phosphorus-radioisotopes and Multiple-Myeloma

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

The association of essential thrombocythemia (ET) and multiple myeloma (MM) is exceedingly rare, with only four such cases reported in the literature until now. In this paper, a patient is reported who developed IgA-lambda MM more than five years after the diagnosis of ET, for which she had received alpha interferon and radioactive phosphor (32P). She died shortly afterwards despite melphalan and prednisone therapy. In four of the five patients in whom the above association has been reported, including the present one, MM appeared some time after ET was initially recognized, with three of them having received alkylating drugs as their treatment for ET. MM was heterogeneous with respect to the M--component type and the clinical course. The possible etiological & pathogenetic link between both these entities is discussed.

Topics: Aged; Female; Humans; Immunoglobulin A; Immunoglobulin lambda-Chains; Immunoglobulin M; Interferon-alpha; Multiple Myeloma; Phosphorus Radioisotopes; Thrombocytosis

We present a patient diagnosed of polycythemia vera who developed a multiple myeloma 13 years after the initial diagnosis of polycythemia vera. Although an unusual finding, another 17 patients with polycythemia and myeloma have been described. In some patients the diagnosis of both diseases was simultaneous but in most cases myeloma developed years after polycythemia vera. Some patients received only venipuncture for treatment of polycythemia vera so the appearance of multiple myeloma could not be explained on the grounds of chemotherapy induced second neoplasm. An explanation for this association is suggested.

Topics: Aged; Bloodletting; Busulfan; Combined Modality Therapy; Humans; Male; Multiple Myeloma; Phosphorus Radioisotopes; Polycythemia Vera

Insulin activates the ras signaling pathway and promotes hematopoietic cell proliferation. One possible mediator in such signaling is the vav proto-oncogene product (p95vav), which is specifically expressed in cells of hematopoietic origin and contains domains typical of guanine nucleotide exchange factors as well as Src homology 2 and Src homology 3 domains. We studied the tyrosine phosphorylation of p95vav in hematopoietic cells expressing insulin receptors. Immunoblotting experiments with an antiphosphotyrosine monoclonal antibody disclosed that insulin induces rapid and transient tyrosine phosphorylation of p95vav in the human U-266 myeloma cell line. These findings were confirmed by immunoprecipitation experiments performed with 32P-labeled cells and phosphoamino acid analysis of the bands corresponding to p95vav. Similarly, insulin-dependent tyrosine phosphorylation of p95vav was observed in the human IM-9 and mouse J558L hematopoietic cell lines. Furthermore, insulin treatment of cells led to the association of the Src homology 2 domain of p95vav with the activated beta-subunit of the insulin receptor in vitro. Altogether, these data suggest that p95vav is a substrate for the insulin receptor tyrosine kinase and may be involved in an insulin signaling pathway linking receptor-generated signals to Ras or other GTP-binding proteins in cells of hematopoietic origin.

Topics: Adenosine Triphosphate; Cell Cycle Proteins; Cell Line; Glutathione Transferase; Humans; Insulin; Multiple Myeloma; Phosphates; Phosphorus Radioisotopes; Phosphorylation; Phosphotyrosine; Protein Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-vav; Proto-Oncogenes; Recombinant Fusion Proteins; Tumor Cells, Cultured; Tyrosine

Topics: Animals; Autoradiography; Cell Nucleus; DNA, Superhelical; Electrophoresis, Polyacrylamide Gel; Histones; Mice; Multiple Myeloma; Phosphorus Radioisotopes; Promoter Regions, Genetic; Ribonuclease H; RNA; Templates, Genetic; Transcription, Genetic; Tumor Cells, Cultured; Uridine Triphosphate

The vav proto-oncogene product (p95vav) is specifically expressed in cells of the hematopoietic system, contains one Src homology 2 and two Src homology 3 domains, and is a substrate for receptor and non-receptor tyrosine kinases. Immunoblotting experiments using an anti-phosphotyrosine monoclonal antibody showed that interferon alpha (IFN alpha) induces rapid tyrosine phosphorylation of p95vav after binding to its cell surface receptor in the U-266 human myeloma cell line. The IFN alpha-induced tyrosine phosphorylation of p95vav was time- and dose-dependent, confirming the specificity of the process. IFN alpha-dependent tyrosine phosphorylation of p95vav was also observed in other hematopoietic cell lines of B-cell origin (Daudi), T-cell origin (MOLT-4), and promyelocytic origin (HL-60). Immunoprecipitation experiments performed with 32P-labeled U-266 cells and phosphoaminoacid analysis of the bands corresponding to p95vav showed that p95vav is phosphorylated on serine residues prior to IFN alpha stimulation of the cells. After IFN alpha stimulation significant amounts of phosphorylation of p95vav on tyrosine residues were detectable. Tyrosine phosphorylation of p95vav in U-266 and HL-60 cells was also induced by two other Type I IFNs, IFN beta and IFN omega. Altogether these data suggest that the vav proto-oncogene product is a substrate for a Type I IFN-regulated tyrosine kinase(s) and may be involved in the signal transduction pathway of Type I IFNs in hematopoietic cells.

Topics: Burkitt Lymphoma; Cell Cycle Proteins; Cell Line; Hematopoiesis; Humans; Interferon Type I; Interferon-beta; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Promyelocytic, Acute; Multiple Myeloma; Phosphorus Radioisotopes; Phosphotyrosine; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-vav; Proto-Oncogenes; Recombinant Proteins; Tumor Cells, Cultured; Tyrosine

Prothymosin alpha is post-translationally modified. When human myeloma cells were metabolically labeled with [32P]orthophosphoric acid, they synthesized [32P]prothymosin alpha. The incorporated radioactivity was resistant to DNase and RNases A, T1, and T2, but could be completely removed by alkaline phosphatase. No evidence was found for an RNA adduct as postulated by Vartapetian et al. [Vartapetian, A., Makarova, T., Koonin, E. V., Agol, V. I., & Bogdanov, A. (1988) FEBS Lett. 232, 35-38]. Thin-layer electrophoresis of partially hydrolyzed [32P]prothymosin alpha indicated that serine residues were phosphorylated. Analysis of peptides derived from bovine prothymosin alpha and human [32P]prothymosin alpha by treatment with endoproteinase Lys-C revealed that the amino-terminal 14-mer, with serine residues at positions 1, 8, and 9, was phosphorylated at a single position. Approximately 2% of the peptide in each case contained phosphate. Further digestion of the phosphopeptide with Asp-N followed by C18 reversed-phase column chromatography produced two peptides: a phosphate-free 9-mer containing amino acids 6-14 and a labeled peptide migrating slightly faster than the N-terminal 5-mer derived from the unmodified 14-mer. Positive identification of the phosphorylated amino acid was obtained by colliding the 14-residue phosphopeptide with helium in the mass spectrometer and finding phosphate only in a nested set of phosphorylated fragments composed of the first three, four, and five amino acids. The results prove that prothymosin alpha contains N-terminal acetylserine phosphate. In a synchronized population of human myeloma cells, phosphorylation occurred throughout the cell cycle. Furthermore, prothymosin alpha appeared to be stable, with a half-life slightly shorter than the generation time. Although prothymosin alpha is known to be essential for cell division, the constancy of both the amount of the protein and the degree of its phosphorylation suggests that prothymosin alpha does not directly govern mitosis.

Topics: Alkaline Phosphatase; Amino Acid Sequence; Animals; Cattle; Cell Cycle; Humans; Molecular Sequence Data; Multiple Myeloma; Phosphates; Phosphorus Radioisotopes; Phosphorylation; Phosphoserine; Protein Precursors; Protein Processing, Post-Translational; Thymosin; Thymus Gland; Tumor Cells, Cultured

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Multiple Myeloma; Phosphorus Radioisotopes

A 74-year-old white man with established polycythemia vera was treated with radioactive phosphorus after phlebotomies alone failed to control his disease. About 2 3/4 years later he died of multiple myeloma. The mutagenic effect of radioactive phosphorus may have caused or possibly accelerated preexisting myeloma. Basic nonmalignant disease deserves careful consideration before radiation or radiomimetic agents are used. One might consider a probably less mutagenic drug such as hydroxyurea in patients with polycythemia vera when phlebotomy alone does not give good control of red cell mass and thrombocytosis.

Topics: Aged; Humans; Male; Multiple Myeloma; Neoplasms, Radiation-Induced; Phosphorus Radioisotopes; Polycythemia Vera

Topics: Administration, Oral; Adult; Aged; Blood Protein Disorders; Drug Evaluation; Female; gamma-Globulins; Humans; Immune System Diseases; Male; Middle Aged; Multiple Myeloma; Pain; Phosphorus Radioisotopes

Topics: Aged; Cyclophosphamide; Hodgkin Disease; Humans; Intestinal Absorption; Leukemia, Lymphoid; Leukemia, Myeloid; Middle Aged; Multiple Myeloma; Phosphates; Phosphorus Radioisotopes

Topics: Animals; Base Sequence; Chromatography; Cytoplasm; Electrophoresis; In Vitro Techniques; Methionine; Mice; Multiple Myeloma; Nucleic Acid Conformation; Nucleotides; Nucleotidyltransferases; Phosphoric Diester Hydrolases; Phosphorus Radioisotopes; Polyribonucleotide Nucleotidyltransferase; Ribonucleases; RNA, Neoplasm; RNA, Transfer; Tritium

Topics: Animals; Cell Count; Cell Line; Centrifugation, Density Gradient; Cytoplasm; Genetic Code; Half-Life; Immunoglobulins; Mice; Molecular Weight; Multiple Myeloma; Neoplasms, Experimental; Phosphorus Radioisotopes; Polyribosomes; RNA, Messenger; Tritium; Uracil Nucleotides; Uridine

Topics: Animals; Base Sequence; Electrophoresis; Electrophoresis, Paper; Mice; Multiple Myeloma; Neoplasm Proteins; Neoplasms, Experimental; Nucleic Acid Conformation; Oligonucleotides; Peptide Chain Initiation, Translational; Phosphorus Radioisotopes; Ribonucleotides; RNA, Neoplasm; RNA, Transfer

Topics: Animals; Cell Fractionation; Cell Line; Cell Nucleus; Centrifugation, Density Gradient; DNA; DNA-Directed RNA Polymerases; Guanosine Triphosphate; Mice; Molecular Weight; Multiple Myeloma; Mycotoxins; Nucleic Acid Hybridization; Nucleoproteins; Phosphorus Radioisotopes; RNA, Neoplasm; RNA, Ribosomal; RNA, Transfer; Transcription, Genetic; Tritium; Xenopus

Topics: Animals; Cell Line; Cell Nucleus; Cytoplasm; Electrophoresis, Polyacrylamide Gel; Female; Immunoglobulin Fragments; Methionine; Molecular Weight; Multiple Myeloma; Myeloma Proteins; Ovum; Phosphorus Radioisotopes; Protein Binding; Protein Biosynthesis; RNA; RNA, Messenger; Sulfur Radioisotopes; Thymidine; Tritium; Xenopus

Topics: Humans; Multiple Myeloma; Phosphorus; Phosphorus Radioisotopes; Phosphorus, Dietary; Plasma Cells; Radioactivity

Topics: Humans; Multiple Myeloma; Phosphorus; Phosphorus Radioisotopes; Phosphorus, Dietary; Plasma Cells; Radioactivity

Topics: Bone and Bones; Bone Neoplasms; Hodgkin Disease; Humans; Leukemia; Multiple Myeloma; Neoplasms; Phosphorus; Phosphorus Radioisotopes; Plasma Cells; Polycythemia Vera; Radioactivity

Topics: Hodgkin Disease; Humans; Leukemia; Lymphoma; Multiple Myeloma; Phosphorus; Phosphorus Radioisotopes; Plasma Cells; Polycythemia Vera

Topics: Cell- and Tissue-Based Therapy; Humans; Multiple Myeloma; Phosphorus; Phosphorus Radioisotopes; Phosphorus, Dietary; Plasma Cells; Radioactivity

Topics: Multiple Myeloma; Neoplasms, Plasma Cell; Phosphorus; Phosphorus Radioisotopes; Phosphorus, Dietary; Plasma Cells; Plasmacytoma; Radioactivity

Topics: Humans; Multiple Myeloma; Phosphorus; Phosphorus Radioisotopes; Phosphorus, Dietary; Plasma Cells

Topics: Humans; Multiple Myeloma; Neoplasms; Phosphorus; Phosphorus Radioisotopes; Radioisotopes; Strontium; Strontium Radioisotopes

Topics: Multiple Myeloma; Neoplasms; Phosphorus; Phosphorus Radioisotopes; Phosphorus, Dietary; Radioactivity; Urethane