Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibitory activity in extract from human blood granulocytes was tested on granulocyte-macrophage colony formation in vitro. The inhibition depended on the type of serum used. With mouse BMC and FCS in the cultures, extract corresponding to 2.5 X 10(4) granulocytes/ml reduced the colony number by 35%, and extract from 2 X 10(5) cells caused maximal inhibition (80-90%). With HS and mouse BMC the colony number was reduced by only 11-12%, but stronger inhibition (55%) was observed when the serum concentration was reduced. With both types of sera the total cell number per culture plate was reduced relatively more than the colony number. Human GM-CFC were as sensitive as mouse GM-CFC, and extract from CML granulocytes inhibited less (p less than 0.01) than extract from normal cells. Biochemical studies indicated that the inhibitor is a protein with a molecular weight of 30-60,000. Lactoferrin, a putative inhibitor of CSF production, did not inhibit spontaneous or CSF-induced colony formation in these studies.
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PMID:Colony inhibiting factor in mature granulocytes from normal individuals and patients with chronic myeloid leukemia. 347 14

The in vitro sensitivity of human chronic myeloid leukemia-blast crisis and chronic phase (CML-BC and CML-CP, respectively) cells as well as adherent cell-depleted, T lymphocyte-depleted normal bone marrow cells (A-T-NBMC) to various concentrations of mafosfamide (ASTA Z7654), was examined by colony formation assay in the presence of IL-3 and GM-CSF, to test the possibility of purging of BMC from CML cells. Colony formation by CML cells was inhibited more efficiently than by NBMC. After the incubation with 50 micrograms/ml or 100 micrograms/ml of mafosfamide, the growth of leukemic CFU-GM was totally abrogated in 2/11 or 9/11 cases of CML-BC and in 1/7 or 6/7 cases of CML-CP, respectively. At the same time the CFU-GM arising from normal BMC were not inhibited totally with 50 or 100 micrograms/ml of the drug in any of five experiments. CML cells were still unable to form secondary colonies, while normal BMC were capable of regrowth. The CD34+ cells isolated form CML-BC and CML-CP patients were also more susceptible to mafosfamide cytotoxicity in comparison to CD34+ cells derived from NBMC. To confirm the possibility of purging, CML-BC cells were mixed with NBMC (1:1) and incubated with mafosfamide. Finally, the growing colonies were examined for the presence of bcr/abl hybrid gene by reverse transcriptase-Taq polymerase chain reaction (RT-PCR) and specific hybridization. The bcr/abl gene was not detected in the colonies growing after 100 micrograms/ml, and the signal was diminished after incubation with 50 micrograms/ml of mafosfamide, as compared to control. These results strongly suggest that high concentrations of mafosfamide may be useful for the purging of autologous BMC from CML cells.
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PMID:Successful mafosfamide purging of bone marrow from chronic myelogenous leukemia (CML) cells. 813 96

We have studied the veto cell-mediated induction of transplant tolerance by allogeneic donor bone marrow cells and have achieved kidney allograft tolerance in a preclinical rhesus monkey model. Here we extend these studies to investigate the veto mechanism of CTLp suppression and the role of CD8 and TGF-beta in these events. Infusion of DR-/dim donor BMC into RATG-treated rhesus monkeys induced functional deletion of donor-specific CTLp and prolongation of kidney allograft survival, whereas depletion of the CD8+ subset from BMC ablated these effects. A role of CD8 in the veto effect was further implicated by rhesus MLR-induced CML experiments in which pretreatment of normal responder cells with MAb to MHC class I, the natural ligand of CD8, blocked the suppressive activity of allogeneic BMC. In addition, pretreatment of the BMC with anti-CD8 MAbs blocked strong veto activity significantly, suggesting that CD8 functions as an accessory or adhesion ligand. In contrast, anti-CD8 treatment significantly enhanced weak BMC-mediated veto activity, suggesting that CD8 might additionally serve as a signal transducer to increase veto activity, perhaps by the induction of cytokine release. The cytokine TGF-beta was studied because it has immunosuppressive properties that are shared by veto cells. Human TGF-beta, like BMC veto cells, inhibited MLR-induced CML in a dose-dependent manner, and anti-TFB-beta Ig relieved the BMC-mediated veto suppressive effect. Active TGF-beta was detected only in the supernatants of CML cultures containing BMC. Pretreatment of BMC with L-leucyl-leucine methyl ester (Leu-leu-OMe), which eliminates cytotoxic precursor and effector lymphocytes and monocytes, did not affect levels of active TGF-beta. In previous studies, the veto effect of BMC was also shown to be Leu-leu-OMe-resistant. Finally, treatment of isolated DR-/dim BMC cultures with anti-CD8 elicited TGF-beta secretion, whereas anti-CD2 or anti-CD3 had no effect. When isolated after stimulation with anti-CD8, only the CD8+ subset of DR-/dim BMC produced detectable levels of active TGF-beta. In summary, these studies demonstrate that CD8 functions as an immunoregulatory molecule in veto effects by freshly isolated rhesus BMC and suggest that CD8-ligand interactions may induce low-level secretion of TGF-beta to mediate or facilitate the veto mechanism of CTLp inactivation in a paracrine manner.
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PMID:A role for transforming growth factor-beta in the veto mechanism in transplant tolerance. 815 38

The protein kinase inhibitor imatinib, also known as Gleevec, has been a notable success in treating chronic myelogenous leukemia. A recent paper in BMC Structural Biology reports a 1.75 A crystal structure of imatinib bound to the oxidoreductase NQO2 and reveals insights into the binding specificity and the off-target effects of the inhibitor.
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PMID:Exploiting the promiscuity of imatinib. 1943 83

Although imatinib is firmly established as an effective therapy for newly diagnosed patients with chronic myeloid leukemia (CML), the field continues to advance on several fronts. In this minireview we cover recent results of second generation tyrosine kinase inhibitors in newly diagnosed patients, investigate the state of strategies to discontinue therapy and report on new small molecule inhibitors to tackle resistant disease, focusing on agents that target the T315I mutant of BCR-ABL. As a result of these advances, standard of care in frontline therapy has started to gravitate toward dasatinib and nilotinib, although more observation is needed to fully support this. Stopping therapy altogether remains a matter of clinical trials, and more must be learned about the mechanisms underlying the persistence of leukemic cells with treatment. However, there is good news for patients with the T315I mutation, as effective drugs such as ponatinib are on their way to regulatory approval. Despite these promising data, accelerated or blastic phase disease remains a challenge, possibly due to BCR-ABL-independent resistance.
BMC Med 2011 Aug 26
PMID:Advances in the treatment of chronic myeloid leukemia. 2186 60