mercaptopurine and Leukemia-Lymphoma--Adult-T-Cell

Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of peripheral T-cell lymphoma. It is associated with an aggressive clinical course, a poor response to conventional treatment, and an exceedingly high mortality rate. Recent reports suggest an excessive number of cases of HSTCL in young patients with Crohn's disease who are treated with thiopurines (azathioprine or 6-mercaptopurine [6-MP]) either in conjunction with or without agents that inhibit tumor necrosis factor-alpha (TNF-alpha). Herein, we describe the case of an 18-year-old man with Crohn's disease who developed HSTCL after 5 years of 6-MP treatment. He died 7 months after diagnosis from chemotherapy-refractory lymphoma. Through a literature review, we identified 28 cases of HSTCL in Crohn's patients. All patients were treated with azathioprine or 6-MP; 22 of 28 (79%) received concomitant treatment with infliximab, and 3 of these 22 patients later received treatment with adalimumab. The median age at diagnosis of HSTCL was 22 years (range, 12-40 years). The median survival for all patients was 8 months (range, 5 days-31+ months), with only 1 patient achieving remission. Additional research is needed to better understand the role of thiopurines and TNF-alpha inhibitors in promoting HSTCL and what can be done to prevent and treat this devastating malignancy in young patients with Crohn's disease.

Topics: Adalimumab; Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azathioprine; Crohn Disease; Fatal Outcome; Humans; Infliximab; Leukemia-Lymphoma, Adult T-Cell; Liver Neoplasms; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Male; Mercaptopurine; Splenic Neoplasms; Tumor Necrosis Factor-alpha

Methotrexate (MTX) and mercaptopurine (MP) are widely used antileukemic agents that inhibit de novo purine synthesis (DNPS) as a mechanism of their antileukemic effects. To elucidate pharmacodynamic differences among children with acute lymphoblastic leukemia (ALL), DNPS was measured in leukemic blasts from newly diagnosed patients before and after therapy with these agents. Patients were randomized to receive low-dose MTX (LDMTX: 6 oral doses of 30 mg/m(2)) or high-dose MTX (HDMTX: intravenous 1 g/m(2)) followed by intravenous MP; or intravenous MP alone (1 g/m(2)), as initial therapy. At diagnosis, the rate of DNPS in bone marrow leukemia cells was 3-fold higher in patients with T-lineage ALL compared with those with B-lineage ALL (769 +/- 189 vs 250 +/- 38 fmol/nmol/h; P =.001). DNPS was not consistently inhibited following MP alone but was markedly inhibited following MTX plus MP (median decrease 3% vs 94%; P <.001). LDMTX plus MP and HDMTX plus MP produced greater antileukemic effects (percentage decrease in circulating leukocyte counts) compared with MP alone (-50% +/- 4%, -56% +/- 3%, and - 20% +/- 4%, respectively; P <.0001). Full DNPS inhibition was associated with greater antileukemic effects compared with partial or no inhibition (-63% +/- 4% vs -37% +/- 4%; P <.0001) in patients with nonhyperdiploid B-lineage and T-lineage ALL. HDMTX plus MP yielded 2-fold higher MTX polyglutamate concentrations than LDMTX plus MP (2148 +/- 298 vs 1075 +/- 114 pmol/10(9) cells; P <.01) and a higher percentage of patients with full DNPS inhibition (78% vs 53%; P <.001). Thus, the extent of DNPS inhibition was related to in vivo antileukemic effects, and a single dose of intravenous MP produced minimal DNPS inhibition and antileukemic effects, whereas MTX plus MP produced greater antileukemic effects and DNPS inhibition, with full inhibition more frequent after HDMTX.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Burkitt Lymphoma; Child; Child, Preschool; Female; Humans; Infant; Leukemia-Lymphoma, Adult T-Cell; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines

From February 1986 to January 1991 the Pediatric Oncology Group (POG) treated 2404 children or adolescents with acute lymphoblastic leukemia (ALL) on immunophenotype (T-, B-, Pre-B, or Early pre-B-cell), age, and leukocyte count based treatment protocols (ALinC 14, T-cell 3, B-cell and infant leukemia studies). The immunophenotypic subgroups comprised 78.9% B-precursor cell, 15.1% T-cell, 2.0% B-cell, and 4% infant ALL. Patients with B-progenitor cell ALL were stratified by age and leukocyte count and randomized to receive induction therapy comprised of vincristine, prednisone, and asparaginase with triple intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine), followed by intensification with moderate-dose MTX (Regimen A), moderate-dose MTX plus asparaginase (Regimen B), moderate-dose MTX plus cytarabine given early (Regimen C), or moderate-dose MTX plus cytarabine given over the first 16 months of therapy (Regimen D). Continuation therapy comprised mercaptopurine and methotrexate with vincristine plus prednisone pulses. Central nervous system preventive treatment was continued for two years. Patients with T-cell or B-cell ALL or infants less than 1 yr old were treated on individual very intensive multiagent therapy protocols. The 4-year event-free survival for all patients was 66.4% +/- 2.4%; B-precursor ALL approximately 72%, T-ALL approximately 50%, B-ALL approximately 60%, and infants less than 1 yr old approximately 16.5%. We conclude that about two-thirds of newly diagnosed children with ALL can be cured with this approach which spares the majority of children exposure to alkylating agents, anthracyclines, epipodophylotoxins, and irradiation, diminishing the risks of serious acute and late effects.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Burkitt Lymphoma; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Flow Cytometry; Humans; Hydrocortisone; Immunophenotyping; Infant; Infant, Newborn; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Vincristine

We present the unusual case of a 16-year-old girl with T-cell acute lymphoblastic leukemia (ALL) with an early thymocyte immunophenotype without myeloid markers, who after 13 months of complete hematological remission relapsed as acute myelogenous leukemia (AML) with minimal differentiation and died of her disease. Whether the AML represented a relapse with lineage switch of the original immature T-cell clone or a new secondary malignancy, could not be proven due to the absence of molecular or clonal markers. This report suggests that a subset of CD7+ T-cell leukemias without mature T-cell antigens (CD4-, CD8-) are minimally differentiated and can relapse as AML.

Topics: Acute Disease; Adolescent; Antigens, CD7; Antigens, Differentiation, T-Lymphocyte; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Cell Differentiation; Cell Lineage; Core Binding Factor Alpha 2 Subunit; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Diagnosis, Differential; Doxorubicin; Etoposide; Fatal Outcome; Female; Gene Dosage; Histone-Lysine N-Methyltransferase; Humans; Immunophenotyping; Karyotyping; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Myeloid-Lymphoid Leukemia Protein; Neoplasms, Second Primary; Neoplastic Stem Cells; Proto-Oncogenes; Recurrence; T-Lymphocyte Subsets; Vincristine

In order to better understand the mechanisms of resistance to thiopurines, we studied two sublines of the MOLT4 T-lymphoblastic leukemia cell line, resistant to 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). We found that the underlying mechanism of resistance in both resistant cell lines was a markedly reduction in initial transport of 6-MP (3- and 5-fold, respectively, in 6-MP- and 6-TG-resistant cells). No significant alteration of activities of hypoxanthine-guanine phosphoribosyl transferase, thiopurine methyltransferase or inosine monophosphate dehydrogenase, the key enzymes involved in the metabolism of thiopurines was detected. We conclude that defected initial transport of thiopurines by cells may very well explain their resistance to these drugs.

Topics: Antimetabolites, Antineoplastic; Biological Transport; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Hypoxanthine Phosphoribosyltransferase; IMP Dehydrogenase; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Methyltransferases; Thioguanine; Time Factors

Low blood levels of zinc are often noted in acute lymphocytic leukemia (ALL), but zinc is not administered as part of any modern chemotherapy program in the treatment of ALL. Upon noting low blood levels of zinc in a 3-year-old 11.3 kg girl, zinc at the rate of 3.18 mg/kg body weight/day was administered from the start of chemotherapy through the full 3 years of maintenance therapy. Dosage was split with 18 mg given at breakfast and 18 mg zinc with supper. The result was a bone marrow remission from 95+% blast cells to an observed zero blast cell count in both hips within the first 14 days of treatment which never relapsed. In addition to the reduction of blast cells to an observed count of zero (not a single leukemic or normal blast), red blood cell production and other hemopoietic functions returned to normal at a clinically remarkable rate. There were no side effects from zinc or chemotherapy at any time, and zinc is hypothesized to have improved the patient's overall ability to withstand toxic effects of chemotherapy. This report identifies zinc treatment as being vital to rapid and permanent recovery from ALL. The extremely broad role of zinc in pre-leukemic adverse health conditions, viral, fungal and tumoral immunity, hemopoietics, cell growth, division and differentiation, genetics and chemotherapy interactions are considered. If a nutrient such as zinc could be shown to strengthen the function of chemotherapy and immune function, then it could be hypothesized that the relapse rate would be lessened since the relapse rate is related to both the rate at which a remission is obtained and the thoroughness of the elimination of leukemic blasts. Identical results also occurred in 13 other children with ALL whose parents chose to treat with zinc adjuvant. Since treatment with zinc and other identified deficient nutrients, particularly magnesium, did not appear injurious in ALL and they appear to be highly beneficial, controlled clinical studies of zinc (3.18 mg/kg body weight/day) with magnesium (8.0 mg/kg body weight/day) as adjuvants to chemotherapy in the treatment of childhood ALL are suggested. Treatment with zinc adjuvant is hypothesized to accelerate recovery from ALL, and in conjunction with chemotherapy, cure ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Chemotherapy, Adjuvant; Chickenpox Vaccine; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Dietary Supplements; Drug Synergism; Female; Gluconates; Humans; Immune System; Leukemia-Lymphoma, Adult T-Cell; Magnesium Deficiency; Mercaptopurine; Methotrexate; Models, Biological; Prednisone; Radiotherapy, Adjuvant; Remission Induction; Survivors; Vincristine; Zinc

We report a 5.5-year-old boy who underwent autologous peripheral blood stem cell transplantation for high-risk acute lymphoblastic leukemia and who had two abdominal masses develop 6 months later. Macroscopically complete resection of the abdominal tumors was performed and revealed a well-differentiated leiomyosarcoma. Smooth muscle tumors, benign or malignant, are increasingly recognized in children with various immunodeficiencies; the association with acute lymphoblastic leukemia is rarely described.

Topics: Abdominal Neoplasms; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cortisone; Disease Susceptibility; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunologic Deficiency Syndromes; Leiomyosarcoma; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Neoplasms, Second Primary; Remission Induction; Transplantation Conditioning; Transplantation, Autologous; Vincristine; Whole-Body Irradiation

Thioguanine and mercaptopurine are prodrugs requiring conversion into thiopurine nucleotides to exert cytotoxicity. Thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism, catabolizes thiopurines into inactive methylated bases, but also produces methylthioguanine nucleotides and methylmercaptopurine nucleotides from thioguanine and mercaptopurine nucleotides, respectively. To study the effect of TPMT on activation versus inactivation of mercaptopurine and thioguanine, we used a retroviral gene transfer technique to develop human CCRF-CEM cell lines that did (TPMT+) and did not (MOCK) overexpress TPMT. After transduction, TPMT activities were 14-fold higher in the TPMT+ versus the MOCK cell lines (P < 0.001). TPMT+ cells were less sensitive to thioguanine than MOCK cells (IC(50) = 1.10+/- 0.12 microM versus 0.55 +/- 0.19 microM; P = 0.02); in contrast, TPMT+ cells were more sensitive to mercaptopurine than MOCK cells (IC(50) = 0.52 +/- 0.20 microM versus 1.50 +/- 0.23 microM; P < 0.01). The lower sensitivity of TPMT+ versus MOCK cells to thioguanine was associated with lower thioguanine nucleotide concentrations (917 +/- 282 versus 1515 +/- 183 pmol/5 x 10(6) cells; P = 0.01), higher methylthioguanine nucleotide concentrations (252 +/- 34 versus 27 +/- 10 pmol/5 x 10(6) cells; P = 0.01), less inhibition of de novo purine synthesis (13 versus 95%; P < 0.01), and lower deoxythioguanosine incorporation into DNA (2.0 +/- 0.6% versus 7.2 +/- 2.0%; P < 0.001). The higher sensitivity of TPMT+ cells to mercaptopurine was associated with higher concentrations of methylmercaptopurine nucleotide (2601 +/- 1055 versus 174 +/- 77 pmol/5 x 10(6) cells; P = 0.01) and greater inhibition of de novo purine synthesis (>99% versus 74%; P < 0.01) compared with MOCK cells. We conclude that methylation of mercaptopurine contributes to the antiproliferative properties of the drug, probably through inhibition of de novo purine synthesis by methylmercaptopurine nucleotides, whereas thioguanine is inactivated primarily by TPMT.

Topics: 3T3 Cells; Animals; Antimetabolites, Antineoplastic; Biotransformation; Cytosol; Deoxyguanosine; DNA, Neoplasm; Gene Transfer Techniques; HeLa Cells; Humans; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Methyltransferases; Mice; Purine Nucleotides; Purines; Retroviridae; Thioguanine; Thionucleosides; Thionucleotides; Tumor Cells, Cultured

During T cell selection in the thymic cortex more than 90% of the thymocytes are eliminated by apoptosis. Based on this biology, we propose to define blasts of T cell acute lymphoblastic leukemia (ALL) with the phenotype of cortical thymocytes (CD1+ and/or CD4+ 8+) as selection-related (SR) and all other T-ALL immunophenotypes as non-selection-related (NSR). The COALL cooperative treatment studies for childhood ALL offer a tool to study the outcome in T-ALL subgroups as children with T-ALL are allocated uniformly to the high risk arm of the protocol. In the COALL-85, -89 and -92 protocols, 39/83 cases presented as SR and 44/83 cases as NSR. Five-year event-free survival of SR phenotype is significantly better compared to the NSR group (0.87 +/- 0.06 vs 0.66 +/- 0.07, log rank test, P = 0.01). T-ALL with SR phenotype is a distinct subgroup of leukemia with excellent prognosis under a high risk treatment protocol.

Topics: Adolescent; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System; Child; Child, Preschool; Clonal Deletion; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Follow-Up Studies; Germany; Humans; Immunophenotyping; Infant; Leukemia-Lymphoma, Adult T-Cell; Leukemic Infiltration; Male; Mercaptopurine; Methotrexate; Multicenter Studies as Topic; Neoplastic Stem Cells; Prednisolone; Remission Induction; Risk; T-Lymphocyte Subsets; Teniposide; Thioguanine; Treatment Outcome; Vincristine

The aims of this study were twofold: (1) to assess the marrow of patients with T-lineage acute lymphoblastic leukemia (T-ALL) for the presence of molecular residual disease (MRD) at different times after diagnosis and determine its value as a prognostic indicator; and (2) to compare the sensitivity, rapidity, and reliability of two methods for routine clinical detection of rearranged T-cell receptor (TCR). Marrow aspirates from 23 patients with T-ALL diagnosed consecutively from 1982 to 1994 at the Division of Pediatric Hematology and Oncology, University of Catania, Italy, were obtained at diagnosis, at the end of induction therapy (6 to 7 weeks after diagnosis), at consolidation and/or reinforced reinduction (12 to 15 weeks after diagnosis), at the beginning of maintenance therapy (34 to 40 weeks after diagnosis), and at the end of therapy (96 to 104 weeks after diagnosis). DNA from the patients' marrow was screened using the polymerase chain reaction (PCR) for the four most common TCR delta rearrangements in T-ALL (Vdelta1 Jdelta1, Vdelta2 Jdelta1, Vdelta3 Jdelta1, and Ddelta2 Jdelta1) and, when negative, further tested for the presence of other possible TCR delta and TCR gamma rearrangements. After identification of junctional rearrangements involving V, D, and J segments by DNA sequencing, clone-specific oligonucleotide probes 5' end-labeled either with fluorescein or with [gamma-32P]ATP were used for heminested PCR or dot hybridization of PCR products of marrows from patients in clinical remission. For 17 patients with samples that were informative at the molecular level, the estimated relapse-free survival (RFS) at 5 years was 48.6% (+/-12%). The sensitivity and specificity for detection of MRD relating to the outcome were 100% and 88.9% for the heminested fluorescence PCR and 71.4% and 88.9% for Southern/dot blot hybridization, respectively. Predictive negative and positive values were 100% and 90.7% for heminested fluorescence PCR, respectively. The probability of RFS based on evidence of MRD as detected by heminested fluorescence PCR at the time of initiation of maintenance therapy was 100% and 0% for MRD-negative and MRD-positive patients, respectively. Thus, the presence of MRD at the beginning of maintenance therapy is a strong predictor of poor outcome, and the molecular detection of MRD at that time might represent the basis for a therapeutic decision about such patients. By contrast, the absence of MRD at any time after initiation of treat

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biomarkers, Tumor; Blotting, Southern; Bone Marrow; Child; Child, Preschool; Cohort Studies; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; DNA, Neoplasm; Evaluation Studies as Topic; Female; Fluorometry; Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; Humans; Immunophenotyping; Infant; Italy; Leucovorin; Leukemia-Lymphoma, Adult T-Cell; Male; Mercaptopurine; Methotrexate; Neoplasm, Residual; Neoplastic Stem Cells; Nucleic Acid Hybridization; Polymerase Chain Reaction; Prednisone; Prognosis; Prospective Studies; Receptors, Antigen, T-Cell, gamma-delta; Remission Induction; Sensitivity and Specificity; Treatment Outcome; Vincristine

We examined drug sensitivity of human T cell acute lymphoblastic leukemia H9 cells chronically infected with simian immunodeficiency virus (SIVmac) and found that the retrovirus-infected H9 cells showed 8.2-fold resistance to 1-beta-D-arabinofuranosylcytosine (Ara-C). In the infected cells, Ara-CTP levels decreased to 20% of that found in uninfected H9 cells after 3 h incubation at Ara-C concentration of 1 microM, and 8.1-fold increase of cytidine deaminase activity was observed in the infected H9 cells. A competitive inhibitor of cytidine deaminase, 3, 4, 5, 6-tetrahydrouridine (THU), at 100 microM reversed Ara-C resistance in the infected cells. These results indicate that inducing increased cytidine deaminase activity by SIVmac infection conferred Ara-C resistance to H9 cells. An understanding of these cellular differences in drug sensitivity may aid in the development of therapeutic strategies against retrovirus-infected cells.

Topics: Cell Division; Cell Line; Cell Survival; Cytarabine; Cytidine Deaminase; Drug Resistance; Fluorouracil; Humans; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Simian Immunodeficiency Virus; Tetrahydrouridine; Tumor Cells, Cultured; Vidarabine; Zalcitabine; Zidovudine

6-Mercaptopurine (6-MP) and methylmercaptopurine ribonucleoside (Me-MPR) are purine anti-metabolites which are both metabolized to methylthio-IMP (Me-tIMP), a strong inhibitor of purine synthesis de novo. Me-MPR is converted directly into Me-tIMP by adenosine kinase. 6-MP is converted into tIMP, and thereafter it is methylated to Me-tIMP by thiopurine methyltransferase, an S-adenosylmethionine (S-Ado-Met)-dependent conversion. S-Ado-Met is formed from methionine and ATP by methionine adenosyltransferase, and is a universal methyl donor, involved in methylation of several macromolecules, e.g. DNA and RNA. Therefore, depletion of S-Ado-Met could result in an altered methylation state of these macromolecules, thereby affecting their functionality, leading to dysregulation of cellular processes and cytotoxicity. In this study the effects of 6-MP and Me-MPR on S-Ado-Met, S-adenosylhomocysteine (S-Ado-Hcy), homocysteine and methionine concentrations are determined. Both drugs cause a decrease in intracellular S-Ado-Met concentrations and an increase in S-Ado-Hcy and methionine concentrations in Molt F4 human malignant lymphoblasts. The effects of both 6-MP and Me-MPR can be ascribed to a decreased conversion of methionine into S-Ado-Met, due to the ATP depletion induced by the inhibition of purine synthesis de novo by Me-tIMP. Both 6-MP and Me-MPR thus affect the methylation state of the cells, and this may result in dysregulation of cellular processes and may be an additional mechanism of cytotoxicity for 6-MP and Me-MPR.

Topics: Adenosine Triphosphate; Cell Division; Cell Survival; Humans; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; S-Adenosylmethionine; Thionucleosides; Tumor Cells, Cultured

To prevent drug resistance, the authors designed a protocol that featured early intensive rotating drug pairs as part of the therapy for acute lymphoblastic leukemia (ALL).. After prednisone, vincristine, asparaginase, and daunorubicin induction, 12 intensive treatments (ABACABACABAC) were given in 30 weeks: A--intermediate-dose methotrexate (IDMTX) plus intermediate-dose mercaptopurine (MP); B--cytosine arabinoside (AC) plus daunorubicin (DNR); C--AC plus teniposide (VM-26). Triple intrathecal chemotherapy (AC, MTX, and hydrocortisone) was given for central nervous system (CNS) prophylaxis. Continuation therapy consisted of weekly MTX and daily MP until 2.5 years of continuous complete remission had been achieved.. Seventy-four children (age range, 1-19 years) at high risk of relapse were treated. Of 55 with B-lineage (early pre-B, pre-B) ALL, 24 have failed (2 induction failures, 2 deaths from infection, and 20 relapses). The event-free survival (EFS) rate at 4 years was 55.5% (standard error [SE] +/- 7.7%). Of 19 patients with T-cell ALL, 12 have failed (2 induction failures and 10 relapses). The EFS rate at 4 years was 32.6% (SE +/- 26.8%). Toxicities were significantly more common after AC and DNR or AC and VM-26 than IDMTX and MP. There were no toxicity-related deaths during intensive treatments.. Early intensive rotating therapy is tolerable and warrants consideration for additional trials of patients with high-risk, B-lineage ALL.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Humans; Hydrocortisone; Infant; Injections, Intramuscular; Injections, Intravenous; Injections, Spinal; Leukemia-Lymphoma, Adult T-Cell; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Teniposide; Treatment Failure

A case of congenital leukemia with monosomy 7 is reported. Immunological study of the blast cells using monoclonal antibodies was suggestive of both myelomegakaryocytic and T-lymphoblastic leukemia. Chromosomal analysis of the bone marrow cells showed monosomy 7. Chemotherapy was initiated with a combination of adriamycin, cytosine arabinoside, 6-mercaptopurine, and prednisolone. The patient obtained complete remission, which has been maintained for 4 years and 1 month. He receives no chemotherapy now. Our case shows that monosomy 7 in congenital leukemia is rare, but the presence of monosomy 7 in congenital leukemia does not necessarily indicate a poor prognosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 7; Cytarabine; Doxorubicin; Humans; Infant, Newborn; Karyotyping; Leukemia; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Megakaryoblastic, Acute; Male; Mercaptopurine; Monosomy; Prednisolone; Remission Induction

Topics: Biotransformation; Carbon Radioisotopes; Cell Division; Cell Line; Cell Survival; Humans; IMP Dehydrogenase; Inosine Monophosphate; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Carbon Radioisotopes; Cell Division; Cell Line; Drug Screening Assays, Antitumor; Drug Synergism; Glycine; Humans; Kinetics; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Methotrexate; Phosphates; Phosphorus Radioisotopes; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Purines; Tetrahydrofolate Dehydrogenase; Thymidine Monophosphate

Recurring paroxysmal abdominal pain developed in a 19-year old woman suffering from acute lymphatic T-cell leukaemia, during induction chemotherapy with cyclophosphamide, cytarabine and mercaptopurine. Both the plain radiograph and CT of the abdomen showed pathognomonic intramural gas accumulations and free air below the right diaphragm, pointing to pneumatosis coli. There was marked pancytopenia (leucocytes 800/microliters,haemoglobin 7.6 g/dl, thrombocytes 10,000/microliters). Whereas the abdominal pain subsided rapidly under oxygen therapy and liquid nourishment, the radiological changes receded gradually. However, fever and diarrhoeas occurred subsequently. Fever persisted for 3 weeks despite treatment with antibiotics (three times 60 mg/d gentamicin, three times 2 g/d mefoxitin and three times 500 mg/d metronidazole, and later 30 mg/d amphotericin B) and subsided only after completion of the induction chemotherapy and an increase of leucocyte count.

Topics: Adult; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Female; Humans; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Pneumatosis Cystoides Intestinalis; Remission Induction; Tomography, X-Ray Computed

Co-incubation of human leukemia cell lines with naturally occurring nucleobases (hypoxanthine or adenine) significantly prevented the cytotoxic activity of 6-thiopurines. Extracellular hypoxanthine decreased the transport of 6-mercaptopurine into cells, but adenine had no significant effect. However, intracellular thioinosine monophosphate accumulation in the presence of 10 microM, 6-mercaptopurine was reduced to below 1% or 10% of that of the controls when 50 microM hypoxanthine or adenine was added, respectively. Finally, in adenine phosphoribosyl transferase deficient mutants, adenine provided no protective effect against 6-thiopurines, whereas hypoxanthine retained its modulating activity. These data suggest that the nucleobases compete with 6-thiopurines for the ribose-phosphate donor, 5'-phosphoribosyl-1-pyrophosphate, thus preventing the formation of active metabolites of 6-thiopurines.

Topics: 2-Aminopurine; Adenine; Adenine Phosphoribosyltransferase; Antineoplastic Agents; Biological Transport; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Inosine Monophosphate; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Promyelocytic, Acute; Mercaptopurine; Thioguanine; Thionucleotides; Tumor Cells, Cultured