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)

Leukaemia inhibitory factor (LIF) or Oncostatin M (OSM), both mitogens for Swiss mouse 3T3 cells, triggers initiation of DNA synthesis without the requirement for mevalonic acid. Thus, Lovastatin (LOV), an inhibitor of the hydroxy methylglutaryl CoA (HMGCoA) reductase, does not block LIF or OSM induced DNA replication and cell multiplication. In contrast, increasing concentrations of LOV from 1 to 60 microM block the mitogenic action of PGF(2alpha) by decreasing the number of cells capable of entering S-phase and dividing. This inhibition by LOV can be reversed by addition of mevanolactone (MEV), an analogue of mevalonic acid. Thus, LIF or OSM triggers initiation of DNA replication independently of mevalonic acid synthesis and therefore without the involvement of isoprenylation of various signalling proteins.
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PMID:Leukaemia inhibitory factor or oncostatin M induction of Swiss 3T3 cells does not require mevalonic acid synthesis nor protein isoprenylation to initiate DNA replication. 1470 31

Clofarabine [Clofarex] is a purine nucleoside in development with Bio-envision, the Southern Research Institute and ILEX Oncology as an anticancer agent. Clofarabine's nucleoside structure is such that both the purine and ribose rings are halogenated, which allows it to inhibit DNA synthesis at two critical junctures: DNA polymerase I and RNA reductase. An intravenous infusion and an oral formulation are undergoing clinical development. Clofarabine was originated by the Southern Research Institute. In August 1998 Bioenvision signed a co-development agreement with the Southern Research Institute, under which it obtained the right to manufacture, market and distribute clofarabine worldwide, except Japan and Southeast Asia. In addition, the company appears to have licensed rights from the Institute that cover the development and marketing of other purine nucleoside analogues that have relevance in the treatment of leukaemia and lymphoma. Bioenvision will pay royalties to the Southern Research Institute for sales of clofarabine. Bioenvision extended its option in May 2004 to manufacture, market and distribute clofarabine in Japan and Southeast Asia, and is seeking a co-marketing partner to convert the option into a license agreement following the terms agreed upon between Bioenvision and the Southern Research Institute. Bioenvision and ILEX Products (a wholly owned subsidiary of ILEX Oncology) signed an agreement in February 2004 that converted ILEX's option (agreed in March 2001) to market and distribute clofarabine in the US and Canada. As part of the deal, Bioenvision received a $US3.5 million payment from ILEX in December 2003. In March 2004, Genzyme Corporation announced that it had signed a merger agreement with ILEX Oncology under which ILEX shareholders will receive shares of Genzyme common stock valued at approximately $US1 billion in equity value. Genzyme's business combination with ILEX is expected to be completed by the middle of 2004, Genzyme will, therefore, acquire a considerable boost to its product portfolio. Bioenvision obtained the exclusive option from the Southern Research Institute in September 2003 to manufacture, market and distribute clofarabine in Japan and Southeast Asia. Bioenvision stated it was actively seeking a co-marketing partner to convert this option into a license. Bioenvision announced in June 2003 that it had formed two separate agreements with Ferro Pfanstiehl Laboratories. The agreements cover worldwide development and supply of clofarabine, excluding the US and Canada. Ferro Pfanstiehl has more than 25 years of experience in potent compound manufacturing. The US FDA granted clofarabine fast-track designation for the treatment of refractory or relapsed acute lymphoblastic leukaemia in children in September 2003. Clofarabine has also been granted orphan drug status by the US FDA for the treatment of adult and paediatric patients with acute lymphocytic leukaemia (ALL) or acute myeloid leukaemia (AML). In December 2001, clofarabine was granted orphan drug status in the EU for the treatment of adult and paediatric patients with ALL. A single-agent phase II study has been completed in patients with acute leukaemia and myelodysplastic syndromes. Results of a phase II study of clofarabine in the treatment of acute myelogenous leukaemia in older adults who are not considered suitable for intensive chemotherapy have been very positive, with a 64% response rate in these patients being reported. In May 2004, Bioenvision announced that it had decided to stop enrollment at 25 evaluable patients (initially anticipated to be approximately 37 patients) because of the encouraging interim results. It said the trial would conclude earlier than expected and be completed by the end of June 2004. The pivotal trial will enroll approximately 65 patients with AML considered unsuitable for intensive chemotherapy. Bioenvision currently has phase II trials ongoing in adult and paediatric patients with acute leukaemia and chronic lymphocytic leukaemia (CLL). In addition, Bioenvision-sponsored phase I/II clinical trials of clofarabine in patients with CLL and non-Hodgkin's lymphoma are underway in Europe. In July 2002, ILEX began two US multicentre, open-label, phase II trials in children with relapsed or refractory AML or ALL. Children enrolled in the studies receive an intravenous infusion of clofarabine over 2 hours for five consecutive days every 2-6 weeks. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), an overall response rate of 28% was reported for clofarabine therapy in heavily pretreated children with acute leukaemia. In September 2003, a multicentre European phase II trial (BIOV-111) was initiated in children with relapsed/refractory ALL. In December 2003, the first of 65 patients received treatment. As part of the global development programme, Bioenvision and ILEX are also conducting a phase II study in adult patients with AML. The companies are planning to investigate the potential use of clofarabine in combination with DNA-damaging agents, because clofarabine has been shown to inhibit DNA repair and may, therefore, potentiate the effects of DNA damaging drugs. A phase I/II trial of clofarabine in combination with cytarabine (Ara-C) in adult patients with first relapse AML, ALL, CML blast crisis and myelodysplastic syndrome was initiated at the University of Texas MD Anderson Cancer Centre in October 2002. Clofarabine has completed US phase I trials, and has reported favourable results in patients with leukaemia and solid tumours, including breast, colorectal and prostate cancers. A phase I/II trial in patients with solid tumours was initiated in July 2002. In addition, ILEX said it intended to develop an oral formulation of clofarabine for the treatment of colorectal cancer.
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PMID:Clofarabine. 1523 Jun 27

Analyses of chromosomal translocation and inversion breakpoints in sporadic acute myeloid leukemias have identified many transcription factors as playing a role in leukemogenesis. Studies of families with a Mendelian predisposition to hematological malignancies have identified the gene coding for the transcription factor RUNX1 as a leukemia-predisposing gene involved in the first steps of leukemogenesis. Using two families, another autosomal dominant familial leukemia locus was linked to chromosome band 16q22 where the CBFB gene maps. Although CBFB forms a core-binding factor transcriptional complex with RUNX1, previous analyses have excluded the CBFB gene as the leukemia-predisposing gene in these families. In the current study, we performed an extended molecular analysis in these families of the four other transcription factor genes in the 16q22 critical region as well as of two other genes with a known association with leukemia. Several previously undescribed but nonpathogenic sequence variants were identified. We demonstrated that the transcription factors E2F4, CTCF, NFATC3, and NFAT5, and the genes coding for NAD(P)H:quinone oxido-reductase 1 (NQO1) and for E-cadherin are not responsible for the leukemia susceptibility in these families. The presence of NQO1 polymorphisms may suggest a role for this gene in disease risk modification in these families.
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PMID:Chromosome band 16q22-linked familial AML: exclusion of candidate genes, and possible disease risk modification by NQO1 polymorphisms. 1533 52

We report a rare case of eosinophilic leukemia transformation in a patient with polycythemia rubra vera on hydroxycarbamide (hydroxyurea) therapy only. Cytogenetic study showed complex abnormalities including -5, -7, +8, suggestive of a secondary leukemia. The leukemogenic risk of hydroxycarbamide, a ribonucleoside reductase, and the risk of natural leukemic transformation of polycythemia rubra vera is discussed in the context of previous PVSG studies.
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PMID:Eosinophilic leukemic transformation in polycythemia rubra vera (PRV). 1562 37

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood Vgamma9/Vdelta2 (gammadelta) T cells of normal donors and multiple myeloma (MM) patients. gammadelta T cells were stimulated with Zol and low doses of interleukin-2 (IL-2), and then analyzed for proliferation, cytokine production, and generation of effector activity against myeloma cell lines and primary myeloma cells. Proliferation of gammadelta T cells was observed in 100% of normal donors and 50% of MM patients. gammadelta T cells produced IFN-gamma, surface mobilized the CD107a and CD107b antigens, and exerted direct cell-to-cell antimyeloma activity irrespective of the ability to proliferate to Zol and IL-2. The memory phenotype was predominant in the MM gammadelta T cells that proliferated in response to Zol (responders), whereas effector cells were predominant in those that did not (nonresponders). Zol induced antimyeloma activity through the monocyte-dependent activation of gammadelta T cells and by enhancing the immunosensitivity of myeloma cells to gammadelta T cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.
Leukemia 2005 Apr
PMID:Effector gammadelta T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma. 1574 46

Differentiation of mouse embryonic stem (ES) cells via embryoid bodies (EB) is established as a suitable model to study cellular processes of development in vitro. ES cells are known to be pluripotent because of their capability to differentiate into cell types of all three germ layers including germ cells. Here, we show that ES cells differentiate into renal cell types in vitro. We found that genes were expressed during EB cultivation, which have been previously described to be involved in renal development. Marker molecules characteristic for terminally differentiated renal cell types were found to be expressed predominantly during late stages of EB cultivation, while marker molecules involved in the initiation of nephrogenesis were already expressed during early steps of EB development. On the cellular level--using immunostaining--we detected cells expressing podocin, nephrin and wt-1, characteristic for differentiated podocytes and other cells, which expressed Tamm-Horsfall protein, a marker for distal tubule epithelial cells of kidney tissue. Furthermore, the proximal tubule marker molecules renal-specific oxido reductase, kidney androgen-related protein and 25-hydroxyvitamin D3alpha-hydroxylase were found to be expressed in EBs. In particular, we could demonstrate that cells expressing podocyte marker molecules assemble to distinct ring-like structures within the EBs. Because the differentiation efficiency into these cell types is still relatively low, application of fibroblast growth factor (FGF)-2 in combination with leukaemia inhibitory factor was tested for induction, but did not enhance ES cell-derived renal differentiation in vitro.
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PMID:Cells differentiated from mouse embryonic stem cells via embryoid bodies express renal marker molecules. 1653 8

Dendritic nanostructures can play a key role in drug delivery, due to the high density and variety of surface functional groups that can facilitate and modulate the delivery process. We have investigated the effect of dendrimer end-functionality on the activity of polyamido amine (PAMAM) dendrimer-methotrexate (MTX) conjugates in MTX-sensitive and MTX-resistant human acute lymphoblastoid leukemia (CCRF-CEM) and Chinese hamster ovary (CHO) cell lines. Two amide-bonded PAMAM dendrimer-MTX conjugates were prepared using a dicyclohexylcarbodiimide (DCC) coupling reaction: one between a carboxylic acid-terminated G2.5 dendrimer and the amine groups of the MTX (conjugate A) and another between an amine-terminated G3 dendrimer and the carboxylic acid group of the MTX (conjugate B). Our studies suggest that conjugate A showed an increased drug activity compared to an equimolar amount of free MTX toward both sensitive and resistant cell lines, whereas conjugate B did not show significant activity on any of the cell lines. Despite substantially impaired MTX transport by MTX-resistant CEM/MTX and RII cells, conjugate A showed sensitivity increases of approximately 8- and 24-fold (based on IC50 values), respectively, compared to free MTX. Co-incubation of the cells with adenosine and thymidine along with either conjugate A or MTX resulted in almost complete protection, suggesting that the conjugate achieves its effect on dihyrofolate reductase (DHFR) enzyme through the same mechanism as that of MTX. The differences in cytotoxicity of these amide-bonded conjugates may be indicative of differences in the intracellular drug release from the cationic dendrimer (conjugate B) versus the anionic dendrimer (conjugate A), perhaps due to the differences in lysosomal residence times dictated by the surface functionality. These findings demonstrate the feasibility of using dendrimers as drug delivery vehicles for achieving higher therapeutic effects in chemotherapy, especially in drug-resistant cells.
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PMID:Activity of dendrimer-methotrexate conjugates on methotrexate-sensitive and -resistant cell lines. 1653 56

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) is a malignancy occurring after exposure to chemotherapy and/or radiotherapy. Polymorphisms involved in chemotherapy/radiotherapy response genes could be related to an increased risk of developing this neoplasia. We have studied 11 polymorphisms in genes of drug detoxification pathways (NQO1, glutathione S-transferase pi) and DNA repair xeroderma pigmentosum, complementation group (3) (XPC(3), X-ray repair cross complementing protein (1)), Nijmegen breakage syndrome (1), excision repair cross-complementing rodent repair deficiency, complementation group (5) and X-ray repair cross complementing protein (3) and in the methylene tetrahydrofolate reductase gene (MTHFR(2), 677C>T, 1298A>C), involved in DNA synthesis. The analyzed groups were a t-MDS/AML patients group (n=81) and a matched control group (n=64) treated similarly, and they did not develop t-MDS/AML. We found no significant differences when the groups were compared globally. However, when analysis was carried out according to the primary neoplasia involved, a significant association was observed between the MTHFR haplotype (single nucleotide polymorphisms 677 and 1298) and the risk of developing t-MDS/AML in the breast cancer patients group (P=0.016) and cyclophosphamide-treated hematological disease group (P=0.005). Risk haplotype was different for each case, corresponding to the 677T1298A haplotype after breast cancer treatment and the 677C1298C haplotype after hematological malignancy treatment. We postulate that such differences are related to variations in chemotherapy schemes between hematological and breast cancers and their differential interaction with the MTHFR route.
Leukemia 2007 Jul
PMID:Role of MTHFR (677, 1298) haplotype in the risk of developing secondary leukemia after treatment of breast cancer and hematological malignancies. 1747 81

Ferricyanide reduction frequently is analyzed to determine the activity of membraneous reductases. An improved, highly sensitive, and rapid method for quantitative endpoint determination of ferrocyanide is presented. Ferrocyanide is oxidized by Fe(3+) in the presence of Ferene-S under acid conditions to form a chromogenic Ferene-S/Fe(2+) complex. The latter is quantitated at 593 nm with a sensitivity of 33.2 mM(-1) . cm(-1). The assay is 60% more sensitive to ferrocyanide (and with a 50% lower detection limit) than the prevailing method of Avron and Shavit, which employs sulfonated bathophenanthroline as the ferrous chromogen. Both pH dependence and potential sources of interference are discussed. Using the method, a sulfhydryl-sensitive, ascorbate-stimulated transplasma membrane ferricyanide reductase was assayed in human chronic myeloid (K562) leukemia cells. Furthermore, malonate-sensitive succinate dehydrogenase activity of heart mitochondria was easily assayed with ferricyanide as terminal electron acceptor. The current method will suit routine applications demanding high throughput, robustness, and sensitivity in a 96-well plate format.
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PMID:A highly sensitive colorimetric microplate ferrocyanide assay applied to ascorbate-stimulated transplasma membrane ferricyanide reduction and mitochondrial succinate oxidation. 1794 76

In this study, the authors evaluated the possible use of 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in anti-leukemic chemotherapy. Cytotoxic potency against HL-60 was as follows; simvastatin (SV)>atorvastatin>cerivastatin>fluvastatin. Interestingly, HL-60-R2, an all-trans retinoic acid (ATRA)-resistant HL-60 variant, was twice as sensitive to SV than HL-60. Further studies revealed the particular mechanism of action of SV-induced apoptosis in leukemia. SV directly and rapidly disordered mitochondria with a loss of its membrane potential, reactive oxygen species (ROS) generation and subsequent irreversible damage with cytochrome c leakage and, finally, SV induced apoptosis through caspase-9 activation, whereas several studies have shown that other statins induced apoptosis to leukemia by the depletion of isoprenoids used for the prenylation of small GTPases, which are essential for cellular signal transduction. Our findings suggest that the mitochondrial pathway plays an important role in the higher potency of SV as a new class of agents for anti-leukemic therapy alone and/or in combination with agents.
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PMID:The possibility of simvastatin as a chemotherapeutic agent for all-trans retinoic acid-resistant promyelocytic leukemia. 1831 Aug 94


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