phosphorus-radioisotopes and Syndrome

Pain in patients with cancer metastatic to bone is a significant cause of morbidity and of referrals from general practice and specialist physicians. Management typically utilizes radiation therapy and the graduated use of opiate analgesics. Bone-seeking radiopharmaceuticals have provided a new option to these management strategies, which is effective and cost effective. Strontium 89 is now in routine clinical use, while rhenium 186 hydroxyethylidene diphosphonate (HEDP) and samarium 153 ethylenediaminetetramethylene phosphonate (EDTMP) are in Phase III trials and tin 117m (4+) diethylene triaminepentacetic acid (DTPA) is in Phase I trials. Evidence taken primarily from the Strontium 89 trial, shows unsealed source therapy with these bone-seeking radiopharmaceuticals to be effective in palliating pain, improving quality of life, reducing the rate at which new painful sites develop, reducing requirements for additional radiation therapy, and reducing lifetime management costs. Indications and contraindications to therapy have now been defined, and retreatment is an option with all radiopharmaceuticals.

Topics: Bone Neoplasms; Clinical Trials as Topic; Etidronic Acid; Female; Humans; Male; Organometallic Compounds; Organophosphorus Compounds; Pain; Pain Management; Palliative Care; Pentetic Acid; Phosphorus Radioisotopes; Radioisotopes; Rhenium; Safety; Strontium Radioisotopes; Syndrome

Defects in mtDNA maintenance range from fatal multisystem childhood diseases, such as Alpers syndrome, to milder diseases in adults, including mtDNA depletion syndromes (MDS) and familial progressive external ophthalmoplegia (AdPEO). Most are associated with defects in genes involved in mitochondrial deoxynucleotide metabolism or utilization, such as mutations in thymidine kinase 2 (TK2) as well as the mtDNA replicative helicase, Twinkle and gamma polymerase (POLG). We have developed an in vitro system to measure incorporation of radiolabelled dNTPs into mitochondria of saponin permeabilized cells. We used this to compare the rates of mtDNA synthesis in cells from 12 patients with diseases of mtDNA maintenance. We observed reduced incorporation of exogenous alpha (32)P-dTTP in fibroblasts from a patient with Alpers syndrome associated with the A467T substitution in POLG, a patient with dGK mutations, and a patient with mtDNA depletion of unknown origin compared to controls. However, incorporation of alpha (32)P-dTTP relative to either cell doubling time or alpha (32)P-dCTP incorporation was increased in patients with thymidine kinase deficiency or PEO as the result of TWINKLE mutations compared with controls. The specific activity of newly synthesized mtDNA depends on the size of the endogenous pool diluting the exogenous labelled nucleotide. Our result is consistent with a deficiency in the intramitochondrial pool of dTTP relative to dCTP in cells from patients with TK2 deficiency and TWINKLE mutations. Such DNA precursor asymmetry could cause pausing of the replication complex and hence exacerbate the propensity for age-related mtDNA mutations. Because deviations from the normal concentrations of dNTPs are known to be mutagenic, we suggest that intramitochondrial nucleotide imbalance could underlie the multiple mtDNA mutations observed in these patients.

Topics: Cell Membrane Permeability; Deoxycytosine Nucleotides; Deoxyribonucleotides; DNA Helicases; DNA Polymerase gamma; DNA-Directed DNA Polymerase; DNA, Mitochondrial; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Models, Biological; Mutation; Phosphorus Radioisotopes; Syndrome; Thymidine Kinase; Thymine Nucleotides

The intracellular distribution of adenosine 5'-triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) was studied in the red cells of a patient with a "high-ATP syndrome" by using 31P nuclear magnetic resonance. In this patient, red cell ATP was increased 2.5-fold, whereas 2,3-DPG was decreased fourfold due to the presence of a hyperactive pyruvate kinase. In oxygenated red cells, these abnormal concentrations were reflected to the same extent in all complexes in which ATP and 2,3-DPG take part. The diminished amount of 2,3-DPG bound to hemoglobin was almost completely replaced by ATP-hemoglobin complexes. Therefore, free hemoglobin was only slightly increased. In deoxygenated cells, the relative distribution of ATP and 2,3-DPG complexes was significantly disturbed. The main difference was a shift in the ratio of magnesium ATP (MgATP) over the ATP-hemoglobin complex; 74% of total ATP was complexed to hemoglobin (45% in normal cells), whereas the concentration of MgATP was only slightly increased with respect to normal. The shortage in 2,3-DPG bound to hemoglobin could partially be replenished by an increase in hemoglobin (Mg) ATP complexes. Therefore, the amount of uncomplexed hemoglobin raised from 15% in normal cells to 38% in the patient's cells. As a result, the oxygen-dissociation curve was only moderately shifted to the left. It is concluded that the regulatory role of 2,3-DPG in oxygen transport is taken over in part by (Mg) ATP in this patient. In both aerobic and anaerobic cells, the increase in magnesium bound to ATP, either free or bound to hemoglobin, exceeds the decrease in 2,3-DPG Mg complex. In spite of this, the amount of intracellular free Mg++ was normal or slightly lowered. This suggests the presence of a compensatory mechanism by which the amount of total cellular magnesium could be increased.

Topics: 2,3-Diphosphoglycerate; Adenosine Triphosphate; Diphosphoglyceric Acids; Erythrocytes; Hemoglobins; Humans; Magnesium; Magnetic Resonance Spectroscopy; Oxygen; Phosphorus Radioisotopes; Phosphorylation; Pyruvate Kinase; Syndrome

Topics: Cell Line; Cell Survival; Centrifugation, Density Gradient; Cobalt Radioisotopes; DNA; DNA Repair; Fibroblasts; Humans; Molecular Weight; Phosphorus Radioisotopes; Progeria; Radiation Effects; Skin; Syndrome; Thymidine; Time Factors; Tritium; Trypsin

Topics: Adult; Anemia, Sickle Cell; Blood Protein Electrophoresis; Chromium Radioisotopes; Diagnosis, Differential; Erythrocyte Count; Erythrocytes; Female; Hematocrit; Hemoglobin, Sickle; Hemoglobinopathies; Hemoglobins, Abnormal; Humans; Male; Oxygen; Phosphorus Radioisotopes; Physical Exertion; Reticulocytes; Syndrome

Topics: Acute Disease; Bloodletting; Female; Hemorrhage; Humans; Leukemia; Male; Middle Aged; Minnesota; Phosphorus Radioisotopes; Polycythemia Vera; Pressure; Primary Myelofibrosis; Retrospective Studies; Sex Factors; Splenectomy; Splenomegaly; Syndrome