mercaptopurine and Down-Syndrome

An adequate number of nerve cells, their connection by dendrites and axons, the transmission of information by chemical mediators are all necessary for normal brain function. Monocarbonic acid residues, purines and pyrimidines and tubulins and biopterin are essential to ensure that the necessary chemical processes can take place. In trisomy 21 the metabolism is disturbed by the enhancement of individual enzyme activities. Particular clinical effects suggest specific therapeutic interventions. The effects can be influenced by way of the monocarbonic acid metabolisms. The action of thyroxine is especially interesting, as it inhibits the disintegration of monocarbonic acids.

Topics: Amyloid beta-Protein Precursor; Biopterins; Brain; Carbonic Acid; Cystathionine beta-Synthase; Down Syndrome; Folic Acid; Guanosine; Humans; Leucovorin; Mercaptopurine; Methionine; Neurons; Phosphofructokinase-1; Purines; Pyrimidines; S100 Proteins; Superoxide Dismutase; Thyroid Gland; Thyroxine

The Children's Cancer Group 1991 study was a clinical trial for children with National Cancer Institute standard-risk acute lymphoblastic leukemia (ALL). This trial demonstrated that 5 doses of vincristine and escalating IV methotrexate (MTX) without leucovorin rescue in the interim maintenance (IM) phases resulted in superior event-free survival (EFS) when compared with 2 doses of vincristine, oral (PO) MTX, PO mercaptopurine, and dexamethasone. This report describes a favorable outcome of this regimen in patients with Down syndrome (DS). Forty-four patients with DS were randomized to the arms containing PO MTX during IM, and 31 to those containing IV MTX. Ten-year EFS rates for patients with DS randomized to IV MTX vs PO MTX were 94.4% ± 5.4% vs 81.5% ± 6.6%, respectively. IV methotrexate with strict escalation parameters, as given in this study, was well tolerated, although the mean total tolerated dose received was lower in patients with DS than in those without DS. There was no increase in hepatic toxicity, systemic infections, or treatment-related deaths in patients with DS during IM on either the IV or PO MTX arms, as compared with those without DS. The incidence of mucositis was increased in patients with DS as compared with patients without DS, particularly among patients who received IV MTX. This trial was registered at www.clinicaltrials.gov as #NCT00005945.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dexamethasone; Disease-Free Survival; Down Syndrome; Female; Humans; Male; Mercaptopurine; Mucositis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate; Vincristine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Child; Child, Preschool; Down Syndrome; Female; Follow-Up Studies; Humans; Infant; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate

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

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Down Syndrome; Female; Guideline Adherence; Humans; Infant; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Patient Compliance; Physician's Role; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome

The early toxicity, incidence of graft-versus-host disease (GVHD) and long-term follow-up were evaluated in two children with Down syndrome (DS) treated for acute lymphoblastic leukemia (ALL) in second complete remission by HLA-matched sibling allogeneic bone marrow transplantation (BMT). Preparative conditioning therapy consisted of cytosine arabinoside (Ara-C) and fractionated total body irradiation (F-TBI) and GVHD prophylaxis of cyclosporin A. The conditioning regimen was well tolerated, the only acute complication being mild mucositis. Engraftment (polymorphonuclear cells >500/microliter) was documented by day +17 in both patients. One child remains in continuous complete remission, without medical problems, 60 months after BMT. The second patient died from complications associated with chronic GVHD 21 months following BMT. Ara-C and F-TBI is a well-tolerated preparative regimen for children with DS undergoing allogeneic BMT.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cytarabine; Daunorubicin; Down Syndrome; Fatal Outcome; Graft vs Host Disease; Humans; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Salvage Therapy; Transplantation, Homologous; Vincristine; Whole-Body Irradiation

The treatment of acute myeloid leukemia (AML) in children with Down's syndrome (DS) has engendered considerable controversy. Because of the concerns for toxicity and increased rate of infections, treatment approaches varied considerably in the past with mixed results. However, experience on the recently completed Pediatric Oncology Group (POG) 8498 AML study suggests that DS children with AML constitute a distinct subgroup that responds well to therapy. Twelve of 285 children on POG 8498 (protocol for newly diagnosed AML) had DS. Children with DS and AML were predominantly male (9 of 12) and were quite younger at diagnosis (< 24 months in 10). The white blood cell count was less than 50 x 10(3)/microL in all 12 and French-American-British types M6 and M7 were frequent (5 of 12). An abnormal cytogenetic marker, in addition to constitutional trisomy 21, was present in 9 of 12 and involved chromosome 8 in 4 of 9. All cases studied (n = 5) were positive for myeloid cell surface markers (CD33, CD13, or CD11b) and, interestingly, were also positive for the CD7 antigen. Chemotherapy included daunorubicin, cytarabine (Ara-C), and 6-thioguanine for remission induction and featured high-dose Ara-C (3 g/m2 per dose) with or without L-asparaginase early in remission. Compared with children without DS, children with DS had a superior event-free survival (EFS at 4 years 100% v 28% +/- 6.2%; P = .003). The EFS remained superior even when compared with non-DS children less than 2 years of age with a white blood cell count less than 10 x 100,000/microL (100% v 48% +/- 17.3%; P = .01).

Topics: Acute Disease; Adolescent; Adult; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Azacitidine; Child; Chromosome Aberrations; Chromosome Disorders; Cytarabine; Daunorubicin; Down Syndrome; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Mercaptopurine; Methotrexate; Prednisone; Remission Induction; Thioguanine; Vincristine

Low doses of 6-mercaptopurine were found to significantly increase the mitotic index in lymphocytes of patients with trisomy 21. This finding implies that excess purine synthesis in Down syndrome is responsible for lymphocyte cytotoxicity. We suggest that, in addition to the three steps already known, other genes involved in the "de novo" purine synthesis pathway might be located on chromosome 21 and that they are responsible for increased adenine nucleotides, nucleotide pool imbalance and perhaps relative guanine nucleotide deficiency. This would open new areas of research into the patho-physiology of trisomy 21.

Topics: Cells, Cultured; Down Syndrome; Humans; In Vitro Techniques; Lymphocytes; Mercaptopurine; Mitosis; Mitotic Index; Purines

3,3'5'-triiodothyronine (rT3) levels have been documented to be low in patients with Down syndrome but the metabolic implications of this finding remain unknown. A highly significant correlation was found between the in vitro variations of the mitotic index in lymphocyte cultures when rT3 or known inhibitors of inosine monophosphate dehydrogenase: mycophenolic acid, 6-mercaptopurine or 2-3-diphosphoglycerate were added. No significant difference was found between the response of trisomy 21 or normal lymphocytes. The finding suggests that rT3 may be a physiological modulator of inosine monophosphate dehydrogenase. The implications on cellular differentiation are discussed.

Topics: 2,3-Diphosphoglycerate; Cells, Cultured; Diphosphoglyceric Acids; Down Syndrome; Humans; IMP Dehydrogenase; Ketone Oxidoreductases; Mercaptopurine; Mitosis; Mitotic Index; Mycophenolic Acid; Triiodothyronine, Reverse

Topics: Adolescent; Adult; Aneuploidy; Blood Cells; Bone Marrow Cells; Bone Marrow Examination; Child; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Down Syndrome; Female; Humans; Infant; Karyotyping; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Vincristine