU-s population doubling times were not significantly different after a single or five DMBA pulses. After three pulses, however, recovery of splenic CFU-s was exceedingly slow until day 5 and subsequently accelerated, but was still slower than after one or five pulses. In the spleen CFU-s recovery was always accompanied by regeneration of total cell numbers with a preference for erythroid regeneration. In the bone marrow this was the case after three DMBA pulses only.
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PMID:Recovery patterns of rat hemopoietic stem cells between pulse doses of 7,12-dimethylbenz(a)anthracene (DMBA) applied in a leukemogenic regimen. 309 51

Oncogene activation induced by chromosomal changes is now regarded as one of the most important phenomena during carcinogenesis. We have reported c-abl activation in a rat leukemia cell line K3D, caused by a secondary chromosomal translocation. Another erythroblastic leukemia cell line D5A1, originally derived from a leukemia induced by 7,12-dimethylbenz(a)anthracene (DMBA) in a Long-Evans rat, is characterized by a marker chromosome 1q+, which also probably occurred as a secondary change. In this cell line, the transcription level of Ha-ras related mRNA increased compared with other cell lines. By the in situ hybridization technique, the c-Ha-ras locus was assigned to 1q43 and the breakpoint 1q+. Because the breakpoint was so near the c-Ha-ras locus on the chromosome, the present system may provide a model of activation of the c-Ha-ras gene brought about by chromosomal translocation.
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PMID:Chromosome marker and enhanced expression of c-Ha-ras in a DMBA-induced erythroleukemia cell line (D5A1). 311 19

Localization of cellular oncogenes (c-onc) near the break points of translocations in tumor cells has indicated involvement of these genes in neoplastic growth. Enhanced transcription of the cellular homolog (c-abl) of the transforming sequence of Abelson murine leukemia virus was observed in K3D, which was one of the cloned cell lines of 7,12-dimethylbenz[a]anthracene-induced rat erythroblastic leukemia. Since the c-abl activation was not observed in the parent cell line (K2D) from which K3D was derived and the latter was different from the former in the presence of a new marker chromosome, t(3;12), this marker may play a role in the expression of c-abl in K3D cells. In contrast to the human c-onc assignments, few rat c-onc assignments have been reported. In situ molecular hybridization studies assigned c-abl to the 3q12 site of the normal chromosome 3 and to the break point of the translocation t(3;12) in K3D cells. Another break point in this translocation chromosome 12p11 involves the nucleolar region, and the 3;12 translocation may involve c-abl and nucleolar cistrons. These results provide evidence of secondary c-onc activation during karyotypic evolution of cloned malignant cells.
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PMID:Secondary activation of c-abl may be related to translocation to the nucleolar organizer region in an in vitro cultured rat leukemia cell line (K3D). 345 63

Sudan III treatment of Long-Evans rats results in increased hepatic monooxygenase activity using ethoxycoumarin and aniline as substrates. Monooxygenase activity towards amino-pyrine and nitrosodimethylamine is not affected. Sudan III treatment results in increased microsomal cytochrome P448 and increased amounts of a protein band which comigrates with purified cytochrome P448 during SDS polyacrylamide gel electrophoresis. The proportions of the different dihydrodiols formed during the incubation of 7,12-dimethylbenz[a]anthracene with microsomes vary between untreated and treated animals. Thus, extracts of microsomes from untreated rats were found to contain materials with chromatographic properties identical to those of the 3,4-dihydrodiol and the 5,6-dihydrodiol when examined on two different h.p.l.c. systems. Extracts of microsomes from Sudan III treated animals were found to contain materials with chromatographic properties identical to those of the 5,6-dihydrodiol and the 8,9-dihydrodiol when similarly examined. These findings suggest that the protective effect of Sudan III against DMBA induced leukaemia is mediated by an alteration in monooxygenase activity.
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PMID:Alterations in the metabolism of 7,12-dimethylbenz[a]anthracene and various xenobiotics by rat hepatic microsomes following Sudan III treatment in vivo. 391 57

A series of 5-[(aminoalkyl)amino]-substituted anthra[1,9-cd] pyrazol-6(2H)ones (anthrapyrazoles) were synthesized. These compounds, which differ from the anthracenediones in that an additional pyrazole ring has been fused to the anthracene system in place of one carbonyl group, were evaluated in vivo for their anticancer activity in eight different mouse tumor systems. Compounds were selected for testing primarily on the basis of their high levels of activity P388 leukemia and occasionally for structural considerations. Sixty-seven % of the 21 analogues studied were curative in the National Cancer Institute P388 screen. Many of the compounds tested were highly active against each of the tumors of the National Cancer Institute panel. Thus 82, 73, 45, and 80% of the compounds tested were curative for L1210 leukemia, B16 melanoma, M5076 sarcoma, and the MX-1 mammary xenograft, respectively. Several of the compounds studied were curative against every tumor of the above panel. Because of the high activity of the anthrapyrazole series as a class in the National Cancer Institute tumor panel, additional testing was necessary to allow selection of clinical candidates. Twenty-one anthrapyrazoles were tested against mammary adenocarcinoma 16C, colon adenocarcinoma 11a, and the Ridgway osteogenic sarcoma. Four compounds, PD 113,309 (Cl-937), PD 113,785 (Cl-941), PD 111,815 (Cl-942), and PD 115,593, were judged superior to the rest on the basis of the expanded panel testing. The preclinical data to date suggest that these anthrapyrazoles are similar to doxorubicin in both degree and spectrum of activity. Each of these anthrapyrazoles were significantly more active than were the other synthetic intercalating agents, the anthracenediones mitoxantrone and ametantrone, against the tumors of the expanded panel. On the basis of their high level of broad spectrum activity in preclinical systems, ease of formulation, possible lack of cross-resistance with doxorubicin, and potential lack of cardiotoxicity, Cl-937, Cl-941, and Cl-942 have been selected for further preclinical evaluation and possible clinical development.
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PMID:Anthrapyrazoles, a new class of intercalating agents with high-level, broad spectrum activity against murine tumors. 405 27

Multiple intravenous injections of an emulsion containing 7,12-dimethylbenz(a)anthracene (DMBA) or 7,8,12-trimethylbenz(a)anthracene (TMBA) induce a high incidence of leukemia in rats. Twenty-four hours after a single injection, about half of the metaphase cells in the marrow have chromosomes with breaks. Although breaks were inflicted on chromosomes of various sizes and morphology, these aberrations were nonrandom in that members of the nos. 1 and 2 chromosome pairs were involved to an extent greater than expected on the basis of their size and number. Distinctive karyotypic abnormalities involving the no. 2 chromosome were observed in half of the leukemic rats, whereas these abnormalities were not observed in nonleukemic, DMBA-treated rats. Benzo(a)pyrene and benzo(e)pyrene, polycyclic aromatic hydrocarbons which did not induce leukemia, produced fewer breaks of the no. 2 (and other) chromosomes than did DMBA or TMBA.
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PMID:Changes in chromosomes of bone marrow after intravenous injections of 7,12-dimethylbenz(a)anthracene and related compounds. 527 51


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