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)

A number of cloned biologic factors are currently available that are candidates for therapy of myelodysplastic syndromes and, by extension, acute nonlymphoblastic leukemia. gamma-Interferon and, to a greater extent, tumor necrosis factor exhibit leukemic differentiative effects without the potential for stimulation of leukemic clones. These effects may be enhanced by combinations of these with one another or with chemical inducers of differentiation such as retinoic acid or vitamin D derivatives. The colony-stimulating factors clearly have potent in vivo effects upon hematopoiesis. The lineage specific factors (G- or M-CSF) may have greater differentiation induction potential and less risk of accelerating emergence of leukemic clones than the earlier acting factors (GM- or multi-CSF). Thus, several potentially fruitful avenues for clinical research are currently available.
Leukemia 1988 Jun
PMID:The basis for treatment of myelodysplastic syndrome and acute nonlymphoblastic leukemia with biologic agents. 245 61

The expression of the myeloperoxidase (MPO) gene was studied, by means of Northern blot analysis in 14 cases of acute myeloid leukemia (AML), 11 cases of chronic myeloid leukemia (CML), and 6 cases of CML blast crisis, and in HL60 cells before and after induction of terminal differentiation with retinoic acid (RA), phorbol esters (TPA), or vitamin D. The expression of a panel of cell cycle-related genes, namely C-MYC, histone H3, ornithine decarboxylase, P53, vimentin, and calcyclin, was also studied in the same cell populations. Our results indicate that: (a) MPO gene expression (steady state mRNA levels) is strictly confined to the first stages of myeloid differentiation, reaching its peak at the promyelocyte stage and becoming undetectable in mature granulocytes and monocytes; (b) cells devoid of any detectable MPO enzymatic activity such as leukemic basophils have a high content of MPO mRNA; and (c) MPO gene expression is not related to the growth activity of the cell population. Finally, our results show that the pattern of expression of growth-regulated genes in the neoplastic myeloid disorders AML, CML, and CML blast crisis is remarkably different.
Leukemia 1989 Jun
PMID:Expression of the myeloperoxidase gene in acute and chronic myeloid leukemias: relationship to the expression of cell cycle-related genes. 254

Several new cytostatic drugs have entered clinical Phase I-II studies for treatment of leukemia: most promising are pyrimidine analogues such as 5-Azacytosine arabinoside, 5-Aza-2-deoxycytidine, 5-Azacytidine, cyclocytidine, and 2'-2'-difluorodeoxycytidine. They act on different biochemical levels towards DNA-synthesis. Fludarabine is a purin analogue and seems very active in treating CLL. Tiazofurin is an antimetabolite counter-acting nicotinic acid with most promising activity in CML blast crisis. Other substances include deoxycoformycin, an adenosine analogue for treatment of T-cell neoplasias, 1, 25-dihydroxy vitamin D 3 as differentiation inducer, and homoharringtonine, an alkylating agent widely used for treating de novo AML in China. New anthracyclines are THP-adriamycin, fluoroadriamycin, and 4-demethoxydaunorubicin. Amsacrine (mAMSA) finally, is a synthetic aminoacridine with DNA-intercalating properties. The intact acridine ring appears essential for antitumor activity. The plasma clearance of both total amsacrine and unchanged parent species is biphasic. There is a considerable influence of hepatic and renal impairment on plasma clearance. Clinical toxicities include marked myelosuppression, gastrointestinal symptomes, phlebitis, mucocutaneous lesions, occasionally alopecia and neurotoxities. It is a very active drug, particularly in treating AML. Studies using mAMSA alone or in combination revealed comparable results to the anthracyclines. The E.O.R.T.C. Leukemia Cooperative Group has used successfully mAMSA in several trials: relapsed and refractory AML, intensive maintenance treatment during first remission in AML, and, still on-going, during intensive consolidation randomized against BMT in AML-patients under the age of 45 years, and randomized against standard consolidation between the age of 45 and 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New drugs in the treatment of acute and chronic leukaemia: current role of mAMSA. 269 2

The retinoid receptors belong to a large superfamily of ligand-inducible transcription factors that include the steroid, vitamin D and thyroid hormone receptors, the peroxisome proliferator-activated receptor, the insect edysteroid receptor, and a number of orphan receptors whose ligands are unknown. All nuclear receptors have several well-characterized structural domains, including a conserved DNA-binding domain, and a ligand binding domain at the carboxyl terminus of the receptor. The RAR and RXR classes of nuclear retinoic acid receptors are each composed of alpha, beta and gamma subtypes with more than one isoform for each receptor subtype. Data from many investigators suggest there are RAR- and RXR-dependent gene pathways, and that the individual receptor subtypes may control distinct gene expression patterns. In addition, RXR has been found to heterodimerize with other nuclear receptors to form active transcriptional complexes, which influence the activity of a variety of gene pathways important in growth and differentiation. As a result, retinoids have been useful clinical agents in Dermatology and Oncology. However, upon prolonged exposure to retinoic acid, resistance to retinoids has often been encountered both in the clinical setting and in long-term cell culture (HL60R and RAC65 cells). In the latter case, retinoid resistance has been associated with a mutation in the RAR gene which transcribes a RAR receptor truncated at the C-terminal end. These mutated RAR receptors exhibit a reduced affinity for retinoic acid while retaining the ability to bind to a retinoic acid response element on DNA. As a result, these mutant receptors exhibit dominant-negative activity by binding to the DNA without activating transcription and by competing with other receptors for sites on the response element. In fact, dominant-negative activity may be very important in the development of many neoplastic diseases, including acute promyelocytic leukemia (APL), where a t(15;17) chromosomal translocation fuses the PML gene to the RAR gene, to produce a PML-RAR fusion protein in large excess in the cell. However, retinoid resistance in the patient is most probably the result of pharmacokinetic problems, whereby, with continuous retinoid treatment, the plasma levels of retinoic acid gradually decrease to below that required to maintain differentiation of leukemic cells in vivo. A major challenge for drug discovery is to design a drug which circumvents these pharmacokinetic problems either by designing novel drug delivery systems or by employing retinoids which do not bind to CRABP, such as 9-c-RA.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1994
PMID:The retinoid receptors. 780 17

The retinoid receptors belong to a large superfamily of ligand-inducible transcription factors that include the steroid, vitamin D and thyroid hormone receptors, the peroxisome proliferator-activated receptor, the insect edysteroid receptor, and a number of orphan receptors whose ligands are unknown. All nuclear receptors have several well-characterized structural domains, including a conserved DNA-binding domain, and a ligand binding domain at the carboxyl terminus of the receptor. The RAR and RXR classes of nuclear retinoic acid receptors are each composed of alpha, beta and gamma subtypes with more than one isoform for each receptor subtype. Data from many investigators suggest there are RAR- and RXR-dependent gene pathways, and that the individual receptor subtypes may control distinct gene expression patterns. In addition, RXR has been found to heterodimerize with other nuclear receptors to form active transcriptional complexes, which influence the activity of a variety of gene pathways important in growth and differentiation. As a result, retinoids have been useful clinical agents in Dermatology and Oncology. However, upon prolonged exposure to retinoic acid, resistance to retinoids has often been encountered both in the clinical setting and in long-term cell culture (HL60R and RAC65 cells). In the latter case, retinoid resistance has been associated with a mutation in the RAR gene which transcribes a RAR receptor truncated at the C-terminal end. These mutated RAR receptors exhibit a reduced affinity for retinoic acid while retaining the ability to bind to a retinoic acid response element on DNA. As a result, these mutant receptors exhibit dominant-negative activity by binding to the DNA without activating transcription and by competing with other receptors for sites on the response element. In fact, dominant-negative activity may be very important in the development of many neoplastic diseases, including acute promyelocytic leukemia (APL), where a t(15;17) chromosomal translocation fuses the PML gene to the RAR gene, to produce a PML-RAR fusion protein in large excess in the cell. However, retinoid resistance in the patient is most probably the result of pharmacokinetic problems, whereby, with continuous retinoid treatment, the plasma levels of retinoic acid gradually decrease to below that required to maintain differentiation of leukemic cells in vivo. A major challenge for drug discovery is to design a drug which circumvents these pharmacokinetic problems either by designing novel drug delivery systems or by employing retinoids which do not bind to CRABP, such as 9-c-RA.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1994 Nov
PMID:The retinoid receptors. 796 25

Retinoids and vitamin D (VD) cooperate to induce the differentiation and inhibit the proliferation of human myelomonocytic leukemia cells. Two classes of retinoids receptors, the RARs and RXRs, respectively, can mediate these effects. RXR forms heterodimers with a variety of nuclear receptors, including RAR and the VD receptor. We have previously found that VD treatment increases RXR alpha levels in myelomonocytic leukemia cells. By immunoanalysis, we observed in the present work that the RAR alpha protein is expressed in proliferating U937, HL-60 and THP-1 human leukemia cells and that VD treatment induces alterations of its electrophoretic pattern, although with large differences between cell lines. In the three cell lines, 9-cis RA, an agonist of both RARs and RXRs, cooperated with VD more efficiently than all-trans RA and RAR-specific synthetic ligands, thus suggesting an involvement of both RAR and RXR pathways in cell differentiation. Using U937 cells as a model, we delineated the relative contributions of RAR and RXR by assessing the effects of receptor-selective synthetic retinoids. The synergy between VD and all-trans RA or RAR-specific agonists (TTNPB and Ro 40-6055) was abrogated by a RAR alpha-specific antagonist (Ro 41-5253), confirming an involvement of RAR alpha. However, the cooperation between VD and 9-cis RA, although reduced, was not suppressed by the antagonist, suggesting also an involvement of the RXR pathway. The role of RXR as a ligand-activated receptor was confirmed using RXR-specific agonists (CD2608 and LGD1069), which also proved able to cooperate with VD. Finally, while each synthetic agonist alone was significantly less potent than 9-cis RA, combinations of the RAR and RXR selective agonists TTNPB and LGD1069 appeared to be as effective as the pan agonist 9-cis-RA. These results confirm that various retinoids can cooperate with VD and demonstrate that, at a whole cell level, optimal effects require the activation of both RAR and RXR receptors.
Leukemia 1997 Feb
PMID:Potentiation of VD-induced monocytic leukemia cell differentiation by retinoids involves both RAR and RXR signaling pathways. 900 84

The ability of the physiologically active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and two novel vitamin D analogues, EB1089 and KH1060 to induce the differentiation of the U937 and HL-60 leukaemic cell lines was evaluated, alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Studies revealed that following 96 h treatment, the vitamin D derivatives inhibited the proliferation, and induced the differentiation of U937 and HL-60 cells in a dose-dependent manner, as determined by cell counts and nitroblue tetrazolium (NBT) reduction assays, respectively. EB1089 and KH1060 were found to be more effective than 1,25(OH)2D3 in exhibiting their antiproliferative and differentiative effects. In contrast, induction of leukaemic cell differentiation with 1 ng/ml GM-CSF after 96 h was less effective when compared with the vitamin D derivatives used individually. Fluorescence activated cell scanning (FACS) analyses indicated that the vitamin D derivatives readily induced the expression of the monocyte-associated cell surface antigen, CD14, and also the beta2-integrins, CD11b and CD18 in both cell lines after 48 h and 96 h treatment. The ability of EB1089 and KH1060 to induce these antigens was achieved with greater efficacy relative to the native hormone. When U937 and HL-60 cell cultures were cotreated for 48 h with the vitamin D compounds and GM-CSF and analysed by FACS, enhanced effects on CD14 and CD11b induction were observed compared to those of the compounds alone. These co-operative effects may occur as a consequence of molecular events which involve the transcription by vitamin D receptors (VDR) of genes required for the responsiveness of immature cells to factors such as GM-CSF, and place these and other related vitamin D analogues as potential therapeutic agents in the treatment of leukaemia.
Leukemia 1997 Jul
PMID:Interaction of vitamin D derivatives and granulocyte-macrophage colony-stimulating factor in leukaemic cell differentiation. 920 85

The vitamin D analogue KH1060 and the retinoids all-trans retinoic acid (ATRA), 9-cis-retinoic acid (9-cRA) and 4-hydroxyphenyl retinamide (4-HPR) induce differentiation and/or apoptosis and inhibit clonal growth of acute promyelocytic leukaemia cells. We have studied the effects of these agents in vitro on cells from 12 patients with other forms of acute myeloblastic leukaemia (AML). Treatment with KH1060 (10(-6) M) caused decreases in cell viability in suspension culture to a median of 44% of control values (P=0.02). However, retinoids had little effect. Subsequent clonal growth in semi-solid medium was inhibited to 5% (median) of control with 10(-6) M KH 1060 (P=0.03) and to 73% with 10(-6) M 9-cRA (P=0.01). Further inhibition of clonal growth by the combination of 5 x 10(-7) M 9-cRA and 5 x 10(-7) M KH1060 was only noted in one case. Following the primary suspension culture, cells from 6/6 CD34 positive samples grew in semi-solid cultures without analogues, whereas cells from 3/6 CD34 negative cultures grew. 10(-6) M KH1060 completely abolished colony growth in all three CD34 negative samples and 10(-6) M 9-cRA inhibited the number of colonies to a median of 11% of control values. In the six CD34 positive samples median colony growth was inhibited to 36% of control values by KH1060 and to 83% of control values by 9-cRA. CD11b expression was increased by 210% (median) with 9-cRA and by 90% (median) with KH1060 in early to intermediate myeloblast (M0, M1, M2) clones. A different pattern was noted in more mature (M4, M5, M6) clones: here there was little or no increase in CD11b expression induced by retinoids or KH1060, but the ratio of apoptotic to viable CD11b+ cells, measured by CD11b/7-AAD double staining, was increased in 6/6 cases treated with KH1060 or the combination of 9-cRA and KH 1060, and in 5/6 cases treated with 9-cRA. No overall significant change in bcl-2 or bax expression on G0/G1 cells was found after 3 days' suspension culture with the analogues. However bcl-x was downregulated in G0/G1 cells treated with KH1060 (median bcl-x relative fluorescence intensity = 45.3 in cells treated with KH1060, compared with 65.7 in control wells, P=0.028). We conclude that CD34+ samples are relatively resistant to the growth inhibition induced by KH1060 and 9-cRA. However, downregulation of bcl-x in cells which have survived treatment with KH1060 may increase the susceptibility of the remaining leukaemic cells to cytotoxic drugs.
Leukemia 1998 Nov
PMID:Blast maturity and CD34 expression determine the effects of the differentiating agents KH1060 and 9-cis-retinoic acid on the differentiation and clonogenicity of non-M3 acute myeloid leukaemia cells. 982 49

A series of analogs of 1,25-dihydroxyergocalciferol (1-4) was synthesized and screened for their antiproliferative activity in vitro. The structure of new analogs was designed based on biological activity of the previously obtained side-chain modified analogs of vitamin D(2) and D(3). The analogs were obtained by the Julia olefination of C(22)-vitamin D sulfone 11 with side-chain aldehyde 15. The analogs were tested for their antiproliferative activity against the cells of human breast cancer lines T47D and MCF7 as well as human and mouse leukemia lines, HL-60 and WEHI-3, respectively. Analog 2 (PRI-1907) showed the strongest antiproliferative activity out of the present series of analogs of 1,25-dihydroxyvitamin D(2) with the mono homologated and double unsaturated side chain. The activity of 2 was 3-150 times stronger, depending on the cell line, than that of 1,25-dihydroxycholecalciferol (calcitriol), used as standard.
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PMID:Synthesis and antiproliferative activity of side-chain unsaturated and homologated analogs of 1,25-dihydroxyvitamin D(2). (24E)-(1S)-24-Dehydro-24a-homo-1,25-dihydroxyergocalciferol and congeners. 1212 91

We originally reported that vitamin K(2) (VK2) effectively induces apoptosis in various types of primary cultured leukemia cells and leukemia cell lines in vitro. In addition, VK2 was shown to induce differentiation of leukemia cells when the cells were resistant against VK2-inducing apoptosis. A novel synthetic vitamin D(3)derivative, 22-oxa-1,25-dihydroxyvitamin D(3) (OCT: oxacarcitriol) shows a more potent differentiation-inducing ability among myeloid leukemia cells in vitro with much lesser extent of the induction of hypercalcemia in vivo as compared to the effects of 1alpha,25(OH)(2)D(3). In the present study, we focused on the effects of a combination of OCT plus VK2 on leukemia cells. Treatment of HL-60 cells with OCT for 72 h induces monocytic differentiation. A combination of OCT plus VK2 dramatically enhances monocytic differentiation as assessed by morphologic features, positivity for non-specific esterase staining, and cell surface antigen expressions. This combined effect far exceeds the maximum differentiation induction ability at the optimal concentrations of either OCT or VK2 alone. In addition, pronounced accumulation of the cells in the G0/G1 phase is observed by combined treatment with OCT plus VK2 as compared with each vitamin alone. In contrast to cell differentiation, caspase-3 activation and apoptosis induction in response to VK2 are significantly suppressed in the presence of OCT in HL-60 cells. These data suggest that monocytic differentiation and apoptosis induction of HL-60 cells are inversely regulated. Furthermore, pronounced induction of differentiation by combined treatment with VK2 plus OCT was also observed in four out of six cases of primary cultured acute myeloid leukemia cells in vitro, suggesting that VK2 plus OCT might be a potent combination for the differentiation-based therapy for acute myeloid leukemias.
Leukemia 2002 Aug
PMID:Combination of 22-oxa-1,25-dihydroxyvitamin D(3), a vitamin D(3) derivative, with vitamin K(2) (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells. 1214 93


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