tretinoin and Down-Syndrome

Recent reports of recurrent mutations in childhood acute myeloid leukemia (AML) have identified potential targets for new therapeutic strategies. Acute promyelocytic leukemia (APL) is characterized commonly by a fusion between the PML gene and the RARA gene, genes targetable by arsenic (ATO) and retinoic acid (ATRA), respectively. A mutation in GATA1, common in AML of Down syndrome (ML-DS), renders cells more susceptible to cytarabine and anthracyclines, thus permitting targeted dose reductions to preserve high survival rates while reducing toxicity. In all other patients, Ras pathway mutations, KMT2A and other methyltransferase mutations, FLT3 mutations, and KIT mutations are all relatively common in childhood AML and all are potentially "druggable". The focus of this review is on those therapies likely to be clinically available in the near future. The preclinical and clinical data providing a rationale for testing in children of specific agents in children is discussed. Whether the expression of a potential target is sufficient to predict response to a targeted therapy is an open question in childhood AML. Development of clinical trials to evaluate targeted therapies in small molecularly defined subsets of AML will be the next great challenge for all cooperative groups in North America and Europe.

Topics: Adolescent; Adult; Arsenic Trioxide; Arsenicals; Child; Child, Preschool; Clinical Trials as Topic; Down Syndrome; Epigenesis, Genetic; GATA1 Transcription Factor; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Medical Oncology; Molecular Medicine; Mutation; Oxides; ras Proteins; Receptor Protein-Tyrosine Kinases; Treatment Outcome; Tretinoin

Children with Down syndrome (DS) are at an increased risk of developing acute leukemia. Acute myeloid leukemia predominates among DS children below 4 years of age but acute promyelocytic leukemia (APL) has rarely been reported in DS. Acute myeloid leukemia in DS is extremely sensitive to treatment but the optimum treatment of de novo or relapsed APL in DS is not known. We describe a child with DS and APL, who despite having a multiply relapsing course, achieved a third remission with ATRA and chemotherapy, which is sustained with maintenance therapy. A brief review of literature is also presented.

Topics: Antineoplastic Agents; Child, Preschool; Down Syndrome; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Tretinoin

Bone formation in vivo is a complex phenomenon whereby recruitment and replication of mesenchymal precursors of osteoblasts, differentiation into preosteoblasts, osteoblasts, and mature osteoblasts ultimately result in the accumulation and mineralization of the extracellular matrix. MC3T3-E1, a clonal osteoblastic cell line, was derived from mouse calvaria and undergoes an ordered and time dependent developmental sequence leading to formation of multilayered bone nodules over a 30 - 35 day period. This developmental pattern is characterized by the replication of preosteoblasts followed by growth arrest and expression of mature osteoblastic characteristics such as matrix maturation and eventual formation of multilayered nodules with a mineralized extracellular matrix. We have found that Ets1 is expressed in proliferating preosteoblastic cells whereas Ets2 is expressed by differentiating and mature osteoblasts. In addition, the expression of Ets1 can be induced in MC3T3-E1 and fetal rat calvaria cells by retinoic acid (RA) which is known to exert profound effects on skeletal growth and development, bone turnover, and induce specific cellular responses in bone cells. Thus the multiple functions of RA in bone cells are likely to be mediated in part by Ets1. Also, Ets2 transgenic mice develop multiple neurocranial, viserocranial, and cervical skeletal abnormalities. Significantly, these abnormalities are similar to the skeletal anomalies found in trisomy-16 mice and in humans with Down's syndrome, wherein the dosage of Ets2 is known to be increased. These results indicate that Ets2 has an important role in skeletal development and that Ets2 overexpression in transgenics is responsible for the genesis of the same type of skeletal abnormalities that are seen in Down's syndrome. Thus the genetic programs regulated by Ets1 and Ets2 may significantly affect the development and differentiation of osteoblasts, and in fact, Ets1 has been shown to interact with the 'quintessential' osteoblast transcription factor CbfA1. This review will examine in detail the role and possible targets of Ets1 and Ets2 in osteoblast differentiation and bone formation.

Topics: Animals; Binding Sites; Bone and Bones; Cartilage; Cell Differentiation; Cell Division; Cell Line; Consensus Sequence; DNA-Binding Proteins; Down Syndrome; Gene Dosage; Gene Expression Regulation, Developmental; Humans; Mesoderm; Mice; Mice, Transgenic; Multigene Family; Musculoskeletal System; Osteoblasts; Osteogenesis; Proto-Oncogene Protein c-ets-1; Proto-Oncogene Protein c-ets-2; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ets; Receptors, Retinoic Acid; Repressor Proteins; Signal Transduction; Skull; Stem Cells; Trans-Activators; Transcription Factors; Tretinoin; Trisomy

Major advances have been made in the past 10 yr in both the understanding of the biologic characteristics of acute nonlymphocytic leukemia and in the treatment of patients with this disease. Advances in the biologic characteristics include: a better understanding of the nature of leukemic cell proliferation and differentiation; a clearer description of the morphological, histochemical, and ultrastructural characteristics of leukemic cells; a recognition that a high percentage of patients may have specific cytogenetic abnormalities; and a recognition that biochemical differences exist between acute nonlymphocytic leukemia (ANLL) and acute lymphoblastic leukemia (ALL). Today, over 70% of children with ANLL can be induced into a complete remission and over 25% are remaining in a continuous remission for over 2 yr. In spite of these improved results, the best method of extending remissions is unknown. It is unlikely that better results of therapy will be achieved in the future by tailoring the treatment according to the biologic characteristics of the patient, since it appears that ANLL is a heterogeneous group of diseases.

Topics: Acute Disease; Adolescent; Adult; Aged; Bone Marrow Transplantation; Brain Diseases; Cell Aggregation; Cell Differentiation; Cytogenetics; Down Syndrome; Doxorubicin; Granulocytes; Hematopoietic Stem Cells; Humans; Injections, Spinal; Kinetics; Leukemia; Leukocyte Count; Macrophages; Methotrexate; Middle Aged; Mitosis; Phagocytosis; Prognosis; Receptors, Drug; Tretinoin

Various methods of intensive chemotherapy have contributed to an improved survival in pediatric acute myeloid leukemia (AML). We here report the long-term results of the two consecutive trials of Tokyo Children's Cancer Study Group (TCCSG), incorporating repetitive use of high-dose cytarabine (HD-Ara-C) based combination chemotherapy in post-remission phase.. A total of 216 eligible children with newly diagnosed AML were treated in the two consecutive multi-center trials of TCCSG, M91-13 and M96-14, from August 1991 to September 1998. In M91-13 trial, patients received eight courses of intensive post-remission chemotherapy, including six HD-Ara-C containing courses, after remission-induction therapy. Autologous hematopoietic stem cell transplantation (HSCT) could be selected by physician's choice, and allogeneic HSCT was allocated if donor was available. In M96-14 trial, the last two HD-Ara-C courses were omitted from the chemotherapy arm.. The remission-induction rate was 88.8% and probability of 5-year Overall survival (OS) and event-free survival (EFS) were 62% (56-69% with 95% Confidence intervals (CIs)) and 56% (49-62%), respectively. Treatment-related mortality (TRM) was 7.8%. Among patients without Down syndrome (DS) or acute promyelocytic leukemia (APL), the presence of t(8;21) or inv(16) was a significant good prognostic factor both in the univariate and multivariate analyses. Children with DS (N = 10) and APL (N = 14) also showed a good survival exceeding 70% in 5 years.. These results suggest that repetitive use of HD-Ara-C was effective and safe for childhood AML. However, further optimization of AML therapy is required.

Topics: Acute Disease; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Down Syndrome; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Hydrocortisone; Infant; Infections; Japan; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Methotrexate; Mitoxantrone; Remission Induction; Survival Analysis; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Tretinoin; Vincristine

Acute promyelocytic leukemia (APL) is rare in patients with Down syndrome (DS). Cytotoxic chemotherapy combined with all-trans retinoic acid (ATRA) has been a standard treatment for APL, but is potentially intolerable for DS patients because of their vulnerability to cytotoxic agents. We report here a case of a 10-year-old girl with DS and APL successfully treated with a combination of ATRA and arsenic trioxide, a therapy emerging as a new standard for APL. She achieved molecular remission and completed the therapy without significant toxicities. ATRA/arsenic trioxide combination therapy would be a preferable option for DS patients with APL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Child; Down Syndrome; Female; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

The function, regulation and cellular distribution of GABA

Topics: Adolescent; Adult; Age Factors; Amyloid beta-Peptides; Animals; Animals, Newborn; Case-Control Studies; Doublecortin Domain Proteins; Down Syndrome; Embryo, Mammalian; Female; Fetus; Gene Expression Regulation, Developmental; Gestational Age; Glutamate Decarboxylase; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins; Middle Aged; Nerve Tissue Proteins; Neuroblastoma; Neurons; Neuropeptides; Peptide Fragments; POU Domain Factors; Protein Subunits; Receptors, GABA-A; Tretinoin; Vesicular Inhibitory Amino Acid Transport Proteins; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Down Syndrome; Drug Administration Schedule; Humans; Leukemia, Promyelocytic, Acute; Male; Tretinoin; Young Adult

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Down Syndrome; Esophageal Stenosis; Esophagectomy; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Tretinoin

There is increasing interest in gliogenesis as the relevance of glia to both brain development and pathology becomes better understood. However, little is known about this process. The use of multidimensional protein identification technology (MudPIT) to identify changes in phosphoprotein levels in rat neural precursor cells treated with cytokines or retinoic acid showed that phosphorylation of the catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K p110alpha) and dephosphorylation of the inositol phosphatase synaptojanin-1 were common to the gliogenic stimuli. Although PI3K was found to be involved in both neuro- and astrogliogenesis, synaptojanin-1 was specifically involved in astrogliogenesis of neural precursor cells. The role of synaptojanin-1 in astrogliogenesis was further confirmed by analysis of neuron- and glia-specific markers in synaptojanin-1 knockout mouse brain. Additional experiments showed that the Sac1-like phosphatase domain of synaptojanin-1 is responsible for the observed astrogliogenic effect. Our results strongly indicate that phosphatidylinositol metabolism plays a key role in astrogliogenesis. The relevance of our findings for Down's syndrome pathology is discussed.

Topics: Animals; Astrocytes; Brain; Cell Differentiation; Cell Line; Cytokines; Down Syndrome; Mice; Mice, Knockout; Nerve Tissue Proteins; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphorylation; Rats; Stem Cells; Tretinoin

We study here the case of a male patient aged 22 years with antecedents of Down syndrome and X-linked ichthyosis. The results obtained from the administration of 13-cis retinoic acid are commented upon. The association with other diseases and the treatment are also reviewed.

Topics: Adult; Connective Tissue Diseases; Down Syndrome; Elastic Tissue; Humans; Ichthyosis; Male; Tretinoin