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)

A six year old Chinese boy with relapsed Acute Promyelocytic Leukaemia (APML) failed to respond to reinduction with Daunorubicin and Cytarabine infusion. He was successfully treated with all trans-Retinoic Acid (45 mg/m2/day) orally. After four weeks of treatment, he was in complete remission. The side effects of all trans-Retinoic Acid were negligible.
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PMID:All trans-retinoic acid in the treatment of promyelocytic leukaemia--a case report. 149 49

Tretinoin is effective in acute promyelocytic leukaemia in adults. Data about its efficacy and safety in children are limited. We have treated 9 children with tretinoin at 45 mg/m2 per day. Pseudotumour cerebri or hyperleucocytosis occurred in 5 patients. Retinoic acid syndrome was seen in 3 cases. 1 of 2 children who developed hyperleucocytosis, pseudotumour cerebri, and retinoic acid syndrome died despite steroids and mechanical ventilation. Complete remissions with tretinoin alone were achieved in 15 patients. All 8 surviving children received consolidation chemotherapy. Our experience with tretinoin therapy suggests that toxicity is frequent in children.
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PMID:Tretinoin toxicity in children with acute promyelocytic leukaemia. 790 75

The c-fes protooncogene is expressed at high levels in the terminal stages of granulocytic differentiation. Its product, p92c-fes, exhibits a tyrosine-kinase activity and is involved in the cellular response to GM-CSF, but its role is not yet clarified. To study this problem, the c-fes protooncogene expression has been inhibited in HL60 cells and in fresh leukemic blast cells of Acute Promyelocytic Leukemia (APL) induced to differentiate with All-Trans-Retinoic Acid (ATRA). Inhibition of c-fes function was obtained by treatment of the cells with a specific antisense oligomer complementary to the 5' region of the c-fes mRNA. It was observed that the cells, rather then differentiate to granulocytes, underwent premature cell death showing the morphological and molecular characteristics of apoptosis. Superimposable results are obtained on blast cells from APL. It is possible to conclude that the loss of cell viability that occurs during the in vitro differentiation of myeloid cells, after the complete inhibition of c-fes expression and treatment with ATRA, is due to activation of programmed cell death rather than an accelerated differentiation. Our data suggest that the c-fes product is essential for the survival of myeloid cells during differentiation.
Leukemia 1994 Apr
PMID:Antiapoptotic effect of c-fes protooncogene during granulocytic differentiation. 815 13

Tretinoin (all-trans retinoic acid), a vitamin A derivative, induces cellular differentiation in several haematological precursor cell lines and cells from patients with acute promyelocytic leukaemia. Drug treatment with tretinoin is associated with morphological and functional maturation of leukaemic promyelocytes and a progressive reduction in the occurrence of the characteristic t(15;17) chromosomal translocation. Recent therapeutic trials indicate that tretinoin induces remission in 64 to 100% of patients with acute promyelocytic leukaemia. In newly diagnosed patients, remission induction treatment with tretinoin followed by intensive chemotherapy resulted in a significant reduction in relapse rate and prolongation of event-free and overall survival compared with chemotherapy alone in 1 comparative trial. Tretinoin alone does not totally eradicate the leukaemic clone and consolidation chemotherapy is recommended as follow-up. The use of reverse transcription polymerase chain reaction (RT-PCR) provides a sensitive and specific technique to assist in prediction and monitoring of a patient's response to treatment and to help detect the presence of residual or recurrent disease. The use of tretinoin is potentially limited by the rapid and almost universal development of drug resistance and occurrence of the often severe retinoic acid syndrome. Useful strategies have been described to manage these effects but current and future efforts must be directed at elucidating the mechanisms involved and determining the optimum therapeutic management. In summary, results to date indicate that the combination of tretinoin and intensive chemotherapy is more effective than chemotherapy alone and appears to improve the prognosis of newly diagnosed patients with acute promyelocytic leukaemia. Further information on the relative efficacy of various induction and post-remission strategies in subsets of patients will help determine optimum use of this promising agent in the management of acute promyelocytic leukaemia.
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PMID:Tretinoin. A review of its pharmacodynamic and pharmacokinetic properties and use in the management of acute promyelocytic leukaemia. 858 32

ERV3 (HERV-R) is a complete, single copy human endogenous retrovirus located on the long arm of chromosome 7. The open reading frame in its envelope gene has been conserved during evolution but the gag and pol genes contain in-frame termination codons. To find a suitable experimental model system for analysis of the functions of the ERV3 genome, an extensive screening study of different normal and neoplastic human tissues was performed. Most tissues express low levels of the ERV3 env mRNA although high expression levels are observed in placenta, sebaceous glands, adrenals, testis, bronchial, epithelium and the monocytic cell line U-937. In U-937 cells the ERV3 env expression varied in a manner related to the differentiation status of the cells; being highest in the terminally differentiated non proliferating cells. U-937 cells can be induced to differentiate from the monoblastic to the mature monocyte/macrophage stage upon stimulation by several substances such as phorbolesters (TPA), Vitamin D3, Retinoic Acid (RA) and combinations of some cytokines. We conclude that the ERV3 locus is expressed in a tissue and differentiation specific way and that the U-937 cell line is a suitable model system to further analyze the proposed functions of ERVs such as immunomodulation, cell fusion and protection against exogenous retroviral infections.
Leukemia 1997 Apr
PMID:Tissue and differentiation specific expression on the endogenous retrovirus ERV3 (HERV-R) in normal human tissues and during induced monocytic differentiation in the U-937 cell line. 920 23

Retinoic Acid (RA) treatment induces disease remission of Acute Promyelocytic Leukaemia (APL) patients by triggering terminal differentiation of neoplastic cells. RA-sensitivity in APL is mediated by its oncogenic protein, which results from the recombination of the PML and the RA receptor alpha (RAR alpha) genes (PML/RAR alpha fusion protein). Ectopic expression of PML/RAR alpha into haemopoietic cell lines results in increased response to RA-induced differentiation. By structure-function analysis of PML/RAR alpha-mediated RA-differentiation, we demonstrated that fusion of PML and RAR alpha sequences and integrity of the PML dimerization domain and of the RAR alpha DNA binding region are required for the effect of PML/RAR alpha on RA-differentiation. Indeed, direct fusion of the PML dimerization domain to the N- or C-terminal extremities of RAR alpha retained full biological activity. All the biologically active PML/RAR alpha mutants formed high molecular weight complexes in vivo. Functional analysis of mutations within the PML dimerization domain revealed that the capacity to form PML/RAR alpha homodimers, but not PML/RAR alpha-PML heterodimers, correlated with the RA-response. These results suggest that targeting of RAR alpha sequences by the PML dimerization domain and formation of nuclear PML/RAR alpha homodimeric complexes are crucial for the ability of PML/RAR alpha to mediate RA-response.
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PMID:Formation of PML/RAR alpha high molecular weight nuclear complexes through the PML coiled-coil region is essential for the PML/RAR alpha-mediated retinoic acid response. 1059 30

Oral chemotherapy agents have been an important component of the treatment of leukaemia for many years. Obstacles such as poor or erratic bioavailability and noncompliance have often limited the utility of oral agents in the treatment of leukaemia. However, recent evaluations of new or existing oral agents have expanded the clinician's options and understanding of the use of these drugs in the treatment of leukaemia. One major advance is the use of tretinoin (all-trans retinoic acid) in the treatment of acute promyelocytic leukaemia (APL). Tretinoin, an oral vitamin A derivative that reverses abnormal differentiation in APL is now an essential component of first-line therapy for APL, replacing standard intravenous chemotherapy induction regimens. Other advances include an increased understanding of the pharmacokinetic and pharmacodynamic profile of oral chemotherapy agents such as etoposide and high dose busulfan, allowing for modifications or individualisation of administration regimens to enhance efficacy or minimise toxicity. Evaluations of noncompliance with oral agents in the treatment of leukaemia have also provided the clinician with important information on how this obstacle to oral therapy may be overcome or minimised.
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PMID:Oral chemotherapy agents in the treatment of leukaemia. 1071 49

A multicenter phase II study was initiated to investigate the efficacy, toxicity and tolerability of an oral regimen of 9-cis retinoic acid (9CRA) as a differentiation-inducing agent stimulating both retinoic acid receptor (RAR) and retinoic X receptor (RXR). Thirty patients with myelodysplastic syndromes (MDS) were enrolled into the study. The MDS subtypes were distributed as follows: 14 refractory anaemia (RA), four refractory anaemia with ringed sideroblasts (RARS), and 12 refractory anaemia with excess blasts (RAEB). The age ranged from 40 to 81 years (median 70). None of these had previously received treatment for MDS other than supportive therapy. 9CRA (Alitretinoin capsules, kindly provided by Allergan-Ligand Retinoid Therapeutics) was given daily at 60 mg/m2 p.o. for 1 week, followed by an intra-patient escalation to 100 mg/m2 during the second week, up to a maximum of 140 mg/m2. The planned treatment duration was 48 weeks. Twenty-five were available for assessment. One patient (4%) with RA achieved complete hematological remission. Four (16%), two with RA, two with RAEB, had minor responses resulting in decreased transfusion requirements or increased neutrophils. Thus, the overall response rate was 20% in evaluable patients with MDS and 17% in the study group on an intention-to-treat basis. The most frequent side-effects included headache (77%), dry skin (57%), arthralgias (30%), and rash (23%). In conclusion, although modest responses were noted in this study, the treatment tolerability was suboptimal. It is conceivable that a lower dosage schedule may be efficacious and better tolerated so enabling prolonged exposure which may be required to induce a differentiation effect.
Leukemia 2000 Sep
PMID:Oral 9-cis retinoic acid (Alitretinoin) in the treatment of myelodysplastic syndromes: results from a pilot study. 1099 4

The fact that treatment of leukemia (Acute Promyelocytic Leukemia) with ATRA (All-Trans Retinoic Acid) was so succeeded that it was considered as a good example for tumor therapy. In the treatment of solid tumors by means of induced differentiation, however, has not been yet so broken-through. DMSO (Dimethylsulfoxide) was a common and simple organic compound, which comprised a variety of biological activities. For example, DMSO induced differentiation of leukemia in many reports. However, the effect of DMSO on solid tumors was to be explored further. In the present study, DMSO was used to human esophageal cancer cell lines in vitro in comparison with the classical inducer ATRA. From the view of morphology, cell cycle, growth inhibition, cytokeratin 4 expression, dye transfer and tumorigenecity, the results demonstrated that DMSO as well as ATRA could induce differentiation of human esophageal cancer cells. Interestingly, DMSO was confirmed to be more effective in inducing differentiation of esophageal cancer cells than ATRA. It suggests that DMSO showed some good prospects for the treatment of solid tumors.
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PMID:[Experimental study on the induced-differentiation of human esophageal cancer cells treated with dimethylsulfoxide]. 1201 58

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R-targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.
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PMID:Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox. 1214 23


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