phosphorus-radioisotopes and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

The use of radioactive phosphorus (32P) to treat the myeloproliferative disorders (chronic leukemia, polycythemia vera and essential thrombocythemia) began in 1939 when John H. Lawrence treated the first patient on the basis of work done in the laboratory animals that found localization of the radioisotope in the spleen, liver, bone and in leukemic cells sufficient to indicate a therapeutic potential. After World War II when 32P became widely available, it was used extensively to treat the chronic leukemias and polycythemia vera. Its use in the treatment of essential thrombocythemia began later in 1950. Today it is not widely used in the treatment of the chronic leukemia, if at all, its use in polycythemia vera appears to have decreased substantially and replaced by hydroxyurea, and its use in the management of essential thrombocythemia is not widespread. In each instance it has been replaced by a drug developed for use in cancer chemotherapy, and in some instances by interferon. It probably has wider use in polycythemia vera in the rest of Western Europe than in the UK, and there are cogent reasons to suggest that it may be the best tool for the treatment of polycythemia vera. Thus have we discarded a treatment modality that in polycythemia vera may be the best?

Topics: Adult; Aged; Alkylating Agents; Chlorambucil; Clinical Trials as Topic; Combined Modality Therapy; Drug Utilization; Humans; Hydroxyurea; Immunologic Factors; Interferons; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Myeloproliferative Disorders; Phlebotomy; Phosphorus Radioisotopes; Polycythemia Vera; Radiotherapy; Thrombocythemia, Essential

Following the development of the cyclotron in 1932, radio-isotopes became available for use in medicine both as tracer substances and therapeutic agents. The father of nuclear medicine, Dr J. H. Lawrence, pioneered their use in a range of disease states and found that radio-isotopes were of enormous value in the diagnosis and treatment of haemopoetic disease, particularly the myeloproliferative disorders. Radioactive phosphorus 32P emerged as the radio-isotope of choice for the myelosuppressive treatment of myeloproliferative disorders. This article also describes the use of radio-isotopes in the treatment of other disorders: chronic myeloid leukaemia, chronic lymphocytic leukaemia and myeloma, work that is now largely forgotten. All myeloproliferative disorders may evolve without treatment into myelodysplastic syndrome or blast-cell transformation. It is accepted that life is prolonged in myeloproliferative disorders treated with 32P or alkylating agents, yet both are leukaemogenic. The ideal form of treatment for polycythaemia vera is unknown and will remain so, for patients with this disorder often outlive their physician and achieve 90% of normal life expectation. 32P remains the treatment of choice for elderly patients with polycythaemia vera.

Topics: Animals; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Multiple Myeloma; Phosphorus Radioisotopes; Polycythemia Vera

BCR is an interesting signaling protein, whose cellular function is currently unknown. Its biochemical properties include serine kinase activity, SH2-binding activity, and a GTPase-activating activity. The SH2-binding activity is particularly interesting because it may link BCR to signaling pathways involving SH2-containing molecules. Since tyrosine phosphorylation of BCR has been detected in CML-derived cell lines and since tyrosine-phosphorylated BCR shows increased affinity toward certain SH2 domains, it seems particularly important to further characterize this activity. This chapter described a simple purification scheme for partial purification of BCR, which can be used to assess in vitro kinase and SH2-binding activities.

Topics: Adenosine Triphosphate; Animals; Binding Sites; Cell Line; Chromatography, Affinity; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Electrophoresis, Polyacrylamide Gel; Exons; GTP Phosphohydrolases; Humans; Kinetics; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Methionine; Oncogene Proteins; Phosphorus Radioisotopes; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcr; Radioisotope Dilution Technique; Recombinant Proteins; Spodoptera; Sulfur Radioisotopes; Transfection; Translocation, Genetic

We have evaluated 230 patients with myeloproliferative disorders treated in the last 15 years with 32P. None of the patients affected by essential thrombocythaemia developed haematological complications. In the larger group of polycythaemia patients (214 subjects) only 38 patients (17 males and 21 females) developed complications. 60.5% of these subjects had a minor complications: 1.8% showed a thrombocytopenia lower than 100.10e9/lt, 2.3% anaemia with Hb lower than 10 g%, 2.6% leukopenia lower than 40.10e9/lt and 2.3% a pancytopenia. All these complications were transient and eventually treated with limited blood transfusions. We could not identify a correlation between the dose used and the development of such complications. We noted only that the occurrence of anaemia, given a similar dose, was more frequent in females. Only 7% of all patients presented a major complication after 32P administration. In this case too, there was no correlation with the dose administered. Myelofibrosis and chronic myeloid leukaemia resulted to be the more frequent complication (9 out of 15) but we could not clarify if they represented a natural evolution of polycythaemia vera or were due to the treatment with 32P. Acute leukaemia developed only in 5 patients and again we could not recognized a correlation with the dose administered. Moreover, the time from the diagnosis of polycythaemia vera the onset of acute leukaemia ranged widely. 32P has a definite effect on the prevention of thrombotic and haemorrhagic complications in polycythaemia patients since it prolongs their life but it also increases the incidence of acute leukaemia.

Topics: Anemia; Female; Follow-Up Studies; Hematologic Diseases; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukopenia; Male; Middle Aged; Phosphorus Radioisotopes; Polycythemia Vera; Primary Myelofibrosis; Radiotherapy; Thrombocytopenia

Topics: Animals; Cell Fractionation; Cell Line; Cell-Free System; Cells, Cultured; Endoribonucleases; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma; Mice; Phosphorus Radioisotopes; Poly A; Polyribosomes; Radioisotope Dilution Technique; Ribonuclease H; RNA, Messenger; RNA, Neoplasm

The breakpoint cluster region gene rearrangement associated with chronic myelogenous leukemia is becoming important in the diagnosis and management of the disease. At this time, the ability to demonstrate the gene rearrangement is limited to a few research laboratories. The problem results partially from unfamiliarity of medical laboratory personnel with DNA technology, but more because of the restricted use of radiolabeled phosphorus in hospital laboratories. With the introduction of biotinylated deoxynucleotides, nucleic acid hybridization procedures can now be performed without the use of radioisotopically labeled gene probes. This article describes the use of biotin-labeled gene probes to detect the gene rearrangement of the breakpoint cluster region of chromosome 22 in chronic myelogenous leukemia. The techniques are reproducible, sensitive, and safe. With the procedures described in this article, the assay can become more available to medical laboratories interested in offering this diagnostic and decision-making tool.

Topics: Biotin; Blotting, Southern; Chromosomes, Human, Pair 22; Deoxyuracil Nucleotides; DNA; DNA Probes; Gene Rearrangement; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Nucleic Acid Hybridization; Phosphorus Radioisotopes

Topics: Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Phosphorus; Phosphorus Radioisotopes; Sex Characteristics

Topics: Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Phosphorus; Phosphorus Radioisotopes