pyrophosphate and Colonic-Neoplasms

The observation by Subramanian and his co-workers that a 99mTc-labeled polyphosphate had excellent affinity for bone has led to widespread use of 99mTc-labeled phosphates as bone scanning agents. Initially, only polyphosphate was employed, but because of somewhat inconstant results and difficulty in preparation of this product, other phosphate compounds were sought. We soon discovered that an inorganic compound, pyrophosphate, appeared to have certain advantages over polyphosphate. Other workers formulated diphosphonates (organic phosphates) which also demonstrated advantages over polyphosphates. Comparison studies in rabbits utilizing 85Sr, 87mSr, 18F, and several phosphates (inorganic and organic) proved the 99mTc-labeled phosphates to be clearly superior in delineating normal skeletal anatomy. Studies in humans confirmed that excellent visualization of bone was obtained with 99mTc-labeled phosphates using either a gamma camera or a rectilinear scanner. What was not known, however, was just how reliable this class of agents would prove to be in detecting bone disease when compared to bone-seeking radiopharmaceuticals such as 85Sr, 87mSr, and 18F. Further comparative analyses have clearly demonstrated that both inorganic and organic 99mTc phosphate complexes are extremely sensitive in revealing more bone disease than the older bone scanning agents.

Topics: Adult; Aged; Animals; Bone Neoplasms; Breast Neoplasms; Carcinoma, Squamous Cell; Colonic Neoplasms; Diphosphates; Female; Fluorine; Hodgkin Disease; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Phosphates; Prostatic Neoplasms; Rabbits; Radioisotopes; Radionuclide Imaging; Strontium Radioisotopes; Technetium

The activities of enzymes responsible for activating 5-fluorouracil (FUra) to 5-fluorouridine-5'-monophosphate (FUMP) were compared in normal and tumor tissues of rodents to assess the potential capacity of uridine phosphorylase to anabolize FUra to the nucleoside in the presence of ribose-1-phosphate (R-1-P). The activity of the alternative pathway to FUMP with a pyrimidine phosphoribosyltransferase [FUra + 1-pyrophosphoribosyl-5-phosphate (PPRP)] was approximately 15 to 17 nmoles/mg protein/hr in bone marrow from mice and rats and ranged from 28 to 47 nmoles/mg protein/hr in tumor tissues. Uridine phosphorylase [measured as the formation of 5-fluorouridine (FUrd) from FUra and R-1-P] was 35-230 nmoles/mg/hr in bone marrow and in two FUra-sensitive solid tumors, colon tumor No. 38 in mice and RPMI colon tumor in rats; the activity of uridine phosphorylase from L5178Y ascites leukemic cells was notably lower, 8 nmoles/mg/hr. Levels of uridine kinase ranged from 55 to 187 nmoles/mg protein/hr. Thus, the activities of the enzymes of the two-step FUra activating pathway were high compared to the PPRP-dependent activity in all tissues except L5178Y; also, the FUra-sensitive tumors yielded extracts with 1.5 to 6.5 times greater enzyme activity than the corresponding activity in bone marrow. Uridine phosphorylase was partially purified from rat liver, RPMI rat tumor and colon tumor No. 38; the apparent Km of FUra averaged 50 microM, almost 9-fold lower than that of uracil, and the apparent Km of R-1-P for condensation with FUra was 33 microM. The tissue concentration of R-1-P was greater than 70 microM in kidney and liver of rodents and somewhat less in spleen. Colon tumor No. 38 and RPMI colon tumor had 12 and 20 microM R-1-P, respectively, but these low values may reflect low tumor viability. The high levels of uridine phosphorylase and uridine kinase activities in normal tissues and even higher levels in tissues from FUra-sensitive tumors, as well as the sufficient concentration of R-1-P relative to its kinetic constant, suggest that FUra metabolism by the two-step pathway to FUMP may be a significant factor in the activity and selectivity of FUra.

Topics: Animals; Bone Marrow; Colonic Neoplasms; Diphosphates; Female; Fluorouracil; Kinetics; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Orotate Phosphoribosyltransferase; Pentosyltransferases; Peritoneal Neoplasms; Rats; Uracil Nucleotides; Uridine Kinase; Uridine Phosphorylase

Bone-to-bone, iliosacral joint-to-os sacrum and joint-to-joint ratios were computed using the region-of-interest technique 2 to 3 hrs. after injection of 99mTc Sn-methylene-diphosphonate or 99mTc Sn-pyrophosphate in 139 patients with skeletal diseases (bone tumours, degenerative changes of the spine and joints, inflammatory changes of joints) as well as in 123 patients with normal skeletal states. In the latter group, iliosacral joint-to-os sacrum ratios decreased with increasing age of the patients. In patients with osseous metastases of the spine ratios of 0.80 to 4.0 occurred ( reference area second vertebra below or above the affected vertebra). In degenerative changes of the spine values of 0.80 to 1.69 were computed. These results show, that 74% of the spine metastases could not be differentiated from benign changes of the spine by determining their relative amounts of bone uptake. In bone tumours of the extremities and in rheumatoid or gouty arthritis of the small joints (hands and feet) the highest ratios, i.e. contrasts, occurred referring to a contralateral reference area. Osteoarthritic and inflammatory alterations of the big joints could not be differentiated because of percentual distribution of the increased joint-to-joint ratios turned out to be nearly identical.

Topics: Adult; Aged; Arthritis; Arthritis, Rheumatoid; Bone Diseases; Bone Neoplasms; Colonic Neoplasms; Diphosphates; Diphosphonates; Extremities; Femur; Gout; Hemangiosarcoma; Humans; Hypertrophy; Lumbar Vertebrae; Melanoma; Middle Aged; Neoplasm Metastasis; Osteoarthritis; Radionuclide Imaging; Spinal Neoplasms; Spinal Osteophytosis; Spondylolisthesis; Technetium