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)

Two translocation--carrying stocks of mice, T(7;15)9H and Rb(4;15) were resistant to chemical leukemogenesis by 7,12-dimethylbenz(a)-anthracene (DMBA) or methylnitroso-N-urea (MNU). Lymphomas were induced in F1 hybrids derived from crossing these two stocks with various susceptible strains. In T-cell leukemias originating from F1 hybrids with Rb(4;15) as one parent and strain CBA or ASW as the other, the translocation chromosome was present in two copies. In trisomic tumors derived from Rb(4;15) X AKR F1 cross, the AKR-derived chromosome 15 was duplicated regularly. In contrast, all trisomic lymphomas of the T(7;15)9H F1 outcrosses showed duplication of the non-translocated chromosome 15 and not of the (7;15) translocation chromosome. It is suggested that the resistance of the T(7;15)9H stock to chemical induction of T-cell leukemia may be related to the position of the translocation on chromosome 15 (band D2). Our previous studies (reviewed by Klein, 1981) have indicated that this area may contain an oncogene that needs to be activated and subsequently undergo duplication in the course of leukemia development. In our previous studies on trisomic leukemias induced in heterozygotes (Wiener et al., 1979, 1980 b), we have found that duplication was non-random in all investigated crosses, unless the normal and the translocation marker carrying chromosomes were derived from the same inbred strain. A "duplication preference" scale could be established between chromosomes No. 15 derived from different strains. This suggested that the likelihood of leukemia development was different, depending on the genetic origin of chromosome 15. In the present study, we have found that the duplication of chromosome 15 occurred at random in the CBAT6T6 X C3H F1 cross. This is attributed to the close genetic relationship between the two strains, as indicated by their shared isoenzyme and other markers.
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PMID:Non-random duplication of chromosome 15 in T-cell leukemias induced in mice heterozygous for reciprocal and Robertsonian translocations. 681 6

Sets of 2-[2-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones with amino and actylamino groups at each of the eight positions on the anthracene nucleus were synthesized from appropriately substituted anthracenes. Their evaluation in in vitro antitumor and cardiotoxicity assays revealed a very strong dependence of potency on the position of substitution. Certain compounds, including the 4-, 5-, 7-, and 9-amino derivatives, showed significantly higher potency than the unsubstituted parent compound, azonafide. Among them, 7-aminoazonafide had low cardiotoxicity relative to cytotoxicity. In general, the acetylamino analogues were less potent than the amino derivatives against tumor cells and neonatal rat heart myocytes; however, 5-(acetylamino)azonafide was highly cardiotoxic. 9-Aminoazonafide was more efficacious than azonafide or amonafide against P388 leukemia in mice. Statistically significant correlations were made between the ability of amino analogues to increase the transition melt temperature (delta Tm) of DNA and their potency against solid tumors, leukemia cells, or cardiac myocytes.
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PMID:Amino-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones. Synthesis, antitumor activity, and quantitative structure--activity relationship. 769 15

Using the inside-out patch clamp technique, we identified a Cl- channel in patches from the membrane of cultured human hematopoietic myeloblastic leukemia ML-1 cells. The Cl- channel was not seen at negative membrane potentials in excised patches until the membrane potential was depolarized to greater than +40 mV. The channel was also activated by addition of cAMP-dependent protein kinase (PKA) catalytic subunit at physiological membrane potential (-40 mV). Biophysical studies of the Cl- channel revealed that the current-voltage (I-V) relationship of the Cl- channel was outwardly rectifying in symmetrical 142 mM Cl- solutions. Single channel conductances were 48 pS for the outward current measured at +60 mV and 27 pS for the inward current at -60 mV. The open time constant of the channel was dependent on the membrane potential and was significantly prolonged at positive membrane potentials. Channels activated by cAMP-dependent protein kinase spent a significantly longer time in the open state compared to those channels activated by depolarization pulses. Pharmacological properties of the Cl- channel were also studied. Two anion transport inhibitors, anthracene-9-carboxylic acid (9-AC) and 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS) caused a flickering block of the channel. Half-inhibitory concentrations (IC50) for 9-AC and DIDS were 174 +/- 20 and 70 +/- 16 microM, respectively. Blockade of the Cl- channel by 9-AC or DIDS was completely reversible. Our findings suggest that outwardly rectifying Cl- channels (ORCC) are present in human hematopoietic myeloblasts. The function of ORCC may be involved in hormone-regulated cell growth, cell volume regulation and immune responses.
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PMID:Protein kinase A-regulated Cl- channel in ML-1 human hematopoietic myeloblasts. 770 54

Intravenous injections of 7,12-dimethylbenz[a]anthracene (DMBA) induce erythroblastic leukemia (erythroleukemia) with No.2 trisomy in Long-Evans rats. Activation of some oncogenes such as abl and Ha-ras has been reported to occur in relation to the secondary chromosomal translocations. In the present studies, a consistent type of mutation, A to T transversion in codon 61 of N-ras gene, was found in all of 6 cultured leukemia cell lines and 5 primary leukemias induced by DMBA. The N-ras mutation was also found in bone marrow cells of 2 out of 8 preleukemias. On the contrary, no mutation was observed in Ha- and Ki-ras genes in all leukemias and preleukemias. The consistent occurrence of above N-ras mutation in leukemias indicates that it plays an important role in DMBA-leukemogenesis.
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PMID:N-ras mutation in 7,12-dimethylbenz[a]anthracene (DMBA)-induced erythroleukemia in Long-Evans rats. 775 91

Synthetic procedures have been developed which lead to the 2-aza congeners 3 and several related N-oxides 4. The analogues 3 exhibited a wide range of in vitro cytotoxicity against L1210 leukemia, the human colon adenocarcinoma cell line LoVo, and the doxorubicin resistant LoVo/DX cell line. Selected analogues of 3 showed significant P388 antileukemic activity in mice with 3c exhibiting high activity. This activity was also retained in the related N-oxide 4a. These heterocyclic bioisosteric models are representative of the first anthracene-9,10-diones which display antileukemic activity comparable to mitoxantrone.
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PMID:6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: synthesis and antitumor evaluations. 814 34

Bisantrene is an anthracene derivative which has demonstrated activity in acute myeloblastic leukemia (AML) and in lymphoma. The present study was designed to assess the reinduction rate and toxicity of bisantrene (250 mg/m2/d x 5) associated with aracytine (100 mg/m2 twice a day x 5) in refractory and relapsed acute childhood leukemia. Patients who relapsed after bone marrow transplantation were eligible. Twenty-six children were included. Diagnoses were as follows: 13 AML, 9 acute lymphoblastic leukemia (ALL), and 4 undifferentiated leukemia (AUL). All patients had been very highly pretreated, especially with anthracyclines, and most of them were of poor prognosis. The overall response rate was 46% with a 95% confidence interval ranging from 27-65%. According to diagnosis, complete remission (CR) rates are: AML: 5/13, ALL: 5/9, and AUL: 2/4. Four children died, three from infection and one from acute lysis syndrome. The major toxicity was infection with grade 3 and 4 episodes occurring in 42% of patients. No significant cardiac toxicity was noted. Hepatic and renal toxicity was noted. Hepatic and renal toxicity were limited and transient. Bisantrene in association with aracytine is effective in both AML and ALL of childhood. Bisantrene should be evaluated with a five-day schedule in other pediatric malignancies. In children with acute leukemia previously treated with high dose aracytine, new combination regimen is warranted.
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PMID:Treatment of relapsed or refractory acute leukemia in childhood with bisantrene combined with high dose aracytine. 825 97

A number of epidemiological studies have indicated association between exposure to extremely low frequency electromagnetic fields and a variety of cancers, including leukaemia and brain tumours among residentially exposed children and among occupationally exposed adults. In order to test if intermittent magnetic fields (MF) act as a tumour promoter, a long-term skin carcinogenicity study of 50 Hz sinusoidal MF with flux densities of 50 muT and 0.5 mT, continuous as well as with an intermittence of 15 s on/off, was performed. Female SENCAR mice were divided into eight groups of 50 animals in each and treated according to an initiation- promotion scheme. 7,12-dimethylbenz[a] anthracene (DMBA) in acetone was applied to the dorsal skin at a subcarcinogenic dose, as an initiator and exposure to MF was performed for 19-21 h/day during 104 weeks starting 1 week after the initiator treatment. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was used as a positive control for skin tumour promoting activity. Two animals from each group were assigned for skin hyperplasia analysis at 2, 6, 12, 18 and 21 months. The animals were observed daily. The appearance of skin lesions and neoplasms were carefully followed and histopathological diagnosis was made for all neoplasms present at death. The experiment was terminated after 105 weeks. DMBA-treatment alone yielded altogether two skin tumours in two tumour-bearing animals and the animals exposed to acetone alone had one skin tumour. The animals exposed to continuous fields showed no skin tumour. Five animals exposed to 0.5 mT on/off had a total of 13 skin tumours and in the group exposed to 50 microT on/off four animals had a total of four skin tumours. The on/off exposed groups differed significantly from the continuously exposed groups (P = 0.014) but the difference between the on/off exposure groups and the DMBA group was not statistically significant when tumour-bearing animals and cumulated skin tumours were compared. There was a statistically significant dose trend (P = 0.045) with flux density and Tesla-h for intermittent MF exposure for cumulated skin tumours per tumour-bearing animals. The epithelial thickness of DMBA + MF-treated animals was of the same magnitude as for DMBA-treated animals indicating that, in the case of a promoting effect being present, another mechanism than one involving sustained hyperplasia may be involved.
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PMID:Intermittent 50 Hz magnetic field and skin tumor promotion in SENCAR mice. 831 1

We have examined the activities of two novel aza-anthracene-9,10-diones (aza), 1-aza and 2-aza, in HL-60 human leukemia cell lines containing type II topoisomerases with different sensitivities to inhibition by other intercalating agents. The sensitive line, HL-60, was sensitive to 2-aza but not to 1-aza, whereas the resistant HL-60/AMSA was sensitive to neither agent. Measurements of 1- and 2-aza-induced, topoisomerase II-mediated DNA cross-linking in the cells revealed patterns of resistance and sensitivity that paralleled the results in the cytotoxicity assays. However, measurements of drug-induced topoisomerase II-mediated DNA cross-linking using purified HL-60 and HL-60/AMSA topoisomerase II indicated that both agents could stabilize a covalent complex between DNA and the HL-60 enzyme. HL-60/AMSA topoisomerase II resisted stabilization by either agent. This suggests that the resistance of HL-60 cells to 1-aza is not due to the inability of this drug to inhibit topoisomerase II but rather to another, undefined mechanism.
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PMID:Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II. 839 77

A new class of antitumor agents, having structural analogy to amonafide, but differing by the addition of a fourth ring in the nucleus, was synthesized conveniently from anthracene. Compounds with a variety of substituents, containing a basic nitrogen atom and located on the imide nitrogen, were prepared. Thirteen of 19 new compounds had greater growth inhibitory potency than amonafide in a panel of cultured murine and human tumor cells using the sulforhodamine B and MTT dye assays. The most active agents were similarly more toxic than amonafide to normal neonatal rat myocytes in vitro, but they had better chemotherapeutic indexes. From these compounds, the one with a 2-(dimethylamino)ethyl side chain (named azonafide) was chosen for further study. It showed high potency against a panel of cultured human colon cancer cells and it was active against ip P388 leukemia and subcutaneous B16 melanoma in mice. Preliminary structure-activity correlations suggest that the basicity of the side-chain nitrogen and the length of side chain are important determinants of antitumor potency in vitro. Steric hindrance and rigidity of the side chains might be other determinants.
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PMID:2-substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent. 845 3

Because of the lack of standard treatment in refractory and relapsed acute myelogenous leukemia (AML) several new drugs have been employed alone to evaluate their efficacy in this peculiar category of patient. Bisantrene, a new anthracene bishydrazone derivative, has shown antileukemic effect in phase I and II clinical trials with acceptable extrahaematological toxicity. Seven patients (six males and one female, median age 41.8 years) received Bisantrene (250 mg/sqm/daily 1-7) as a single agent in relapsed or refractory leukemia. 5 out of 7 patients achieved complete remission, one attained partial remission and one was resistant. However, haematological toxicity was severe with prolonged myelosuppression. Hepatic toxicity was the main extrahaematological side effect and occurred in 3 of 7 patients, however all of them recovered within 40 days. No cardiovascular dysfunction occurred although all the patients had been heavily previously treated with anthracyclines. Our data confirm that Bisantrere is active in relapsed and refractory AML and suggest the need for larger clinical trials to better evaluate its efficacy.
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PMID:Bisantrene in relapsed and refractory acute myelogenous leukemia. 847 80


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